Science.gov

Sample records for agent doxorubicin dox

  1. Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells.

    PubMed

    Chakravarty, Geetika; Mathur, Aditi; Mallade, Pallavi; Gerlach, Samantha; Willis, Joniece; Datta, Amrita; Srivastav, Sudesh; Abdel-Mageed, Asim B; Mondal, Debasis

    2016-05-01

    Development of multidrug resistance (MDR) remains a significant problem in cancer chemotherapy and underscores the importance of using chemosensitizers. Well known MDR mechanisms include: (i) upregulation of drug-efflux; (ii) increased signaling via AKT; and (iii) decreased apoptosis. Therefore, chemosensitizers should target multiple resistance mechanisms. We investigated the efficacy of nelfinavir (NFV), a clinically approved anti-HIV drug, in increasing doxorubicin (DOX) toxicity in a MDR breast cancer cell line, MCF-7/Dox. As compared to parental MCF-7 cells, the MCF-7/Dox were 15-20 fold more resistant to DOX-induced cytotoxicity at 48 h post-exposure (DOX IC50 = 1.8 μM vs. 32.4 μM). Coexposures to NFV could significantly (p < 0.05) decrease DOX-IC50 in MCF-7/Dox cells. Multiple exposures to physiologic concentrations of NFV (2.25 μM or 6.75 μM) decreased DOX-IC50 by 21-fold and 50-fold, respectively. Interestingly, although single exposure to NFV transiently induced P-glycoprotein (P-gp) levels, multiple treatments with NFV inhibited both P-gp expression and efflux function, which increased intracellular DOX concentrations. Single exposure to NFV augmented the markers of cell-survival (AKT) and autophagy (LC3-II), whereas multiple exposures enabled suppression of both total AKT (t-AKT) and insulin like growth factor-1 (IGF-1)-induced phosphorylated AKT (p-AKT) levels. Multiple exposures to NFV also resulted in increased unfolded protein response (UPR) transducers, e.g. Grp78, p-PERK, p-eIF2α, and ATF-4; and endoplasmic reticulum (ER) stress induced death sensors, e.g. CHOP & TRIB-3. Multiple exposures to NFV also abrogated the mitogenic effects of IGF-1. In mice carrying MCF-7/Dox tumor xenografts, intraperitoneal (i.p.) injection of NFV (20 mg/kg/day) and DOX (2 mg/kg/twice/wk) decreased tumor growth more significantly (p < 0.01) than either agent alone. Immunohistochemical (IHC) analysis revealed decreased p-AKT and Ki-67 levels. Thus

  2. Reversal of multidrug resistance by 5,5’-dimethoxylariciresinol-4-O-β-D-glucoside in doxorubicin-resistant human leukemia K562/DOX

    PubMed Central

    Wang, Tian-Xiao; Shi, Xiao-Yan; Cong, Yue; Wang, Shi-Guang; Wang, Ying-Ying; Zhang, Zhong-Qin

    2013-01-01

    Objective: The objective of this study was to investigate the reversal effects of 5,5’-dimethoxylariciresinol-4’-O-β-D-glucoside (DMAG) extracted from traditional Chinese medicines Mahonia on multidrug resistance (MDR) of human leukemia cells to chemotherapeutic agents. Materials and Methods: MTT(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to determine the effect of DMAG on doxorubicin sensitivity to K562/DOX cells. Propidium iodide /Hoechst 33342 double staining assay was used to investigate the effect of DMAG on doxorubicin-induced cellular apoptosis. Intracellular accumulation of doxorubicin and rhodamine 123 assay were performed to evaluate the effect of DMAG on drugs efflux activity of P-glycoprotein. Results: DMAG significantly enhanced the doxorubicin cytotoxicity to K562/DOX cells. In the presence of 1.0 μM of DMAG, the IC50 of doxorubicin decreased from 34.93 ± 1.37 μM to 12.51 ± 1.28 μM. DMAG of 1.0 μM significantly enhanced doxorubicin-induced cell apoptosis in K562/DOX cells and the enhancement was time-dependent. A significant increase in accumulation of doxorubicin in the presence of DMAG was observed. After treatment of the K562/DOX cells for 1 h with 15.0 μM doxorubicin alone, the fluorescence intensity was 33093.12. With the addition of 1.0 μM of DMAG, the fluorescence intensity of doxorubicin was 2.3-fold higher. A significant increase of accumulation of rhodamine 123 in the presence of DMAG was also observed. With the addition of 1.0 μM of DMAG, the fluorescence intensity was increased by 49.11% compared with rhodamine 123 alone. Conclusion: DMAG was shown to effectively enhance chemosensitivity of resistant cells, which makes it might be a suitable candidate for potential MDR-reversing agents. PMID:24347768

  3. Differential effects of peroxisome proliferator-activated receptor agonists on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells.

    PubMed

    Yousefi, B; Samadi, N; Baradaran, B; Rameshknia, V; Shafiei-Irannejad, V; Majidinia, M; Targhaze, N; Zarghami, N

    2015-01-01

    P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor cells is still a main obstacle for the chemotherapeutic treatment of cancers. Therefore, identification of safe and effective MDR reversing compounds with minimal adverse side effects is an important approach in the cancer treatment. Studies show that peroxisome proliferator-activated receptor (PPARs) ligands can inhibit cell growth in many cancers. Here, we investigated the effect of different PPAR agonists include fenofibrate, troglitazone and aleglitazar on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effects of doxorubicin (DOX) following treatment with PPAR agonists on cell viability were evaluated using MTT assay and the reversal fold (RF) values. Rhodamine123 (Rh123) assays were used to determine P-gp functioning. P-gp mRNA/protein expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis after incubation with troglitazone and aleglitazar. Our results showed that troglitazone and aleglitazar significantly enhanced the cytotoxicity of DOX and decreased the RF values in K562/DOX cells, however, no such results were found for fenofibrate. Troglitazone and aleglitazar significantly down regulated P-gp expression in K562/DOX cells; in addition, the present study revealed that aleglitazar elevated intracellular accumulation of Rh123in K562/DOX cells as short-term effects, which also contribute to the reversal of MDR. These findings show that troglitazone and especially aleglitazar exhibited potent effects in the reversal of P-gp-mediated MDR, suggesting that these compounds may be effective for combination therapy strategies and circumventing MDR in K562/DOX cells to other conventional chemotherapeutic drugs. PMID:26718439

  4. Efficacy and safety of Stealth liposomal doxorubicin in AIDS-related Kaposi's sarcoma. The International SL-DOX Study Group.

    PubMed Central

    Goebel, F. D.; Goldstein, D.; Goos, M.; Jablonowski, H.; Stewart, J. S.

    1996-01-01

    The utility of current chemotherapeutic regimens in the treatment of AIDS-related Kaposi's sarcoma (AIDS-KS) is often compromised by both limited efficacy and substantial toxicity. Pegylated (Stealth) liposomal doxorubicin hydrochloride (SL-DOX) has been demonstrated specifically to deliver high concentrations of doxorubicin to Kaposi's sarcoma (KS) lesions. This phase II study was performed to evaluate the efficacy and safety of SL-DOX in the treatment of moderate to severe AIDS-KS. Patients were treated biweekly with 10, 20, or 40 mg m-2 SL-DOX. Tumour response was assessed according to AIDS Clinical Trials Groups (ACTG) criteria before each cycle. Best response was determined for 238 patients and was achieved after a mean of 2.3 cycles (range 1-20). Fifteen patients (6.3%) had a complete response to SL-DOX, 177 (74.4%) had a partial response, 44 (18.5%) had stable disease and two (0.8%) had disease progression. SL-DOX was well tolerated: ten patients discontinued therapy because of adverse events, in four cases because of neutropenia. Grade 3 or 4 neutropenia occurred after 281 of 2023 cycles (13.9%) but involved 137 of 240 patients (57.1%) for whom data were available. SL-DOX has substantial activity in AIDS-KS. Best response is typically seen after fewer than three cycles of chemotherapy and in some cases may be prolonged. The most important adverse event is neutropenia, which occurs after a minority of cycles but which may occur in over half of all patients. PMID:8611437

  5. Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking

    PubMed Central

    Mohan, Praveena; Rapoport, Natalya

    2010-01-01

    Doxorubicin (DOX) is one of the most commonly used chemotherapeutic drugs and a popular research tool due to the inherent fluorescence of the DOX molecule. After DOX injection, fluorescence imaging of organs or cells can provide information on drug biodistribution. Therapeutic and imaging capabilities combined in a DOX molecule make it an excellent theranostic agent. However, DOX fluorescence depends on a number of factors that should be taken into consideration when interpreting results of DOX fluorescence measurements. Discussing these problems is the main thrust of the current paper. The sensitivity of DOX fluorescence intensity to DOX concentration, local microenvironment, and interaction with model cellular components is illustrated by fluorescence spectra of paired DOX/phosphilipid, DOX/histone, DOX/DNA, and triple DOX/histone/DNA and DOX/phospholipid/DNA systems. DOX fluorescence is dramatically quenched upon intercalation into the DNA; DOX fluorescence is also self-quenched at high concentrations of molecularly dissolved DOX; in contrast, DOX fluorescence is increased after binding to the histone or partitioning into the phospholipid phase of PEG-phospholipid micelles or hydrophobic cores of polymeric micelles. While flow cytometry is commonly used for characterization of DOX intracellular uptake, the above aspects of DOX fluorescence may significantly complicate interpretation of flow cytometry results. High cell fluorescence measured by flow cytometry may provide deceptive information on the actual intracellular DOX concentration and may not correlate with the therapeutic efficacy if DOX does not penetrate into the site of action in cell nuclei. These problems are illustrated in the experiments on the intracellular trafficking of DOX encapsulated in poly(ethylene oxide)-co-polycaprolactone (PEG-PCL) micelles or PEG-PCL stabilized perfluorocarbon nanodroplets, with and without the application of ultrasound used as an external trigger. For efficient

  6. Combination of Protoporphyrin IX-mediated Sonodynamic Treatment with Doxorubicin Synergistically Induced Apoptotic Cell Death of a Multidrug-Resistant Leukemia K562/DOX Cell Line.

    PubMed

    Wang, Xiaobing; Jia, Yali; Su, Xiaomin; Wang, Pan; Zhang, Kun; Feng, Xiaolan; Liu, Quanhong

    2015-10-01

    The main objective of this study was to evaluate the efficacy of administration of doxorubicin (DOX) in combination with protoporphyrin IX (PpIX)-assisted low-level therapeutic ultrasound (US) in K562/DOX cells as a potential strategy in cancer therapy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine the cytotoxicity of different treatments. Apoptosis was analyzed using annexin V-PE/7-amino-actinomycin D staining. Changes in DNA fragmentation, intracellular reactive oxygen species production, cellular membrane permeability, P-glycoprotein expression and DOX uptake were analyzed with flow cytometry. Under optimal conditions, PpIX-US significantly aggravated DOX-induced K562/DOX cell death, compared with either monotherapy. Synergistic potentiation of DNA damage, generation of reactive oxygen species and P-glycoprotein inhibition were observed. Plasma membrane integrity changed slightly after US exposure, and DOX uptake was notably improved after PpIX-US exposure. The results indicate that PpIX-US could increase the susceptibility of tumors to antineoplastic drugs, suggesting a clinical potential method for sonodynamic therapy-mediated tumor chemotherapy. PMID:26166458

  7. BME, a novel compound of anthraquinone, down regulated P-glycoprotein expression in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells via generation of reactive oxygen species.

    PubMed

    Wang, Jianhong; Liu, Lu; Cen, Juan; Ji, Biansheng

    2015-09-01

    P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor cells is still a main obstacle for the chemotherapeutic treatment of cancers. Thus, development of effective MDR reversing agents is an important approach in the clinic. The present study revealed that BME, a novel compound of anthraquinone, elevated intracellular accumulation of the P-gp substrates and reduced concentration resulting in 50% inhibition of cell growth (IC50) values for doxorubicin (DOX) in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. Further more, BME was also reported to down regulated P-gp expression accompanying with generation of nontoxic low level of intracellular reactive oxygen species (iROS) and activation of extracellular signal-regulated kinase (ERK)1/2 as well as c-JUN N-terminal kinase (JNK). However, treatment with N-acetyl-cysteine (NAC), U0216 and SP600125 almost abolished actions of the BME mentioned above. These results indicated that the effect of the BME on the P-gp may be involved in generation of nontoxic low level of iROS and activation of ERK1/2 or JNK, which suggested valuable clues to screen and develop P-gp reversing agents.

  8. Multifunctional PEG modified DOX loaded mesoporous silica nanoparticle@CuS nanohybrids as photo-thermal agent and thermal-triggered drug release vehicle for hepatocellular carcinoma treatment

    NASA Astrophysics Data System (ADS)

    Wu, Lingjie; Wu, Ming; Zeng, Yongyi; Zhang, Da; Zheng, Aixian; Liu, Xiaolong; Liu, Jingfeng

    2015-01-01

    The combination of a multi-therapeutic mode with a controlled fashion is a key improvement in nanomedicine. Here, we synthesized polyethylene glycol (PEG)-modified doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) @CuS nanohybrids as efficient drug delivery carriers, combined with photothermal therapy and chemotherapy to enhance the therapeutic efficacy on hepatocellular carcinoma (HCC). The physical properties of the nanohybrids were characterized by transmission electron microscopy (TEM), N2 adsorption and desorption experiments and by the Vis-NIR absorption spectra. The results showed that the doxorubicin could be stored in the inner pores of mesoporous silica nanoparticles; the CuS nanoparticles, which are coated on the surface of a mesoporous silica nanoparticle, could serve as efficient photothermal therapy (PTT) agents; the loaded drug release could be easily triggered by NIR irradiation. The combination of the PTT treatment with controlled chemotherapy could further enhance the cancer ablation ability compared to any of the single approaches alone. Hence, the reported PEG-modified DOX-loaded mesoporous silica nanoparticle@CuS nanohybrids might be very promising therapeutic agents for HCC treatment.

  9. Complex of C60 Fullerene with Doxorubicin as a Promising Agent in Antitumor Therapy

    NASA Astrophysics Data System (ADS)

    Prylutska, Svitlana V.; Skivka, Larysa M.; Didenko, Gennadiy V.; Prylutskyy, Yuriy I.; Evstigneev, Maxim P.; Potebnya, Grygoriy P.; Panchuk, Rostyslav R.; Stoika, Rostyslav S.; Ritter, Uwe; Scharff, Peter

    2015-12-01

    The main aim of this work was to evaluate the effect of doxorubicin in complex with C60 fullerene (C60 + Dox) on the growth and metastasis of Lewis lung carcinoma in mice and to perform a primary screening of the potential mechanisms of C60 + Dox complex action. We found that volume of tumor from mice treated with the C60 + Dox complex was 1.4 times less than that in control untreated animals. The number of metastatic foci in lungs of animals treated with C60 + Dox complex was two times less than that in control untreated animals. Western blot analysis of tumor lysates revealed a significant decrease in the level of heat-shock protein 70 in animals treated with C60 + Dox complex. Moreover, the treatment of tumor-bearing mice was accompanied by the increase of cytotoxic activity of immune cells. Thus, the potential mechanisms of antitumor effect of C60 + Dox complex include both its direct action on tumor cells by inducing cell death and increasing of stress sensitivity and an immunomodulating effect. The obtained results provide a scientific basis for further application of C60 + Dox nanocomplexes as treatment agents in cancer chemotherapy.

  10. Sirtuin-3 (SIRT3) protein attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Doxorubicin (DOX) is a chemotherapeutic agent effective in the treatment of many cancers. However, cardiac dysfunction caused by DOX limits its clinical use. DOX is believed to be harmful to cardiomyocytes by interfering with the mitochondrial phospholipid cardiolipin and causing inefficient electro...

  11. A Novel Agent Enhances the Chemotherapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells

    PubMed Central

    Wang, Liang; Chan, Judy Y.; Zhou, Xinhua; Cui, Guozhen; Yan, Zhixiang; Wang, Li; Yan, Ru; Di, Lijun; Wang, Yuqiang; Hoi, Maggie P.; Shan, Luchen; Lee, Simon M.

    2016-01-01

    We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS, or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confer synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity. PMID:27559313

  12. Development and Optimization of a Doxorubicin Loaded Poly Lactic Acid Contrast Agent for Ultrasound Directed Drug Delivery

    PubMed Central

    Eisenbrey, J.R.; Burstein, O. Mualem; Kambhampati, R.; Forsberg, F.; Liu, J-B.; Wheatley, M.A.

    2010-01-01

    An echogenic, intravenous drug delivery platform is proposed in which an encapsulated chemotherapeutic can travel to a desired location and drug delivery can be triggered using external, focused ultrasound at the area of interest. Three methods of loading poly lactic acid (PLA) shelled ultrasound contrast agents (UCA) with doxorubicin are presented. Effects on encapsulation efficiency, in vitro enhancement, stability, particle size, morphology and release during UCA rupture are compared by loading method and drug concentration. An agent containing doxorubicin within the shell was selected as an ideal candidate for future hepatocellular carcinoma studies. The agent achieved a maximal drug load of 6.2 mg Dox/g PLA with an encapsulation efficiency of 20.5%, showed a smooth surface morphology and tight size distribution (poly dispersity index = 0.309) with a peak size of 1865 nm. Acoustically, the agent provided 19 dB of enhancement in vitro at a dosage of 10 µg/ml, with a half life of over 15 mins. In vivo, the agent provided ultrasound enhancement of 13.4 ± 1.6 dB within the ascending aorta of New Zealand rabbits at a dose of 0.15 ml/kg. While the drug-incorporated agent is thought to be well suited for future drug delivery experiments, this study has shown that agent properties can be tailored for specific applications based on choice of drug loading method. PMID:20060024

  13. Monoclonal antibody-targeted PEGylated liposome-ICG encapsulating doxorubicin as a potential theranostic agent.

    PubMed

    Lozano, Neus; Al-Ahmady, Zahraa S; Beziere, Nicolas S; Ntziachristos, Vasilis; Kostarelos, Kostas

    2015-03-30

    Indocyanine green (ICG) is an FDA-approved, strongly photo-absorbent/fluorescent probe that has been incorporated into a clinically-relevant PEGylated liposome as a flexible optoacoustic contrast agent platform. This study describes the engineering of targeted PEGylated liposome-ICG using the anti-MUC-1 "humanized" monoclonal antibody (MoAb) hCTM01 as a tumour-specific theranostic system. We aimed to visualise non-invasively the tumour accumulation of these MoAb-targeted liposomes over time in tumour-bearing mice using multispectral optoacoustic tomography (MSOT). Preferential accumulation of targeted PEGylated liposome-ICG was studied after intravenous administration in comparison to non-targeted PEGylated liposome-ICG using both fast growing (4T1) and slow growing (HT-29) MUC-1 positive tumour models. Monitoring liposomal ICG in the tumour showed that both targeted and non-targeted liposome-ICG formulations preferentially accumulated into the tumour models studied. Rapid accumulation was observed for targeted liposomes at early time points mainly in the periphery of the tumour volume suggesting binding to available MUC-1 receptors. In contrast, non-targeted PEGylated liposomes showed accumulation at the centre of the tumour at later time points. In an attempt to take this a step further, we successfully encapsulated the anticancer drug, doxorubicin (DOX) into both targeted and non-targeted PEGylated liposome-ICG. The engineering of DOX-loaded targeted ICG liposome systems present a novel platform for combined tumour-specific therapy and diagnosis. This can open new possibilities in the design of advanced image-guided cancer therapeutics.

  14. Monoclonal antibody-targeted PEGylated liposome-ICG encapsulating doxorubicin as a potential theranostic agent.

    PubMed

    Lozano, Neus; Al-Ahmady, Zahraa S; Beziere, Nicolas S; Ntziachristos, Vasilis; Kostarelos, Kostas

    2015-03-30

    Indocyanine green (ICG) is an FDA-approved, strongly photo-absorbent/fluorescent probe that has been incorporated into a clinically-relevant PEGylated liposome as a flexible optoacoustic contrast agent platform. This study describes the engineering of targeted PEGylated liposome-ICG using the anti-MUC-1 "humanized" monoclonal antibody (MoAb) hCTM01 as a tumour-specific theranostic system. We aimed to visualise non-invasively the tumour accumulation of these MoAb-targeted liposomes over time in tumour-bearing mice using multispectral optoacoustic tomography (MSOT). Preferential accumulation of targeted PEGylated liposome-ICG was studied after intravenous administration in comparison to non-targeted PEGylated liposome-ICG using both fast growing (4T1) and slow growing (HT-29) MUC-1 positive tumour models. Monitoring liposomal ICG in the tumour showed that both targeted and non-targeted liposome-ICG formulations preferentially accumulated into the tumour models studied. Rapid accumulation was observed for targeted liposomes at early time points mainly in the periphery of the tumour volume suggesting binding to available MUC-1 receptors. In contrast, non-targeted PEGylated liposomes showed accumulation at the centre of the tumour at later time points. In an attempt to take this a step further, we successfully encapsulated the anticancer drug, doxorubicin (DOX) into both targeted and non-targeted PEGylated liposome-ICG. The engineering of DOX-loaded targeted ICG liposome systems present a novel platform for combined tumour-specific therapy and diagnosis. This can open new possibilities in the design of advanced image-guided cancer therapeutics. PMID:25445515

  15. The survivin suppressant YM155 reverses doxorubicin resistance in osteosarcoma

    PubMed Central

    Zhang, Zhuo; Zhang, Yunfeng; Lv, Jiayin; Wang, Jincheng

    2015-01-01

    Doxorubicin (DOX) is one of the widely used chemotherapeutic drugs for the treatment of human osteosarcoma (OS). However, acquisition of DOX resistance is common in patients with OS, leading to local and distant failure. In this study, we demonstrate that survivin expression is significantly upregulated in OS primary tumors compared to paired normal tissue. In addition, survivin expression was further increased in DOX resistant cells (MG63/DOX) as compared to its parent cells (MG63). Thus, we hypothesize that targeting of survivin in OS could reverse the DOX resistant phenotype in tumor cells thereby enhancing the therapeutic efficacy of DOX. We test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with DOX in vitro and in vivo. We found that combination treatment of YM155 and DOX in DOX resistant cells (MG63/DOX) could significantly inhibited cell proliferation and colony formation, induce cell apoptosis and promoted caspase-3, -8, and -9 activity in vitro, and promoted tumor regression in established OS xenograft models. Taken together, the evidence presented here supports the favorable preclinical evaluation that YM155 could overcome DOX the resistance in tumor cells thereby enhancing the effectiveness of DOX in OS, suggesting that YM155 in combination with DOX has potential in the treatment of osteosarcoma. PMID:26770398

  16. Multifunctional reduction-responsive SPIO&DOX-loaded PEGylated polymeric lipid vesicles for magnetic resonance imaging-guided drug delivery

    NASA Astrophysics Data System (ADS)

    Wang, Sheng; Yang, Weitao; Du, Hongli; Guo, Fangfang; Wang, Hanjie; Chang, Jin; Gong, Xiaoqun; Zhang, Bingbo

    2016-04-01

    Multifunctional superparamagnetic iron-oxide (SPIO)-based nanoparticles have been emerging as candidate nanosystems for cancer diagnosis and therapy. Here, we report the use of reduction- responsive SPIO/doxorubicin (DOX)-loaded poly(ethylene glycol) monomethyl ether (PEG)ylated polymeric lipid vesicles (SPIO&DOX-PPLVs) as a novel theranostic system for tumor magnetic resonance imaging (MRI) diagnosis and controlled drug delivery. These SPIO&DOX-PPLVs are composed of SPIOs that function as MR contrast agents for tumor enhancement and PPLVs as polymer matrices for encapsulating SPIO and antitumor drugs. The in vitro characterizations show that the SPIO&DOX-PPLVs have nanosized structures (˜80 nm), excellent colloidal stability, good biocompatibility, as well as T 2-weighted MRI capability with a relatively high T 2 relaxivity (r 2 = 213.82 mM-1 s-1). In vitro drug release studies reveal that the release rate of DOX from the SPIO&DOX-PPLVs is accelerated in the reduction environment. An in vitro cellular uptake study and an antitumor study show that the SPIO&DOX-PPLVs have magnetic targeting properties and effective antitumor activity. In vivo studies show the SPIO&DOX-PPLVs have excellent T 2-weighted tumor targeted MRI capability, image-guided drug delivery capability, and high antitumor effects. These results suggest that the SPIO&DOX-PPLVs are promising nanocarriers for MRI diagnosis and cancer therapy applications.

  17. Multifunctional reduction-responsive SPIO&DOX-loaded PEGylated polymeric lipid vesicles for magnetic resonance imaging-guided drug delivery.

    PubMed

    Wang, Sheng; Yang, Weitao; Du, Hongli; Guo, Fangfang; Wang, Hanjie; Chang, Jin; Gong, Xiaoqun; Zhang, Bingbo

    2016-04-22

    Multifunctional superparamagnetic iron-oxide (SPIO)-based nanoparticles have been emerging as candidate nanosystems for cancer diagnosis and therapy. Here, we report the use of reduction- responsive SPIO/doxorubicin (DOX)-loaded poly(ethylene glycol) monomethyl ether (PEG)ylated polymeric lipid vesicles (SPIO&DOX-PPLVs) as a novel theranostic system for tumor magnetic resonance imaging (MRI) diagnosis and controlled drug delivery. These SPIO&DOX-PPLVs are composed of SPIOs that function as MR contrast agents for tumor enhancement and PPLVs as polymer matrices for encapsulating SPIO and antitumor drugs. The in vitro characterizations show that the SPIO&DOX-PPLVs have nanosized structures (∼80 nm), excellent colloidal stability, good biocompatibility, as well as T2-weighted MRI capability with a relatively high T2 relaxivity (r2 = 213.82 mM(-1) s(-1)). In vitro drug release studies reveal that the release rate of DOX from the SPIO&DOX-PPLVs is accelerated in the reduction environment. An in vitro cellular uptake study and an antitumor study show that the SPIO&DOX-PPLVs have magnetic targeting properties and effective antitumor activity. In vivo studies show the SPIO&DOX-PPLVs have excellent T2-weighted tumor targeted MRI capability, image-guided drug delivery capability, and high antitumor effects. These results suggest that the SPIO&DOX-PPLVs are promising nanocarriers for MRI diagnosis and cancer therapy applications. PMID:26941226

  18. Tea nanoparticle, a safe and biocompatible nanocarrier, greatly potentiates the anticancer activity of doxorubicin

    PubMed Central

    Wang, Yi-Jun; Huang, Yujian; Anreddy, Nagaraju; Zhang, Guan-Nan; Zhang, Yun-Kai; Xie, Meina; Lin, Derrick; Yang, Dong-Hua; Zhang, Mingjun; Chen, Zhe-Sheng

    2016-01-01

    An infusion-dialysis based procedure has been developed as an approach to isolate organic nanoparticles from green tea. Tea nanoparticle (TNP) can effectively load doxorubicin (DOX) via electrostatic and hydrophobic interactions. We established an ABCB1 overexpressing tumor xenograft mouse model to investigate whether TNP can effectively deliver DOX into tumors and bypass the efflux function of the ABCB1 transporter, thereby increasing the intratumoral accumulation of DOX and potentiating the anticancer activity of DOX. MTT assays suggested that DOX-TNP showed higher cytotoxicity toward CCD-18Co, SW620 and SW620/Ad300 cells than DOX. Animal study revealed that DOX-TNP resulted in greater inhibitory effects on the growth of SW620 and SW620/Ad300 tumors than DOX. In pharmacokinetics study, DOX-TNP greatly increased the SW620 and SW620/Ad300 intratumoral concentrations of DOX. But DOX-TNP had no effect on the plasma concentrations of DOX. Furthermore, TNP is a safe nanocarrier with excellent biocompatibility and minimal toxicity. Ex vivo IHC analysis of SW620 and SW620/Ad300 tumor sections revealed evidence of prominent antitumor activity of DOX-TNP. In conclusion, our findings suggested that natural nanomaterials could be useful in combating multidrug resistance (MDR) in cancer cells and potentiating the anticancer activity of chemotherapeutic agents in cancer treatment. PMID:26716507

  19. Biodistribution and in Vivo Activities of Tumor-Associated Macrophage-Targeting Nanoparticles Incorporated with Doxorubicin

    PubMed Central

    2015-01-01

    Tumor-associated macrophages (TAMs) are increasingly considered a viable target for tumor imaging and therapy. Previously, we reported that innovative surface-functionalization of nanoparticles may help target them to TAMs. In this report, using poly(lactic-co-glycolic) acid (PLGA) nanoparticles incorporated with doxorubicin (DOX) (DOX-NPs), we studied the effect of surface-modification of the nanoparticles with mannose and/or acid-sensitive sheddable polyethylene glycol (PEG) on the biodistribution of DOX and the uptake of DOX by TAMs in tumor-bearing mice. We demonstrated that surface-modification of the DOX-NPs with both mannose and acid-sensitive sheddable PEG significantly increased the accumulation of DOX in tumors, enhanced the uptake of the DOX by TAMs, but decreased the distribution of DOX in mononuclear phagocyte system (MPS), such as liver. We also confirmed that the acid-sensitive sheddable PEGylated, mannose-modified DOX-nanoparticles (DOX-AS-M-NPs) targeted TAMs because depletion of TAMs in tumor-bearing mice significantly decreased the accumulation of DOX in tumor tissues. Furthermore, in a B16-F10 tumor-bearing mouse model, we showed that the DOX-AS-M-NPs were significantly more effective than free DOX in controlling tumor growth but had only minimum effect on the macrophage population in mouse liver and spleen. The AS-M-NPs are promising in targeting cytotoxic or macrophage-modulating agents into tumors to improve tumor therapy. PMID:25314115

  20. Effect of linalool as a component of Humulus lupulus on doxorubicin-induced antitumor activity.

    PubMed

    Miyashita, Michiko; Sadzuka, Yasuyuki

    2013-03-01

    As malignant neoplasm is a major public health problem, there is a need for the development of a novel modulator that enhances antitumor activity and reduces adverse reactions to antitumor agents. In this study, the effects of some volatile oil components in Humulus lupulus on doxorubicin (DOX) permeability in tumor cells and DOX-induced antitumor activity were examined. In vitro, DOX levels in tumor cells by combined linalool as its component significantly increased in the DOX influx system, and the increased effect by linalool on DOX cytotoxicity was shown. In vivo, the combination of DOX with linalool significantly decreased tumor weight compared with that of DOX alone treated group. The promotion of DOX influx level by combined linalool did not depend on energy, whereas it was suppressed by the absence of Na(+). This promoting effect was suppressed by the presence of S-(4-nitrobenzyl)-6-thioinosine and inhibited dependently on phlorizin concentration. It is considered that linalool promoted DOX influx in tumor cells because of its action on DOX transport through concentrative Na(+)-dependent nucleoside transporter 3, which increased DOX concentration in tumor cells and thus enhanced the antitumor activity of DOX. Therefore, linalool as a food component is anticipated to be an effective DOX modulator. PMID:23220514

  1. Tea nanoparticle, a safe and biocompatible nanocarrier, greatly potentiates the anticancer activity of doxorubicin.

    PubMed

    Wang, Yi-Jun; Huang, Yujian; Anreddy, Nagaraju; Zhang, Guan-Nan; Zhang, Yun-Kai; Xie, Meina; Lin, Derrick; Yang, Dong-Hua; Zhang, Mingjun; Chen, Zhe-Sheng

    2016-02-01

    An infusion-dialysis based procedure has been developed as an approach to isolate organic nanoparticles from green tea. Tea nanoparticle (TNP) can effectively load doxorubicin (DOX) via electrostatic and hydrophobic interactions. We established an ABCB1 overexpressing tumor xenograft mouse model to investigate whether TNP can effectively deliver DOX into tumors and bypass the efflux function of the ABCB1 transporter, thereby increasing the intratumoral accumulation of DOX and potentiating the anticancer activity of DOX. MTT assays suggested that DOX-TNP showed higher cytotoxicity toward CCD-18Co, SW620 and SW620/Ad300 cells than DOX. Animal study revealed that DOX-TNP resulted in greater inhibitory effects on the growth of SW620 and SW620/Ad300 tumors than DOX. In pharmacokinetics study, DOX-TNP greatly increased the SW620 and SW620/Ad300 intratumoral concentrations of DOX. But DOX-TNP had no effect on the plasma concentrations of DOX. Furthermore, TNP is a safe nanocarrier with excellent biocompatibility and minimal toxicity. Ex vivo IHC analysis of SW620 and SW620/Ad300 tumor sections revealed evidence of prominent antitumor activity of DOX-TNP. In conclusion, our findings suggested that natural nanomaterials could be useful in combating multidrug resistance (MDR) in cancer cells and potentiating the anticancer activity of chemotherapeutic agents in cancer treatment. PMID:26716507

  2. Effect of linalool as a component of Humulus lupulus on doxorubicin-induced antitumor activity.

    PubMed

    Miyashita, Michiko; Sadzuka, Yasuyuki

    2013-03-01

    As malignant neoplasm is a major public health problem, there is a need for the development of a novel modulator that enhances antitumor activity and reduces adverse reactions to antitumor agents. In this study, the effects of some volatile oil components in Humulus lupulus on doxorubicin (DOX) permeability in tumor cells and DOX-induced antitumor activity were examined. In vitro, DOX levels in tumor cells by combined linalool as its component significantly increased in the DOX influx system, and the increased effect by linalool on DOX cytotoxicity was shown. In vivo, the combination of DOX with linalool significantly decreased tumor weight compared with that of DOX alone treated group. The promotion of DOX influx level by combined linalool did not depend on energy, whereas it was suppressed by the absence of Na(+). This promoting effect was suppressed by the presence of S-(4-nitrobenzyl)-6-thioinosine and inhibited dependently on phlorizin concentration. It is considered that linalool promoted DOX influx in tumor cells because of its action on DOX transport through concentrative Na(+)-dependent nucleoside transporter 3, which increased DOX concentration in tumor cells and thus enhanced the antitumor activity of DOX. Therefore, linalool as a food component is anticipated to be an effective DOX modulator.

  3. In situ DOX-calcium phosphate mineralized CPT-amphiphilic gelatin nanoparticle for intracellular controlled sequential release of multiple drugs.

    PubMed

    Li, Wei-Ming; Su, Chia-Wei; Chen, Yu-Wei; Chen, San-Yuan

    2015-03-01

    A co-delivery strategy has been developed to achieve the synergistic effect of a hydrophobic drug (camptothecin, CPT) and a hydrophilic drug (doxorubicin, DOX) by utilizing the unique structure of amphiphilic gelatin/camptothecin @calcium phosphate-doxorubicin (AG/CPT@CaP-DOX) nanoparticles as a carriers in order to replace double emulsions while preserving the advantages of inorganic materials. The hydrophobic agent (CPT) was encapsulated via emulsion with an amphiphilic gelatin core, and subsequently mineralized by CaP-hydrophilic drug (DOX) through precipitation to form a CaP shell on the CPT-AG amphiphilic gelatin core so that drug molecules with different characteristics (i.e. hydrophobic and hydrophilic) can be encapsulated in different regions to avoid their interaction. The existence of the CaP shell can protect the DOX against free release and cause an increased transfer of DOX across membranes, overcoming multidrug resistance. Release studies from core-shell carriers showed the possibility of achieving sequential release of more than one type of drug by controlling the pH-sensitive CaP shell and degradable AG core. The highly pH-responsive behavior of the carrier can modulate the dual-drug-release of DOX/CPT, specifically in acidic intracellular pH environments. The AG/CPT@CaP-DOX nanoparticles also exhibited higher drug efficiencies against MCF-7/ADR cells than MCF-7 cells, thanks to a synergistic cell cycle arrest/apoptosis-inducing effect between CPT and DOX. As such, this core-shell system can serve as a general platform for the localized, controlled, sequential delivery of multiple drugs to treat several diseases, especially for multidrug-resistant cancer cells.

  4. Codelivery of doxorubicin and curcumin with lipid nanoparticles results in improved efficacy of chemotherapy in liver cancer.

    PubMed

    Zhao, Xiaojing; Chen, Qi; Liu, Wei; Li, Yusang; Tang, Hebin; Liu, Xuhan; Yang, Xiangliang

    2015-01-01

    Liver cancer is a leading cause of cancer deaths worldwide. The combination therapy of cytotoxic and chemosensitizing agents loaded in nanoparticles has been highlighted as an effective treatment for different cancers. However, such studies in liver cancer remain very limited. In our study, we aim to develop a novel lipid nanoparticles loaded with doxorubicin (DOX) (an effective drug for liver cancer) and curcumin (Cur) (a chemosensitizer) simultaneously, and we examined the efficacy of chemotherapy in liver cancer. DOX and Cur codelivery lipid nanoparticles (DOX/Cur-NPs) were successfully prepared using a high-pressure microfluidics technique, showing a mean particle size of around 90 nm, a polydispersity index <0.3, and a zeta potential <-10 mV. The encapsulation efficacy was >90% for both DOX and Cur. The blank lipid nanoparticles were nontoxic, as determined by a cell cytotoxicity study in human normal liver cells L02 and liver cancer cells HepG2. In vitro DOX release studies revealed a sustained-release pattern until 48 hours in DOX/Cur-NPs. We found enhanced cytotoxicity and decreased inhibitory concentration (IC)50 in HepG2 cells and reduced cytotoxicity in L02 cells treated with DOX/Cur-NPs, suggesting the synergistic effects of DOX/Cur-NPs compared with free DOX and DOX nanoparticles (NPs). The optimal weight ratio of DOX and Cur was 1:1. Annexin-V-fluorescein isothiocyanate/propidium iodide double staining showed enhanced apoptosis in HepG2 cells treated with DOX/Cur-NPs compared with free DOX and DOX-NPs. An in vivo experiment showed the synergistic effect of DOX/Cur-NPs compared with DOX-NPs on liver tumor growth inhibition. Taken together, the simultaneous delivery of DOX and Cur by DOX/Cur-NPs might be a promising treatment for liver cancer.

  5. The role of frataxin in doxorubicin-mediated cardiac hypertrophy.

    PubMed

    Mouli, Shravanthi; Nanayakkara, Gayani; AlAlasmari, Abdullah; Eldoumani, Haitham; Fu, Xiaoyu; Berlin, Avery; Lohani, Madhukar; Nie, Ben; Arnold, Robert D; Kavazis, Andreas; Smith, Forrest; Beyers, Ronald; Denney, Thomas; Dhanasekaran, Muralikrishnan; Zhong, Juming; Quindry, John; Amin, Rajesh

    2015-09-01

    Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy. PMID:26209053

  6. A mouse model for juvenile doxorubicin-induced cardiac dysfunction.

    PubMed

    Zhu, Wuqiang; Shou, Weinian; Payne, R Mark; Caldwell, Randall; Field, Loren J

    2008-11-01

    Doxorubicin (DOX) is a potent antitumor agent. DOX can also induce cardiotoxicity, and high cumulative doses are associated with recalcitrant heart failure. Children are particularly sensitive to DOX-induced heart failure. The ability to genetically modify mice makes them an ideal experimental system to study the molecular basis of DOX-induced cardiotoxicity. However, most mouse DOX studies rely on acute drug administration in adult animals, which typically are analyzed within 1 wk. Here, we describe a juvenile mouse model of chronic DOX-induced cardiac dysfunction. DOX treatment was initiated at 2 wk of age and continued for a period of 5 wk (25 mg/kg cumulative dose). This resulted in a decline in cardiac systolic function, which was accompanied by marked atrophy of the heart, low levels of cardiomyocyte apoptosis, and decreased growth velocity. Other animals were allowed to recover for 13 wk after the final DOX injection. Cardiac systolic function improved during this recovery period but remained depressed compared with the saline injected controls, despite the reversal of cardiac atrophy. Interestingly, increased levels of cardiomyocyte apoptosis and concomitant myocardial fibrosis were observed after DOX withdrawal. These data suggest that different mechanisms contribute to cardiac dysfunction during the treatment and recovery phases. PMID:18614963

  7. Multifunctional SPIO/DOX-loaded A54 Homing Peptide Functionalized Dextran-g-PLGA Micelles for Tumor Therapy and MR Imaging

    PubMed Central

    Situ, Jun-Qing; Wang, Xiao-Juan; Zhu, Xiu-Liang; Xu, Xiao-Ling; Kang, Xu-Qi; Hu, Jing-Bo; Lu, Chen-Ying; Ying, Xiao-Ying; Yu, Ri-Sheng; You, Jian; Du, Yong-Zhong

    2016-01-01

    Specific delivery of chemotherapy drugs and magnetic resonance imaging (MRI) contrast agent into tumor cells is one of the issues to highly efficient tumor targeting therapy and magnetic resonance imaging. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA could self-assemble to form micelles with a low critical micelle concentration of 22.51 μg. mL−1 and diameter of about 50 nm. The synthetic A54-Dex-PLGA micelles can encapsulate doxorubicin (DOX) as a model anti-tumor drug and superparamagnetic iron oxide (SPIO) as a contrast agent for MRI. The drug-encapsulation efficiency was about 80% and the in vitro DOX release was prolonged to 72 hours. The DOX/SPIO-loaded micelles could specifically target BEL-7402 cell line. In vitro MRI results also proved the specific binding ability of A54-Dex-PLGA/DOX/SPIO micelles to hepatoma cell BEL-7402. The in vivo MR imaging experiments using a BEL-7402 orthotopic implantation model further validated the targeting effect of DOX/SPIO-loaded micelles. In vitro and in vivo anti-tumor activities results showed that A54-Dex-PLGA/DOX/SPIO micelles revealed better therapeutic effects compared with Dex-PLGA/DOX/SPIO micelles and reduced toxicity compared with commercial adriamycin injection. PMID:27775017

  8. Astragalus polysaccharide improves cardiac function in doxorubicin-induced cardiomyopathy through ROS-p38 signaling

    PubMed Central

    Zhou, Liangliang; Chen, Lanping; Wang, Jing; Deng, Yijun

    2015-01-01

    Doxorubicin (DOX) is widely used as an antitumor agent, but it is significantly challenged by clinical workers due to the severe and acute cardiotoxitity. Astragalus polysaccharide (APS) is characterized by an anti-inflammation and anti-oxidant features. In the current study, we explored the effects and specific mechanisms of APS on DOX-induced-cardiomyopathy in mouse primary myocardial cells. To explore the effect of DOX on ROS production, DHE staining and flow cytometry analysis were used in primary cardiomyocytes treated with 1 μM DOX for 24 h. MTT assay was applied to determine the effect of DOX on cell viability. The effects of DOX on rat cardiomyocytes apoptosis by Hoechst staining and annexin V-PI staining, while caspase3 activity was determined using an assay kit. Two-dimensional echocardiography of rats was performed to determine left ventricular fraction and relative wall thickness. Activation of p38 and Akt was analyzed using western blot. ROS production was significantly enhanced by DOX stimulation in primary cardiomyocytes. DOX reduced rat cardiomyocytes viability in a time- and dose-dependent manner. DOX induced apoptosis in rat cardiomyocytes via activation of caspase-3. Cardiac function was significantly impaired by enhanced p38 activation. APS treatment reduced DOX-induced rat cardiomyocytes apoptosis by decreasing ROS production. To conclude, APS reduced DOX-induced cell apoptosis and ROS production by reduced activation of p38 signaling pathway. PMID:26885153

  9. Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

    PubMed Central

    Li, Haoyu; Chen, Zhenghu; Hu, Ting; Wang, Long; Yu, Yang; Zhao, Yanling; Sun, Wenijing; Guan, Shan; Pang, Jonathan C.; Woodfield, Sarah E.; Liu, Qing; Yang, Jianhua

    2016-01-01

    Neuroblastoma (NB) is the most common extracranial malignant solid tumor seen in children and continues to lead to the death of many pediatric cancer patients. The poor outcome in high risk NB is largely attributed to the development of chemoresistant tumor cells. Doxorubicin (dox) has been widely employed as a potent anti-cancer agent in chemotherapeutic regimens; however, it also leads to chemoresistance in many cancer types including NB. Thus, developing novel small molecules that can overcome dox-induced chemoresistance is a promising strategy in cancer therapy. Here we show that the second generation proteasome inhibitor ixazomib (MLN9708) not only inhibits NB cell proliferation and induces apoptosis in vitro but also enhances dox-induced cytotoxicity in NB cells. Ixazomib inhibits dox-induced NF-κB activity and sensitizes NB cells to dox-induced apoptosis. More importantly, ixazomib demonstrated potent anti-tumor efficacy in vivo by enhancing dox-induced apoptosis in an orthotopic xenograft NB mouse model. Collectively, our study illustrates the anti-tumor efficacy of ixazomib in NB both alone and in combination with dox, suggesting that combination therapy including ixazomib with traditional therapeutic agents such as dox is a viable strategy that may achieve better outcomes for NB patients. PMID:27687684

  10. Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues.

    PubMed

    Zara, Gian Paolo; Cavalli, Roberta; Bargoni, Alessandro; Fundarò, Anna; Vighetto, Daniela; Gasco, Maria Rosa

    2002-06-01

    The pharmacokinetics and tissue distribution of doxorubicin incorporated in non-stealth solid lipid nanoparticles (SLN) and in stealth solid lipid nanoparticles (SSLN) (three formulations at increasing concentrations of stearic acid-PEG 2000 as stealth agent) after intravenous administration to conscious rabbits have been studied. The control was the commercial doxorubicin solution. The experiments lasted 6 h and blood samples were collected at fixed times after the injections. In all samples, the concentration of doxorubicin and doxorubicinol were determined. Doxorubicin AUC increased as a function of the amount of stealth agent present in the SLN. Doxorubicin was still present in the blood 6 h after the injection of SLN or SSLN, while no doxorubicin was detectable after the i.v. injection of doxorubicin solution. Tissue distribution of doxorubicin was determined 30 min, 2 and 6 h after the administration of the five formulations. Doxorubicin was present in the brain only after the SLN administration. The increase in the stealth agent affected the doxorubicin transported into the brain; 6 h after injection, doxorubicin was detectable in the brain only with the SSLN at the highest amount of stealth agent. In the other rabbit tissues (liver, lungs, spleeen, heart and kidneys) the amount of doxorubicin present was always lower after the injection of any of the four types of SLN than after the commercial solution. In particular, all SLN formulations significantly decreased heart and liver concentrations of doxorubicin.

  11. Propolis attenuates doxorubicin-induced testicular toxicity in rats.

    PubMed

    Rizk, Sherine M; Zaki, Hala F; Mina, Mary A M

    2014-05-01

    Doxorubicin (Dox), an effective anticancer agent, can impair testicular function leading to infertility. The present study aimed to explore the protective effect of propolis extract on Dox-induced testicular injury. Rats were divided into four groups (n=10). Group I (normal control), group II received propolis extract (200 mg kg(-1); p.o.), for 3 weeks. Group III received 18 mg kg(-1) total cumulative dose of Dox i.p. Group IV received Dox and propolis extract. Serum and testicular samples were collected 48 h after the last treatment. In addition, the effects of propolis extract and Dox on the growth of solid Ehrlich carcinoma in mice were investigated. Dox reduced sperm count, markers of testicular function, steroidogenesis and gene expression of testicular 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) and steroidogenic acute regulatory protein (StAR). In addition, it increased testicular oxidative stress, inflammatory and apoptotic markers. Morphometric and histopathologic studies supported the biochemical findings. Treatment with propolis extract prevented Dox-induced changes without reducing its antitumor activity. Besides, administration of propolis extract to normal rats increased serum testosterone level coupled by increased activities and gene expression of 3ß-HSD and 17ß-HSD. Propolis extract may protect the testis from Dox-induced toxicity without reducing its anticancer potential.

  12. p21{sup WAF1/Cip1/Sdi1} knockout mice respond to doxorubicin with reduced cardiotoxicity

    SciTech Connect

    Terrand, Jerome; Xu, Beibei; Morrissy, Steve; Dinh, Thai Nho; Williams, Stuart; Chen, Qin M.

    2011-11-15

    Doxorubicin (Dox) is an antineoplastic agent that can cause cardiomyopathy in humans and experimental animals. As an inducer of reactive oxygen species and a DNA damaging agent, Dox causes elevated expression of p21{sup WAF1/Cip1/Sdi1} (p21) gene. Elevated levels of p21 mRNA and p21 protein have been detected in the myocardium of mice following Dox treatment. With chronic treatment of Dox, wild type (WT) animals develop cardiomyopathy evidenced by elongated nuclei, mitochondrial swelling, myofilamental disarray, reduced cardiac output, reduced ejection fraction, reduced left ventricular contractility, and elevated expression of ANF gene. In contrast, p21 knockout (p21KO) mice did not show significant changes in the same parameters in response to Dox treatment. In an effort to understand the mechanism of the resistance against Dox induced cardiomyopathy, we measured levels of antioxidant enzymes and found that p21KO mice did not contain elevated basal or inducible levels of glutathione peroxidase and catalase. Measurements of 6 circulating cytokines indicated elevation of IL-6, IL-12, IFN{gamma} and TNF{alpha} in Dox treated WT mice but not p21KO mice. Dox induced elevation of IL-6 mRNA was detected in the myocardium of WT mice but not p21KO mice. While the mechanism of the resistance against Dox induced cardiomyopathy remains unclear, lack of inflammatory response may contribute to the observed cardiac protection in p21KO mice. -- Highlights: Black-Right-Pointing-Pointer Doxorubicin induces p21 elevation in the myocardium. Black-Right-Pointing-Pointer Doxorubicin causes dilated cardiomyopathy in wild type mice. Black-Right-Pointing-Pointer p21 Knockout mice are resistant against doxorubicin induced cardiomyopathy. Black-Right-Pointing-Pointer Lack of inflammatory response correlates with the resistance in p21 knockout mice.

  13. Sulforaphane protects the heart from doxorubicin-induced toxicity

    PubMed Central

    Singh, Preeti; Sharma, Rajendra; McElhanon, Kevin; Allen, Charles D.; Megyesi, Judit K.; Beneš, Helen; Singh, Sharda P.

    2015-01-01

    Cardiotoxicity is one of the major side effects encountered during cancer chemotherapy with doxorubicin (DOX) and other anthracyclines. Previous studies have shown that oxidative stress caused by DOX is one of the primary mechanisms for its toxic effects on the heart. Since the redox-sensitive transcription factor, Nrf2, plays a major role in protecting cells from the toxic metabolites generated during oxidative stress, we examined the effects of the phytochemical sulforaphane (SFN), a potent Nrf2-activating agent, on DOX-induced cardiotoxicity. These studies were carried out both in vitro and in vivo using rat H9c2 cardiomyoblast cells and wild type 129/sv mice, and involved SFN pretreatment followed by SFN administration during DOX exposure. SFN treatment protected H9c2 cells from DOX cytotoxicity and also resulted in restored cardiac function and a significant reduction in DOX-induced cardiomyopathy and mortality in mice. Specificity of SFN induction of Nrf2 and protection of H9c2 cells was demonstrated in Nrf2 knockdown experiments. Cardiac accumulation of 4-hydroxynonenal (4-HNE) protein adducts, due to lipid peroxidation following DOX-induced oxidative stress, was significantly attenuated by SFN treatment. The respiratory function of cardiac mitochondria isolated from mice exposed to DOX alone was repressed, while SFN treatment with DOX significantly elevated mitochondrial respiratory complex activities. Co-administration of SFN reversed the DOX-associated reduction in nuclear Nrf2 binding activity and restored cardiac expression of Nrf2-regulated genes, at both the RNA and protein levels. Together, our results demonstrate for the first time that the Nrf2 inducer, SFN, has the potential to provide protection against DOX-mediated cardiotoxicity. PMID:26025579

  14. Enhanced Ehrlich tumor inhibition using DOX-NP™ and gold nanoparticles loaded liposomes

    NASA Astrophysics Data System (ADS)

    Mady, M. M.; Al-Shaikh, F. H.; Al-Farhan, F. F.; Aly, A. A.; Al-Mohanna, M. A.; Ghannam, M. M.

    2016-04-01

    Treatment with doxorubicin (DOX) is a common regime in treating various types of cancer. DOX-NP™ is one of a well established marketed liposomal formulation for DOX. It offers distinct advantages over conventional DOX in reducing the cardiac toxicity and increasing the tolerability and efficacy. Gold nanoparticles (GNPs), a typical biocompatible nanomaterial, have been widely used in biomedical engineering and bioanalytical applications such as biomedical imaging and biosensors. Ehrlich tumors were grown in female balb mice by subcutaneous injection of Ehrlich ascites carcinoma cells. Mice bearing Ehrlich tumor were injected with saline, free doxorubicin (DOX) in solution, gold nanoparticles loaded liposomes and commercial liposomal encapsulated doxorubicin (DOX-NP™). The results showed that GNPs loaded liposomes could enhance the antitumor activity of commercial liposomal formulation (DOX-NP™) and displayed significantly decreased systemic toxicity compared with free DOX and commercial liposomal formulation (DOX-NP™) at the equivalent dose. So the combination of GNPs and liposomes is expected to significantly increase the likelihood of cell killing and make it a promising new approach to cancer therapy.

  15. Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

    SciTech Connect

    Aguilar, David; Strom, Joshua; Chen, Qin M.

    2014-04-01

    Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found Glucocorticoid-Induced Leucine Zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes. - Highlights: • Corticosteroids act as a cytoprotective agent in cardiomyocytes • Corticosteroids induce GILZ expression in cardiomyocytes • Elevated GILZ results in resistance against apoptosis induced by doxorubicin • GILZ induces Bcl-xL protein without inducing Bcl-xL mRNA.

  16. Cardioprotective Potentials of Plant-Derived Small Molecules against Doxorubicin Associated Cardiotoxicity

    PubMed Central

    Ojha, Shreesh; Al Taee, Hasan; Goyal, Sameer; Mahajan, Umesh B.; Patil, Chandrgouda R.; Arya, D. S.; Rajesh, Mohanraj

    2016-01-01

    Doxorubicin (DOX) is a potent and widely used anthracycline antibiotic for the treatment of several malignancies. Unfortunately, the clinical utility of DOX is often restricted due to the elicitation of organ toxicity. Particularly, the increased risk for the development of dilated cardiomyopathy by DOX among the cancer survivors warrants major attention from the physicians as well as researchers to develop adjuvant agents to neutralize the noxious effects of DOX on the healthy myocardium. Despite these pitfalls, the use of traditional cytotoxic drugs continues to be the mainstay treatment for several types of cancer. Recently, phytochemicals have gained attention for their anticancer, chemopreventive, and cardioprotective activities. The ideal cardioprotective agents should not compromise the clinical efficacy of DOX and should be devoid of cumulative or irreversible toxicity on the naïve tissues. Furthermore, adjuvants possessing synergistic anticancer activity and quelling of chemoresistance would significantly enhance the clinical utility in combating DOX-induced cardiotoxicity. The present review renders an overview of cardioprotective effects of plant-derived small molecules and their purported mechanisms against DOX-induced cardiotoxicity. Phytochemicals serve as the reservoirs of pharmacophore which can be utilized as templates for developing safe and potential novel cardioprotective agents in combating DOX-induced cardiotoxicity. PMID:27313831

  17. Potential Therapeutic Advantages of Doxorubicin when Activated by Formaldehyde to Function as a DNA Adduct-Forming Agent.

    PubMed

    Cutts, Suzanne M; Rephaeli, Ada; Nudelman, Abraham; Ugarenko, Michal; Phillips, Don R

    2015-01-01

    Doxorubicin has been in use as a key anticancer drug for forty years, either as a single agent or in combination chemotherapy. It functions primarily by interfering with topoisomerase II activity but in the presence of formaldehyde, it forms adducts with DNA, mainly with the exocyclic amine of guanine at GpC sites and these adducts are more cytotoxic than topoisomerase II induced damage. High levels of adducts form spontaneously from the endogenous level of formaldehyde in tumour cells (1,300 adducts per cell after a 4 hr treatment with doxorubicin), but substantially higher levels form with the addition of exogenous sources of formaldehyde, such as formaldehyde releasing prodrugs. The enhanced cytotoxicity of adducts has been confirmed in mouse models, with adduct-forming conditions resulting in much improved inhibition of tumour growth, as well as cardioprotection. Doxorubicin cardiotoxicity has been attributed to topoisomerase II poisoning, and the cardioprotection is consistent with a mechanism switch from topoisomerase II poisoning to covalent adduct formation. Although the adducts have a half-life of less than one day, a population remains as essentially permanent lesions. The capacity of doxorubicin to form adducts offers a range of potential advantages over the conventional use of doxorubicin (as a topoisomerase II poison), including: enhanced cell kill; tumour-selective activation, hence tumour-selective cell kill; decreased cardiotoxicity; decreased resistance to prolonged doxorubicin treatment. There is therefore enormous potential to improve clinical responses to doxorubicin by using conditions which favour the formation of doxorubicin-DNA adducts.

  18. Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Elberry, Ahmed A; Abdel-Naim, Ashraf B; Abdel-Sattar, Essam A; Nagy, Ayman A; Mosli, Hisham A; Mohamadin, Ahmed M; Ashour, Osama M

    2010-05-01

    Doxorubicin (DOX) is a widely used cancer chemotherapeutic agent. However, it generates free oxygen radicals that result in serious dose-limiting cardiotoxicity. Supplementations with berries were proven effective in reducing oxidative stress associated with several ailments. The aim of the current study was to investigate the potential protective effect of cranberry extract (CRAN) against DOX-induced cardiotoxicity in rats. CRAN was given orally to rats (100mg/kg/day for 10 consecutive days) and DOX (15mg/kg; i.p.) was administered on the seventh day. CRAN protected against DOX-induced increased mortality and ECG changes. It significantly inhibited DOX-provoked glutathione (GSH) depletion and accumulation of oxidized glutathione (GSSG), malondialdehyde (MDA), and protein carbonyls in cardiac tissues. The reductions of cardiac activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were significantly mitigated. Elevation of cardiac myeloperoxidase (MPO) activity in response to DOX treatment was significantly hampered. Pretreatment of CRAN significantly guarded against DOX-induced rise of serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), creatine kinase-MB (CK-MB) as well as troponin I level. CRAN alleviated histopathological changes in rats' hearts treated with DOX. In conclusion, CRAN protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to CRAN's antioxidant activity.

  19. Skeletal Muscle an Active Compartment in the Sequestering and Metabolism of Doxorubicin Chemotherapy

    PubMed Central

    Fabris, Sergio; MacLean, David A.

    2015-01-01

    Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood. The purpose of the current study was to examine the accumulation of doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) in skeletal muscle of the rat up to 8 days after the administration of a 1.5 or 4.5 mg kg-1 i.p. dose. Subsequent to either dose, DOX and DOXol were observed in skeletal muscle throughout the length of the experiment. Interestingly an efflux of DOX was examined after 96 hours, followed by an apparent re-uptake of the drug which coincided with a spike and rapid decrease of plasma DOX concentrations. The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation. Furthermore, there was no evidence that DOX preferentially accumulated in a specific muscle group with either dose. It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered. PMID:26401619

  20. Efficient Delivery of DOX to Nuclei of Hepatic Carcinoma Cells in the Subcutaneous Tumor Model Using pH-Sensitive Pullulan-DOX Conjugates.

    PubMed

    Li, Huanan; Cui, Yani; Sui, Junhui; Bian, Shaoquan; Sun, Yong; Liang, Jie; Fan, Yujiang; Zhang, Xingdong

    2015-07-29

    A series of pullulan-doxorubicin conjugates (Pu-DOXs) were investigated for effectively delivering DOX to nuclei of hepatic carcinoma cells in subcutaneous tumor model. These Pu-DOXs were prepared by conjugating DOX onto pullulan molecule via pH-responsive hydrazone bond using spacers with different alkane chain length. The highest drug loading content of Pu-DOXs went up to nearly 50%, and the diameter of Pu-DOX nanoparticles ranged from 50 to 170 nm, as measured by DLS and TEM. These Pu-DOX nanoparticles could rapidly release DOX in the acidic environment at pH = 5.0 while being kept relatively stable in neural conditions. The in vitro cell coculture experiments revealed that these Pu-DOX nanoparticles were selectively internalized by hepatic carcinoma cells through receptor-mediated endocytosis via asialoglycoprotein receptor on the hepatic carcinoma cell surface. DOX was rapidly released from Pu-DOX nanoparticles in acidic endosome/lysosome, diffused into cell nuclei due to its strong affinity to nucleic acid, inhibited the cell proliferation, and accelerated the cell apoptosis. In the nude mice subcutaneous hepatic carcinoma model, Pu-DOX nanoparticles efficiently accumulated in the tumor site through the enhanced permeation and retention effect. Then DOX was specifically internalized by hepatic carcinoma cells and rapidly diffused into the nuclei of cells. Compared with the control group in in vivo experiments, these Pu-DOX nanoparticles effectively inhibited solid tumor growth, prolonging the lifetime of the experimental animal. These pH sensitive nanoparticles might provide an important clinical implication for targeted hepatic carcinoma therapy with high efficiency and low systematic toxicity.

  1. ALDH2 attenuates Dox-induced cardiotoxicity by inhibiting cardiac apoptosis and oxidative stress

    PubMed Central

    Gao, Yawen; Xu, Yan; Hua, Songwen; Zhou, Shenghua; Wang, Kangkai

    2015-01-01

    The anthracycline chemotherapy drug doxorubicin (DOX) is cardiotoxic. This study aimed to explore the effect of acetaldehyde dehydrogenase 2 (ALDH2), a detoxifying protein, on DOX-induced cardiotoxicity and unveil the underlying mechanisms. BALB/c mice were randomly divided in four groups: control group (no treatment), DOX group (DOX administration for myocardial damage induction), DOX + Daidzin group (DOX administration + Daidzin, an ALDH2 antagonist) and DOX + Alda-1 group (DOX administration + Alda-1, an ALDH2 agonist). Then, survival, haemodynamic parameters, expression of pro- and anti-apoptosis markers, reactive oxygen species (ROS) and 4-Hydroxynonenal (4-HNE) levels, expression and localization of NADPH oxidase 2 (NOX2) and its cytoplasmic subunit p47PHOX, and ALDH2 expression and activity were assessed. Mortality rates of 0, 35, 5, and 70% were obtained in the control, DOX, DOX + Alda-1, and DOX + Daidzin groups, respectively, at the ninth weekend. Compared with control animals, DOX treatment resulted in significantly reduced left ventricular systolic pressure (LVSP) and ± dp/dt, and overtly increased left ventricular end-diastolic pressure (LVEDP); increased Bax expression and caspase-3/7 activity, and reduced Bcl-2 expression in the myocardium; increased ROS (about 2 fold) and 4-HNE adduct (3 fold) levels in the myocardium; increased NOX2 protein expression and membrane translocation of P47PHOX. These effects were aggravated in the DOX + Daidzin group, DOX + Alda-1 treated animals showed partial or complete alleviation. Finally, Daidzin further reduced the DOX-repressed ALDH2 activity, which was partially rescued by Alda-1. These results indicated that ALDH2 attenuates DOX-induced cardiotoxicity by inhibiting oxidative stress, NOX2 expression and activity, and reducing myocardial apoptosis. PMID:26221217

  2. Doxorubicin induced dilated cardiomyopathy in a rabbit model: an update.

    PubMed

    Gava, Fábio N; Zacché, Evandro; Ortiz, Edna M G; Champion, Tatiana; Bandarra, Marcio B; Vasconcelos, Rosemeri O; Barbosa, José C; Camacho, Aparecido A

    2013-02-01

    Dilated cardiomyopathy (DCM) is characterized by chamber dilation and cardiac dysfunction. Because of the poor prognosis, models are needed for the investigation of and development of new therapeutic approaches, as well as stem cell therapy. Doxorubicin (DOX), used as chemotherapeutic agent, is reported to be cumulative cardiotoxic causing DCM. The aim of the study was to investigate the onset of systolic dysfunction using echocardiography in rabbits receiving two different doses of DOX (1mg/kg twice a week and 2 mg/kg once a week). Twenty rabbits were treated with doxorubicin in two different doses for 6 weeks and compared with a control group treated with NaCl 0.9%. The effect of doxorubicin on the myocardium was investigated with histological analysis and scanning electron microscopy of left ventricle (LV), as well as in the interventricular septum (IVS) and right ventricle (RV). The results showed a high mortality rate for rabbits receiving 2 mg/kg once a week. A significant reduction in systolic function was present in animals treated with DOX after 6 weeks, with decreased ejection fraction and shortening fraction. Histology and electron microscopy revealed vacuolization, intracytoplasmic granulation, necrosis and interstitial fibrosis in LV, as well as in the IVS and RV. Doxorubicin induced changes are present in the LV, RV and IVS, and the administration at the dose of 1 mg/kg twice a week for only 6 weeks is safe and sufficient to induce DCM in rabbits.

  3. Fabrication of doxorubicin nanoparticles by controlled antisolvent precipitation for enhanced intracellular delivery.

    PubMed

    Tam, Yu Tong; To, Kenneth Kin Wah; Chow, Albert Hee Lum

    2016-03-01

    Over-expression of ATP-binding cassette transporters is one of the most important mechanisms responsible for multidrug resistance. Here, we aimed to develop a stable polymeric nanoparticle system by flash nanoprecipitation (FNP) for enhanced anticancer drug delivery into drug resistant cancer cells. As an antisolvent precipitation process, FNP works best for highly lipophilic solutes (logP>6). Thus we also aimed to evaluate the applicability of FNP to drugs with relatively low lipophilicity (logP=1-2). To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate with a logP of 1.3, was selected as a model drug for the assessment. DOX was successfully incorporated into the amphiphilic diblock copolymer, polyethylene glycol-b-polylactic acid (PEG-b-PLA), by FNP using a four-stream multi-inlet vortex mixer. Optimization of key processing parameters and co-formulation with the co-stabilizer, polyvinylpyrrolidone, yielded highly stable, roughly spherical DOX-loaded PEG-b-PLA nanoparticles (DOX.NP) with mean particle size below 100nm, drug loading up to 14%, and drug encapsulation efficiency up to 49%. DOX.NP exhibited a pH-dependent drug release profile with higher cumulative release rate at acidic pHs. Surface analysis of DOX.NP by XPS revealed an absence of DOX on the particle surface, indicative of complete drug encapsulation. While there were no significant differences in cytotoxic effect on P-gp over-expressing LCC6/MDR cell line between DOX.NP and free DOX in buffered aqueous media, DOX.NP exhibited a considerably higher cellular uptake and intracellular retention after efflux. The apparent lack of cytotoxicity enhancement with DOX.NP may be attributable to its slow DOX release inside the cells.

  4. Fabrication of doxorubicin nanoparticles by controlled antisolvent precipitation for enhanced intracellular delivery.

    PubMed

    Tam, Yu Tong; To, Kenneth Kin Wah; Chow, Albert Hee Lum

    2016-03-01

    Over-expression of ATP-binding cassette transporters is one of the most important mechanisms responsible for multidrug resistance. Here, we aimed to develop a stable polymeric nanoparticle system by flash nanoprecipitation (FNP) for enhanced anticancer drug delivery into drug resistant cancer cells. As an antisolvent precipitation process, FNP works best for highly lipophilic solutes (logP>6). Thus we also aimed to evaluate the applicability of FNP to drugs with relatively low lipophilicity (logP=1-2). To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate with a logP of 1.3, was selected as a model drug for the assessment. DOX was successfully incorporated into the amphiphilic diblock copolymer, polyethylene glycol-b-polylactic acid (PEG-b-PLA), by FNP using a four-stream multi-inlet vortex mixer. Optimization of key processing parameters and co-formulation with the co-stabilizer, polyvinylpyrrolidone, yielded highly stable, roughly spherical DOX-loaded PEG-b-PLA nanoparticles (DOX.NP) with mean particle size below 100nm, drug loading up to 14%, and drug encapsulation efficiency up to 49%. DOX.NP exhibited a pH-dependent drug release profile with higher cumulative release rate at acidic pHs. Surface analysis of DOX.NP by XPS revealed an absence of DOX on the particle surface, indicative of complete drug encapsulation. While there were no significant differences in cytotoxic effect on P-gp over-expressing LCC6/MDR cell line between DOX.NP and free DOX in buffered aqueous media, DOX.NP exhibited a considerably higher cellular uptake and intracellular retention after efflux. The apparent lack of cytotoxicity enhancement with DOX.NP may be attributable to its slow DOX release inside the cells. PMID:26724466

  5. Protective effect of guggulsterone against cardiomyocyte injury induced by doxorubicin in vitro

    PubMed Central

    2012-01-01

    Background Doxorubicin (DOX) is an effective antineoplastic drug; however, clinical use of DOX is limited by its dose-dependent cardiotoxicity. It is well known that reactive oxygen species (ROS) play a vital role in the pathological process of DOX-induced cardiotoxicity. For this study, we evaluated the protective effects of guggulsterone (GS), a steroid obtained from myrrh, to determine its preliminary mechanisms in defending against DOX-induced cytotoxicity in H9C2 cells. Methods In this study, we used a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release measurements, and Hoechst 33258 staining to evaluate the protective effect of GS against DOX-induced cytotoxicity in H9C2 cells. In addition, we observed the immunofluorescence of intracellular ROS and measured lipid peroxidation, caspase-3 activity, and apoptosis-related proteins by using Western blotting. Results The MTT assay and LDH release showed that treatment using GS (1–30 μM) did not cause cytotoxicity. Furthermore, GS inhibited DOX (1 μM)-induced cytotoxicity in a concentration-dependent manner. Hoechst 33258 staining showed that GS significantly reduced DOX-induced apoptosis and cell death. Using GS at a dose of 10–30 μM significantly reduced intracellular ROS and the formation of MDA in the supernatant of DOX-treated H9C2 cells and suppressed caspase-3 activity to reference levels. In immunoblot analysis, pretreatment using GS significantly reversed DOX-induced decrease of PARP, caspase-3 and bcl-2, and increase of bax, cytochrome C release, cleaved-PARP and cleaved-caspase-3. In addition, the properties of DOX-induced cancer cell (DLD-1 cells) death did not interfere when combined GS and DOX. Conclusion These data provide considerable evidence that GS could serve as a novel cardioprotective agent against DOX-induced cardiotoxicity. PMID:22920231

  6. Salvianolic acid A as a multifunctional agent ameliorates doxorubicin-induced nephropathy in rats

    PubMed Central

    Fan, Hua-Ying; Yang, Ming-Yan; Qi, Dong; Zhang, Zuo-Kai; Zhu, Lin; Shang-Guan, Xiu-Xin; Liu, Ke; Xu, Hui; Che, Xin

    2015-01-01

    Nephrotic syndrome (NS) is still a therapeutic challenge. To date there is no ideal treatment. Evidence suggest that multidrug therapy has more effect than monotherapy in amelioration of renal injury. Salvianolic acid A (SAA) is the major active component of Salviae Miltiorrhizae Bunge. Previous studies have demonstrated that SAA is a multi-target agent and has various pharmacological activities. The pleiotropic properties of SAA predict its potential in the treatment of NS. The study investigated the effect of SAA on doxorubicin-induced nephropathy. The kidney function related-biochemical changes, hemorheological parameters and oxidative stress status were determined, and histological examination using light and transmission electron microcopies and western blot analysis were also performed. Results revealed that treatment with SAA alleviated histological damages, relieved proteinuria, hypoalbuminemia and hyperlipidemia, reduced oxidative stress, as well as improving hemorheology. Furthermore, SAA restored podocin expression, down-regulated the expression of NF-κB p65 and p-IκBα while up-regulating IκBα protein expression. Overall, as a multifunctional agent, SAA has a favorable renoprotection in doxorubicin-induced nephropathy. The anti-inflammation, antioxidant, amelioration of podocyte injury, improvement of hemorheology and hypolipidemic properties may constituent an important part of its therapeutic effects. All these indicate that SAA is likely to be a promising agent for NS. PMID:26194431

  7. Doxorubicin and resveratrol co-delivery nanoparticle to overcome doxorubicin resistance

    PubMed Central

    Zhao, Yuan; Huan, Meng-lei; Liu, Miao; Cheng, Ying; Sun, Yang; Cui, Han; Liu, Dao-zhou; Mei, Qi-bing; Zhou, Si-yuan

    2016-01-01

    With the extensive application of doxorubicin (DOX), DOX resistance has become one of the main obstacles to the effective treatment of breast cancer. In this paper, DOX and resveratrol (RES) were co-encapsulated in a modified PLGA nanoparticle (NPS) to overcome the DOX resistance. CLSM results indicated that DOX and RES were simultaneously delivered into the nucleus of DOX-resistant human breast cancer cells by DOX/RES-loaded NPS. Consequently, DOX/RES-loaded NPS showed significant cytotoxicity on MDA-MB-231/ADR cells and MCF-7/ADR cells. Furthermore, DOX/RES-loaded NPS could overcome DOX resistance by inhibiting the expression of drug resistance-related protein such as P-gp, MRP-1 and BCRP, and induce apoptosis through down-regulating the expression of NF-κB and BCL-2. In tumor-bearing mice, DOX/RES-loaded NPS mainly delivered DOX and RES to tumor tissue. Compared with free DOX, DOX/RES-loaded NPS significantly inhibited the DOX-resistant tumor growth in tumor-bearing mice without causing significant systemic toxicity. In a word, DOX/RES-loaded NPS could overcome the DOX resistance and had the potential in the treatment of DOX-resistant breast cancer. PMID:27731405

  8. Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress.

    PubMed

    Marques-Aleixo, Inês; Santos-Alves, Estela; Mariani, Diogo; Rizo-Roca, David; Padrão, Ana I; Rocha-Rodrigues, Sílvia; Viscor, Ginés; Torrella, J Ramon; Ferreira, Rita; Oliveira, Paulo J; Magalhães, José; Ascensão, António

    2015-01-01

    Doxorubicin (DOX) is an anti-cancer agent whose clinical usage results in a cumulative and dose-dependent cardiotoxicity. We have previously shown that exercise performed prior to DOX treatment reduces the resulting cardiac(mito) toxicity. We sought to determine the effects on cardiac mitochondrial toxicity of two distinct chronic exercise models (endurance treadmill training-TM and voluntary free-wheel activity-FW) when used prior and during DOX treatment. Male-young Sprague-Dawley rats were divided into six groups (n=6 per group): SAL+SED (saline sedentary), SAL+TM (12-weeks TM), SAL+FW (12-weeks FW), DOX+SED (7-weeks of chronic DOX treatment 2mg/kg per week), DOX+TM and DOX+FW. DOX administration started 5weeks after the beginning of the exercise protocol. Heart mitochondrial ultrastructural alterations, mitochondrial function (oxygen consumption and membrane potential), semi-quantification of oxidative phosphorylation (OXPHOS) proteins and their in-gel activity, as well as proteins involved in mitochondrial oxidative stress (SIRT3, p66shc and UCP2), biogenesis (PGC1α and TFAM), acetylation and markers for oxidative damage (carbonyl groups, MDA,SH, aconitase, Mn-SOD activity) were evaluated. DOX treatment resulted in ultrastructural and functional alterations and decreased OXPHOS. Moreover, DOX decreased complex I activity and content, mitochondrial biogenesis (TFAM), increased acetylation and oxidative stress. TM and FW prevented DOX-induced alteration in OXPHOS, the increase in oxidative stress, the decrease in complex V activity and in complex I activity and content. DOX-induced decreases in TFAM and SIRT3 content were prevented by TM only. Both chronic models of physical exercise performed before and during the course of sub-chronic DOX treatment translated into an improved mitochondrial bioenergetic fitness, which may result in part from the prevention of mitochondrial oxidative stress and damage. PMID:25446396

  9. Design and biological activity of epidermal growth factor receptor-targeted peptide doxorubicin conjugate.

    PubMed

    Fan, Mingliang; Yang, Danbo; Liang, Xiaofei; Ao, Junping; Li, Zonghai; Wang, Hongyang; Shi, Bizhi

    2015-03-01

    The nonspecific toxicity of anticancer drug doxorubicin (DOX) toward both tumor and normal cells can result in serious side effects, thereby limiting its clinical applications. In this wok, epidermal growth factor receptor (EGFR) antagonist peptide GE11 was introduced into DOX structure via a disulfide bond which can be cleaved by reduced glutathione (GSH). We have investigated the intracellular delivery and in vitro cytotoxicity of GE11-DOX conjugate and free DOX in high (SMMC-7721) and low (MCF-7) EGFR expressing cancer cell models. GE11-DOX accumulated at higher levels in SMMC-7721 cells than in MCF-7 cells, while the cellular uptake of free DOX was almost the same in both cells. Furthermore, pretreating with anti-EGFR monoclonal antibody reduced intracellular accumulation of GE11-DOX in SMMC-7721, indicating the involvement of EGFR pathway in the transport of conjugate. Our results suggest that GE11-DOX conjugate has the potential to be a therapeutic agent for treating EGFR overexpressing tumor.

  10. Functionalization of Carbon Nanomaterial Surface by Doxorubicin and Antibodies to Tumor Markers

    NASA Astrophysics Data System (ADS)

    Perepelytsina, Olena M.; Yakymchuk, Olena M.; Sydorenko, Mychailo V.; Bakalinska, Olga N.; Bloisi, Francesco; Vicari, Luciano Rosario Maria

    2016-06-01

    The actual task of oncology is effective treatment of cancer while causing a minimum harm to the patient. The appearance of polymer nanomaterials and technologies launched new applications and approaches of delivery and release of anticancer drugs. The goal of work was to test ultra dispersed diamonds (UDDs) and onion-like carbon (OLCs) as new vehicles for delivery of antitumor drug (doxorubicin (DOX)) and specific antibodies to tumor receptors. Stable compounds of UDDs and OLCs with DOX were obtained. As results of work, an effectiveness of functionalization was 2.94 % w/ w for OLC-DOX and 2.98 % w/ w for UDD-DOX. Also, there was demonstrated that UDD-DOX and OLC-DOX constructs had dose-dependent cytotoxic effect on tumor cells in the presence of trypsin. The survival of adenocarcinoma cells reduced from 52 to 28 % in case of incubation with the UDD-DOX in concentrations from 8.4-2.5 to 670-20 μg/ml and from 72 to 30 % after incubation with OLC-DOX. Simultaneously, antibodies to epidermal growth factor maintained 75 % of the functional activity and specificity after matrix-assisted pulsed laser evaporation deposition. Thus, the conclusion has been made about the prospects of selected new methods and approaches for creating an antitumor agent with capabilities targeted delivery of drugs.

  11. Protective effect of bilberry (Vaccinium myrtillus) against doxorubicin-induced oxidative cardiotoxicity in rats

    PubMed Central

    Ashour, Osama M.; Elberry, Ahmed A.; Alahdal, Abdulrahman M.; Al Mohamadi, Ameen M.; Nagy, Ayman A.; Abdel-Naim, Ashraf B.; Abdel-Sattar, Essam A.; Mohamadin, Ahmed M.

    2011-01-01

    Summary Background Doxorubicin (DOX) is a commonly used chemotherapeutic agent. It is associated with serious dose-limiting cardiotoxicity, which is at least partly caused by generation of reactive oxygen species (ROS). Supplementations with bilberries were effective in reducing oxidative stress in many tissue injuries due their high content of antioxidants. The present study investigated the potential protective effect of bilberry extract against DOX-induced cardiotoxicity in rats. Material/Methods Rats were treated orally with a methanolic extract of bilberry for 10 days. DOX was injected intraperitoneally on day 7. Twenty-four hours after the last bilberry administration, rats were subjected to ECG study. Blood was then withdrawn and cardiac tissues were dissected for assessment of oxidative stress and cardiac tissue injury. Cardiac tissues were also subjected to histopathological examination. Results Bilberry extract significantly inhibited DOX-provoked reduced glutathione depletion and accumulation of oxidized glutathione, malondialdehyde and protein carbonyls in cardiac tissues. This was accompanied by significant amelioration of reduced cardiac catalase, superoxide dismutase, and glutathione peroxidase activities; and increased cardiac myeloperoxidase activity in response to DOX challenge. Pretreatment with bilberry significantly guarded against DOX-induced increase in serum activities of lactate dehydrogenase, creatine phosphokinase and creatine kinase-MB, as well as the level of troponin I. Bilberry alleviated ECG changes in rats treated with DOX and attenuated its pathological changes. Conclusions Bilberry protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to its antioxidant activity. PMID:21455099

  12. Functionalization of Carbon Nanomaterial Surface by Doxorubicin and Antibodies to Tumor Markers.

    PubMed

    Perepelytsina, Olena M; Yakymchuk, Olena M; Sydorenko, Mychailo V; Bakalinska, Olga N; Bloisi, Francesco; Vicari, Luciano Rosario Maria

    2016-12-01

    The actual task of oncology is effective treatment of cancer while causing a minimum harm to the patient. The appearance of polymer nanomaterials and technologies launched new applications and approaches of delivery and release of anticancer drugs. The goal of work was to test ultra dispersed diamonds (UDDs) and onion-like carbon (OLCs) as new vehicles for delivery of antitumor drug (doxorubicin (DOX)) and specific antibodies to tumor receptors. Stable compounds of UDDs and OLCs with DOX were obtained. As results of work, an effectiveness of functionalization was 2.94 % w/w for OLC-DOX and 2.98 % w/w for UDD-DOX. Also, there was demonstrated that UDD-DOX and OLC-DOX constructs had dose-dependent cytotoxic effect on tumor cells in the presence of trypsin. The survival of adenocarcinoma cells reduced from 52 to 28 % in case of incubation with the UDD-DOX in concentrations from 8.4-2.5 to 670-20 μg/ml and from 72 to 30 % after incubation with OLC-DOX. Simultaneously, antibodies to epidermal growth factor maintained 75 % of the functional activity and specificity after matrix-assisted pulsed laser evaporation deposition. Thus, the conclusion has been made about the prospects of selected new methods and approaches for creating an antitumor agent with capabilities targeted delivery of drugs.

  13. Inhibition of chymotryptic-like standard proteasome activity exacerbates doxorubicin-induced cytotoxicity in primary cardiomyocytes.

    PubMed

    Spur, Eva-Margarete; Althof, Nadine; Respondek, Dorota; Klingel, Karin; Heuser, Arnd; Overkleeft, Hermen S; Voigt, Antje

    2016-04-15

    The anthracycline doxorubicin (DOX) is a potent anticancer agent for multiple myeloma (MM). A major limitation of this drug is the induction of death in cardiomyocytes leading to heart failure. Here we report on the role of the ubiquitin-proteasome system (UPS) as a critical surveillance pathway for preservation of cell vitality counteracting DOX treatment. Since in addition to DOX also suppression of proteasome activity is a rational therapeutic strategy for MM, we examined how small molecular compounds with clinically relevant proteasome subunit specificity affect DOX cytotoxicity. We found that during DOX-treatment, the activity of the β5 standard proteasome subunit is crucial for limiting off-target cytotoxicity in primary cardiomyocytes. In contrast, we demonstrate that the β5 equivalent LMP7 of the immunoproteasome represents a safe target for subunit-specific inhibitors in DOX-exposed cardiomyocytes. Neither inhibition of LMP7 in primary cardiomyocytes nor genetic ablation of LMP7 in heart tissue influenced the development of DOX cardiotoxicity. Our results indicate that as compared to compounds like carfilzomib, which target both the β5 standard proteasome and the LMP7 immunoproteasome subunit, immunoproteasome-specific inhibitors with known anti-tumor capacity for MM cells might be advantageous for reducing cardiomyocyte death, when a combination therapy with DOX is envisaged.

  14. Protective effects of madecassoside against Doxorubicin induced nephrotoxicity in vivo and in vitro

    PubMed Central

    Su, Zhonghao; Ye, Jin; Qin, Zhenxia; Ding, Xianting

    2015-01-01

    Madecassoside (MA), a triterpenoid saponin isolated from C. asitica, exerts various pharmacological activity including antioxidative and antinflammatory. Doxorubicin (DOX), a common chemotherapeutic drug, has been reported to induce numerous toxic side effects including renal-toxicity. We hypothesized that MA administration may decrease renal-toxicity caused by DOX. In this study, we investigated this hypothesis by introducing MA and DOX into the culture of Human Proximal Tubule Cells HK-2 and mice model. Our in vivo study demonstrated that MA (12 mg/kg), treatment for two weeks attenuated DOX-induced renal injury via protecting renal function, recovering antioxidant enzyme activity, inhibiting Bax, p-ERK1/2, NF-κB p65, iNOS expression and increasing Bcl-2 expression. Similar findings were obtained in our in vitro studies with treatment of DOX and/or MA. Further studies with application of iNOS inhibitor and ERK1/2 kinase inhibitor indicated that the inhibitory effects of MA on DOX-induced apoptosis and inflammation might be mediated by the suppression of the activation of cleaved caspase-3, ERK1/2 pathways, NF-κB p65 and NO production. These results suggest that MA is a promising protective agent for DOX-induced renal toxicity and can be a potential candidate to protect against renal toxicity in DOX-treated cancer patients. PMID:26658818

  15. Functionalization of Carbon Nanomaterial Surface by Doxorubicin and Antibodies to Tumor Markers.

    PubMed

    Perepelytsina, Olena M; Yakymchuk, Olena M; Sydorenko, Mychailo V; Bakalinska, Olga N; Bloisi, Francesco; Vicari, Luciano Rosario Maria

    2016-12-01

    The actual task of oncology is effective treatment of cancer while causing a minimum harm to the patient. The appearance of polymer nanomaterials and technologies launched new applications and approaches of delivery and release of anticancer drugs. The goal of work was to test ultra dispersed diamonds (UDDs) and onion-like carbon (OLCs) as new vehicles for delivery of antitumor drug (doxorubicin (DOX)) and specific antibodies to tumor receptors. Stable compounds of UDDs and OLCs with DOX were obtained. As results of work, an effectiveness of functionalization was 2.94 % w/w for OLC-DOX and 2.98 % w/w for UDD-DOX. Also, there was demonstrated that UDD-DOX and OLC-DOX constructs had dose-dependent cytotoxic effect on tumor cells in the presence of trypsin. The survival of adenocarcinoma cells reduced from 52 to 28 % in case of incubation with the UDD-DOX in concentrations from 8.4-2.5 to 670-20 μg/ml and from 72 to 30 % after incubation with OLC-DOX. Simultaneously, antibodies to epidermal growth factor maintained 75 % of the functional activity and specificity after matrix-assisted pulsed laser evaporation deposition. Thus, the conclusion has been made about the prospects of selected new methods and approaches for creating an antitumor agent with capabilities targeted delivery of drugs. PMID:27356561

  16. The synergistic effect between vanillin and doxorubicin in ehrlich ascites carcinoma solid tumor and MCF-7 human breast cancer cell line.

    PubMed

    Elsherbiny, Nehal M; Younis, Nahla N; Shaheen, Mohamed A; Elseweidy, Mohamed M

    2016-09-01

    Despite the remarkable anti-tumor activity of doxorubicin (DOX), its clinical application is limited due to multiple organ toxicities. Products with less side effects are therefore highly requested. The current study investigated the anti-cancer activities of vanillin against breast cancer and possible synergistic potentiation of DOX chemotherapeutic effects by vanillin. Vanillin (100mg/kg), DOX (2mg/kg) and their combination were administered i.p. to solid Ehrlich tumor-bearing mice for 21days. MCF-7 human breast cancer cell line was treated with vanillin (1 and 2mM), DOX (100μM) or their combination. Protection against DOX-induced nephrotoxicity was studied in rats that received vanillin (100mg/kg, ip) for 10days with a single dose of DOX (15mg/kg) on day 6. Vanillin exerted anticancer effects comparable to DOX and synergesticlly potentiated DOX anticancer effects both in-vivo and in-vitro. The anticancer potency of vanillin in-vivo was mediated via apoptosis and antioxidant capacity. It also offered an in-vitro growth inhibitory effect and cytotoxicity mediated by apoptosis (increased caspase-9 and Bax:Bcl-2 ratio) along with anti-metasasis effect. Vanillin protected against DOX-induced nephrotoxicity in rats. In conclusion, vanillin can be a potential lead molecule for the development of non-toxic agents for the treatment of breast cancer either alone or combined with DOX. PMID:27493101

  17. Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy.

    PubMed

    Min, Kisuk; Kwon, Oh-Sung; Smuder, Ashley J; Wiggs, Michael P; Sollanek, Kurt J; Christou, Demetra D; Yoo, Jeung-Ki; Hwang, Moon-Hyon; Szeto, Hazel H; Kavazis, Andreas N; Powers, Scott K

    2015-04-15

    Although doxorubicin (DOX) is a highly effective anti-tumour agent used to treat a variety of cancers, DOX administration is associated with significant side effects, including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted anti-oxidant to prevent DOX-induced increases in mitochondrial ROS emission, whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibres and the prevention of DOX-induced increases in mitochondrial ROS emission protects against fibre atrophy and contractile dysfunction in both cardiac and skeletal muscles. Furthermore, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and, importantly, calpain activation is a major contributor to DOX-induced myopathy. Taken together, these findings show that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibres.

  18. The synergistic effect between vanillin and doxorubicin in ehrlich ascites carcinoma solid tumor and MCF-7 human breast cancer cell line.

    PubMed

    Elsherbiny, Nehal M; Younis, Nahla N; Shaheen, Mohamed A; Elseweidy, Mohamed M

    2016-09-01

    Despite the remarkable anti-tumor activity of doxorubicin (DOX), its clinical application is limited due to multiple organ toxicities. Products with less side effects are therefore highly requested. The current study investigated the anti-cancer activities of vanillin against breast cancer and possible synergistic potentiation of DOX chemotherapeutic effects by vanillin. Vanillin (100mg/kg), DOX (2mg/kg) and their combination were administered i.p. to solid Ehrlich tumor-bearing mice for 21days. MCF-7 human breast cancer cell line was treated with vanillin (1 and 2mM), DOX (100μM) or their combination. Protection against DOX-induced nephrotoxicity was studied in rats that received vanillin (100mg/kg, ip) for 10days with a single dose of DOX (15mg/kg) on day 6. Vanillin exerted anticancer effects comparable to DOX and synergesticlly potentiated DOX anticancer effects both in-vivo and in-vitro. The anticancer potency of vanillin in-vivo was mediated via apoptosis and antioxidant capacity. It also offered an in-vitro growth inhibitory effect and cytotoxicity mediated by apoptosis (increased caspase-9 and Bax:Bcl-2 ratio) along with anti-metasasis effect. Vanillin protected against DOX-induced nephrotoxicity in rats. In conclusion, vanillin can be a potential lead molecule for the development of non-toxic agents for the treatment of breast cancer either alone or combined with DOX.

  19. Synthesis, identification and in vivo studies of tumor-targeting agent peptide doxorubicin (PDOX) to treat peritoneal carcinomatosis of gastric cancer with similar efficacy but reduced toxicity

    PubMed Central

    2014-01-01

    Background This work aimed to synthesize a cathepsin B (CTSB)-cleavable tumor-targeting prodrug peptide doxorubicin (PDOX) and study the in vivo efficacy and toxicities on an animal model of gastric peritoneal carcinomatosis (PC). Methods PDOX was synthesized using doxorubicin (DOX) attaching to a CTSB-cleavable dipeptide Ac-Phe-Lys and a para-amino-benzyloxycarbonyl (PABC) spacer. PC model was established by injecting VX2 tumor cells into the gastric sub-mucosa of 40 rabbits, which then were randomized into 4 groups: the Control (n = 10) without treatment, the HIPEC (n = 10) receiving cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), the PDOX (n = 10) and the DOX (n = 10) receiving systemic chemotherapy with PDOX 50.0 mg/kg or DOX 5.0 mg/kg, respectively, after CRS + HIPEC. Results The median overall survivals (OS) were 23.0 d (95% CI: 19.9 d - 26.1 d) in the Control, 41.0 d (36.9 d - 45.1 d) in the HIPEC, 65.0 d (44.1 d - 71.9 d) in the PDOX, and 58.0 d (39.6 d - 54.4 d) in the DOX. Compared with the Control, the OS was extended by 70% in the HIPEC (p < 0.001) and further extended by 40% in the DOX (p = 0.029) and by 58% in the PDOX (p = 0.021), and the PC severity was decreased in the HIPEC and further decreased in the PDOX and DOX. Animals receiving DOX treatment showed hematological toxicities with marked reduction of white blood cells and platelets, as well as cardiac toxicities with significant increases in creatine kinase mb isoenzyme, evident myocardium coagulation necrosis, significant nuclear degeneration, peri-nucleus mitochondria deletion, mitochondria-pyknosis, and abnormal intercalated discs. But these toxicities were not evident in the PDOX. Conclusions PDOX is a newly synthesized tumor-targeting prodrug of DOX. Compared with DOX, PDOX has similar efficacy but reduced hematological and cardiac toxicities in treating rabbit model of gastric PC. PMID:24588871

  20. Effective co-delivery of doxorubicin and dasatinib using a PEG-Fmoc nanocarrier for combination cancer chemotherapy.

    PubMed

    Zhang, Peng; Li, Jiang; Ghazwani, Mohammed; Zhao, Wenchen; Huang, Yixian; Zhang, Xiaolan; Venkataramanan, Raman; Li, Song

    2015-10-01

    A simple PEGylated peptidic nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-Cbz-lysine)2 (PLFCL), was developed for effective co-delivery of doxorubicin (DOX) and dasatinib (DAS) for combination chemotherapy. Significant synergy of DOX and DAS in inhibition of cancer cell proliferation was demonstrated in various types of cancer cells, including breast, prostate, and colon cancers. Co-encapsulation of the two agents was facilitated by incorporation of 9-Fluorenylmethoxycarbonyl (Fmoc) and carboxybenzyl (Cbz) groups into a nanocarrier for effective carrier-drug interactions. Spherical nanomicelles with a small size of ∼30 nm were self-assembled by PLFCL. Strong carrier/drug intermolecular π-π stacking was demonstrated in fluorescence quenching and UV absorption. Fluorescence study showed more effective accumulation of DOX in nuclei of cancer cells following treatment with DOX&DAS/PLFCL in comparison with cells treated with DOX/PLFCL. DOX&DAS/PLFCL micelles were also more effective than other treatments in inhibiting the proliferation and migration of cultured cancer cells. Finally, a superior anti-tumor activity was demonstrated with DOX&DAS/PLFCL. A tumor growth inhibition rate of 95% was achieved at a respective dose of 5 mg/kg for DOX and DAS in a murine breast cancer model. Our nanocarrier may represent a simple and effective system that could facilitate clinical translation of this promising multi-agent regimen in combination chemotherapy.

  1. Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models

    PubMed Central

    Lamas, DJMartinel; Nicoud, MB; Sterle, HA; Carabajal, E; Tesan, F; Perazzo, JC; Cremaschi, GA; Rivera, ES; Medina, VA

    2015-01-01

    The aim of the present work was to evaluate the potential protective effect of histamine on Doxorubicin (Dox)-induced hepatic and cardiac toxicity in different rodent species and in a triple-negative breast tumor-bearing mice model. Male Sprague Dawley rats and Balb/c mice were divided into four groups: control (received saline), histamine (5 mg/kg for rats and 1 mg/kg for mice, daily subcutaneous injection starting 24 h before treatment with Dox), Dox (2 mg/kg, intraperitoneally injected three times a week for 2 weeks) and Dox+histamine (received both treatments). Tissue toxicity was evaluated by histopathological studies and oxidative stress and biochemical parameters. The combined effect of histamine and Dox was also investigated in vitro and in vivo in human MDA-MB-231 triple-negative breast cancer model. Heart and liver of Dox-treated animals displayed severe histological damage, loss of tissue weight, increased TBARS levels and DNA damage along with an augment in serum creatine kinase-myocardial band. Pretreatment with histamine prevented Dox-induced tissue events producing a significant preservation of the integrity of both rat and mouse myocardium and liver, through the reduction of Dox-induced oxidative stress and apoptosis. Histamine treatment preserved anti-tumor activity of Dox, exhibiting differential cytotoxicity and increasing the Dox-induced inhibition of breast tumor growth. Findings provide preclinical evidence indicating that histamine could be a promising candidate as a selective cytoprotective agent for the treatment of Dox-induced cardiac and hepatic toxicity, and encourage the translation to clinical practice. PMID:27551485

  2. Ultrasound/Magnetic Targeting with SPIO-DOX-Microbubble Complex for Image-Guided Drug Delivery in Brain Tumors

    PubMed Central

    Fan, Ching-Hsiang; Cheng, Yu-Hang; Ting, Chien-Yu; Ho, Yi-Ju; Hsu, Po-Hung; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-01

    One of the greatest challenges in the deployment of chemotherapeutic drugs against brain tumors is ensuring that sufficient drug concentrations reach the tumor, while minimizing drug accumulation at undesired sites. Recently, injection of therapeutic agents following blood-brain barrier (BBB) opening by focused ultrasound (FUS) with microbubbles (MBs) has been shown to enhance drug delivery in targeted brain regions. Nevertheless, the distribution and quantitative deposition of agents delivered to the brain are still hard to estimate. Based on our previous work on superparamagnetic iron oxide (SPIO)-loaded MBs, we present a novel theranostic complex of SPIO-Doxorubicin (DOX)-conjugated MB (SD-MB) for drug delivery to the brain. Magnetic labeling of the drug enables direct visualization via magnetic resonance imaging, and also facilitates magnetic targeting (MT) to actively enhance targeted deposition of the drug. In a rat glioma model, we demonstrated that FUS sonication can be used with SD-MBs to simultaneously facilitate BBB opening and allow dual ultrasound/magnetic targeting of chemotherapeutic agent (DOX) delivery. The accumulation of SD complex within brain tumors can be significantly enhanced by MT (25.7 fold of DOX, 7.6 fold of SPIO). The change in relaxation rate R2 (1/T2) within tumors was highly correlated with SD deposition as quantified by high performance liquid chromatography (R2 = 0.93) and inductively coupled plasma-atomic emission spectroscopy (R2 = 0.94), demonstrating real-time monitoring of DOX distribution. Our results suggest that SD-MBs can serve as multifunction agents to achieve advanced molecular theranostics. PMID:27446489

  3. Assessment of pro-apoptotic activity of doxorubicin-transferrin conjugate in cells derived from human solid tumors.

    PubMed

    Szwed, Marzena; Kania, Katarzyna Dominika; Jozwiak, Zofia

    2016-01-01

    Conjugates of anthracyclines are a new possibility for anticancer agent delivery, which seems to be a very promising alternative to the currently used cancer treatment strategies. In our study, we investigated the ability of a doxorubicin-transferrin (DOX-TRF) conjugate to induce cell death in two solid tumor cell lines: non-small cell lung cancer (A549) and hepatocellular liver carcinoma (HepG2). The observed effects of the DOX-TRF conjugate on these cell cultures were compared with those of free doxorubicin (DOX), a widely used antineoplastic therapeutic agent. Our results provided direct evidence that the investigated conjugate is considerably more cytotoxic to the examined human cancer cell lines than is DOX alone. Moreover, we confirmed that the antitumor efficacy of DOX-TRF conjugate is related to its apoptosis-inducing ability, which was shown during measurements of typical features of programmed cell death. In solid tumor cell lines, the DOX-TRF conjugate induced changes in cellular morphology, mitochondrial membrane potential and caspases-3 and -9 activities. Furthermore, all of the analyzed hallmarks of apoptosis were confirmed by the oligonucleosomal DNA fragmentation assay and by a real-time PCR quantitative study, which displayed the superiority of the conjugate-induced programmed cell death over free drug-triggered cell death.

  4. Enhanced tumor delivery and antitumor response of doxorubicin-loaded albumin nanoparticles formulated based on a Schiff base.

    PubMed

    Li, Fang; Zheng, Chunli; Xin, Junbo; Chen, Fangcheng; Ling, Hua; Sun, Linlin; Webster, Thomas J; Ming, Xin; Liu, Jianping

    2016-01-01

    A novel method was developed here to prepare albumin-based nanoparticles (NPs) for improving the therapeutic and safety profiles of chemotherapeutic agents. This approach involved crosslinking bovine serum albumin (BSA) using a Schiff base-containing vanillin, into NPs and loading doxorubicin (DOX) into the NPs by incubation. The resultant NPs (DOX-BSA-V-NPs) displayed a particle size of 100.5±1.3 nm with a zeta potential of -23.05±1.45 mV and also showed high drug-loading efficiency and excellent stability with respect to storage and temperature. The encapsulation of DOX into the BSA-V-NPs was confirmed by dynamic scanning calorimetry and Raman spectroscopy. DOX-BSA-V-NPs exhibited a significantly faster DOX release at pH 6.5 than pH 7.4, as well as in a solution with a higher glutathione concentration. In vitro studies showed that the cellular uptake of DOX-BSA-V-NPs was time-dependent, concentration-dependent, and faster than free DOX, while the cytotoxicity of DOX-BSA-V-NPs (IC50 value of 3.693 μg/mL) was superior to free DOX (IC50 value of 4.007 μg/mL). More importantly, DOX-BSA-V-NPs showed a longer mean survival time of 24.83 days, a higher tumor inhibition rate of 56.66%, and a decreased distribution in the heart than other DOX formulations in animal studies using a tumor xenograft model. Thus, the vanillin-based albumin NPs were shown here to be a promising carrier for tumor-targeted delivery of chemotherapeutic agents and, thus, should be further studied. PMID:27574421

  5. Enhanced tumor delivery and antitumor response of doxorubicin-loaded albumin nanoparticles formulated based on a Schiff base

    PubMed Central

    Li, Fang; Zheng, Chunli; Xin, Junbo; Chen, Fangcheng; Ling, Hua; Sun, Linlin; Webster, Thomas J; Ming, Xin; Liu, Jianping

    2016-01-01

    A novel method was developed here to prepare albumin-based nanoparticles (NPs) for improving the therapeutic and safety profiles of chemotherapeutic agents. This approach involved crosslinking bovine serum albumin (BSA) using a Schiff base-containing vanillin, into NPs and loading doxorubicin (DOX) into the NPs by incubation. The resultant NPs (DOX-BSA-V-NPs) displayed a particle size of 100.5±1.3 nm with a zeta potential of −23.05±1.45 mV and also showed high drug-loading efficiency and excellent stability with respect to storage and temperature. The encapsulation of DOX into the BSA-V-NPs was confirmed by dynamic scanning calorimetry and Raman spectroscopy. DOX-BSA-V-NPs exhibited a significantly faster DOX release at pH 6.5 than pH 7.4, as well as in a solution with a higher glutathione concentration. In vitro studies showed that the cellular uptake of DOX-BSA-V-NPs was time-dependent, concentration-dependent, and faster than free DOX, while the cytotoxicity of DOX-BSA-V-NPs (IC50 value of 3.693 μg/mL) was superior to free DOX (IC50 value of 4.007 μg/mL). More importantly, DOX-BSA-V-NPs showed a longer mean survival time of 24.83 days, a higher tumor inhibition rate of 56.66%, and a decreased distribution in the heart than other DOX formulations in animal studies using a tumor xenograft model. Thus, the vanillin-based albumin NPs were shown here to be a promising carrier for tumor-targeted delivery of chemotherapeutic agents and, thus, should be further studied. PMID:27574421

  6. Doxorubicin-induced dilated cardiomyopathy for modified radical mastectomy: A case managed under cervical epidural anaesthesia

    PubMed Central

    Jain, Anuj; Kishore, Kamal

    2013-01-01

    Doxorubicin (Dox) is an antineoplastic agent used in a wide variety of malignancies. Its use is limited because of a cumulative, dose-dependent irreversible cardiomyopathy. We report a case of Dox induced cardiomyopathy, posted for modified radical mastectomy. The patient had poor LV function along with moderate pulmonary hypertension. Regional anaesthesia was planned as the risk associated with general anaesthesia was more. A cervical epidural was placed and a block adequate for surgery could be achived. The haemodynamic parameters as measured by esophageal doppler showed a stable trend. The surgery could be managed well under cervical epidural and also provided a good postoperative pain relief. PMID:23825820

  7. A novel combination of TRAIL and doxorubicin enhances antitumor effect based on passive tumor-targeting of liposomes

    NASA Astrophysics Data System (ADS)

    Guo, Liangran; Fan, Li; Ren, Jinfeng; Pang, Zhiqing; Ren, Yulong; Li, Jingwei; Wen, Ziyi; Jiang, Xinguo

    2011-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel anticancer agent for non-small cell lung cancer (NSCLC). However, approximately half of NSCLC cell lines are highly resistant to TRAIL. Doxorubicin (DOX) can sensitize NSCLC cells to TRAIL-induced apoptosis, indicating the possibility of combination therapy. Unfortunately, the therapeutic effect of a DOX and TRAIL combination is limited by multiple factors including the short serum half-life of TRAIL, poor compliance and application difficulty in the clinic, chronic DOX-induced cardiac toxicity, and the multidrug resistance (MDR) property of NSCLC cells. To solve such problems, we developed the combination of TRAIL liposomes (TRAIL-LP) and DOX liposomes (DOX-LP). An in vitro cytotoxicity study indicated that DOX-LP sensitized the NSCLC cell line A-549 to TRAIL-LP-induced apoptosis. Furthermore, this combination therapy of TRAIL-LP and DOX-LP displayed a stronger antitumor effect on NSCLC in xenografted mice when compared with free drugs or liposomal drugs alone. Therefore, the TRAIL-LP and DOX-LP combination therapy has excellent potential to become a new therapeutic approach for patients with advanced NSCLC.

  8. Co-Encapsulation of Combretastatin-A4 Phosphate and Doxorubicin in Polymersomes for Synergistic Therapy of Nasopharyngeal Epidermal Carcinoma.

    PubMed

    Zhu, Jinfang; Xu, Xiaoping; Hu, Mengying; Qiu, Liyan

    2015-06-01

    In this study, we designed biodegradable polymersomes for co-delivery of an antiangiogenic drug combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) to collapse tumor neovasculature and inhibit cancer cell proliferation with the aim to achieve synergistic antitumor effects. The polymersomes co-encapsulating DOX and CA4P (Ps-DOX-CA4P) were prepared by solvent evaporation method using methoxy poly(ethylene glycol)-b-polylactide (mPEG-PLA) block copolymers as drug carriers. The resulting Ps-DOX-CA4P has vesicles shape with uniform sizes of about 50 nm and controlled co-encapsulation ratios of DOX to CA4P. More importantly, Ps-DOX-CA4P (1:10) showed strong synergistic cytotoxicity (combination index CI = 0.31) against human nasopharyngeal epidermal carcinoma (KB) cells. Furthermore, Ps-DOX-CA4P accumulated remarkably in KB tissues xenografts in nude mice. Consistent with these observations, Ps-DOX-CA4P (1:10) achieved significant antitumor potency because of fast tumor vasculature disruption and sustained tumor cells proliferation inhibition in vivo. The overall findings indicate that co-delivery of an antiangiogenic drug and a chemotherapeutic agent in polymersomes is a potentially promising strategy for cancer therapy.

  9. Doxorubicin-loaded silicon nanowires for the treatment of drug-resistant cancer cells.

    PubMed

    Peng, Fei; Su, Yuanyuan; Ji, Xiaoyuan; Zhong, Yiling; Wei, Xinpan; He, Yao

    2014-06-01

    Multidrug resistance (MDR) remains a major challenge for cancer treatment thus far. Free doxorubicin (DOX, one of the most widely used chemotherapy agents for cancer treatment) generally features a large value of resistant factor (RF), which is regarded as a significant parameter to assess therapeutic efficiency of cross-resistance. To address this issue, we herein present a kind of silicon nanowires (SiNWs)-based drug nanocarriers (SiNW-DOX), which is high-efficacy for treatment of drug-resistant cancer cells. Typically, drug-resistance cancer cells (e.g., MCF-7/ADR cells) can be significantly inhibited by the SiNWs-based nanocarriers, exhibiting ∼10% cell viability during 72-h incubation with the SiNWs-DOX (80 μg mL(-1) DOX), which is in sharp contrast to free DOX-treated cells preserving ∼40% cell viability. Remarkably, the RF value of SiNW-DOX is as low as ∼2.0, which is much better than that (∼300) of free DOX under the same experiment conditions. To the best of our knowledge, it is the lowest RF value ever reported by nanomaterials-based drug carriers (3.3-24.7).

  10. Investigating the mechanism of enhanced cytotoxicity of HPMA copolymer-Dox-AGM in breast cancer cells.

    PubMed

    Greco, Francesca; Vicent, María J; Gee, Siobhan; Jones, Arwyn T; Gee, Julia; Nicholson, Robert I; Duncan, Ruth

    2007-01-22

    Recently we have described an HPMA copolymer conjugate carrying both the aromatase inhibitor aminoglutethimide (AGM) and doxorubicin (Dox) as combination therapy. This showed markedly enhanced in vitro cytotoxicity compared to the HPMA copolymer-Dox (FCE28068), a conjugate that demonstrated activity in chemotherapy refractory breast cancer patients during early clinical trials. To better understand the superior activity of HPMA copolymer-Dox-AGM, here experiments were undertaken using MCF-7 and MCF-7ca (aromatase-transfected) breast cancer cell lines to: further probe the synergistic cytotoxic effects of AGM and Dox in free and conjugated form; to compare the endocytic properties of HPMA copolymer-Dox-AGM and HPMA copolymer-Dox (binding, rate and mechanism of cellular uptake); the rate of drug liberation by lysosomal thiol-dependant proteases (i.e. conjugate activation), and also, using immunocytochemistry, to compare their molecular mechanism of action. It was clearly shown that attachment of both drugs to the same polymer backbone was a requirement for enhanced cytotoxicity. FACS studies indicated both conjugates have a similar pattern of cell binding and endocytic uptake (at least partially via a cholesterol-dependent pathway), however, the pattern of enzyme-mediated drug liberation was distinctly different. Dox release from PK1 was linear with time, whereas the release of both Dox and AGM from HPMA copolymer-Dox-AGM was not, and the initial rate of AGM release was much faster than that seen for the anthracycline. Immunocytochemistry showed that both conjugates decreased the expression of ki67. However, this effect was more marked for HPMA copolymer-Dox-AGM and, moreover, only this conjugate decreased the expression of the anti-apoptotic protein bcl-2. In conclusion, the superior in vitro activity of HPMA copolymer-Dox-AGM cannot be attributed to differences in endocytic uptake, and it seems likely that the synergistic effect of Dox and AGM is due to the

  11. Beet root juice protects against doxorubicin toxicity in cardiomyocytes while enhancing apoptosis in breast cancer cells.

    PubMed

    Das, Sayantanee; Filippone, Scott M; Williams, Denise S; Das, Anindita; Kukreja, Rakesh C

    2016-10-01

    Doxorubicin (DOX, Adriamycin) is a broad-spectrum chemotherapeutic drug used to treat a variety of cancers, although its clinical use is restricted by irreversible cardiotoxicity. Earlier studies show that beet root juice (BRJ), a natural and safe herbal product with high levels of nitrate and antioxidants, is a potent chemopreventive agent; however, its cardioprotective function is yet to be established. The goal of this study was to determine the protective effect of BRJ against DOX-induced cardiotoxicity, and its effect on DOX-induced cytotoxicity in MDA-MB-231 breast cancer cells. Adult rat cardiomyocytes and MDA-MB-231 cells were exposed to different concentrations of BRJ (0.5, 5, 50, 250, and 500 µg/ml) with or without DOX. Cell death, measured by trypan blue staining, was significantly reduced in cardiomyocytes but increased in MDA-MB-231 following 24 h of co-treatment with BRJ and DOX. Cell viability was also significantly reduced after BRJ and DOX co-treatment in MDA-MB-231 cells. Similarly, DOX-induced apoptosis, as determined by TUNEL assay, was significantly reduced following treatment with BRJ for 48 h in cardiomyocytes. In contrast, BRJ significantly increased DOX-mediated apoptosis in cancer cells with activation of poly(ADP-ribose) polymerase (PARP) and increased the Bax:Bcl-2 ratio. DOX-induced generation of reactive oxygen species (ROS) was reduced following co-treatment with BRJ in cardiomyocytes but increased dose-dependently with BRJ in MDA-MB-231 cells. In conclusion, lower concentrations of BRJ with DOX represented the most effective combination of cardioprotection and chemoprevention. These findings provide insight into the possible cardioprotective ability of BRJ in cancer patients treated with anthracycline chemotherapeutic drugs. PMID:27565811

  12. Design and evaluation of doxorubicin-containing microbubbles for ultrasound-triggered doxorubicin delivery: cytotoxicity and mechanisms involved.

    PubMed

    Lentacker, Ine; Geers, Bart; Demeester, Joseph; De Smedt, Stefaan C; Sanders, Niek N

    2010-01-01

    Drug delivery with microbubbles and ultrasound is gaining more and more attention in the drug delivery field due to its noninvasiveness, local applicability, and proven safety in ultrasonic imaging techniques. In this article, we tried to improve the cytotoxicity of doxorubicin (DOX)-containing liposomes by preparing DOX-liposome-containing microbubbles for drug delivery with therapeutic ultrasound. In this way, the DOX release and uptake can be restricted to ultrasound-treated areas. Compared to DOX-liposomes, DOX-loaded microbubbles killed at least two times more melanoma cells after exposure to ultrasound. After treatment of the melanoma cells with DOX-liposome-loaded microbubbles and ultrasound, DOX was mainly present in the nuclei of the cancer cells, whereas it was mainly detected in the cytoplasm of cells treated with DOX-liposomes. Exposure of cells to DOX-liposome-loaded microbubbles and ultrasound caused an almost instantaneous cellular entry of the DOX. At least two mechanisms were identified that explain the fast uptake of DOX and the superior cell killing of DOX-liposome-loaded microbubbles and ultrasound. First, exposure of DOX-liposome-loaded microbubbles to ultrasound results in the release of free DOX that is more cytotoxic than DOX-liposomes. Second, the cellular entry of the released DOX is facilitated due to sonoporation of the cell membranes. The in vitro results shown in this article indicate that DOX-liposome-loaded microbubbles could be a very interesting tool to obtain an efficient ultrasound-controlled DOX delivery in vivo.

  13. Preparation of pH-Sensitive Dextran Nanoparticle for Doxorubicin Delivery.

    PubMed

    Wang, Bi; Liu, Peng; Shi, Bihua; Gao, Jihua; Gong, Ping

    2015-04-01

    One of challenge for cancer therapy is efficient delivery of anticancer agents into tumor sites to increase efficiency of drugs and reduce side effects. To overcome this challenge, we designed pH- sensitive doxorubicin prodrug (DEX-PEI-DOX) nanoparticles based on dextran-poly(ethylene imine) copolymers (DEX-PEI). The DEX-PEI-DOX conjugates were conveniently prepared by grafting PEI to dextran, and then anticancer drug doxorubicin (DOX) were conjugated to DEX-PEI through acid cleavable cis-aconityl bonds. The experiments of dynamic light scattering (DLS) and transmission electron microscopy (TEM) represented that size of dextran nanoparticles was about 120 nm with uniform spherical shape. In vitro drug release from self-assembled nanoparticles was dependent on the pH of medium due to the cis-aconityl linkage. Confocal images revealed that dextran based pH-sensitive DOX delivery nanoparticle could enter into Human breast carcinoma (MCF-7) cells easily. Therapeutic efficacy against MCF-7 cells in vitro was evaluated through MTT assays and the results showed that dextran nanoparticle had obvious anticancer ability. All above results indicated this pH-sensitive DOX-loaded nanoparticles system would be a useful candidate for cancer therapy. PMID:26353472

  14. Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: The role of glutathione

    SciTech Connect

    Brechbuhl, Heather M.; Kachadourian, Remy; Min, Elysia; Chan, Daniel; Day, Brian J.

    2012-01-01

    We hypothesized that flavonoid-induced glutathione (GSH) efflux through multi-drug resistance proteins (MRPs) and subsequent intracellular GSH depletion is a viable mechanism to sensitize cancer cells to chemotherapies. This concept was demonstrated using chrysin (5–25 μM) induced GSH efflux in human non-small cell lung cancer lines exposed to the chemotherapeutic agent, doxorubicin (DOX). Treatment with chrysin resulted in significant and sustained intracellular GSH depletion and the GSH enzyme network in the four cancer cell types was predictive of the severity of chrysin induced intracellular GSH depletion. Gene expression data indicated a positive correlation between basal MRP1, MRP3 and MRP5 expression and total GSH efflux before and after chrysin exposure. Co-treating the cells for 72 h with chrysin (5–30 μM) and DOX (0.025–3.0 μM) significantly enhanced the sensitivity of the cells to DOX as compared to 72-hour DOX alone treatment in all four cell lines. The maximum decrease in the IC{sub 50} values of cells treated with DOX alone compared to co-treatment with chrysin and DOX was 43% in A549 cells, 47% in H157 and H1975 cells and 78% in H460 cells. Chrysin worked synergistically with DOX to induce cancer cell death. This approach could allow for use of lower concentrations and/or sensitize cancer cells to drugs that are typically resistant to therapy. -- Graphical abstract: Possible mechanisms by which chrysin enhances doxorubicin-induced toxicity in cancer cells. Highlights: ► Chyrsin sustains a significant depletion of GSH levels in lung cancer cells. ► Chyrsin synergistically potentiates doxorubicin-induced cancer cell cytotoxicity. ► Cancer cell sensitivity correlated with GSH and MRP gene network expression. ► This approach could allow for lower side effects and targeting resistant tumors.

  15. Doxorubicin Induces Inflammatory Modulation and Metabolic Dysregulation in Diabetic Skeletal Muscle.

    PubMed

    Supriya, Rashmi; Tam, Bjorn T; Pei, Xiao M; Lai, Christopher W; Chan, Lawrence W; Yung, Benjamin Y; Siu, Parco M

    2016-01-01

    Anti-cancer agent doxorubicin (DOX) has been demonstrated to worsen insulin signaling, engender muscle atrophy, trigger pro-inflammation, and induce a shift to anaerobic glycolytic metabolism in skeletal muscle. The myotoxicity of DOX in diabetic skeletal muscle remains largely unclear. This study examined the effects of DOX on insulin signaling, muscle atrophy, pro-/anti-inflammatory microenvironment, and glycolysis metabolic regulation in skeletal muscle of db/db diabetic and db/+ non-diabetic mice. Non-diabetic db/+ mice and diabetic db/db mice were randomly assigned to the following groups: db/+CON, db/+DOX, db/dbCON, and db/dbDOX. Mice in db/+DOX and db/dbDOX groups were intraperitoneally injected with DOX at a dose of 15 mg per kg body weight whereas mice in db/+CON and db/dbCON groups were injected with the same volume of saline instead of DOX. Gastrocnemius was immediately harvested, weighed, washed with cold phosphate buffered saline, frozen in liquid nitrogen, and stored at -80°C for later analysis. The effects of DOX on diabetic muscle were neither seen in insulin signaling markers (Glut4, pIRS1Ser(636∕639), and pAktSer(473)) nor muscle atrophy markers (muscle mass, MuRF1 and MAFbx). However, DOX exposure resulted in enhancement of pro-inflammatory favoring microenvironment (as indicated by TNF-α, HIFα and pNFκBp65) accompanied by diminution of anti-inflammatory favoring microenvironment (as indicated by IL15, PGC1α and pAMPKβ1Ser108). Metabolism of diabetic muscle was shifted to anaerobic glycolysis after DOX exposure as demonstrated by our analyses of PDK4, LDH and pACCSer(79). Our results demonstrated that there might be a link between inflammatory modulation and the dysregulation of aerobic glycolytic metabolism in DOX-injured diabetic skeletal muscle. These findings help to understand the pathogenesis of DOX-induced myotoxicity in diabetic muscle. PMID:27512375

  16. Doxorubicin Induces Inflammatory Modulation and Metabolic Dysregulation in Diabetic Skeletal Muscle

    PubMed Central

    Supriya, Rashmi; Tam, Bjorn T.; Pei, Xiao M.; Lai, Christopher W.; Chan, Lawrence W.; Yung, Benjamin Y.; Siu, Parco M.

    2016-01-01

    Anti-cancer agent doxorubicin (DOX) has been demonstrated to worsen insulin signaling, engender muscle atrophy, trigger pro-inflammation, and induce a shift to anaerobic glycolytic metabolism in skeletal muscle. The myotoxicity of DOX in diabetic skeletal muscle remains largely unclear. This study examined the effects of DOX on insulin signaling, muscle atrophy, pro-/anti-inflammatory microenvironment, and glycolysis metabolic regulation in skeletal muscle of db/db diabetic and db/+ non-diabetic mice. Non-diabetic db/+ mice and diabetic db/db mice were randomly assigned to the following groups: db/+CON, db/+DOX, db/dbCON, and db/dbDOX. Mice in db/+DOX and db/dbDOX groups were intraperitoneally injected with DOX at a dose of 15 mg per kg body weight whereas mice in db/+CON and db/dbCON groups were injected with the same volume of saline instead of DOX. Gastrocnemius was immediately harvested, weighed, washed with cold phosphate buffered saline, frozen in liquid nitrogen, and stored at −80°C for later analysis. The effects of DOX on diabetic muscle were neither seen in insulin signaling markers (Glut4, pIRS1Ser636∕639, and pAktSer473) nor muscle atrophy markers (muscle mass, MuRF1 and MAFbx). However, DOX exposure resulted in enhancement of pro-inflammatory favoring microenvironment (as indicated by TNF-α, HIFα and pNFκBp65) accompanied by diminution of anti-inflammatory favoring microenvironment (as indicated by IL15, PGC1α and pAMPKβ1Ser108). Metabolism of diabetic muscle was shifted to anaerobic glycolysis after DOX exposure as demonstrated by our analyses of PDK4, LDH and pACCSer79. Our results demonstrated that there might be a link between inflammatory modulation and the dysregulation of aerobic glycolytic metabolism in DOX-injured diabetic skeletal muscle. These findings help to understand the pathogenesis of DOX-induced myotoxicity in diabetic muscle. PMID:27512375

  17. Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95.

    PubMed

    Das, Anindita; Durrant, David; Mitchell, Clint; Dent, Paul; Batra, Surinder K; Kukreja, Rakesh C

    2016-01-26

    We previously reported that Sildenafil enhances apoptosis and antitumor efficacy of doxorubicin (DOX) while attenuating its cardiotoxic effect in prostate cancer. In the present study, we investigated the mechanism by which sildenafil sensitizes DOX in killing of prostate cancer (PCa) cells, DU145. The death receptor Fas (APO-1 or CD95) induces apoptosis in many carcinoma cells, which is negatively regulated by anti-apoptotic molecules such as FLIP (Fas-associated death domain (FADD) interleukin-1-converting enzyme (FLICE)-like inhibitory protein). Co-treatment of PCa cells with sildenafil and DOX for 48 hours showed reduced expression of both long and short forms of FLIP (FLIP-L and -S) as compared to individual drug treatment. Over-expression of FLIP-s with an adenoviral vector attentuated the enhanced cell-killing effect of DOX and sildenafil. Colony formation assays also confirmed that FLIP-S over-expression inhibited the DOX and sildenafil-induced synergistic killing effect as compared to the cells infected with an empty vector. Moreover, siRNA knock-down of CD95 abolished the effect of sildenafil in enhancing DOX lethality in cells, but had no effect on cell killing after treatment with a single agent. Sildenafil co-treatment with DOX inhibited DOX-induced NF-κB activity by reducing phosphorylation of IκB and nuclear translocation of the p65 subunit, in addition to down regulation of FAP-1 (Fas associated phosphatase-1, a known inhibitor of CD95-mediated apoptosis) expression. This data provides evidence that the CD95 is a key regulator of sildenafil and DOX mediated enhanced cell death in prostate cancer. PMID:26716643

  18. Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95

    PubMed Central

    Das, Anindita; Durrant, David; Mitchell, Clint; Dent, Paul; Batra, Surinder K.; Kukreja, Rakesh C.

    2016-01-01

    We previously reported that Sildenafil enhances apoptosis and antitumor efficacy of doxorubicin (DOX) while attenuating its cardiotoxic effect in prostate cancer. In the present study, we investigated the mechanism by which sildenafil sensitizes DOX in killing of prostate cancer (PCa) cells, DU145. The death receptor Fas (APO-1 or CD95) induces apoptosis in many carcinoma cells, which is negatively regulated by anti-apoptotic molecules such as FLIP (Fas-associated death domain (FADD) interleukin-1-converting enzyme (FLICE)-like inhibitory protein). Co-treatment of PCa cells with sildenafil and DOX for 48 hours showed reduced expression of both long and short forms of FLIP (FLIP-L and -S) as compared to individual drug treatment. Over-expression of FLIP-s with an adenoviral vector attentuated the enhanced cell-killing effect of DOX and sildenafil. Colony formation assays also confirmed that FLIP-S over-expression inhibited the DOX and sildenafil-induced synergistic killing effect as compared to the cells infected with an empty vector. Moreover, siRNA knock-down of CD95 abolished the effect of sildenafil in enhancing DOX lethality in cells, but had no effect on cell killing after treatment with a single agent. Sildenafil co-treatment with DOX inhibited DOX-induced NF-κB activity by reducing phosphorylation of IκB and nuclear translocation of the p65 subunit, in addition to down regulation of FAP-1 (Fas associated phosphatase-1, a known inhibitor of CD95-mediated apoptosis) expression. This data provides evidence that the CD95 is a key regulator of sildenafil and DOX mediated enhanced cell death in prostate cancer. PMID:26716643

  19. Pharmacokinetics and pharmacodynamics evaluation of a thermosensitive chitosan based hydrogel containing liposomal doxorubicin.

    PubMed

    Ren, Shuangxia; Dai, Yu; Li, Cuiyun; Qiu, Zhixia; Wang, Xin; Tian, Fengjie; Zhou, Sufeng; Liu, Qi; Xing, Han; Lu, Yang; Chen, Xijing; Li, Ning

    2016-09-20

    In situ gelling thermosensitive hydrogel formulation has been reported to effectively sustain the release of macromolecules for a long time. However, the low-molecular-weight hydrophilic drugs, such as doxorubicin (DOX), are not suitable for intratumoral injection because the release will complete within one day. In this study, liposomal doxorubicin (LipDOX) was added into the hydrogel to form a novel thermosensitive formulation which prolonged the sustained release of DOX. DOX+C/GP (doxorubicin in chitosan/β-glycerophosphate) was prepared to compare with LipDOX+C/GP (liposomal doxorubicin in chitosan/β-glycerophosphate hydrogel). The particle size of DOX-loaded liposome was 94.2nm and the encapsulation efficiency of DOX was near 98%. In vitro release experiments, the release of DOX in both DOX+C/GP group and LipDOX+C/GP group increased along with the increasing pH of buffers. However, the LipDOX+C/GP group with lower initial burst release had a much longer releasing duration than DOX+C/GP group (21days vs. 24h). In vitro and in vivo antitumor experiments demonstrated that LipDOX+C/GP group had better antineoplastic effect and less toxicity than DOX+C/GP group. Pharmacokinetics study showed LipDOX+C/GP exhibited a higher AUC0-t and longer MRT than DOX+C/GP in blood and tumor, which indicated that LipDOX+C/GP obtained an enhanced antitumor activity compared with DOX+C/GP. In addition, the lower distribution index (the ratio of AUC of normal tissue/AUC of tumor tissue) of the LipDOX+C/GP implied it had lower toxicity to normal tissues than DOX+C/GP. Therefore, the novel thermosensitive hydrogel formulation was potential for clinical application in cancer treatment. PMID:27388491

  20. Cardioprotective effect of saffron extracts against acute doxorubicin toxicity in isolated rabbit hearts submitted to ischemia-reperfusion injury.

    PubMed

    Chahine, Nathalie; Makhlouf, Hassane; Duca, Laurent; Martiny, Laurent; Chahine, Ramez

    2014-01-01

    Doxorubicin (DOX) is an anthracycline antibiotic routinely used as a chemotherapeutic agent for the treatment of solid tumours. However, DOX possesses an acute and cumulative cardiotoxicity due to free radical production. The present study was designed to investigate the possible protective effects of saffron (Crocus sativus) extracts against DOX-induced acute cardiotoxicity in isolated rabbit hearts submitted to 30 min global ischemia followed by 40 min reperfusion. DOX was delivered during reperfusion, without or with saffron given 5 min before ischemia or at reperfusion. Cardiodynamic, biochemical, and histopathological parameters were determined. In addition, to determine the expression of the AKT/mTOR/4EBP1 pathway, the levels of p38 MAPK and cardiac troponin T in heart homogenates were visualized by Western blotting. DOX administration during 40 min of reperfusion increased ischemic tissue damage, but did not act synergistically. Administration of saffron extracts during the first minutes of reperfusion significantly reduced oxidative myocardial damage, but was less effective when given before ischemia. Subsequent Western blot analysis revealed that saffron administration preserved cardiac troponin T proteins, inhibited the p38 MAPK pathway, and activated the AKT/mTOR/4EBP1 pathway in reperfusion- and DOX-treated rabbit hearts. In conclusion, saffron extracts, acting through antioxidant and antiapoptotic mechanisms, exhibited a protective effect against DOX-induced cardiotoxicity under ischemic condition.

  1. Chondroitin sulfate-capped super-paramagnetic iron oxide nanoparticles as potential carriers of doxorubicin hydrochloride.

    PubMed

    Mallick, Neha; Anwar, Mohammed; Asfer, Mohammed; Mehdi, Syed Hassan; Rizvi, Mohammed Moshahid Alam; Panda, Amulya Kumar; Talegaonkar, Sushama; Ahmad, Farhan Jalees

    2016-10-20

    Chondroitin-4-sulfate (CS), a glycosaminoglycan, was used to prepare CS-capped super-paramagnetic iron oxide nanoparticles, which were further employed for loading a water-soluble chemotherapeutic agent (doxorubicin hydrochloride, DOX). CS-capped SPIONs have potential biomedical application in cancer targeting. The optimized formulation had a hydrodynamic size of 91.2±0.8nm (PDI; 0.228±0.004) and zeta potential of -49.1±1.66mV. DOX was loaded onto the formulation up to 2% (w/w) by physical interaction with CS. TEM showed nano-sized particles having a core-shell structure. XRD confirmed crystal phase of iron oxide. FT-IR conceived the interaction of iron oxide with CS as bidentate chelation and also confirmed DOX loading. Vibration sample magnetometry confirmed super-paramagnetic nature of nanoparticles, with saturation magnetization of 0.238emug(-1). In vitro release profile at pH 7.4 showed that 96.67% of DOX was released within 24h (first order kinetics). MTT assay in MCF7 cells showed significantly higher (p<0.0001) cytotoxicity for DOX in SPIONs than DOX solution (IC50 values 6.294±0.4169 and 11.316±0.1102μgmL(-1), respectively). PMID:27474599

  2. Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance.

    PubMed

    Cheng, Tangjian; Liu, Jinjian; Ren, Jie; Huang, Fan; Ou, Hanlin; Ding, Yuxun; Zhang, Yumin; Ma, Rujiang; An, Yingli; Liu, Jianfeng; Shi, Linqi

    2016-01-01

    Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance. PMID:27375779

  3. Magnetic field-enhanced cellular uptake of doxorubicin loaded magnetic nanoparticles for tumor treatment

    NASA Astrophysics Data System (ADS)

    Venugopal, Indu; Pernal, Sebastian; Duproz, Alexandra; Bentley, Jeromy; Engelhard, Herbert; Linninger, Andreas

    2016-09-01

    Cancer remains the second most common cause of death in the US, accounting for nearly 1 out of every 4 deaths. In recent years, several varieties of nanoparticles (NPs) have been synthesized with the intent of being utilized as tumor drug delivery vehicles. We have produced superparamagnetic, gold-coated magnetite (Fe3O4@Au) NPs and loaded them with the chemotherapeutic drug doxorubicin (DOX) for magnetic drug targeting (MDT) of tumors. The synthetic strategy uses the food thickening agent gellan gum (Phytagel) as a negatively charged shell around the Fe3O4@Au NP onto which the positively charged DOX molecules are loaded via electrostatic attraction. The resulting DOX-loaded magnetic nanoparticles (DOX-MNPs) were characterized using transmission electron microscopy, energy dispersive x-ray spectroscopy, superconducting quantum interference device magnetometry, surface area electron diffraction, zeta potential measurements, fourier transform infrared spectroscopy as well as UV/Vis and fluorescence spectroscopy. Cytotoxicity of the DOX-MNPs was demonstrated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay on C6 glioma cells. Cellular uptake of DOX-MNPs was enhanced with magnetic fields, which was quantitatively determined using flow cytometry. This improved uptake also led to greater tumor cell death, which was measured using MTT assay. These MDT results are promising for a new therapy for cancer.

  4. Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance

    PubMed Central

    Cheng, Tangjian; Liu, Jinjian; Ren, Jie; Huang, Fan; Ou, Hanlin; Ding, Yuxun; Zhang, Yumin; Ma, Rujiang; An, Yingli; Liu, Jianfeng; Shi, Linqi

    2016-01-01

    Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance. PMID:27375779

  5. Strawberry consumption alleviates doxorubicin-induced toxicity by suppressing oxidative stress.

    PubMed

    Giampieri, Francesca; Alvarez-Suarez, Jose M; Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Y; Afrin, Sadia; Bompadre, Stefano; Rubini, Corrado; Zizzi, Antonio; Astolfi, Paola; Santos-Buelga, Celestino; González-Paramás, Ana M; Quiles, Josè L; Mezzetti, Bruno; Battino, Maurizio

    2016-08-01

    Doxorubicin (Dox), one of the most used chemotherapeutic agents, is known to generate oxidative stress and block DNA synthesis, which result in severe dose-limiting toxicity. A strategy to protect against Dox toxic effects could be to use dietary antioxidants of which fruits and vegetable are a rich source. In this context, strawberry consumption is associated with the maintenance of good health and the prevention of several diseases, thanks to the antioxidant capacities of its bioactive compounds. The aim of the present study was to evaluate the protective effects of strawberry consumption against oxidative stress induced by Dox in rats. Animals were fed with strawberry enriched diet (15% of the total calories) for two months and Dox (10 mg/kg; i.p.) was injected at the end of the experimental period. Strawberry consumption significantly inhibited ROS production and oxidative damage biomarkers accumulation in plasma and liver tissue and alleviated histopathological changes in rat livers treated with Dox. The reduction of antioxidant enzyme activities was significantly mitigated after strawberry consumption. In addition, strawberry enriched diet ameliorated liver mitochondrial antioxidant levels and functionality. In conclusion, strawberry intake protects against Dox-induced toxicity, at plasma, liver and mitochondrial levels thanks to its high contents of bioactive compounds. PMID:27286747

  6. Investigating the Fluorescence Quenching of Doxorubicin in Folic Acid Solutions and its Relation to Ligand-Targeted Nanocarriers.

    PubMed

    Husseini, Ghaleb A; Kanan, Sofian; Al-Sayah, Mohammad

    2016-02-01

    Folic acid (FA) is one of the most utilized moieties in active (ligand) drug delivery. The folate receptor is widely expressed on the surface of several cell lines and tumors; including ovarian, brain, kidney, breast, and lung cancers. During our previous experiments with Doxorubicin (Dox) encapsulated in folate-targeted micelles, we found that flow cytometry underestimated the amount of drug that accu- mulates inside cells. We attributed this effect to the quenching of Dox by FA and herein investigate this phenomenon in an attempt to obtain a correction factor that could be applied to the fluorescence of Dox in the presence of FA. Initially, we examine the effect of pH on the fluorescence spectra of FA, Dox, equimolar solutions of FA and Dox in water, HCI (0.1 M), and NaOH (0.1 M) solutions. We then measure the effect of the gradual increase of FA concentration on the fluorescence intensity of Dox in phosphate-buffered saline (PBS) solutions (pH of 7.4). Using the Stern-Volmer equation, we estimate the association constant of FA-Dox to be K(SV) = 1.5 x 10(4) M(-1). Such an association constant indicates that at the concentrations of FA used in targeted drug delivery systems, a significant concentration of Dox exists as FA-Dox complexes with a quenched fluorescence. Therefore, we conclude that when Dox is used in FA-active drug delivery systems, a correction factor is needed to predict the correct fluorescence intensity of agent in vitro and in vivo. PMID:27433596

  7. Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1α pathway.

    PubMed

    Guo, Jiabin; Guo, Qian; Fang, Haiqing; Lei, Lei; Zhang, Tingfen; Zhao, Jun; Peng, Shuangqing

    2014-08-15

    Metallothionein (MT) has been shown to inhibit cardiac oxidative stress and protect against the cardiotoxicity induced by doxorubicin (DOX), a potent and widely used chemotherapeutic agent. However, the mechanism of MT׳s protective action against DOX still remains obscure. Mitochondrial biogenesis impairment has been implicated to play an important role in the etiology and progression of DOX-induced cardiotoxicity. Increasing evidence indicates an intimate link between MT-mediated cardioprotection and mitochondrial biogenesis. This study was aimed to explore the possible contribution of mitochondrial biogenesis in MT׳s cardioprotective action against DOX. Adult male MT-I/II-null (MT(-/-)) and wild-type (MT(+/+)) mice were given a single dose of DOX intraperitoneally. Our results revealed that MT deficiency significantly sensitized mice to DOX-induced cardiac dysfunction, ultrastructural alterations, and mortality. DOX disrupted cardiac mitochondrial biogenesis indicated by mitochondrial DNA copy number and decreased mitochondrial number, and these effects were greater in MT(-/-) mice. Basal MT effectively protected against DOX-induced inhibition on the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, and its downstream factors including mitochondrial transcription factor A. Moreover, MT was found to preserve the protein expression of manganese superoxide dismutase, a transcriptional target of PGC-1α. in vitro study showed that MT absence augmented DOX-induced increase of mitochondrial superoxide production in primary cultured cardiomyocytes. These findings suggest that MT׳s cardioprotection against DOX is mediated, at least in part, by preservation of mitochondrial biogenesis involving PGC-1α pathway. PMID:24858368

  8. Synergistic growth inhibitory effect of deracoxib with doxorubicin against a canine mammary tumor cell line, CMT-U27

    PubMed Central

    BAKIREL, Tülay; ALKAN, Fulya Üstün; ÜSTÜNER, Oya; ÇINAR, Suzan; YILDIRIM, Funda; ERTEN, Gaye; BAKIREL, Utku

    2016-01-01

    Cyclooxygenase (COX) inhibitors have been shown to exert anti-angiogenic and anti-tumor activities on many types of malignant tumors. These anticancer properties make it worthwhile to examine the possible benefit of combining COX inhibitors with other anti-cancer agents. In the present study, we evaluated the potential of deracoxib (DER) in potentiating antitumor activity of doxorubicin (DOX) in canine mammary carcinoma cells (CMT-U27). DER (50–250 µM) enhanced the antiproliferative activity of DOX by reducing the IC50 (approximately 3- to 3.5 fold). Interaction analysis of the data showed that combinations of DOX at 0.9 µM with DER (100–250 µM) produced synergism in the CMT-U27 cell line, with a ratio index ranging from 1.98 to 2.33. In additional studies identifying the mechanism of observed synergistic effect, we found that DER strongly potentiated DOX-caused G0/G1 arrest in cell cycle progression. Also, DER (100–250 µM) augmented apoptosis induction with approximately 1.35- and 1.37- fold increases in apoptotic response caused by DOX in the cells. DER enhanced the antiproliferative effect of DOX in conjunction with induction of apoptosis by modulation of Bcl-2 expression and changes in the cell cycle of the CMT-U27 cell line. Although the exact molecular mechanism of the alterations in the cell cycle and apoptosis observed with DER and DOX combinations require further investigations, the results suggest that the synergistic effect of DOX and DER combinations in CMT therapy may be achieved at relatively lower doses of DOX with lesser side effects. Therefore, combining DER with DOX may prove beneficial in the clinical treatment of canine mammary cancer. PMID:26822118

  9. Doxorubicin-loaded fucoidan capped gold nanoparticles for drug delivery and photoacoustic imaging.

    PubMed

    Manivasagan, Panchanathan; Bharathiraja, Subramaniyan; Bui, Nhat Quang; Jang, Bian; Oh, Yun-Ok; Lim, In Gweon; Oh, Junghwan

    2016-10-01

    Polymer nanoparticles are emerging as a useful tool for a wide variety of biomedical and therapeutic applications. The present study demonstrates the multifunctional doxorubicin-loaded fucoidan capped gold nanoparticles (DOX-Fu AuNPs) for drug delivery and photoacoustic imaging (PAI). Biocompatible AuNPs were synthesized using a naturally occurring fucoidan (Fu) as a capping and reducing agent. The Fu AuNPs synthesis was determined using UV-visible spectrum, and it was further characterized using high resolution transmission electron microscopy, energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction analysis. The release of DOX from DOX-Fu AuNPs was greater in acidic pH (4.5) than in neutral pH (7.4). The in vitro cytotoxic effect of fucoidan, Fu AuNPs, DOX, and DOX-Fu AuNPs inhibited the proliferation of human breast cancer cells with an inhibitory concentration of 35μg/mL, 30μg/mL, 15μg/mL, and 5μg/mL at 24h. DOX-Fu AuNPs induced both early and late apoptosis in a concentration-dependent manner compared with untreated control cells. The ability of DOX-Fu AuNPs as a contrast agent for in vitro breast cancer imaging with PAI has been evaluated. These results suggest that the multifunctional DOX-Fu AuNPs for drug delivery and PAI can soon provide considerable contribution to human health.

  10. Immobilized transferrin Fe3O4@SiO2 nanoparticle with high doxorubicin loading for dual-targeted tumor drug delivery

    PubMed Central

    Ding, Wence; Guo, Lin

    2013-01-01

    Transferrin (Tf) was immobilized onto Fe3O4@SiO2 nanoparticles with high doxorubicin (DOX) loading (TfDMP), for dual targeting of cancer, by chemically coupling both Tf and DOX with dual-function magnetic nanoparticles (DMPs) using a multi-armed crosslinker, poly-L-glutamic acid. With high trapping efficiency for magnetic targeting, TfDMP exhibits a Tf receptor-targeting function. Moreover, the DOX loading percentage of TfDMP is high, and can be controlled by adjusting the reactant ratio. TfDMP presents a narrow size distribution, and is sensitive to pH for drug release. Compared with DOX-coupled DMP without Tf modification (DDMP), TfDMP exhibits enhanced uptake by Tf receptor-expressing tumor cells, and displays stronger cancer cell cytotoxicity. This study provides an efficient method for the dual-targeted delivery of therapeutic agents to tumors, with controlled low carrier toxicity and high efficiency. PMID:24348038

  11. Influence of doxorubicin on apoptosis and oxidative stress in breast cancer cell lines.

    PubMed

    Pilco-Ferreto, Nesstor; Calaf, Gloria M

    2016-08-01

    Breast cancer is one of the leading causes of mortality among women worldwide due to aggressive behavior, early metastasis, resistance to existing chemotherapeutic agent and high mortality rate. Doxorubicin (Dox) is a powerful antitumoral drug. It is one of the most active agents for treatment of breast cancer. The aim of the present study was to evaluate the influence of Dox in apoptosis and oxidative stress in the breast cancer cell lines MCF-10F, MCF-7 and MDA-MB-231. These studies showed that Dox decreased anti-apoptotic Bcl-2 protein expression and affected oxidative stress by increasing hydrogen peroxide production and simultaneously decreasing NF-κB gene and protein expression in MCF-7, a tumorigenic triple-positive cell line. Results also indicated that Dox induced apoptosis by upregulating Bax, caspase-8 and caspase-3 and downregulation of Bcl-2 protein expression. On the contrary, ROS damage decreased by increasing SOD2 gene and protein expression and hydrogen peroxide production with parallel NF-κB protein expression decrease in MDA-MB-231, a tumorigenic triple-negative breast cancer cell line. It can be concluded that Dox activated apoptosis by inducing proteolytic processing of Bcl-2 family, caspases and simultaneously decreased oxidative stress by influencing ROS damage in MCF-7 and MDA-MB-231 cell lines. PMID:27278553

  12. Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.

    PubMed

    Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Haskó, György; Mechoulam, Raphael; Pacher, Pál

    2015-01-06

    Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may

  13. Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.

    PubMed

    Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Haskó, György; Mechoulam, Raphael; Pacher, Pál

    2015-01-01

    Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may

  14. Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for targeted therapy of bone metastatic cancer

    PubMed Central

    Ye, Wei-liang; Zhao, Yi-pu; Li, Huai-qiu; Na, Ren; Li, Fei; Mei, Qi-bing; Zhao, Ming-gao; Zhou, Si-yuan

    2015-01-01

    In order to increase the therapeutic effect of doxorubicin (DOX) on bone metastases, a multifunctional micelle was developed by combining pH-sensitive characteristics with bone active targeting capacity. The DOX loaded micelle was self-assembled by using doxorubicin-poly (ethylene glycol)-alendronate (DOX-hyd-PEG-ALN) as an amphiphilic material. The size and drug loading of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 24.3%. In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS. In addition, with the increase of incubation time, more red DOX fluorescence was observed in tumor cells and trafficked from cytoplasm to nucleus. The IC50 of DOX loaded DOX-hyd-PEG-ALN micelle on A549 cells was obviously lower than that of free DOX in 48 h. Furthermore, the in vivo image experimental results indicated that a larger amount of DOX was accumulated in the bone metastatic tumor tissue after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, which was confirmed by histological analysis. Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX. In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor. PMID:26419507

  15. In vitro evaluation of doxorubicin-incorporated magnetic albumin nanospheres.

    PubMed

    Zeybek, Ayça; Şanlı-Mohamed, Gülşah; Ak, Güliz; Yılmaz, Habibe; Şanlıer, Şenay H

    2014-07-01

    Magnetic albumin nanospheres that incorporate doxorubicin (M-DOX-BSA-NPs) were prepared previously by our research group to develop magnetically responsive drug carrier system. This nanocarrier was synthesized as a drug delivery system for targeted chemotherapy. In this work, cytotoxic effects of doxorubicin (DOX)-loaded/unloaded or magnetic/non-magnetic nanoparticles and free DOX against PC-3 cells and A549 cells were determined with the MTT test and the results were compared with each other. DOX-loaded magnetic albumin nanospheres (M-DOX-BSA-NPs) were found more cytotoxic than other formulations. The quantitative data obtained from flow cytometry analysis further verified the higher targeting and killing ability of M-DOX-BSA-NPs than free DOX on both of the cancer cell lines. Additionally, the results of cell cycle analysis have showed that M-DOX-BSA-NPs affected G1 and G2 phases. Finally, cell images were obtained using spin-disk confocal microscopy, and cellular uptake of M-DOX-BSA-NPs was visualized. The findings of this study suggest that M-DOX-BSA-NPs represent a potential doxorubicin delivery system for targeted drug transport into prostate and lung cancer cells.

  16. Using acoustic cavitation to enhance chemotherapy of DOX liposomes: experiment in vitro and in vivo.

    PubMed

    Zhao, Ying-Zheng; Dai, Dan-Dan; Lu, Cui-Tao; Lv, Hai-Feng; Zhang, Yan; Li, Xing; Li, Wen-Feng; Wu, Yan; Jiang, Lei; Li, Xiao-Kun; Huang, Pin-Tong; Chen, Li-Juan; Lin, Min

    2012-09-01

    Experiments in vitro and in vivo were designed to investigate tumor growth inhibition of chemotherapeutics-loaded liposomes enhanced by acoustic cavitation. Doxorubicin-loaded liposomes (DOX liposomes) were used in experiments to investigate acoustic cavitation mediated effects on cell viability and chemotherapeutic function. The influence of lingering sensitive period after acoustic cavitation on tumor inhibition was also investigated. Animal experiment was carried out to verify the practicability of this technique in vivo. From experiment results, blank phospholipid-based microbubbles (PBM) combined with ultrasound (US) at intensity below 0.3 W/cm² could produce acoustic cavitation which maintained cell viability at high level. Compared with DOX solution, DOX liposomes combined with acoustic cavitation exerted effective tumor inhibition in vitro and in vivo. The lingering sensitive period after acoustic cavitation could also enhance the susceptibility of tumor to chemotherapeutic drugs. DOX liposomes could also exert certain tumor inhibition under preliminary acoustic cavitation. Acoustic cavitation could enhance the absorption efficiency of DOX liposomes, which could be used to reduce DOX adverse effect on normal organs in clinical chemotherapy.

  17. CYP1B1 inhibition attenuates doxorubicin-induced cardiotoxicity through a mid-chain HETEs-dependent mechanism.

    PubMed

    Maayah, Zaid H; Althurwi, Hassan N; Abdelhamid, Ghada; Lesyk, Gabriela; Jurasz, Paul; El-Kadi, Ayman O S

    2016-03-01

    Doxorubicin (DOX) has been reported to be a very potent and effective anticancer agent. However, clinical treatment with DOX has been greatly limited due to its cardiotoxicity. Furthermore, several studies have suggested a role for cytochrome P450 1B1 (CYP1B1) and mid-chain hydroxyeicosatetraenoic acids (mid-chain HETEs) in DOX-induced cardiac toxicity. Therefore, we hypothesized that DOX induced cardiotoxicity is mediated through the induction of CYP1B1 and its associated mid-chain HETEs metabolite. To test our hypothesis, Sprague-Dawley rats and RL-14 cells were treated with DOX in the presence and absence of 2,3',4,5'-tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor. Thereafter, cardiotoxicity parameters were determined using echocardiography, histopathology, and gene expression. Further, the level of mid-chain HETEs was quantified using liquid chromatography-electron spray ionization-mass spectrometry. Our results showed that DOX induced cardiotoxicity in vivo and in vitro as evidenced by deleterious changes in echocardiography, histopathology, and hypertrophic markers. Importantly, the TMS significantly reversed these changes. Moreover, the DOX-induced cardiotoxicity was associated with a proportional increase in the formation of cardiac mid-chain HETEs both in vivo and in our cell culture model. Interestingly, the inhibition of cardiotoxicity by TMS was associated with a dramatic decrease in the formation of cardiac mid-chain HETEs suggesting a mid-chain HETEs-dependent mechanism. Mechanistically, the protective effect of TMS against DOX-induced cardiotoxicity was mediated through the inhibition of mitogen activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). In conclusion, our study provides the first evidence that the inhibition of CYP1B1 and mid-chain HETE formation attenuate DOX-induced cardiotoxicity.

  18. Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery

    PubMed Central

    Qiu, Liang; Hong, Chun-Yan; Pan, Cai-Yuan

    2015-01-01

    Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP)ns, have been successively prepared by two steps of reversible addition–fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2′-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP)ns (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system. PMID:26056444

  19. Nilotinib reverses ABCB1/P-glycoprotein-mediated multidrug resistance but increases cardiotoxicity of doxorubicin in a MDR xenograft model.

    PubMed

    Zhou, Zhi-Yong; Wan, Li-Li; Yang, Quan-Jun; Han, Yong-Long; Li, Dan; Lu, Jin; Guo, Cheng

    2016-09-30

    The BCR-Abl tyrosine kinase inhibitor (TKI), nilotinib, was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia-positive chronic myelogenous leukemia. Recent studies have shown that nilotinib induces potent sensitization to anticancer agents by blocking the functions of ABCB1/P-glycoprotein (P-gp) in multidrug resistance (MDR). However, changes in P-gp expression or function affect the cardiac disposition and prolong the presence of both doxorubicin (DOX) and doxorubicinol (DOXol) in cardiac tissue, thus, enhancing the risk of cardiotoxicity. In this study, we used a MDR xenograft model to evaluate the antitumor activity, tissue distribution and cardiotoxicity of DOX when co-administered with nilotinib. This information will provide more insight into the pharmacological role of nilotinib in MDR reversal and the risk of DOX cardiotoxicity. Our results showed that nilotinib significantly enhanced DOX cytotoxicity and increased intracellular rhodamine 123 accumulation in MG63/DOX cells in vitro and strongly enhanced DOX inhibition of growth of P-gp-overexpressing MG63/DOX cell xenografts in nude mice. Additionally, nilotinib significantly increased DOX and DOXol accumulation in serum, heart, liver and tumor tissues. Importantly, nilotinib induced a disproportionate increase in DOXol in cardiac tissue. In the co-administration group, CBR1 and AKR1A1 protein levels were significantly increased in cardiac tissue, with more severe necrosis and vacuole formation. These results indicate that nilotinib reverses P-gp- mediated MDR by blocking the efflux function and potentiates DOX-induced cardiotoxicity. These findings represent a guide for the design of future clinical trials and studies of pharmacokinetic interactions and may be useful in guiding the use of nilotinib in combination therapy of cancer in clinical practice.

  20. Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery.

    PubMed

    Qiu, Liang; Hong, Chun-Yan; Pan, Cai-Yuan

    2015-01-01

    Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP)(n)s, have been successively prepared by two steps of reversible addition-fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2'-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP)(n)s (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system. PMID:26056444

  1. Protective effect of oleanolic acid on oxidative injury and cellular abnormalities in doxorubicin induced cardiac toxicity in rats

    PubMed Central

    Goyal, Sameer N; Mahajan, Umesh B; Chandrayan, Govind; Kumawat, Vivek S; Kamble, Sarika; Patil, Pradip; Agrawal, Yogeeta O; Patil, Chandragouda R; Ojha, Shreesh

    2016-01-01

    The prevention of doxorubicin (Dox) induced cardiotoxicity may be co-operative to recover future Dox treatment. The aim of this study was to explore the cardioprotective effects of oleanolic acid (OA), an antioxidant agent, on Dox induced cardiotoxicity. OA is a triterpenoid compound, which exist widely in plant kingdom in free acid form or as a glycosidic triterpenoids saponins. Cardiotoxicity was induced in Wistar rats with single intravenous injection of doxorubicin at dose of 67.75 mg/kg i.v for 48 hrs. At 12 hrs of interval following Dox administration the cardioprotective effect of OA (1.5 mg/kg, i.v.) and Amifostine (AMF) (90 mg/kg i.v., single dose prior 30 min) were evaluated. Induction of cardiotoxicity was confirmed by increase in systolic, diastolic, mean arterial pressures, maximal positive rate of developed left ventricular pressure (+LVdP/dtmax, an indicator of myocardial contraction), maximal negative rate of developed left ventricular pressure (-LVdP/dtmax, a meter of myocardial relaxation) and an increase in left ventricular end-diastolic pressure (LVEDP, a marker of pre-load). Cardiac markers in such as CK-MB, LDH and alterations in ECG. Dox administration showed alteration in Biochemical parameters and endogenous antioxidants. Administration of OA Showed maximal protection against Dox induced cardiac toxicity as observed by reduction in blood pressure, prevention of left ventricular function and attenuation of biochemical and antioxidant parameters. Based on the findings, its concluded that OA can be used as an adjuvant with Dox therapy in treating cancers. PMID:27069540

  2. Covalent attachment of Mn-porphyrin onto doxorubicin-loaded poly(lactic acid) nanoparticles for potential magnetic resonance imaging and pH-sensitive drug delivery.

    PubMed

    Jing, Lijia; Liang, Xiaolong; Li, Xiaoda; Yang, Yongbo; Dai, Zhifei

    2013-12-01

    In this paper, theranostic nanoparticles (MnP-DOX NPs) were fabricated by conjugating Mn-porphyrin onto the surface of doxorubicin (DOX)-loaded poly(lactic acid) (PLA) nanoparticles (DOX NPs) for potential T1 magnetic resonance imaging and pH-sensitive drug delivery. An in vitro drug release study showed that the release rate of DOX from MnP-DOX NPs was slow at neutral pH but accelerated significantly in acidic conditions. It was found that MnP-DOX NPs could be easily internalized by HeLa cells and effectively suppressed the growth of HeLa cells and HT-29 cells due to the accelerated drug release in acidic lysosomal compartments. Magnetic resonance imaging (MRI) scanning analysis demonstrated that MnP-DOX NPs had much higher longitudinal relaxivity in water (r1 value of 27.8 mM(-1) s(-1) of Mn(3+)) than Mn-porphyrin (Mn(III)TPPS3NH2; r1 value of 6.70 mM(-1) s(-1) of Mn(3+)), behaving as an excellent contrast agent for T1-weighted MRI both in vitro and in vivo. In summary, such a smart and promising nanoplatform integrates multiple capabilities for effective cancer diagnosis and therapy.

  3. Doxorubicin represses CARP gene transcription through the generation of oxidative stress in neonatal rat cardiac myocytes: possible role of serine/threonine kinase-dependent pathways.

    PubMed

    Aihara, Y; Kurabayashi, M; Tanaka, T; Takeda, S I; Tomaru, K; Sekiguchi, K I; Ohyama, Y; Nagai, R

    2000-08-01

    Doxorubicin (Dox), an anthracyclin antineoplastic agent, causes dilated cardiomyopathy. CARP has been identified as a nuclear protein whose mRNA levels are exquisitely sensitive to Dox. In this study we investigated the molecular mechanisms underlying the repression of CARP expression by Dox in cultured neonatal rat cardiac myocytes. Dox (1 micromol/l)-mediated decrease in CARP mRNA levels was strongly correlated with BNP but not with ANP mRNA levels. Hydrogen peroxide scavenger catalase (1 mg/ml) but not hydroxyl radical scavengers dimethylthiourea (10 mmol/l) or mannitol (10 mmol/l) blunted the Dox-mediated decrease in CARP and BNP expression. Superoxide dismutase inhibitor diethyldithiocarbamic acid (10 mmol/l), which inhibits the generation of hydrogen peroxide from superoxide metabolism, attenuated the repression. PD98059 (MEK1 inhibitor, 50 micromol/l), SB203580 (p38 MAP kinase inhibitor, 10 micromol/l), calphostin C (protein kinase C (PKC) inhibitor, 1 micromol/l), non-selective protein tyrosine kinase inhibitors genistein (50 micromol/l) or herbimycin A (1 micromol/l) failed to abrogate the downregulation of CARP and BNP expression by Dox. In contrast, H7 (30 micromol/l), a potent inhibitor of serine/threonine kinase, significantly blocked Dox-mediated downregulation of CARP and BNP expression. Transient transfection of a series of 5'-deletion and site-specific mutation constructs revealed that M-CAT element located at -37 of the human CARP promoter mediates Dox-induced repression of CARP promoter activity. These results suggest that a genetic response to Dox is mediated through the generation of hydrogen peroxide, which is selectively linked to the activation of H7-sensitive serine/threonine kinase distinct from PKC and well characterized mitogen-activated protein (MAP) kinases (ERK and p38MAP kinase). Furthermore, our data implicated M-CAT element as a Dox-response element within the CARP promoter in cardiac myocytes.

  4. Improving anticancer activity and reducing systemic toxicity of doxorubicin by self-assembled polymeric micelles

    NASA Astrophysics Data System (ADS)

    Gou, MaLing; Shi, HuaShan; Guo, Gang; Men, Ke; Zhang, Juan; Zheng, Lan; Li, ZhiYong; Luo, Feng; Qian, ZhiYong; Zhao, Xia; Wei, YuQuan

    2011-03-01

    In an attempt to improve anticancer activity and reduce systemic toxicity of doxorubicin (Dox), we encapsulated Dox in monomethoxy poly(ethylene glycol)-poly(ɛ-caprolactone) (MPEG-PCL) micelles by a novel self-assembly procedure without using surfactants, organic solvents or vigorous stirring. These Dox encapsulated MPEG-PCL (Dox/MPEG-PCL) micelles with drug loading of 4.2% were monodisperse and ~ 20 nm in diameter. The Dox can be released from the Dox/MPEG-PCL micelles; the Dox-release at pH 5.5 was faster than that at pH 7.0. Encapsulation of Dox in MPEG-PCL micelles enhanced the cellular uptake and cytotoxicity of Dox on the C-26 colon carcinoma cell in vitro, and slowed the extravasation of Dox in the transgenic zebrafish model. Compared to free Dox, Dox/MPEG-PCL micelles were more effective in inhibiting tumor growth in the subcutaneous C-26 colon carcinoma and Lewis lung carcinoma models, and prolonging survival of mice bearing these tumors. Dox/MPEG-PCL micelles also induced lower systemic toxicity than free Dox. In conclusion, incorporation of Dox in MPEG-PCL micelles enhanced the anticancer activity and decreased the systemic toxicity of Dox; these Dox/MPEG-PCL micelles are an interesting formulation of Dox and may have potential clinical applications in cancer therapy.

  5. Phase I Pharmacokinetic and Pharmacodynamic Evaluation of Combined Valproic Acid/Doxorubicin Treatment in Dogs with Spontaneous Cancer

    PubMed Central

    Wittenburg, Luke A.; Gustafson, Daniel L.; Thamm, Douglas H.

    2010-01-01

    Purpose Histone deacetylase inhibitors (HDACi) are targeted anti-cancer agents with a well-documented ability to act synergistically with cytotoxic agents. We recently demonstrated that the HDACi valproic acid (VPA) sensitizes osteosarcoma cells to doxorubicin (DOX) in vitro and in vivo. As there are no published reports on the clinical utility of HDACi in dogs with spontaneous cancers, we sought to determine a safe and biologically effective dose of VPA administered prior to a standard dose of DOX. Methods 21 dogs were enrolled into eight cohorts in an accelerated dose-escalation trial consisting of pre-treatment with oral VPA followed by DOX on a three-week cycle. Blood and tumor tissue were collected for determination of serum VPA concentration and evaluation of pharmcodynamic effects by immunofluorescence cytochemistry and immunohistochemistry. Serum and complete blood counts were obtained for determination of changes in DOX pharmacokinetics or hematologic effects. Results All doses of VPA were well tolerated. Serum VPA concentrations increased linearly with dose. DOX pharmacokinetics were comparable to those in dogs receiving DOX alone. A positive correlation was detected between VPA dose and histone hyperacetylation in PBMC. No potentiation of DOX-induced myelosuppression was observed. Histone hyperacetylation was documented in tumor and PBMC. Responses included 2/21 complete, 3/21 partial, 5/21 stable disease, and 11/21 progressive disease. Conclusions VPA can be administered to dogs at doses up to 240 mg/kg/day prior to a standard dose of DOX. In addition, we have developed the PK/PD tools necessary for future studies of novel HDACi in the clinical setting of canine cancer. PMID:20705615

  6. Design and Evaluation of Doxorubicin-containing Microbubbles for Ultrasound-triggered Doxorubicin Delivery: Cytotoxicity and Mechanisms Involved

    PubMed Central

    Lentacker, Ine; Geers, Bart; Demeester, Joseph; De Smedt, Stefaan C; Sanders, Niek N

    2009-01-01

    Drug delivery with microbubbles and ultrasound is gaining more and more attention in the drug delivery field due to its noninvasiveness, local applicability, and proven safety in ultrasonic imaging techniques. In this article, we tried to improve the cytotoxicity of doxorubicin (DOX)-containing liposomes by preparing DOX-liposome-containing microbubbles for drug delivery with therapeutic ultrasound. In this way, the DOX release and uptake can be restricted to ultrasound-treated areas. Compared to DOX-liposomes, DOX-loaded microbubbles killed at least two times more melanoma cells after exposure to ultrasound. After treatment of the melanoma cells with DOX-liposome-loaded microbubbles and ultrasound, DOX was mainly present in the nuclei of the cancer cells, whereas it was mainly detected in the cytoplasm of cells treated with DOX-liposomes. Exposure of cells to DOX-liposome-loaded microbubbles and ultrasound caused an almost instantaneous cellular entry of the DOX. At least two mechanisms were identified that explain the fast uptake of DOX and the superior cell killing of DOX-liposome-loaded microbubbles and ultrasound. First, exposure of DOX-liposome-loaded microbubbles to ultrasound results in the release of free DOX that is more cytotoxic than DOX-liposomes. Second, the cellular entry of the released DOX is facilitated due to sonoporation of the cell membranes. The in vitro results shown in this article indicate that DOX-liposome-loaded microbubbles could be a very interesting tool to obtain an efficient ultrasound-controlled DOX delivery in vivo. PMID:19623162

  7. Efficacy and Hemotoxicity of Stealth Doxorubicin-Loaded Magnetic Nanovectors on Breast Cancer Xenografts.

    PubMed

    Gautier, J; Allard-Vannier, E; Burlaud-Gaillard, J; Domenech, J; Chourpa, I

    2015-01-01

    In the field of oncology, research is now focused on the development of theranostic nanosystems that combine the functions of drug delivery and imaging for diagnosis/monitoring. In this context, we designed polyethylene glycol (PEG)ylated superparamagnetic iron oxide nanoparticles (SPIONs) for the delivery of doxorubicin (DOX), an antineoplastic agent. These DOX-loaded PEGylated SPIONs, or DLPS, should be useful for the delivery of DOX in vivo, as well as for magnetic drug targeting (MDT) and magnetic resonance imaging (MRI). The aim of this study was to evaluate the potential applications of DLPS in vivo as drug carrier systems for the reduction of xenograft breast tumors induced in nude mice. Prior to the animal model experiments, the main internalization pathways for the nanovectors in MDA-MB435 breast cancer cells were determined to be based on caveolae- and clathrin-mediated endocytosis. The time- and quantity-dependence of the nanoparticle uptake by the cells altered the in vitro cytotoxicity of the DLPS. The in vitro antiproliferative effect of the DLPS was dependent not only on DOX concentration, but also on the efficacy of nanoparticle internalization. Evaluation of the effect of DLPS treatment on xenograft tumors in nude mice showed that DLPS limited tumor growth in a manner comparable to that of free DOX under normal conditions of tumor growth. The application of an external magnetic field on tumors, i.e., MDT, did not improve the efficacy of the DLPS treatment. Nevertheless, the vectorization of DOX with DLPS appears to limit the hematologic side effects usually associated with DOX treatment.

  8. Efficacy and Hemotoxicity of Stealth Doxorubicin-Loaded Magnetic Nanovectors on Breast Cancer Xenografts.

    PubMed

    Gautier, J; Allard-Vannier, E; Burlaud-Gaillard, J; Domenech, J; Chourpa, I

    2015-01-01

    In the field of oncology, research is now focused on the development of theranostic nanosystems that combine the functions of drug delivery and imaging for diagnosis/monitoring. In this context, we designed polyethylene glycol (PEG)ylated superparamagnetic iron oxide nanoparticles (SPIONs) for the delivery of doxorubicin (DOX), an antineoplastic agent. These DOX-loaded PEGylated SPIONs, or DLPS, should be useful for the delivery of DOX in vivo, as well as for magnetic drug targeting (MDT) and magnetic resonance imaging (MRI). The aim of this study was to evaluate the potential applications of DLPS in vivo as drug carrier systems for the reduction of xenograft breast tumors induced in nude mice. Prior to the animal model experiments, the main internalization pathways for the nanovectors in MDA-MB435 breast cancer cells were determined to be based on caveolae- and clathrin-mediated endocytosis. The time- and quantity-dependence of the nanoparticle uptake by the cells altered the in vitro cytotoxicity of the DLPS. The in vitro antiproliferative effect of the DLPS was dependent not only on DOX concentration, but also on the efficacy of nanoparticle internalization. Evaluation of the effect of DLPS treatment on xenograft tumors in nude mice showed that DLPS limited tumor growth in a manner comparable to that of free DOX under normal conditions of tumor growth. The application of an external magnetic field on tumors, i.e., MDT, did not improve the efficacy of the DLPS treatment. Nevertheless, the vectorization of DOX with DLPS appears to limit the hematologic side effects usually associated with DOX treatment. PMID:26301312

  9. Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

    PubMed Central

    Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Haskó, György; Mechoulam, Raphael; Pacher, Pál

    2015-01-01

    Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX’s cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may

  10. Gambogic acid sensitizes resistant breast cancer cells to doxorubicin through inhibiting P-glycoprotein and suppressing survivin expression.

    PubMed

    Wang, Shengpeng; Wang, Lu; Chen, Meiwan; Wang, Yitao

    2015-06-25

    The development of resistance to chemotherapeutic agents remains a major challenge to breast cancer chemotherapy. Overexpression of drug efflux transporters like P-glycoprotein (P-gp) and resistance to apoptosis are the two key factors that confer cancer drug resistance. Gambogic acid (GA), a major component of Gamboge resin, has potent anticancer effects and can inhibit the growth of several types of human cancers. However, the potential and underlying mechanisms of GA in reversing cancer resistance remain poorly understood. In the present study, we found that GA can markedly sensitize doxorubicin (DOX)-resistant breast cancer cells to DOX-mediated cell death. GA increased the intracellular accumulation of DOX by inhibiting both P-gp expression and activity. Meanwhile, the combination effect was associated with the generation of intracellular reactive oxygen species (ROS) and the suppression of anti-apoptotic protein survivin. Scavenging intracellular ROS or overexpression of survivin blocked the sensitizing effects of GA in DOX-induced apoptosis. Furthermore, ROS-mediated activation of p38 MAPK was revealed in GA-mediated suppression of survivin expression. This study gives rise to the possibility of applying GA as an anticancer agent for the purpose of combating DOX-resistant breast cancer.

  11. Hybridized doxorubicin-Au nanospheres exhibit enhanced near-infrared surface plasmon absorption for photothermal therapy applications.

    PubMed

    Zhou, Jialin; Wang, Zuhua; Li, Qingpo; Liu, Fei; Du, Yongzhong; Yuan, Hong; Hu, Fuqiang; Wei, Yinghui; You, Jian

    2015-03-19

    Photothermal therapy (PTT) employs photosensitizing agents, which are taken up by cells and generate heat when irradiated with near-infrared (NIR) light, to enable the photoablation of cancer cells. High absorption in the NIR region is crucial for a photosensitizing agent to achieve efficient PTT. Different combinations between gold nanoparticles and fluorescent agents always influence their spectrum properties. Herein, we fabricated a novel combination of a fluorescent agent (doxorubicin, DOX, also a popular chemotherapeutic agent) with gold nanospheres by synthesizing hybridized DOX-Au nanospheres (DAuNS), where a part of the DOX molecules and Au co-formed a hybridized matrix as the shell and the remaining DOX molecules precipitated as the core. The unique structure of DAuNS induced interesting changes in the characteristics including spectrum properties, morphology, drug loading and antitumor activity. We observed that DAuNS exhibited a significantly enhanced surface plasmon absorption in the NIR region, inducing a more efficient photothermal conversion and stronger tumor-cell killing ability under NIR laser irradiation. In addition, our study presents a new and simple platform to load a drug into nanoparticles. DAuNS could be a promising nanoparticle with the "two punch" efficacy of PTT and chemotherapy and could be used in clinical applications due to its controllable synthesis, small size, and narrow size distribution.

  12. CaMKII-dependent SR Ca leak contributes to doxorubicin-induced impaired Ca handling in isolated cardiac myocytes

    PubMed Central

    Sag, Can M.; Köhler, Anne C.; Anderson, Mark E.; Backs, Johannes; Maier, Lars S.

    2011-01-01

    Objective Doxorubicin (DOX) is one of the most effective chemotherapeutic agents, but cardiotoxicity limits DOX therapy. Although the mechanisms are not entirely understood, reactive oxygen species (ROS) appear to be involved in DOX cardiotoxicity. Ca/calmodulin dependent protein kinase II (CaMKII) can be activated by ROS through oxidation and is known to contribute to myocardial dysfunction through Ca leakage from the sarcoplasmic reticulum (SR). Rationale We hypothesized that CaMKII contributes to DOX-induced defects in intracellular Ca ([Ca]i) handling. Methods Cardiac myocytes were isolated from wild-type (WT) adult rat hearts and from mouse hearts lacking the predominant myocardial CaMKII isoform (CaMKIIδ−/−, KO) vs. WT. Isolated cardiomyocytes were investigated 30 min after DOX (10 µmol/L) superfusion, using epifluorescence and confocal microscopy. Intracellular ROS-generation ([ROS]i) and [Ca]i handling properties were assessed. In a subset of experiments, KN-93 or AIP (each 1 µmol/L) were used to inhibit CaMKII. Melatonin (Mel, 100 µmol/L) served as ROS-scavenger. Western blots were performed to determine the amount of CaMKII phosphorylation and oxidation. Results DOX increased [ROS]i and led to significant diastolic [Ca]i overload in rat myocytes. This was associated with reduced [Ca]i transients, a 5.8-fold increased diastolic SR Ca leak and diminished SR Ca content. ROS-scavenging partially rescued Ca handling. Western blots revealed increased CaMKII phosphorylation, but not CaMKII oxidation after DOX. Pharmacological CaMKII inhibition attenuated diastolic [Ca]i overload after DOX superfusion and led to partially restored [Ca]i transients and SR Ca content, presumably due to reduced Ca spark frequency. In line with this concept, isoform-specific CaMKIIδ-KO attenuated diastolic [Ca]i overload and Ca spark frequency. Conclusions DOX exposure induces CaMKII-dependent SR Ca leakage, which partially contributes to impaired cellular [Ca]i homeostasis

  13. [Selective toxicity of cytostatic agents: studies on the cardiotoxicity of doxorubicin, its pathogenesis and contraindications].

    PubMed

    Lenzhofer, R

    1983-01-01

    In the past few years the medical treatment of malignant diseases has steadily increased in scope and importance. However, the tumor regimens described in the textbooks still are rather schematic recommendations, which are inadequately tailored to the needs of the individual case. Current tumor therapy is based on the results of the statistical analysis using empirical data collected in randomized trials. While patients can today be given a statistical value which expresses their computed chance of a cure versus that of a defined population, there is still no generally valid method which could serve as a rational basis for individualized counselling. But cytostatic chemotherapy has yet another major shortcoming: the collective assessment of toxicity, which is related to one of the basic properties of cytostatic drugs, i.e. their extremely low therapeutic index. Many of the side effects of cytostatics may cause severe irreversible, at times even fatal, organ dysfunction. Consequently, the definition of the therapeutic risks involved on the basis of an objective identification of potential organ toxicity is a major challenge. "Surgery without a knife", as K.H. Spitzy has called chemotherapy, should be subjected to objective criteria for its indications and contraindications so that patients can truly benefit from what are become increasingly aggressive measures. The principle of weighing the benefits desired in the individual case against the potential risks involved in a specific treatment, which Paul Ehrlich postulated for antibacterial chemotherapy, should also be applied to cytostatic chemotherapy with a view to facilitating the decision for or against therapy in borderline cases. The present contribution which is designed to shed light on the cardiotoxicity of doxorubicin should be interpreted in light of this situation. Pathogenetic aspects and animal experiments on drug-induced lipid peroxidation will be discussed and clinical trials on both acute and chronic

  14. Doxorubicin and chloroquine coencapsulated liposomes: preparation and improved cytotoxicity on human breast cancer cells.

    PubMed

    Qiu, Liyan; Yao, Mingfei; Gao, Menghua; Zhao, Qinghe

    2012-09-01

    Doxorubicin, as a widely used chemotherapeutic, always causes multidrug resistance in human cancer cells. To circumvent drug resistance, we developed a novel formulation where doxorubicin hydrochloride (DOX) and chloroquine phosphate (CQ) were simultaneously loaded into liposomes by a pH-gradient method where CQ played the role of a chemical sensitizer. The various factors were investigated to optimize the formulation and manufacturing conditions of DOX and CQ coencapsulated liposomes (DCL). The resultant DCLs achieved the high encapsulation efficiency of both drugs over 90%. Further, DCLs significantly displayed resistance reversal action on a doxorubicin-resistant human breast cancer cell line (MCF-7/ADR) through the cooperation of CQ with DOX. The reversal fold of DCL with the DOX/CQ/soybean phosphatidylcholine weight ratio of 0.5:1:50 was 5.7, compared to free DOX. These results demonstrate that DCL is a promising formulation for the treatment of DOX-resistant breast cancer. PMID:22607110

  15. Astragaloside IV inhibits doxorubicin-induced cardiomyocyte apoptosis mediated by mitochondrial apoptotic pathway via activating the PI3K/Akt pathway.

    PubMed

    Jia, Yuanyuan; Zuo, Daiying; Li, Zengqiang; Liu, Hanmo; Dai, Zhengning; Cai, Jiayi; Pang, Lili; Wu, Yingliang

    2014-01-01

    Doxorubicin (DOX) is a widely used antitumor drug whose application is seriously limited by its cardiotoxicity. Mitochondria-mediated cardiomyocyte apoptosis plays a critical role in DOX-induced cardiotoxicity (DIC). The aim of the present study was to investigate the protective effect of astragaloside IV (3-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyranosyl-cycloastragenol, AS-IV), a pure saponin isolated from Astragalus membranaceus, against DOX-induced cardiomyocyte apoptosis in primary cultured neonatal rat cardiomyocytes. Immunocytochemistry and Microculture Tetrazolium (MTT) assays showed that AS-IV significantly reduced DOX-induced cardiomyocyte loss. Additionally, AS-IV markedly ameliorated DOX-caused cardiomyocyte dysfunction via restoring the beating cell ratio and beating rate in cardiomyocytes. Furthermore, AS-IV substantially reduced the mitochondrial reactive oxygen species (ROS) production and lactate dehydrogenase (LDH), creatine kinase-MB isoenzyme (CK-MB) and cytochrome c (CytC) release, and restored the reduced ATP level, succinate dehydrogenase (SDH) and ATP synthase activities induced by DOX, suggesting that AS-IV significantly attenuated DOX-induced mitochondrial damage and dysfunction. It was further observed that DOX-induced cardiomyocyte apoptosis, as qualitatively evaluated by Hoechst 33258 staining and accurately quantified by flow cytometry, was markedly inhibited by AS-IV. Western blot analysis manifested that AS-IV significantly inhibited the activation of mitochondrial apoptotic pathway (MAP) via inducing the phosphorylation of Akt and Bad. Furthermore, phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) remarkably inhibited the anti-apoptotic effect of AS-IV. Moreover, AS-IV didn't compromise the antitumor activity of DOX. Taken together, our findings indicate that AS-IV ameliorates DIC, and this beneficial effect appears to be dependent on the activation of the PI3K

  16. Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Alleviates Doxorubicin-Induced Depressive-Like Behaviors and Neurotoxicity in Rats: Involvement of Oxidative Stress and Neuroinflammation.

    PubMed

    Wu, Yan-Qin; Dang, Rui-Li; Tang, Mi-Mi; Cai, Hua-Lin; Li, Huan-De; Liao, De-Hua; He, Xin; Cao, Ling-Juan; Xue, Ying; Jiang, Pei

    2016-04-23

    Doxorubicin (DOX) is a chemotherapeutic agent widely used in human malignancies. Its long-term use can cause neurobiological side-effects associated with depression. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), the essential fatty acids found in fish oil, possess neuroprotecitve and antidepressant activities. Thus, the aim of this study was to explore the potential protective effects of ω-3 PUFAs against DOX-induced behavioral changes and neurotoxicity. ω-3 PUFAs were given daily by gavage (1.5 g/kg) over three weeks starting seven days before DOX administration (2.5 mg/kg). Open-field test (OFT) and forced swimming test (FST) were conducted to assess exploratory activity and despair behavior, respectively. Our data showed that ω-3 PUFAs supplementation significantly mitigated the behavioral changes induced by DOX. ω-3 PUFAs pretreatment also alleviated the DOX-induced neural apoptosis. Meanwhile, ω-3 PUFAs treatment ameliorated DOX-induced oxidative stress in the prefrontal cortex and hippocampus. Additionally, gene expression of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, and the protein levels of NF-κB and iNOS were significantly increased in brain tissues of DOX-treated group, whereas ω-3 PUFAs supplementation significantly attenuated DOX-induced neuroinflammation. In conclusion, ω-3 PUFAs can effectively protect against DOX-induced depressive-like behaviors, and the mechanisms underlying the neuroprotective effect are potentially associated with its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

  17. Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery

    PubMed Central

    Cochran, Michael C.; Eisenbrey, John; Ouma, Richard O.; Soulen, Michael; Wheatley, Margaret A.

    2011-01-01

    A polymer ultrasound contrast agent (UCA) developed in our lab has been shown to greatly reduce in size when exposed to ultrasound, resulting in nanoparticles less than 400 nm in diameter capable of escaping the leaky vasculature of a tumor to provide a sustained release of drug. Previous studies with the hydrophilic drug doxorubicin (DOX) demonstrated enhanced drug delivery to tumors when triggered with ultrasound. However the therapeutic potential has been limited due to the relatively low payload of DOX. This study compares the effects of loading the hydrophobic drug paclitaxel (PTX) on the agent’s acoustic properties, drug payload, tumoricidal activity, and the ability to deliver drugs through 400 nm pores. A maximum payload of 129.46 ± 1.80 μg PTX/mg UCA (encapsulation efficiency 71.92 ± 0.99 %) was achieved, 20 times greater than the maximum payload of DOX (6.2 μg/mg), while maintaining the acoustic properties. In vitro, the tumoricidal activity of paclitaxel loaded UCA exposed to ultrasound was significantly greater than controls not exposed to ultrasound (p<0.0016). This study has shown that PTX loaded UCA triggered with focused ultrasound have the potential to provide a targeted and sustained delivery of drug to tumors. PMID:21609756

  18. Interaction of doxorubicin with the subcellular structures of the sensitive and Bcl-xL-overexpressing MCF-7 cell line: confocal and low-energy-loss transmission electron microscopy.

    PubMed

    Mhawi, A Amir

    2009-10-01

    The present investigation was directed to examine the interaction of the anti-cancer agent doxorubicin (DOX) with the subcellular compartments of the drug sensitive and Bcl-xL-overexpressing (Bcl-xL) MCF-7 cells using confocal and low-energy-loss transmission electron microscopy (LELTEM). Intracellular detection of DOX with LELTEM was carried out without specific antibodies or heavy metal stains but via the electron-induced molecular orbital excitation of the drug. Cells were incubated with 10 microM DOX for 1 min, 1, 24, and 48 h and then examined live by confocal microscope and as very thin sections in an electron microscope equipped with an energy filter having an energy resolution of 1eV. Ultrastructural localization of DOX, obtained from pairs of images taken at energy losses of 3+/-1 and 10+/-1eV, were analyzed and correlated with the confocal observations. When the sensitive and Bcl-xL cells were examined under the confocal microscope after 1 min, DOX uptake could not be detected in the nuclei nor in the cytoplasm whereas LELTEM observation revealed that at this stage of incubation the drug has already been incorporated by both cell types and that the nuclear membrane, nucleolus, and mitochondria of the Bcl-xL cells were temporally less DOX-responsive as compared to the sensitive cells. As the incubation time increased, nuclear membranes and nucleoli of both cell types appeared equally sensitive to DOX, nonetheless, mitochondria of the Bcl-xL cells remained invulnerable to DOX for 24h. The results point to LELTEM feasibility to better characterize yet unresolved cellular events caused by DOX and suggest a transitory role for Bcl-xL overexpression in protecting the cellular compartments from DOX invasion. PMID:19502069

  19. PROTECTIVE EFFECT OF LACTUCA SERRIOLA ON DOXORUBICIN-INDUCED TOXICITY IN H9C2 CELLS.

    PubMed

    Hosseini, Azar; Mahdian, Davood

    2016-01-01

    The use of doxorubicin (DOX) is limited by its dose-dependency because of its cardiotoxicity. Reactive oxygen species (ROS) play an important role in the pathological process. The aim of this study is to evaluate the protective effect of Lactuca seniola against DOX-induced apoptosis and death in H9C2 cells. The cells were incubated with different concentrations of extract for 4 h which continued in the presence or absence of 5 µM doxorubicin for 24 h. Cell viability, apoptotic induction and the level of apoptotic proteins were determined by using MTT, PI and immunoblotting assays, respectively. The level of lipid peroxidation was measured by fluorimetric method. DOX significantly decreased cell viability which was accompanied by an increase in ROS production and lipid peroxidation. Pretreatment with Lactuca seniola increased the viability of cardiomyocytes and could decrease lipid peroxidation. Also, Lactuca seriola inhibited the reduction of anti-apoptotic Bcl-2 protein and elevation of apoptotic Bax and caspase-3 proteins. In conclusion, Lactuca seniola exerts protective effect against oxidative stress-induced cardiomyocytes damage. Therefore, it has the potential to be used as cardioprotective agent by the patients with cardiovascular diseases. PMID:27476284

  20. Doxorubicin-loaded magnetic nanoparticle clusters for chemo-photothermal treatment of the prostate cancer cell line PC3.

    PubMed

    Zhang, Weibing; Zheng, Xinmin; Shen, Shun; Wang, Xinghuan

    2015-10-16

    In addition to the conventional cancer treatment such as radiotherapy, chemotherapy and surgical management, nanomedicine-based approaches have attracted widespread attention in recent years. In this paper, a promising nanocarrier, magnetic nanoparticle clusters (MNCs) as porous materials which provided enough room on the surface, was developed for loading chemotherapeutic agent of doxorubicin (DOX). Moreover, MNCs are a good near-infrared (NIR) photothermal mediator. Thus, MNCs have great potential both in photothermal therapy (PTT) and drug delivery for chemo-photothermal therapy of cancer. We firstly explored the destruction of prostate cancer in vitro by the combination of PTT and chemotherapy using DOX@MNCs. Upon NIR irradiation at 808 nm, more cancer cells were killed when PC3 cells incubated with DOX@MNCs, owing to both MNCs-mediated photothermal ablation and cytotoxicity of light-triggered DOX release. Compared with PTT or chemotherapy alone, the chemo-photothermal therapy by DOX@MNCs showed a synergistically higher therapeutic efficacy.

  1. Combination of Potassium Pentagamavunon-0 and Doxorubicin Induces Apoptosis and Cell Cycle Arrest and Inhibits Metastasis in Breast Cancer Cells.

    PubMed

    Putri, Herwandhani; Jenie, Riris Istighfari; Handayani, Sri; Kastian, Ria Fajarwati; Meiyanto, Edy

    2016-01-01

    A salt compound of a curcumin analogue, potassium pentagamavunon-0 (K PGV-0) has been synthesized to improve solubility of pentagamavunon-0 which has been proven to have anti-proliferative effects on several cancer cells. The purpose of this study was to investigate cytotoxic activity and metastasis inhibition by K PGV- 0 alone and in combination with achemotherapeutic agent, doxorubicin (dox), in breast cancer cells. Based on MTT assay analysis, K PGV-0 showed cytotoxic activity in T47D and 4T1 cell lines with IC50 values of 94.9 μM and 49.0±0.2 μM, respectively. In general, K PGV-0+dox demonstrated synergistic effects and decreased cell viability up to 84.7% in T47D cells and 62.6% in 4T1 cells. Cell cycle modulation and apoptosis induction were examined by flow cytometry. K PGV-0 and K PGV-0+dox caused cell accumulation in G2/M phase and apoptosis induction. Regarding cancer metastasis, while K PGV-0 alone did not show any inhibition of 4T1 cell migration, K PGV-0+dox exerted inhibition. K PGV-0 and its combination with dox inhibited the activity of MMP-9 which has a pivotal role in extracellular matrix degradation. These results show that a combination of K PGV-0 and doxorubicin inhibits cancer cell growth through cell cycling, apoptosis induction, and inhibition of cell migration and MMP-9 activity. Therefore, K PGV-0 may have potential for development as a co-chemotherapeutic agent. PMID:27268651

  2. Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells.

    PubMed

    Sriraman, Shravan Kumar; Pan, Jiayi; Sarisozen, Can; Luther, Ed; Torchilin, Vladimir

    2016-02-01

    Current research in cancer therapy is beginning to shift toward the use of combinational drug treatment regimens. However, the efficient delivery of drug combinations is governed by a number of complex factors in the clinical setting. Therefore, the ability to synchronize the pharmacokinetics of the individual therapeutic agents present in combination not only to allow for simultaneous tumor accumulation but also to allow for a synergistic relationship at the intracellular level could prove to be advantageous. In this work, we report the development of a novel folic acid-targeted liposomal formulation simultaneously co-loaded with C6 ceramide and doxorubicin [FA-(C6+Dox)-LP]. In vitro cytotoxicity assays showed that the FA-(C6+Dox)-LP was able to significantly reduce the IC50 of Dox when compared to that after the treatment with the doxorubicin-loaded liposomes (Dox-LP) as well as the untargeted drug co-loaded (C6+Dox)-LP on HeLa, A2780-ADR, and H69-AR cells. The analysis of the cell cycle distribution showed that while the C6 liposomes (C6-LP) did not cause cell cycle arrest, all the Dox-containing liposomes mediated cell cycle arrest in HeLa cells in the G2 phase at Dox concentrations of 0.3 and 1 μM and in the S phase at the higher concentrations. It was also found that this arrest in the S phase precedes the progression of the cells to apoptosis. The targeted FA-(C6+Dox)-LP were able to significantly enhance the induction of apoptotic events in HeLa cell monolayers as compared to the other treatment groups. Next, using time-lapse phase holographic imaging microscopy, it was found that upon treatment with the FA-(C6+Dox)-LP, the HeLa cells underwent rapid progression to apoptosis after 21 h as evidenced by a drastic drop in the average area of the cells after loss of cell membrane integrity. Finally, upon evaluation in a HeLa spheroid cell model, treatment with the FA-(C6+Dox)-LP showed significantly higher levels of cell death compared to those with C6-LP and

  3. Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells.

    PubMed

    Sriraman, Shravan Kumar; Pan, Jiayi; Sarisozen, Can; Luther, Ed; Torchilin, Vladimir

    2016-02-01

    Current research in cancer therapy is beginning to shift toward the use of combinational drug treatment regimens. However, the efficient delivery of drug combinations is governed by a number of complex factors in the clinical setting. Therefore, the ability to synchronize the pharmacokinetics of the individual therapeutic agents present in combination not only to allow for simultaneous tumor accumulation but also to allow for a synergistic relationship at the intracellular level could prove to be advantageous. In this work, we report the development of a novel folic acid-targeted liposomal formulation simultaneously co-loaded with C6 ceramide and doxorubicin [FA-(C6+Dox)-LP]. In vitro cytotoxicity assays showed that the FA-(C6+Dox)-LP was able to significantly reduce the IC50 of Dox when compared to that after the treatment with the doxorubicin-loaded liposomes (Dox-LP) as well as the untargeted drug co-loaded (C6+Dox)-LP on HeLa, A2780-ADR, and H69-AR cells. The analysis of the cell cycle distribution showed that while the C6 liposomes (C6-LP) did not cause cell cycle arrest, all the Dox-containing liposomes mediated cell cycle arrest in HeLa cells in the G2 phase at Dox concentrations of 0.3 and 1 μM and in the S phase at the higher concentrations. It was also found that this arrest in the S phase precedes the progression of the cells to apoptosis. The targeted FA-(C6+Dox)-LP were able to significantly enhance the induction of apoptotic events in HeLa cell monolayers as compared to the other treatment groups. Next, using time-lapse phase holographic imaging microscopy, it was found that upon treatment with the FA-(C6+Dox)-LP, the HeLa cells underwent rapid progression to apoptosis after 21 h as evidenced by a drastic drop in the average area of the cells after loss of cell membrane integrity. Finally, upon evaluation in a HeLa spheroid cell model, treatment with the FA-(C6+Dox)-LP showed significantly higher levels of cell death compared to those with C6-LP and

  4. Enhanced Cellular Uptake and Pharmacokinetic Characteristics of Doxorubicin-Valine Amide Prodrug.

    PubMed

    Park, Yohan; Park, Ju-Hwan; Park, Suryeon; Lee, Song Yi; Cho, Kwan Hyung; Kim, Dae-Duk; Shim, Won-Sik; Yoon, In-Soo; Cho, Hyun-Jong; Maeng, Han-Joo

    2016-09-22

    In this study, we synthesized the valine (Val)-conjugated amide prodrug of doxorubicin (DOX) by the formation of amide bonds between DOX and Val. The synthesis of the DOX-Val prodrug was identified by a proton nuclear magnetic resonance (¹H-NMR) assay. In the MCF-7 cells (human breast adenocarcinoma cell; amino acid transporter-positive cell), the cellular accumulation efficiency of DOX-Val was higher than that of DOX according to the flow cytometry analysis data. Using confocal laser scanning microscopy (CLSM) imaging, it was confirmed that DOX-Val as well as DOX was mainly distributed in the nucleus of cancer cells. DOX-Val was intravenously administered to rats at a dose of 4 mg/kg, and the plasma concentrations of DOX-Val (prodrug) and DOX (formed metabolite) were quantitatively determined. Based on the systemic exposure (represented as area under the curve (AUC) values) of DOX-Val (prodrug) and DOX (formed metabolite), approximately half of DOX-Val seemed to be metabolized into DOX. However, it is expected that the remaining DOX-Val may exert improved cellular uptake efficiency in cancer cells after its delivery to the cancer region.

  5. Enhanced Cellular Uptake and Pharmacokinetic Characteristics of Doxorubicin-Valine Amide Prodrug.

    PubMed

    Park, Yohan; Park, Ju-Hwan; Park, Suryeon; Lee, Song Yi; Cho, Kwan Hyung; Kim, Dae-Duk; Shim, Won-Sik; Yoon, In-Soo; Cho, Hyun-Jong; Maeng, Han-Joo

    2016-01-01

    In this study, we synthesized the valine (Val)-conjugated amide prodrug of doxorubicin (DOX) by the formation of amide bonds between DOX and Val. The synthesis of the DOX-Val prodrug was identified by a proton nuclear magnetic resonance (¹H-NMR) assay. In the MCF-7 cells (human breast adenocarcinoma cell; amino acid transporter-positive cell), the cellular accumulation efficiency of DOX-Val was higher than that of DOX according to the flow cytometry analysis data. Using confocal laser scanning microscopy (CLSM) imaging, it was confirmed that DOX-Val as well as DOX was mainly distributed in the nucleus of cancer cells. DOX-Val was intravenously administered to rats at a dose of 4 mg/kg, and the plasma concentrations of DOX-Val (prodrug) and DOX (formed metabolite) were quantitatively determined. Based on the systemic exposure (represented as area under the curve (AUC) values) of DOX-Val (prodrug) and DOX (formed metabolite), approximately half of DOX-Val seemed to be metabolized into DOX. However, it is expected that the remaining DOX-Val may exert improved cellular uptake efficiency in cancer cells after its delivery to the cancer region. PMID:27669201

  6. Co-delivery of doxorubicin and arsenite with reduction and pH dual-sensitive vesicle for synergistic cancer therapy

    NASA Astrophysics Data System (ADS)

    Zhang, Lu; Xiao, Hong; Li, Jingguo; Cheng, Du; Shuai, Xintao

    2016-06-01

    Drug resistance is the underlying cause for therapeutic failure in clinical cancer chemotherapy. A prodrug copolymer mPEG-PAsp(DIP-co-BZA-co-DOX) (PDBD) was synthesized and assembled into a nanoscale vesicle comprising a PEG corona, a reduction and pH dual-sensitive hydrophobic membrane and an aqueous lumen encapsulating doxorubicin hydrochloride (DOX.HCl) and arsenite (As). The dual stimulation-sensitive design of the vesicle gave rise to rapid release of the physically entrapped DOX.HCl and arsenite inside acidic lysosomes, and chemically conjugated DOX inside the cytosol with high glutathione (GSH) concentration. In the optimized concentration range, arsenite previously recognized as a promising anticancer agent from traditional Chinese medicine can down-regulate the expressions of anti-apoptotic and multidrug resistance proteins to sensitize cancer cells to chemotherapy. Consequently, the DOX-As-co-loaded vesicle demonstrated potent anticancer activity. Compared to the only DOX-loaded vesicle, the DOX-As-co-loaded one induced more than twice the apoptotic ratio of MCF-7/ADR breast cancer cells at a low As concentration (0.5 μM), due to the synergistic effects of DOX and As. The drug loading strategy integrating chemical conjugation and physical encapsulation in stimulation-sensitive carriers enabled efficient drug loading in the formulation.Drug resistance is the underlying cause for therapeutic failure in clinical cancer chemotherapy. A prodrug copolymer mPEG-PAsp(DIP-co-BZA-co-DOX) (PDBD) was synthesized and assembled into a nanoscale vesicle comprising a PEG corona, a reduction and pH dual-sensitive hydrophobic membrane and an aqueous lumen encapsulating doxorubicin hydrochloride (DOX.HCl) and arsenite (As). The dual stimulation-sensitive design of the vesicle gave rise to rapid release of the physically entrapped DOX.HCl and arsenite inside acidic lysosomes, and chemically conjugated DOX inside the cytosol with high glutathione (GSH) concentration. In the

  7. Lipomer of doxorubicin hydrochloride for enhanced oral bioavailability.

    PubMed

    Benival, Derajram M; Devarajan, Padma V

    2012-02-28

    The present study discusses design of doxorubicin hydrochloride (Dox) loaded lipid based nanocarrier (LIPOMER) for oral delivery. High entrapment (>90 %) and high loading (38.11 ± 0.37 %w/w) of hydrophilic Dox in lipid nanocarrier of polyglyceryl-6-distearate was achieved using poly(methyl vinyl ether-co-maleic anhydride) (Gantrez AN 119) and a modified nanoprecipitation method. Dox-LIPOMER revealed nanosize (314 ± 16.80 nm) and negative zeta potential (-25.00 ± 2.41 mV). Dox-LIPOMER exhibits sustained release in vitro and was influenced by ionic strength of dissolution medium. DSC and XRD studies suggested amorphous nature of Dox in LIPOMER. TEM revealed spherical morphology of Dox-LIPOMER. Dox-LIPOMER was stable up to 12 months at 25 °C/60 % RH. A 384 % enhancement in oral bioavailability compared to Dox solution was observed following Dox-LIPOMER administration at 10 mg/kg body weight. Superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) assay data of heart and kidney tissues of rats treated with Dox-LIPOMER were comparable with untreated rats. Dox-LIPOMER represents a potential safe drug delivery system for oral administration. PMID:22155412

  8. Crocin treatment prevents doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Razmaraii, Nasser; Babaei, Hossein; Mohajjel Nayebi, Alireza; Assadnassab, Gholamreza; Ashrafi Helan, Javad; Azarmi, Yadollah

    2016-07-15

    Doxorubicin (DOX)-induced cardiotoxicity is well-known as a serious complication of chemotherapy in patients with cancer. It is unknown whether crocin (CRO), main component of Crocus sativus L. (Saffron), could reduce the severity of DOX-induced cardiotoxicity. Therefore, this study was undertaken to assess the protective impact of CRO on DOX-induced cardiotoxicity in rats. The rats were divided into four groups: control, DOX (2mg/kg/48h, for 12days), and CRO groups that receiving DOX as in group 2 and CRO (20 and 40mg/kg/24h, for 20days) starting 4days prior to first DOX injection and throughout the study. Echocardiographic, electrocardiographic and hemodynamic studies, along with histopathological examination and MTT test were carried out. Our findings demonstrate that DOX resulted in cardiotoxicity manifested by decreased the left ventricular (LV) systolic and diastolic pressures, rate of rise/drop of LV pressure, ejection fraction, fractional shortening and contractility index, as compared to control group. In addition, histopathological analysis of heart confirmed adverse structural changes in myocardial cells following DOX administration. The results also showed that CRO treatment significantly improved DOX-induced heart damage, structural changes in the myocardium and ventricular function. In addition, CRO did not affect the in vitro antitumor activity of DOX. Taken together, our data confirm that CRO is protective against cardiovascular-related disorders produced by DOX, and clinical studies are needed to examine these findings in human. PMID:27297631

  9. Self-assembled nanoparticles based on hydrophobically modified chitosan as carriers for doxorubicin.

    PubMed

    Zhang, Jing; Chen, Xi Guang; Li, Yan Yan; Liu, Cheng Sheng

    2007-12-01

    In this study self-assembled nanoparticles based on oleoyl-chitosan (OCH) were prepared with a mean diameter of 255.3 nm and an almost spherical shape. The toxicity profile of OCH nanoparticles was evaluated in vitro via hemolysis test and MTT assay. The hemolysis rates of OCH nanoparticles tested in different conditions came well within permissible limits (5%). The OCH nanoparticles showed no cytotoxicity to mouse embryo fibroblasts. Doxorubicin (DOX) was efficiently loaded into OCH nanoparticles with an encapsulation efficiency of 52.6%. The drug was rapidly and completely released from the nanoparticles (DOX-OCH nanoparticles) at pH 3.8, whereas at pH 7.4 there was a sustained release after a burst release. The inhibitory rates of DOX-OCH nanoparticle suspension to different human cancer cells (A549, Bel-7402, HeLa, and SGC-7901) significantly outperformed that of DOX solution. These results revealed the potential of OCH nanoparticles as carriers for hydrophobic antitumor agents.

  10. Enhanced antitumoral activity of doxorubicin against lung cancer cells using biodegradable poly(butylcyanoacrylate) nanoparticles

    PubMed Central

    Melguizo, Consolación; Cabeza, Laura; Prados, Jose; Ortiz, Raúl; Caba, Octavio; Rama, Ana R; Delgado, Ángel V; Arias, José L

    2015-01-01

    Doxorubicin (Dox) is widely used for the combined chemotherapy of solid tumors. However, the use of these drug associations in lung cancer has low antitumor efficacy. To improve its efficacious delivery and activity in lung adenocarcinoma cells, we developed a biodegradable and noncytotoxic nanoplatform based on biodegradable poly(butylcyanoacrylate) (PBCA). The reproducible formulation method was based on an anionic polymerization process of the PBCA monomer, with the antitumor drug being entrapped within the nanoparticle (NP) matrix during its formation. Improved drug-entrapment efficiencies and sustained (biphasic) drug-release properties were made possible by taking advantage of the synthesis conditions (drug, monomer, and surfactant-agent concentrations). Dox-loaded NPs significantly enhanced cellular uptake of the drug in the A549 and LL/2 lung cancer cell lines, leading to a significant improvement of the drug’s antitumoral activity. In vivo studies demonstrated that Dox-loaded NPs clearly reduced tumor volumes and increased mouse-survival rates compared to the free drug. These results demonstrated that PBCA NPs may be used to optimize the antitumor activity of Dox, thus exhibiting a potential application in chemotherapy against lung adenocarcinoma. PMID:26715840

  11. Enhanced antitumoral activity of doxorubicin against lung cancer cells using biodegradable poly(butylcyanoacrylate) nanoparticles.

    PubMed

    Melguizo, Consolación; Cabeza, Laura; Prados, Jose; Ortiz, Raúl; Caba, Octavio; Rama, Ana R; Delgado, Ángel V; Arias, José L

    2015-01-01

    Doxorubicin (Dox) is widely used for the combined chemotherapy of solid tumors. However, the use of these drug associations in lung cancer has low antitumor efficacy. To improve its efficacious delivery and activity in lung adenocarcinoma cells, we developed a biodegradable and noncytotoxic nanoplatform based on biodegradable poly(butylcyanoacrylate) (PBCA). The reproducible formulation method was based on an anionic polymerization process of the PBCA monomer, with the antitumor drug being entrapped within the nanoparticle (NP) matrix during its formation. Improved drug-entrapment efficiencies and sustained (biphasic) drug-release properties were made possible by taking advantage of the synthesis conditions (drug, monomer, and surfactant-agent concentrations). Dox-loaded NPs significantly enhanced cellular uptake of the drug in the A549 and LL/2 lung cancer cell lines, leading to a significant improvement of the drug's antitumoral activity. In vivo studies demonstrated that Dox-loaded NPs clearly reduced tumor volumes and increased mouse-survival rates compared to the free drug. These results demonstrated that PBCA NPs may be used to optimize the antitumor activity of Dox, thus exhibiting a potential application in chemotherapy against lung adenocarcinoma.

  12. Intracellular Doxorubicin Delivery of a Core Cross-linked, Redox-responsive Polymeric Micelles.

    PubMed

    Lili, Yu; Ruihua, Mu; Li, Li; Fei, Liang; Lin, Yao; Li, Su

    2016-02-10

    Redox-responsive micelles based on amphiphilic polyethylene glycol-polymethyl methacrylate with the introduction of disulfide containing cross-linked agent (mPEG-PMMA-SS) were developed for intracellular drug release. Benefiting from the amphiphilicity, mPEG-PMMA-SS could self-assembled into core cross-linked micelles in aqueous medium with tunable sizes (85-151 nm), appropriate zeta potential (-24.8 mV), and desirable critical micelle concentration (CMC) (0.18 mg/mL). Doxorubicin (DOX) could efficiently load into the micelles with satisfactory entrapment efficiency. As expected, the in vitro release studies displayed that DOX release from mPEG-PMMA-SS micelles was about 75% within 10h under tumor-relevant reductive condition, whereas only about 25% DOX was released in non-reductive medium. SRB assays indicated that these mPEG-PMMA-SS micelles were biocompatible and nontoxic up to a concentration of 50 μg/mL. The cytotoxicity studies and the intracellular drug delivery demonstrated that the drug release behavior in cells was related to the concentration of GSH in cytoplasm. Furthermore, the cell experiments using fluorescence microscopy showed clearly that DOX was delivered by micelles to the cytoplasm, released in cytoplasm under reductive environment, and then accumulated in cell nucleus. These results suggest that such redox-responsive micelles may develop into an efficient cytoplasmic delivery for hydrophobic anticancer drugs.

  13. Nano-Aggregates of Doxorubicin-Conjugated Methoxy Poly(ethylene glycol)-b-Carboxymethyl Dextran Copolymer.

    PubMed

    Lee, Sang Joon; Kang, Mi-Sun; Oh, Jong-Suk; Jeong, Young-Il; Park, In-Kyu; Lee, Hyun Chul

    2015-08-01

    Block copolymer composed of carboxymethyl dextran (CMDex) and methoxy poly(ethylene glycol) (MPEG) (abbreviated as CMDexPEG) was synthesized and doxorubicin (DOX) was conjugated with carboxyl groups of CMDexPEG. DOX-conjugated CMDexPEG block copolymer formed nanoparticles in water with sizes less than 100 nm. DOX-conjugated nanoparticles enhanced DOX delivery to the DOX-resistant CT26 cells and showed higher anticancer activity in vitro. DOX-conjugated nanoparticles inhibited growth of CT26 solid tumor at tumor-bearing mouse model study. In near infrared (NIR)-dye study, nanoparticles were retained in the tumor tissues for a longer period. PMID:26369118

  14. Efficient intravesical therapy of bladder cancer with cationic doxorubicin nanoassemblies

    PubMed Central

    Jin, Xun; Zhang, Peilan; Luo, Li; Cheng, Hao; Li, Yunzu; Du, Ting; Zou, Bingwen; Gou, Maling

    2016-01-01

    Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol) (DPP) nanoparticles to deliver doxorubicin (Dox) for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65 nm and a mean zeta potential of +19.6 mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer.

  15. Efficient intravesical therapy of bladder cancer with cationic doxorubicin nanoassemblies

    PubMed Central

    Jin, Xun; Zhang, Peilan; Luo, Li; Cheng, Hao; Li, Yunzu; Du, Ting; Zou, Bingwen; Gou, Maling

    2016-01-01

    Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol) (DPP) nanoparticles to deliver doxorubicin (Dox) for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65 nm and a mean zeta potential of +19.6 mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer. PMID:27660445

  16. A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas

    PubMed Central

    Jones, Robin L.; Rossen, Philip Blach; Lind-Hansen, Maja; Knoblauch, Poul

    2016-01-01

    Background. Belinostat is a novel histone deacetylase inhibitor. Primary Objectives. Maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumours (phase I) and response rate (RR) in soft tissue sarcomas (phase II). Methods. Bel was administered as a 30-minute IV infusion on days 1–5 and on day 5 with Dox. The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m2 and 50 mg/m2 Dox, cohort 2: Bel 600 mg/m2 and 75 mg/m2 Dox, cohort 3: Bel 800 mg/m2 and 75 mg/m2 Dox, and cohort 4: Bel 1000 mg/m2 and 75 mg/m2 Dox. Results. 41 patients were included (25 in phase I, 16 in phase II). Adverse events were fatigue (95%), nausea (76%), and alopecia (63%). There was one DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1000 mg/m2/d and Dox 75 mg/m2. Four responses were seen: 2 PR in phase I, RR of 8%; in phase II, 1 PR/1 CR, RR of 13%, and 9 patients (56%) with SD. Conclusion. The combination was well tolerated. Response rate was moderate but median time to progression was 6.0 months (95% CI, 1.6–9.7 months) which is superior to some reports of single-agent Dox. PMID:27403082

  17. SW43-DOX ± loading onto drug-eluting bead, a potential new targeted drug delivery platform for systemic and locoregional cancer treatment – An in vitro evaluation

    PubMed Central

    Ludwig, Johannes M.; Gai, Yongkang; Sun, Lingyi; Xiang, Guangya; Zeng, Dexing; Kim, Hyun S.

    2016-01-01

    Treatment of unresectable primary cancer and their distant metastases, with the liver representing one of the most frequent location, is still plagued by insufficient treatment success and poor survival rates. The Sigma-2 receptor is preferentially expressed on many tumor cells making it an appealing target for therapy. Thus, we developed a potential targeted drug conjugate consisting of the Sigma-2 receptor ligand SW43 and Doxorubicin (SW43-DOX) for systemic cancer therapy and for locoregional treatment of primary and secondary liver malignancies when loaded onto drug-eluting bead (DEB) which was compared in vitro to the treatment with Doxorubicin alone. SW43-DOX binds specifically to the Sigma-2 receptor expressed on hepatocellular (Hep G2, Hep 3B), pancreatic (Panc-1) and colorectal (HT-29) carcinoma cell lines with high affinity and subsequent early specific internalization. Free SW43-DOX showed superior concentration and time depended cancer toxicity than treatment with Doxorubicin alone. Action mechanisms analysis revealed an apoptotic cell death with increased caspase 3/7 activation and reactive oxygen species (ROS) production. Only ROS scavenging with α-Tocopherol, but not the caspase inhibition (Z-VAD-FMK), partly reverted the effect. SW43-DOX could successfully be loaded onto DEB and showed prolonged eluting kinetics compared to Doxorubicin. SW43-DOX loaded DEB vs. Doxorubicin loaded DEB showed a significantly greater time dependent toxicity in all cell lines. In conclusion, the novel conjugate SW43-DOX ± loading onto DEB is a promising drug delivery platform for targeted systemic and locoregional cancer therapy. PMID:27262893

  18. Doxorubicin-Nanocarriers Enhance Doxorubicin Uptake and Clathrin-Mediated Endocytosis in Drug-Resistant Ovarian Cancer Cells

    NASA Astrophysics Data System (ADS)

    Abdullah, Mohammed

    We tested Fe3O4 TiO2 metal oxide core-shell nanocomposites as carriers for doxorubicin and investigated the distribution of "doxorubicin-nanocarriers" and free doxorubicin in doxorubicin-sensitive and -resistant ovarian cancer cell lines. We hypothesized that doxorubicin-nanocarriers (DOX-NCs) would increase doxorubicin uptake in a drug-resistant cell line. Our expectation was that doxorubicin would bind to the TiO2 surface either by a labile monodentate link or through adsorption and subsequent disassociation from the nanocomposite carriers upon acidification in cell endosomes. Released doxorubicin could then traverse the intracellular milieu to enter the cell nucleus, overcoming the p-glycoprotein mediated doxorubicin resistance. Using a combination of confocal fluorescent microscopy, flow cytometry, and X-ray fluorescence microscopy we were able to evaluate the uptake and distribution of doxorubicin-nanocarriers in cells. Moreover, we found that nanocomposite treatment modulates the simultaneous uptake and distribution of fluorescent transferrin in ovarian cancer cell lines. This increased transferrin uptake still occurred by clathrin-mediated endocytosis; it appears that the nanocomposites and DOX-NCs alike may interfere with trans-Golgi apparatus function.

  19. Cellulose conjugated FITC-labelled mesoporous silica nanoparticles: intracellular accumulation and stimuli responsive doxorubicin release.

    PubMed

    Hakeem, Abdul; Zahid, Fouzia; Duan, Ruixue; Asif, Muhammad; Zhang, Tianchi; Zhang, Zhenyu; Cheng, Yong; Lou, Xiaoding; Xia, Fan

    2016-03-01

    Herein, we design novel cellulose conjugated mesoporous silica nanoparticle (CLS-MSP) based nanotherapeutics for stimuli responsive intracellular doxorubicin (DOX) delivery. DOX molecules are entrapped in pores of the fabricated mesoporous silica nanoparticles (MSPs) while cellulose is used as an encapsulating material through esterification on the outlet of the pores of the MSPs to avoid premature DOX release under physiological conditions. In in vitro studies, stimuli responsive DOX release is successfully achieved from DOX loaded cellulose conjugated mesoporous silica nanoparticles (DOX/CLS-MSPs) by pH and cellulase triggers. Intracellular accumulation of DOX/CLS-MSPs in human liver cancer cells (HepG2 cells) is investigated through confocal microscope magnification. Cell viability of HepG2 cells is determined as the percentage of the cells incubated with DOX/CLS-MSPs compared with that of non-incubated cells through an MTT assay.

  20. A Multifunctional PB@mSiO2-PEG/DOX Nanoplatform for Combined Photothermal-Chemotherapy of Tumor.

    PubMed

    Su, Yun Yan; Teng, Zhaogang; Yao, Hui; Wang, Shou Ju; Tian, Ying; Zhang, Yun Lei; Liu, Wen Fei; Tian, Wei; Zheng, Li Juan; Lu, Nan; Ni, Qian Qian; Su, Xiao Dan; Tang, Yu Xia; Sun, Jing; Liu, Ying; Wu, Jiang; Yang, Gui Fen; Lu, Guang Ming; Zhang, Long Jiang

    2016-07-13

    In this work, we design mesoporous silica-coated Prussian blue nanocubes with PEGyltation to construct multifunctional PB@mSiO2-PEG nanocubes. The PB@mSiO2-PEG nanocubes have good biocompatibility, excellent photothermal transformation capacity, in vivo magnetic resonance and photoacoustic imaging ability. After loading antitumor drug doxorubicin (DOX) in the PB@mSiO2-PEG nanocubes, the constructured PB@mSiO2-PEG/DOX nanoplatforms show an excellent pH-responsive drug release character within 48 h, namely, an ultralow cumulative drug release amount of 3.1% at pH 7.4 and a high release amount of 46.6% at pH 5.0. Upon near-infrared laser irradiation, the PB@mSiO2-PEG/DOX nanoplatforms show an enhanced synergistic photothermal and chemical therapeutic efficacy for breast cancer than solo photothermal therapy or chemotherapy. PMID:27065014

  1. Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer.

    PubMed

    Zhang, Yumin; Yang, Cuihong; Wang, Weiwei; Liu, Jinjian; Liu, Qiang; Huang, Fan; Chu, Liping; Gao, Honglin; Li, Chen; Kong, Deling; Liu, Qian; Liu, Jianfeng

    2016-01-01

    Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff's base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff's base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy. PMID:26876480

  2. Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer

    NASA Astrophysics Data System (ADS)

    Zhang, Yumin; Yang, Cuihong; Wang, Weiwei; Liu, Jinjian; Liu, Qiang; Huang, Fan; Chu, Liping; Gao, Honglin; Li, Chen; Kong, Deling; Liu, Qian; Liu, Jianfeng

    2016-02-01

    Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff’s base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff’s base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.

  3. Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer

    PubMed Central

    Zhang, Yumin; Yang, Cuihong; Wang, Weiwei; Liu, Jinjian; Liu, Qiang; Huang, Fan; Chu, Liping; Gao, Honglin; Li, Chen; Kong, Deling; Liu, Qian; Liu, Jianfeng

    2016-01-01

    Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff’s base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff’s base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy. PMID:26876480

  4. Cellulose conjugated FITC-labelled mesoporous silica nanoparticles: intracellular accumulation and stimuli responsive doxorubicin release

    NASA Astrophysics Data System (ADS)

    Hakeem, Abdul; Zahid, Fouzia; Duan, Ruixue; Asif, Muhammad; Zhang, Tianchi; Zhang, Zhenyu; Cheng, Yong; Lou, Xiaoding; Xia, Fan

    2016-02-01

    Herein, we design novel cellulose conjugated mesoporous silica nanoparticle (CLS-MSP) based nanotherapeutics for stimuli responsive intracellular doxorubicin (DOX) delivery. DOX molecules are entrapped in pores of the fabricated mesoporous silica nanoparticles (MSPs) while cellulose is used as an encapsulating material through esterification on the outlet of the pores of the MSPs to avoid premature DOX release under physiological conditions. In in vitro studies, stimuli responsive DOX release is successfully achieved from DOX loaded cellulose conjugated mesoporous silica nanoparticles (DOX/CLS-MSPs) by pH and cellulase triggers. Intracellular accumulation of DOX/CLS-MSPs in human liver cancer cells (HepG2 cells) is investigated through confocal microscope magnification. Cell viability of HepG2 cells is determined as the percentage of the cells incubated with DOX/CLS-MSPs compared with that of non-incubated cells through an MTT assay.Herein, we design novel cellulose conjugated mesoporous silica nanoparticle (CLS-MSP) based nanotherapeutics for stimuli responsive intracellular doxorubicin (DOX) delivery. DOX molecules are entrapped in pores of the fabricated mesoporous silica nanoparticles (MSPs) while cellulose is used as an encapsulating material through esterification on the outlet of the pores of the MSPs to avoid premature DOX release under physiological conditions. In in vitro studies, stimuli responsive DOX release is successfully achieved from DOX loaded cellulose conjugated mesoporous silica nanoparticles (DOX/CLS-MSPs) by pH and cellulase triggers. Intracellular accumulation of DOX/CLS-MSPs in human liver cancer cells (HepG2 cells) is investigated through confocal microscope magnification. Cell viability of HepG2 cells is determined as the percentage of the cells incubated with DOX/CLS-MSPs compared with that of non-incubated cells through an MTT assay. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08753h

  5. pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel.

    PubMed

    Ma, Yakun; Fan, Xiaohui; Li, Lingbing

    2016-02-10

    A doxorubicin conjugated prodrug incorporated acid-sensitive linkage between drug and Pluronic F127-chitosan (F127-CS) polymer was successfully synthesized. Subsequently a pH-sensitive polymeric micelle system was designed based on the conjugated prodrugs (F127-CS-DOX) to co-deliver doxorubicin and paclitaxel. Paclitaxel (PTX) was physically entrapped in the hydrophobic inner core of the micelles simultaneously. The structures of conjugates were analyzed by means of (1)H NMR and UV-vis spectrum. Size distribution and morphology of the micelles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results indicated that obtained micelles had good dispersity and the diameter was between 56.3 and 403.4 nm. The loading of PTX into the micelle increased with higher DOX content. DOX and PTX release from polymeric micelles followed an acid-triggered manner. Furthermore, in vivo pharmacokinetic study also showed that the area under the plasma concentration time curve (AUC0-∞) values of PTX and DOX for PTX-loaded F127-CS-DOX micelles in rats were 3.97 and 4.38-fold higher than those for PTX plus DOX solution. These results suggested the PTX-loaded F127-CS-DOX micelles would be a promising carrier for co-delivering DOX and PTX. PMID:26686101

  6. Improved cytotoxicity and preserved level of cell death induced in colon cancer cells by doxorubicin after its conjugation with iron-oxide magnetic nanoparticles.

    PubMed

    Augustin, Ewa; Czubek, Bartłomiej; Nowicka, Anna M; Kowalczyk, Agata; Stojek, Zbigniew; Mazerska, Zofia

    2016-06-01

    A promising strategy for overcoming the problem of limited efficacy in antitumor drug delivery and in drug release is the use of a nanoparticle-conjugated drug. Doxorubicin (Dox) anticancer chemotherapeutics has been widely studied in this respect, because of severe cardiotoxic side effects. Here, we investigated the cytotoxic effects, the uptake process, the changes in cell cycle progression and the cell death processes in the presence of iron-oxide magnetic nanoparticles (Nps) and doxorubicin conjugates (Dox-Nps) in human colon HT29 cells. The amount of Dox participated in biological action of Dox-Nps was determined by cyclic voltammetry and thermogravimetric measurements. The cytotoxicity of Dox-Nps was shown to be two/three times higher than free Dox, whereas Nps alone did not inhibit cell proliferation. Dox-Nps penetrated cancer cells with higher efficacy than free Dox, what could be a consequence of Dox-Nps aggregation with proteins in culture medium and/or with cell surface. The treatment of HT29 cells with Dox-Nps and Dox at IC50 concentration resulted in G2/M arrest followed by late apoptosis and necrosis. Summing up, the application of iron-oxide magnetic nanoparticles improved Dox-Nps cell penetration compared to free Dox and achieved the cellular response to Dox-Nps conjugates similar to that of Dox alone. PMID:26911730

  7. Doxorubicin Cardiomyopathy

    PubMed Central

    Chatterjee, Kanu; Zhang, Jianqing; Honbo, Norman; Karliner, Joel S.

    2010-01-01

    Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered. PMID:20016174

  8. Poly(PEGA)-b-poly(L-lysine)-b-poly(L-histidine) Hybrid Vesicles for Tumoral pH-Triggered Intracellular Delivery of Doxorubicin Hydrochloride.

    PubMed

    Johnson, Renjith P; Uthaman, Saji; John, Johnson V; Lee, Hye Ri; Lee, Sang Joon; Park, Huiju; Park, In-Kyu; Suh, Hongsuk; Kim, Il

    2015-10-01

    A series of poly(ethylene glycol) methyl ether acrylate-block-poly(L-lysine)-block-poly(L-histidine) [p(PEGA)30-b-p(Lys)25-b-p(His)n] (n = 25, 50, 75, 100) triblock copolypeptides were designed and synthesized for tumoral pH-responsive intracellular release of anticancer drug doxorubicin hydrochloride (Dox). The tumoral acidic pH-responsive hybrid vesicles fabricated were stable at physiological pH 7.4 and could gradually destabilize in acidic pH as a result of pH-induced swelling of the p(His) block. The blank vesicles were nontoxic over a wide concentration range (0.01-100 μg/mL) in normal cell lines. The tumor acidic pH responsiveness of these vesicles was exploited for intracellular delivery of Dox. Vesicles efficiently encapsulated Dox, and pH-induced destabilization resulted in the controlled and sustained release of Dox in CT26 murine cancer cells, and dose-dependent cytotoxicity. The tumor-specific controlled release Dox from vesicles demonstrates this system represents a promising theranostic agent for tumor-targeted delivery. PMID:26375278

  9. Gp130-mediated STAT3 activation by S-propargyl-cysteine, an endogenous hydrogen sulfide initiator, prevents doxorubicin-induced cardiotoxicity.

    PubMed

    Wu, J; Guo, W; Lin, S-Z; Wang, Z-J; Kan, J-T; Chen, S-Y; Zhu, Y-Z

    2016-01-01

    Doxorubicin (Dox) could trigger a large amount of apoptotic cells in the myocardium, which leads to dilated cardiomyopathy and heart failure. S-propargyl-cysteine (SPRC), a producing agent of endogenous hydrogen sulfide (H2S), possesses cardioprotective efficacy. However, the specific effect and mechanism of SPRC in Dox-induced cardiotoxicity remain elusive. Given gp130 with its main downstream signaling molecule, signal transducer and activator of transcription 3 (STAT3), is involved in cardiac myocyte survival and growth; the present study was performed to elucidate whether SPRC counteracts Dox-induced cardiotoxicity, and if so, whether the gp130/STAT3 pathway is involved in this cardioprotective activity. SPRC stimulated the activation of STAT3 via gp130-mediated transduction tunnel in vitro and in vivo. In Dox-stimulated cardiotoxicity, SPRC enhanced cell viability, restored expression of gp130/STAT3-regulated downstream genes, inhibited apoptosis and oxidative stress, and antagonized mitochondrial dysfunction and intracellular Ca(2+) overload. Intriguingly, blockade of gp130/STAT3 signaling abrogated all these beneficial capacities of SPRC. Our findings present the first piece of evidence for the therapeutic properties of SPRC in alleviating Dox cardiotoxicity, which could be attributed to the activation of gp130-mediated STAT3 signaling. This will offer a novel molecular basis and therapeutic strategy of H2S donor for the treatment of heart failure. PMID:27537522

  10. Luteinizing hormone-releasing hormone targeted poly(methyl vinyl ether maleic acid) nanoparticles for doxorubicin delivery to MCF-7 breast cancer cells.

    PubMed

    Varshosaz, Jaleh; Jahanian-Najafabadi, Ali; Ghazzavi, Jila

    2016-08-01

    The purpose of this study was to design a targeted anti-cancer drug delivery system for breast cancer. Therefore, doxorubicin (DOX) loaded poly(methyl vinyl ether maleic acid) nanoparticles (NPs) were prepared by ionic cross-linking method using Zn(2+) ions. To optimise the effect of DOX/polymer ratio, Zn/polymer ratio, and stirrer rate a full factorial design was used and their effects on particle size, zeta potential, loading efficiency (LE, %), and release efficiency in 72 h (RE72, %) were studied. Targeted NPs were prepared by chemical coating of tiptorelin/polyallylamin conjugate on the surface of NPs by using 1-ethyl-3-(3-dimethylaminopropyl) carboiimid HCl as cross-linking agent. Conjugation efficiency was measured by Bradford assay. Conjugated triptorelin and targeted NPs were studied by Fourier-transform infrared spectroscopy (FTIR). The cytotoxicity of DOX loaded in targeted NPs and non-targeted ones were studied on MCF-7 cells which overexpress luteinizing hormone-releasing hormone (LHRH) receptors and SKOV3 cells as negative LHRH receptors using Thiazolyl blue tetrazolium bromide assay. The best results obtained from NPs prepared by DOX/polymer ratio of 5%, Zn/polymer ratio of 50%, and stirrer rate of 960 rpm. FTIR spectrum confirmed successful conjugation of triptorelin to NPs. The conjugation efficiency was about 70%. The targeted NPs showed significantly less IC50 for MCF-7 cells compared to free DOX and non-targeted NPs. PMID:27463791

  11. Preparation and Characterization of Lipophilic Doxorubicin Pro-drug Micelles.

    PubMed

    Li, Feng; Snow-Davis, Candace; Du, Chengan; Bondarev, Mikhail L; Saulsbury, Marilyn D; Heyliger, Simone O

    2016-01-01

    Micelles have been successfully used for the delivery of anticancer drugs. Amphiphilic polymers form core-shell structured micelles in an aqueous environment through self-assembly. The hydrophobic core of micelles functions as a drug reservoir and encapsulates hydrophobic drugs. The hydrophilic shell prevents the aggregation of micelles and also prolongs their systemic circulation in vivo. In this protocol, we describe a method to synthesize a doxorubicin lipophilic pro-drug, doxorubicin-palmitic acid (DOX-PA), which will enhance drug loading into micelles. A pH-sensitive hydrazone linker was used to conjugate doxorubicin with the lipid, which facilitates the release of free doxorubicin inside cancer cells. Synthesized DOX-PA was purified with a silica gel column using dichloromethane/methanol as the eluent. Purified DOX-PA was analyzed with thin layer chromatography (TLC) and (1)H-Nuclear Magnetic Resonance Spectroscopy ((1)H-NMR). A film dispersion method was used to prepare DOX-PA loaded DSPE-PEG micelles. In addition, several methods for characterizing micelle formulations are described, including determination of DOX-PA concentration and encapsulation efficiency, measurement of particle size and distribution, and assessment of in vitro anticancer activities. This protocol provides useful information regarding the preparation and characterization of drug-loaded micelles and thus will facilitate the research and development of novel micelle-based cancer nanomedicines. PMID:27584689

  12. Impact of dendrimer surface functional groups on the release of doxorubicin from dendrimer carriers.

    PubMed

    Zhang, Mengen; Guo, Rui; Kéri, Mónika; Bányai, István; Zheng, Yun; Cao, Mian; Cao, Xueyan; Shi, Xiangyang

    2014-02-13

    Generation 5 (G5) poly(amidoamine) dendrimers with acetyl (G5.NHAc), glycidol hydroxyl (G5.NGlyOH), and succinamic acid (G5.SAH) terminal groups were used to physically encapsulate an anticancer drug doxorubicin (DOX). Both UV-vis spectroscopy and multiple NMR techniques including one-dimensional NMR and two-dimensional NMR were applied to investigate the interactions between different dendrimers and DOX. The influence of the surface functional groups of G5 dendrimers on the DOX encapsulation, release kinetics, and cancer cell inhibition effect was investigated. We show that all three types of dendrimers are able to effectively encapsulate DOX and display therapeutic inhibition effect to cancer cells, which is solely associated with the loaded DOX. The relatively stronger interactions of G5.NHAc or G5.NGlyOH dendrimers with DOX than that of G5.SAH dendrimers with DOX demonstrated by NMR techniques correlate well with the slow release rate of DOX from G5.NHAc/DOX or G5.NGlyOH/DOX complexes. In contrast, the demonstrated weak interaction between G5.SAH and DOX causes a fast release of DOX, suggesting that the G5.SAH/DOX complex may not be a proper option for further in vivo research. Our findings suggest that the dendrimer surface functional groups are crucial for further design of multifunctional dendrimer-based drug delivery systems for various biomedical applications.

  13. Versatile preparation of intracellular-acidity-sensitive oxime-linked polysaccharide-doxorubicin conjugate for malignancy therapeutic.

    PubMed

    Xu, Weiguo; Ding, Jianxun; Xiao, Chunsheng; Li, Lingyu; Zhuang, Xiuli; Chen, Xuesi

    2015-06-01

    Recently, chemotherapy has been one of the most important therapeutic approaches for malignant tumors. The tumor tissular or intracellular microenvironment-sensitive polymer-doxorubicin (DOX) conjugates demonstrate great potential for improved antitumor efficacy and reduced side effects. In this work, the acid-sensitive dextran-DOX conjugate (noted as Dex-O-DOX) was synthesized through the versatile efficient oximation reaction between the terminal aldehyde group of polysaccharide and the amino group in DOX in the buffer solution of sodium acetate/acetic acid. The insensitive one, i.e., Dex-b-DOX, was prepared similarly as Dex-O-DOX with a supplemented reduction reaction. The DOX release from Dex-O-DOX was pH-dependent and accelerated by the decreased pH. The efficient intracellular DOX release from Dex-O-DOX toward the human hepatoma HepG2 cells was further confirmed. Furthermore, Dex-O-DOX exhibited a closer antiproliferative activity to free DOX·HCl as the extension of time. More importantly, compared with Dex-b-DOX, Dex-O-DOX exhibited higher antitumor activity and lower toxicity, which were further confirmed by the systemic histological and immunohistochemical analyses. Hence, the facilely prepared smart polysaccharide-DOX conjugates, i.e., Dex-O-DOX, exhibited great potential in the clinical chemotherapy of malignancy.

  14. Versatile preparation of intracellular-acidity-sensitive oxime-linked polysaccharide-doxorubicin conjugate for malignancy therapeutic.

    PubMed

    Xu, Weiguo; Ding, Jianxun; Xiao, Chunsheng; Li, Lingyu; Zhuang, Xiuli; Chen, Xuesi

    2015-06-01

    Recently, chemotherapy has been one of the most important therapeutic approaches for malignant tumors. The tumor tissular or intracellular microenvironment-sensitive polymer-doxorubicin (DOX) conjugates demonstrate great potential for improved antitumor efficacy and reduced side effects. In this work, the acid-sensitive dextran-DOX conjugate (noted as Dex-O-DOX) was synthesized through the versatile efficient oximation reaction between the terminal aldehyde group of polysaccharide and the amino group in DOX in the buffer solution of sodium acetate/acetic acid. The insensitive one, i.e., Dex-b-DOX, was prepared similarly as Dex-O-DOX with a supplemented reduction reaction. The DOX release from Dex-O-DOX was pH-dependent and accelerated by the decreased pH. The efficient intracellular DOX release from Dex-O-DOX toward the human hepatoma HepG2 cells was further confirmed. Furthermore, Dex-O-DOX exhibited a closer antiproliferative activity to free DOX·HCl as the extension of time. More importantly, compared with Dex-b-DOX, Dex-O-DOX exhibited higher antitumor activity and lower toxicity, which were further confirmed by the systemic histological and immunohistochemical analyses. Hence, the facilely prepared smart polysaccharide-DOX conjugates, i.e., Dex-O-DOX, exhibited great potential in the clinical chemotherapy of malignancy. PMID:25907041

  15. Free DOX and chitosan-N-arginine conjugate stabilized indocyanine green nanoparticles for combined chemophotothermal therapy.

    PubMed

    Jheng, Pei-Ru; Lu, Kun-Ying; Yu, Shu-Huei; Mi, Fwu-Long

    2015-12-01

    Indocyanine green (ICG) is a FDA-approved near-infrared (NIR) cyanine dye used in medical diagnostics. However, the utility of ICG remains limited by its unstable optical property, and concentration-dependent aggregation and precipitation. A chitosan-arginine conjugate (CS-N-Arg) was developed to increase the stability of ICG in physiological buffer saline via formation of strong electrostatic interactions between ICG and CS-N-Arg. The CS-N-Arg/ICG complex prevented ICG from aggregation and precipitation, thus it could serve as a theranostic nanomaterial for image-guided photothermal cancer therapy. The CS-N-Arg/ICG NPs showed excellent photostability, clear fluorescent images, and rapid temperature rise under laser irradiation. Cell viability assay indicated that CS-N-Arg/ICG NPs could efficiently suppress the growth of doxorubicin (DOX) resistant breast cancer cell (MCF-7/ADR cells) under NIR photothermal treatments. In combination of DOX with CS-N-Arg/ICG NPs, a combined effect was observed in MCF-7/ADR breast cancer cells due to dual hyperthermia and chemical therapeutic effects. The present observations suggest that CS-N-Arg/ICG NPs can effectively deliver ICG molecules to MCF-7/ADR breast cancer cells and overcome DOX resistance in the cells by hyperthermia.

  16. Chemosensetizing and cardioprotective effects of resveratrol in doxorubicin- treated animals

    PubMed Central

    2013-01-01

    Background Doxorubicin (DOX), an anthracycline antibiotic is one of the most effective anticancer drug used in the treatment of variety of cancers .Its use is limited by its cardiotoxicity. The present study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of mammary carcinoma (Ehrlich ascites carcinoma) to the action of DOX and at the same time its protective effect against DOX-induced cardiotoxicity in rats. Methods Ehrlich ascites carcinoma bearing mice were used in this study. Percent survival of tumor bearing mice was used for determination of the Cytotoxic activity of DOX in presence and absence of RSVL. Uptake and cell cycle effect of DOX in tumor cells in the presence of RSVL was also determined. Histopatholgical examination of heart tissues after DOX and/or RSVL therapy was also investigated. Results DOX at a dose level of 15 mg/kg increased the mean survival time of tumor bearing mice to 21 days compared with 15 days for non tumor-bearing control mice. Administration of RSVL at a dose level of 10 mg/kg simultaneously with DOX increased the mean survival time to 30 days with 70% survival of the tumor-bearing animals. RSVL increased the intracellular level of DOX and there was a strong correlation between the high cellular level of DOX and its cytotoxic activity. Moreover, RSVL treatment showed 4.8 fold inhibition in proliferation index of cells treated with DOX. Histopathological analysis of rat heart tissue after a single dose of DOX (20 mg/kg) showed myocytolysis with congestion of blood vessels, cytoplasmic vacuolization and fragmentation. Concomitant treatment with RSVL, fragmentation of the muscle fiber revealed normal muscle fiber. Conclusion This study suggests that RSVL could increase the cytotoxic activity of DOX and at the same time protect against its cardiotoxicity. PMID:23714221

  17. Anti-miR21 oligonucleotide enhances chemosensitivity of T98G cell line to doxorubicin by inducing apoptosis.

    PubMed

    Giunti, Laura; da Ros, Martina; Vinci, Serena; Gelmini, Stefania; Iorio, Anna Lisa; Buccoliero, Anna Maria; Cardellicchio, Stefania; Castiglione, Francesca; Genitori, Lorenzo; de Martino, Maurizio; Giglio, Sabrina; Genuardi, Maurizio; Sardi, Iacopo

    2015-01-01

    Various signal transduction pathways seem to be involved in chemoresistance mechanism of glioblastomas (GBMs). miR-21 is an important oncogenic miRNA which modulates drug resistance of tumor cells. We analyzed the expression of 5 miRNAs, previously found to be dysregulated in high grade gliomas, in 9 pediatric (pGBM) and in 5 adult (aGBM) GBMs. miR-21 was over-expressed, with a significant difference between pGBMs and aGBMs represented by a 4 times lower degree of expression in the pediatric compared to the adult series (p = 0.001). Doxorubicin (Dox) seems to be an effective anti-glioma agent with high antitumor activity also against glioblastoma stem cells. We therefore evaluated the chemosensitivity to Dox in 3 GBM cell lines (A172, U87MG and T98G). Dox had a cytotoxic effect after 48 h of treatment in A172 and U87MG, while T98G cells were resistant. TUNEL assay verified that Dox induced apoptosis in A172 and U87MG but not in T98G. miR-21 showed a low basal expression in treated cells and was over-expressed in untreated cells. To validate the possible association of miR-21 with drug resistance of T98G cells, we transfected anti-miR-21 inhibitor into the cells. The expression level of miR-21 was significantly lower in T98G transfected cells (than in the parental control cells). Transfected cells showed a high apoptotic rate compared to control after Dox treatment by TUNEL assay, suggesting that combined Dox and miR-21 inhibitor therapy can sensitize GBM resistant cells to anthracyclines by enhancing apoptosis. PMID:25628933

  18. Deficiency in Cardiolipin Reduces Doxorubicin-Induced Oxidative Stress and Mitochondrial Damage in Human B-Lymphocytes

    PubMed Central

    Aryal, Baikuntha; Rao, V. Ashutosh

    2016-01-01

    Cardiolipin (CL) is an inner mitochondrial membrane phospholipid which plays an important role in mitochondrial function. Perturbation in CL biosynthesis alters mitochondrial bioenergetics causing a severe genetic disorder commonly known as Barth syndrome. Barth syndrome patients are known to have a reduced concentration and altered composition of CL. Cardiolipin is also known to have a high affinity for the chemotherapeutic agent doxorubicin (Dox), resulting in an extensive mitochondrial accumulation of the drug. Our results indicate that B-lymphocytes from healthy individuals are more sensitive to Dox-induced oxidative stress and cellular toxicity compared to the B-lymphocytes from Barth syndrome as indicated by greater cell death and greater level of cleaved caspase-3 following Dox treatment. Barth lymphocytes, when compared to healthy lymphocytes, showed a greater basal level of mitochondrial reactive oxygen species (mito-ROS), yet exhibited a lower level of induced mito-ROS production in response to Dox. Significantly less ATP content and slightly greater OXPHOS protein levels were detected in healthy cells compared to Barth cells after Dox treatment. Consistent with greater mitochondrial ROS, treatment with Dox induced a higher level of lipid peroxidation and protein carbonylation in healthy lymphocytes compared to Barth lymphocytes. The final remodeling of CL during CL synthesis is catalyzed by the tafazzin protein. Knockdown of tafazzin gene in H9c2 cardiomyocytes using siRNA showed decreased oxidant-induced damage, as observed in Barth lymphocytes. Our findings demonstrate that a deficiency in CL might provide a therapeutic advantage in favor of oxidant-induced anticancer activities. PMID:27434059

  19. Anti-miR21 oligonucleotide enhances chemosensitivity of T98G cell line to doxorubicin by inducing apoptosis

    PubMed Central

    Giunti, Laura; da Ros, Martina; Vinci, Serena; Gelmini, Stefania; Iorio, Anna Lisa; Buccoliero, Anna Maria; Cardellicchio, Stefania; Castiglione, Francesca; Genitori, Lorenzo; de Martino, Maurizio; Giglio, Sabrina; Genuardi, Maurizio; Sardi, Iacopo

    2015-01-01

    Various signal transduction pathways seem to be involved in chemoresistance mechanism of glioblastomas (GBMs). miR-21 is an important oncogenic miRNA which modulates drug resistance of tumor cells. We analyzed the expression of 5 miRNAs, previously found to be dysregulated in high grade gliomas, in 9 pediatric (pGBM) and in 5 adult (aGBM) GBMs. miR-21 was over-expressed, with a significant difference between pGBMs and aGBMs represented by a 4 times lower degree of expression in the pediatric compared to the adult series (p = 0.001). Doxorubicin (Dox) seems to be an effective anti-glioma agent with high antitumor activity also against glioblastoma stem cells. We therefore evaluated the chemosensitivity to Dox in 3 GBM cell lines (A172, U87MG and T98G). Dox had a cytotoxic effect after 48 h of treatment in A172 and U87MG, while T98G cells were resistant. TUNEL assay verified that Dox induced apoptosis in A172 and U87MG but not in T98G. miR-21 showed a low basal expression in treated cells and was over-expressed in untreated cells. To validate the possible association of miR-21 with drug resistance of T98G cells, we transfected anti-miR-21 inhibitor into the cells. The expression level of miR-21 was significantly lower in T98G transfected cells (than in the parental control cells). Transfected cells showed a high apoptotic rate compared to control after Dox treatment by TUNEL assay, suggesting that combined Dox and miR-21 inhibitor therapy can sensitize GBM resistant cells to anthracyclines by enhancing apoptosis. PMID:25628933

  20. Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity

    PubMed Central

    Biswas, Swati; Dodwadkar, Namita S.; Deshpande, Pranali P.; Parab, Shruti; Torchilin, Vladimir P.

    2014-01-01

    Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL® or Lipodox®) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol–dioleoyl phosphatidylethanolamine (PEG–DOPE) amphiphilic co-polymer. The resultant R8–PEG–PE conjugate was introduced into the lipid bilayer of liposomes at 2 mol% of total lipid amount via spontaneous micelle-transfer technique. The liposomal modification did not alter the particle size distribution, as measured by Particle Size Analyzer and transmission electron microscopy (TEM). However, surface-associated cationic peptide increased zeta potential of the modified liposomes. R8-functionalized liposomes (R8-Dox-L) markedly increased the intracellular and intratumoral delivery of doxorubicin as measured by flow cytometry and visualizing by confocal laser scanning microscopy (CLSM) compared to unmodified Doxorubicin-loaded PEGylated liposomes (Dox-L). R8-Dox-L delivered loaded Doxorubicin to the nucleus, being released from the endosomes at higher efficiency compared to unmodified liposomes, which had marked entrapment in the endosomes at tested time point of 1 h. The significantly higher accumulation of loaded drug to its site of action for R8-Dox-L resulted in improved cytotoxic activity in vitro (cell viability of 58.5 ± 7% for R8-Dox-L compared to 90.6 ± 2% for Dox-L at Dox dose of 50 μg/mL for 4 h followed by 24 h incubation) and enhanced suppression of tumor growth (348 ± 53 mm3 for R8-Dox-L, compared to 504 ± 54 mm3 for Dox-L treatment) in vivo compared to Dox-L. R8-modification has the potential for broadening the therapeutic window of pegylated liposomal doxorubicin treatment, which could lead to lower non-specific toxicity. PMID:23333899

  1. Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity.

    PubMed

    Biswas, Swati; Dodwadkar, Namita S; Deshpande, Pranali P; Parab, Shruti; Torchilin, Vladimir P

    2013-08-01

    Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL or Lipodox) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol-dioleoyl phosphatidylethanolamine (PEG-DOPE) amphiphilic co-polymer. The resultant R8-PEG-PE conjugate was introduced into the lipid bilayer of liposomes at 2 mol% of total lipid amount via spontaneous micelle-transfer technique. The liposomal modification did not alter the particle size distribution, as measured by Particle Size Analyzer and transmission electron microscopy (TEM). However, surface-associated cationic peptide increased zeta potential of the modified liposomes. R8-functionalized liposomes (R8-Dox-L) markedly increased the intracellular and intratumoral delivery of doxorubicin as measured by flow cytometry and visualizing by confocal laser scanning microscopy (CLSM) compared to unmodified Doxorubicin-loaded PEGylated liposomes (Dox-L). R8-Dox-L delivered loaded Doxorubicin to the nucleus, being released from the endosomes at higher efficiency compared to unmodified liposomes, which had marked entrapment in the endosomes at tested time point of 1h. The significantly higher accumulation of loaded drug to its site of action for R8-Dox-L resulted in improved cytotoxic activity in vitro (cell viability of 58.5 ± 7% for R8-Dox-L compared to 90.6 ± 2% for Dox-L at Dox dose of 50 μg/mL for 4h followed by 24h incubation) and enhanced suppression of tumor growth (348 ± 53 mm(3) for R8-Dox-L, compared to 504 ± 54 mm(3) for Dox-L treatment) in vivo compared to Dox-L. R8-modification has the potential for broadening the therapeutic window of pegylated liposomal doxorubicin treatment, which could lead to lower non-specific toxicity. PMID:23333899

  2. Modeling localized delivery of Doxorubicin to the brain following focused ultrasound enhanced blood-brain barrier permeability

    NASA Astrophysics Data System (ADS)

    Nhan, Tam; Burgess, Alison; Lilge, Lothar; Hynynen, Kullervo

    2014-10-01

    Doxorubicin (Dox) is a well-established chemotherapeutic agent, however it has limited efficacy in treating brain malignancies due to the presence of the blood-brain barrier (BBB). Recent preclinical studies have demonstrated that focused ultrasound induced BBB disruption (BBBD) enables efficient delivery of Dox to the brain. For future treatment planning of BBBD-based drug delivery, it is crucial to establish a mathematical framework to predict the effect of transient BBB permeability enhancement on the spatiotemporal distribution of Dox at the targeted area. The constructed model considers Dox concentrations within three compartments (plasma, extracellular, intracellular) that are governed by various transport processes (e.g. diffusion in interstitial space, exchange across vessel wall, clearance by cerebral spinal fluid, uptake by brain cells). By examining several clinical treatment aspects (e.g. sonication scheme, permeability enhancement, injection mode), our simulation results support the experimental findings of optimal interval delay between two consecutive sonications and therapeutically-sufficient intracellular concentration with respect to transfer constant Ktrans range of 0.01-0.03 min-1. Finally, the model suggests that infusion over a short duration (20-60 min) should be employed along with single-sonication or multiple-sonication at 10 min interval to ensure maximum delivery to the intracellular compartment while attaining minimal cardiotoxicity via suppressing peak plasma concentration.

  3. Hydrogen-containing saline attenuates doxorubicin-induced heart failure in rats.

    PubMed

    Wu, Shujing; Zhu, Liqun; Yang, Jing; Fan, Zhixin; Dong, Yanli; Luan, Rui; Cai, Jingjing; Fu, Lu

    2014-08-01

    Interactions between doxorubicin (DOX) and iron generate reactive oxygen species and contribute to DOX-induced heart failure. Hydrogen, as a selective antioxidant, is a promising potential therapeutic option for the treatment of a variety of diseases. Therefore, we investigated the preventive effects of hydrogen treatment on DOX-induced heart failure in rats. We found that cardiac function was significantly improved and that the plasma levels of oxidative-stress markers and myocardial autophagic activity were decreased in animals treated with hydrogen-containing saline. Therefore, we conclude that hydrogen-containing saline may have beneficial effects for doxorubicin-induced heart failure.

  4. Fabrication of doxorubicin and heparin co-loaded microcapsules for synergistic cancer therapy.

    PubMed

    Chen, Jing-Xiao; Liang, Yan; Liu, Wen; Huang, Jin; Chen, Jing-Hua

    2014-08-01

    In this study, a layer-by-layer (LbL) assembly (HEP/CHI)5 microcapsule with doxorubicin hydrochloride (DOX) encapsulating inside was fabricated via alternatively depositing heparin (HEP) and chitosan (CHI) onto DOX-loaded CaCO3 templates. The microcapsules were of stable architecture and had good dispersity in aqueous medium. Fluorescence observation showed that DOX distributed both in the wall and in the cavity of microcapsules, while HEP presented in the capsule wall. The release rate of DOX increased at acidic pH as compared with that at basic pH, suggesting a pH-responsive drug release behavior. The microcapsules with positively charged CHI lying on the outer layer could protect HEP from heparanase degradation and achieve intracellular co-delivery of both DOX and HEP. Thus, the DOX-loaded microcapsules could have improved inhibition activity against A549 cells by combining pharmacological actions of DOX and HEP. PMID:24954272

  5. Mechanisms of cardioprotective effect of aged garlic extract against Doxorubicin-induced cardiotoxicity.

    PubMed

    Alkreathy, Huda M; Damanhouri, Zoheir A; Ahmed, Nessar; Slevin, Mark; Osman, Abdel-Moneim M

    2012-12-01

    Aged garlic has been extensively studied and has been shown to have a number of medicinal properties, including immunomodulatory, hepatoprotective, antimutagenic, anticarcinogenic, and antioxidant effects. The objective of this study was to investigate the mechanisms of the cardioprotective effect of aged garlic extract (AGE), a widely used herbal medicine with potent antioxidant activity, against doxorubicin-induced cardiotoxicity. Moreover, the study investigated if the cardioprotective effect of AGE might be at the expense of the antitumor effect of the anticancer drug doxorubicin (DOX). Primary cultured neonatal rat cardiac myocytes were treated with DOX, AGE, and their combination for 24 hours. DOX increased p53 and caspase 3 activity-induced apoptotic cell death, whereas AGE pretreatment suppressed the action of DOX. AGE pretreatment did not interfere with the cytotoxic activity of DOX, but it increased the DOX uptake into tumor cells and increased the long term survivors of tumor-bearing mice from 30% to 70%. In conclusion, DOX impairs viability of cardiac myocytes, at least partially by activating the p53-mediated apoptotic signaling. AGE can effectively and extensively counteract this action of DOX and may potentially protect the heart from severe toxicity of DOX. At the same time, AGE did not interfere with antitumor activity of DOX. PMID:22172987

  6. Enhancing Anti-Tumor Efficacy of Doxorubicin by Non-Covalent Conjugation to Gold Nanoparticles – In Vitro Studies on Feline Fibrosarcoma Cell Lines

    PubMed Central

    Wójcik, Michał; Lewandowski, Wiktor; Król, Magdalena; Pawłowski, Karol; Mieczkowski, Józef; Lechowski, Roman; Zabielska, Katarzyna

    2015-01-01

    Background Feline injection-site sarcomas are malignant skin tumors of mesenchymal origin, the treatment of which is a challenge for veterinary practitioners. Methods of treatment include radical surgery, radiotherapy and chemotherapy. The most commonly used cytostatic drugs are cyclophosphamide, doxorubicin and vincristine. However, the use of cytostatics as adjunctive treatment is limited due to their adverse side-effects, low biodistribution after intravenous administration and multidrug resistance. Colloid gold nanoparticles are promising drug delivery systems to overcome multidrug resistance, which is a main cause of ineffective chemotherapy treatment. The use of colloid gold nanoparticles as building blocks for drug delivery systems is preferred due to ease of surface functionalization with various molecules, chemical stability and their low toxicity. Methods Stability and structure of the glutathione-stabilized gold nanoparticles non-covalently modified with doxorubicin (Au-GSH-Dox) was confirmed using XPS, TEM, FT-IR, SAXRD and SAXS analyses. MTT assay, Annexin V and Propidium Iodide Apoptosis assay and Rhodamine 123 and Verapamil assay were performed on 4 feline fibrosarcoma cell lines (FFS1WAW, FFS1, FFS3, FFS5). Statistical analyses were performed using Graph Pad Prism 5.0 (USA). Results A novel approach, glutathione-stabilized gold nanoparticles (4.3 +/- 1.1 nm in diameter) non-covalently modified with doxorubicin (Au-GSH-Dox) was designed and synthesized. A higher cytotoxic effect (p<0.01) of Au-GSH-Dox than that of free doxorubicin has been observed in 3 (FFS1, FFS3, FFS1WAW) out of 4 feline fibrosarcoma cell lines. The effect has been correlated to the activity of glycoprotein P (main efflux pump responsible for multidrug resistance). Conclusions The results indicate that Au-GSH-Dox may be a potent new therapeutic agent to increase the efficacy of the drug by overcoming the resistance to doxorubicin in feline fibrosarcoma cell lines. Moreover, as

  7. Doxorubicin nanoconjugates.

    PubMed

    Deepa, Kannan; Singha, Siddhartha; Panda, Tapobrata

    2014-01-01

    Doxorubicin is one of the most widely administered drugs for treatment of cancer. The shortcomings commonly encountered with this drug are severe cardiotoxicity, narrow therapeutic indices, and the development of multiple drug resistance. Hence, several nanoparticulate drug delivery systems have been designed to overcome these limitations and to improvise the overall therapeutic efficacy of doxorubicin. This review outlines the doxorubicin delivery systems, viz., metals and metal oxide nanoparticles, carbon nanotubes, liposomes, nanoparticles of solid lipid materials, lipid microemulsions, polymer-based nanoparticles, protein-attached nanoparticles, polysaccharide nanoparticles, functional polymers, and nanoparticles of virus. PMID:24730306

  8. Doxorubicin nanoconjugates.

    PubMed

    Deepa, Kannan; Singha, Siddhartha; Panda, Tapobrata

    2014-01-01

    Doxorubicin is one of the most widely administered drugs for treatment of cancer. The shortcomings commonly encountered with this drug are severe cardiotoxicity, narrow therapeutic indices, and the development of multiple drug resistance. Hence, several nanoparticulate drug delivery systems have been designed to overcome these limitations and to improvise the overall therapeutic efficacy of doxorubicin. This review outlines the doxorubicin delivery systems, viz., metals and metal oxide nanoparticles, carbon nanotubes, liposomes, nanoparticles of solid lipid materials, lipid microemulsions, polymer-based nanoparticles, protein-attached nanoparticles, polysaccharide nanoparticles, functional polymers, and nanoparticles of virus.

  9. Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance

    PubMed Central

    Yan, Fengjiao; Sun, Mingna; Du, Lingran; Peng, Wei; Li, Qiuli; Feng, Yinghong; Zhou, Yi

    2015-01-01

    Resistance to treatment with anticancer drugs is a significant obstacle and a fundamental cause of therapeutic failure in cancer therapy. Functional doxorubicin (DOX) nanoparticles for targeted delivery of the classical cytotoxic anticancer drug DOX to tumor cells, using folate-terminated polyrotaxanes along with dequalinium, have been developed and proven to overcome this resistance due to specific molecular features, including a size of approximately 101 nm, a zeta potential of 3.25 mV and drug-loading content of 18%. Compared with free DOX, DOX hydrochloride, DOX nanoparticles, and targeted DOX nanoparticles, the functional DOX nanoparticles exhibited the strongest anticancer efficacy in vitro and in the drug-resistant MCF-7/ Adr (DOX) xenograft tumor model. More specifically, the nanoparticles significantly increased the intracellular uptake of DOX, selectively accumulating in mitochondria and the endoplasmic reticulum after treatment, with release of cytochrome C as a result. Furthermore, the caspase-9 and caspase-3 cascade was activated by the functional DOX nanoparticles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the antiapoptotic protein Bcl-2, thereby enhancing apoptosis by acting on the mitochondrial signaling pathways. In conclusion, functional DOX nanoparticles may provide a strategy for increasing the solubility of DOX and overcoming multidrug-resistant cancers. PMID:25605018

  10. Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

    NASA Astrophysics Data System (ADS)

    Deng, Senyi; Wu, Qinjie; Zhao, Yuwei; Zheng, Xin; Wu, Ni; Pang, Jing; Li, Xuejing; Bi, Cheng; Liu, Xinyu; Yang, Li; Liu, Lei; Su, Weijun; Wei, Yuquan; Gong, Changyang

    2015-03-01

    Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti-tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti-tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy.

  11. High-intensity focused ultrasound-mediated doxorubicin delivery with thermosensitive liposomes

    NASA Astrophysics Data System (ADS)

    Escoffre, Jean-Michel; Mannaris, Christophoros; Novell, Anthony; Rioc, Laëtitia; Meyre, Marie-Edith; Germain, Matthieu; Averkiou, Michalakis; Bouakaz, Ayache

    2012-10-01

    Local drug delivery of doxorubicin holds promise to improve the therapeutic efficacy and to reduce toxicity profiles. Here, we investigated the release of doxorubicin from thermosensitive liposomes (Dox-TSL) into human glioblastoma (U-87MG) cells. Using Dox-TSL, experiments were carried out in a water bath and showed that 15 min incubation of TSL at 43°C induced the release of 80% doxorubicin loaded TSL compared to the release at 37°C. The cytotoxicity of a range of concentrations of Dox-TSL was also evaluated on U-87MG cells. At 37°C, no cytotoxicity was observed, whereas at 43°C the results showed that the cytotoxicity is dose dependent. At maximal dose of doxorubicin (30 μg/mL), the cell viability was less than 20%. Application of 15 min of HIFU at 1 MHz, 1.5 MPa and 50% duty cycle induced the release of 100% of doxorubicin from Dox-TSL. In the same experimental condition, the cell viability decreased to 40% and 20% at 12h and 48h, respectively, in comparison to that obtained during the incubation of cells with Dox-TSL alone without HIFU. In conclusion, a significant release of doxorubicin from temperature-sensitive liposomes can be achieved leading to an efficient treatment and cell death of tumor cells using HIFU.

  12. Raman micro spectroscopy for in vitro drug screening: subcellular localisation and interactions of doxorubicin.

    PubMed

    Farhane, Z; Bonnier, F; Casey, A; Byrne, H J

    2015-06-21

    Vibrational spectroscopy, including Raman micro spectroscopy, has been widely used over the last few years to explore potential biomedical applications. Indeed, Raman micro spectroscopy has been demonstrated to be a powerful non-invasive tool in cancer diagnosis and monitoring. In confocal microscopic mode, the technique is also a molecularly specific analytical tool with optical resolution which has potential applications in subcellular analysis of biochemical processes, and therefore as an in vitro screening tool of the efficacy and mode of action of, for example, chemotherapeutic agents. In order to demonstrate and explore the potential in this field, established, model chemotherapeutic agents can be valuable. In this study paper, Raman micro spectroscopy coupled with confocal microscopy were used for the localization and tracking of the commercially available drug, doxorubicin (DOX), in the intracellular environment of the lung cancer cell line, A549. Cytotoxicity assays were employed to establish clinically relevant drug doses for 24 h exposure, and Confocal Laser Scanning Fluorescence Microscopy was conducted in parallel with Raman micro spectroscopy profiling to confirm the drug internalisation and localisation. Multivariate statistical analysis, consisting of PCA (principal components analysis) was used to highlight doxorubicin interaction with cancer cells and spectral variations due to its effects before and after DOX spectral features subtraction from nuclear and nucleolar spectra, were compared to non-exposed control spectra. Results show that Raman micro spectroscopy is not only able to detect doxorubicin inside cells and profile its specific subcellular localisation, but, it is also capable of elucidating the local biomolecular changes elicited by the drug, differentiating the responses in different sub cellular regions. Further analysis clearly demonstrates the early apoptotic effect in the nuclear regions and the initial responses of cells to this

  13. Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training.

    PubMed

    Calvé, Annie; Haddad, Rami; Barama, Sarah-Neiel; Meilleur, Melissa; Sebag, Igal A; Chalifour, Lorraine E

    2012-05-15

    The impact of cancer therapies on adult cardiac function is becoming a concern as more children survive their initial cancer. Cardiovascular disease is now a significant problem to adult survivors of childhood cancer. Specifically, doxorubicin (DOX) may be particularly harmful in young girls. The objective of this study was to characterize DOX damage and determine the ability of dexrazoxane (DEX) to reduce DOX-mediated cardiac damage in sedentary and swim-trained female rats. Female Sprague-Dawley rats were left intact or ovariectomized (OVX) at weaning then injected with DEX (60 mg/kg) before DOX (3 mg/kg), DOX alone, or PBS. Rats were separated into sedentary and swim cohorts. Body weight was reduced in DOX:DEX- but not PBS- or DOX-treated rats. Echocardiographic parameters were similar in sedentary rats. Swim training revealed greater concentric remodeling in DOX-treated rats and reduced fractional shortening in DOX:DEX-treated rats. Calsequestrin 2 was reduced with DOX and increased with DOX:DEX postswim. Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a was reduced and calsequestrin 2 reduced further by swim training only in intact rats. OVX rats were heavier and developed eccentric remodeling post-swim with DOX and eccentric hypertrophy with DOX:DEX. Changes in SERCA2a and calsequestrin 2 expression were not observed. Ovariectomized DOX- and DOX:DEX-treated rats stopped growing during swim training. DEX coinjection did not relieve DOX-mediated cardiotoxicity in intact or hormone-deficient rats. DOX-mediated reductions in growth, cardiac function, and expression of calcium homeostasis proteins were exacerbated by swim. DEX coadministration did not substantially relieve DOX-mediated cardiotoxicity in young female rats. Ovarian hormones reduce DOX-induced cardiotoxicity.

  14. Hyaluronic Acid Modified Tantalum Oxide Nanoparticles Conjugating Doxorubicin for Targeted Cancer Theranostics.

    PubMed

    Jin, Yushen; Ma, Xibo; Feng, Shanshan; Liang, Xiao; Dai, Zhifei; Tian, Jie; Yue, Xiuli

    2015-12-16

    Theranostic tantalum oxide nanoparticles (TaOxNPs) of about 40 nm were successfully developed by conjugating functional molecules including polyethylene glycol (PEG), near-infrared (NIR) fluorescent dye, doxorubicin (DOX), and hyaluronic acid (HA) onto the surface of the nanoparticles (TaOx@Cy7-DOX-PEG-HA NPs) for actively targeting delivery, pH-responsive drug release, and NIR fluorescence/X-ray CT bimodal imaging. The obtained nanoagent exhibits good biocompatibility, high cumulative release rate in the acidic microenvironments, long blood circulation time, and superior tumor-targeting ability. Both in vitro and in vivo experiments show that it can serve as an excellent contrast agent to simultaneously enhance fluorescence imaging and CT imaging greatly. Most importantly, such a nanoagent could enhance the therapeutic efficacy of the tumor greatly and the tumor growth inhibition was evaluated to be 87.5%. In a word, multifunctional TaOx@Cy7-DOX-PEG-HA NPs can serve as a theranostic nanomedicine for fluorescence/X-ray CT bimodal imaging, remote-controlled therapeutics, enabling personalized detection, and treatment of cancer with high efficacy.

  15. Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis

    NASA Astrophysics Data System (ADS)

    Yu, Caitong; Zhou, Mengjiao; Zhang, Xiujuan; Wei, Weijia; Chen, Xianfeng; Zhang, Xiaohong

    2015-03-01

    Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance.Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in

  16. Doxorubicin-CdS nanoparticles: a potential anticancer agent for enhancing the drug uptake of cancer cells.

    PubMed

    Li, Jingyuan; Wu, Chunhui; Dai, Yongyuan; Zhang, Renyun; Wang, Xuemei; Fu, Degang; Chen, Baoan

    2007-02-01

    A novel strategy of enhancing the drug uptake by cancer cells through the combination of anticancer drug doxorubicin with cadium sulfide (CdS) nanoparticles has been explored by using confocal fluorescence scanning microscopy as well as electrochemical studies, which demonstrates that CdS nanoparticles can readily conjugate with doxorubicin on the targeted cancer cells and facilitate the uptake of drug molecules in the human leukemia K562 cells. Besides, our observations also indicate that the aggregation of the leukemia cells occured when CdS nanoparticles were introduced into the relative target system together with doxorubicin, suggesting that the specific association of CdS nanoparticles with biologically active molecules on the surface of leukemia K562 cells may change some biorecognition or signal transfer pathway among cancer cells. It is suggested that the competitive binding of CdS nanoparticles with accompanying anticancer drug to the membrane of leukemia K562 cells could efficiently prevent the drug release by the drug resistant leukemia cells and thus inhibit the relative multidrug resistance (MDR) of targeted cancer cells.

  17. Nanodiamonds enhance therapeutic efficacy of doxorubicin in treating metastatic hormone-refractory prostate cancer

    NASA Astrophysics Data System (ADS)

    Salaam, Amanee D.; Hwang, Patrick T. J.; Poonawalla, Aliza; Green, Hadiyah N.; Jun, Ho-wook; Dean, Derrick

    2014-10-01

    Enhancing therapeutic efficacy is essential for successful treatment of chemoresistant cancers such as metastatic hormone-refractory prostate cancer (HRPC). To improve the efficacy of doxorubicin (DOX) for treating chemoresistant disease, the feasibility of using nanodiamond (ND) particles was investigated. Utilizing the pH responsive properties of ND, a novel protocol for complexing NDs and DOX was developed using a pH 8.5 coupling buffer. The DOX loading efficiency, loading on the NDs, and pH responsive release characteristics were determined utilizing UV-Visible spectroscopy. The effects of the ND-DOX on HRPC cell line PC3 were evaluated with MTS and live/dead cell viability assays. ND-DOX displayed exceptional loading efficiency (95.7%) and drug loading on NDs (23.9 wt%) with optimal release at pH 4 (80%). In comparison to treatment with DOX alone, cell death significantly increased when cells were treated with ND-DOX complexes demonstrating a 50% improvement in DOX efficacy. Of the tested treatments, ND-DOX with 2.4 μg mL-1 DOX exhibited superior efficacy (60% cell death). ND-DOX with 1.2 μg mL-1 DOX achieved 42% cell death, which was comparable to cell death in response to 2.4 μg mL-1 of free DOX, suggesting that NDs aid in decreasing the DOX dose necessary to achieve a chemotherapeutic efficacy. Due to its enhanced efficacy, ND-DOX can be used to successfully treat HRPC and potentially decrease the clinical side effects of DOX.

  18. Doxorubicin: the good, the bad and the ugly effect.

    PubMed

    Carvalho, Cristina; Santos, Renato X; Cardoso, Susana; Correia, Sónia; Oliveira, Paulo J; Santos, Maria S; Moreira, Paula I

    2009-01-01

    The anthracycline doxorubicin (DOX) is widely used in chemotherapy due to its efficacy in fighting a wide range of cancers such as carcinomas, sarcomas and hematological cancers. Despite extensive clinical utilization, the mechanisms of action of DOX remain under intense debate. A growing body of evidence supports the view that this drug can be a double-edge sword. Indeed, injury to nontargeted tissues often complicates cancer treatment by limiting therapeutic dosages of DOX and diminishing the quality of patients' life during and after DOX treatment. The literature shows that the heart is a preferential target of DOX toxicity. However, this anticancer drug also affects other organs like the brain, kidney and liver. This review is mainly devoted to discuss the mechanisms underlying not only DOX beneficial effects but also its toxic outcomes. Additionally, clinical studies focusing the therapeutic efficacy and side effects of DOX treatment will be discussed. Finally, some potential strategies to attenuate DOX-induced toxicity will be debated. PMID:19548866

  19. Redox-responsive polymer-drug conjugates based on doxorubicin and chitosan oligosaccharide-g-stearic acid for cancer therapy.

    PubMed

    Su, Yigang; Hu, Yingwen; Du, Yongzhong; Huang, Xuan; He, Jiabei; You, Jian; Yuan, Hong; Hu, Fuqiang

    2015-04-01

    Here, a biodegradable polymer-drug conjugate of doxorubicin (DOX) conjugated with a stearic acid-grafted chitosan oligosaccharide (CSO-SA) was synthesized via disulfide linkers. The obtained polymer-drug conjugate DOX-SS-CSO-SA could self-assemble into nanosized micelles in aqueous medium with a low critical micelle concentration. The size of the micelles was 62.8 nm with a narrow size distribution. In reducing environments, the DOX-SS-CSO-SA could rapidly disassemble result from the cleavage of the disulfide linkers and release the DOX. DOX-SS-CSO-SA had high efficiency for cellular uptake and rapidly released DOX in reductive intracellular environments. In vitro antitumor activity tests showed that the DOX-SS-CSO-SA had higher cytotoxicity against DOX-resistant cells than free DOX, with reversal ability up to 34.8-fold. DOX-SS-CSO-SA altered the drug distribution in vivo, which showed selectively accumulation in tumor and reduced nonspecific accumulation in hearts. In vivo antitumor studies demonstrated that DOX-SS-CSO-SA showed efficient suppression on tumor growth and relieved the DOX-induced cardiac injury. Therefore, DOX-SS-CSO-SA is a potential drug delivery system for safe and effective cancer therapy.

  20. Coencapsulated doxorubicin and bromotetrandrine lipid nanoemulsions in reversing multidrug resistance in breast cancer in vitro and in vivo.

    PubMed

    Cao, Xi; Luo, Jingwen; Gong, Tao; Zhang, Zhi-Rong; Sun, Xun; Fu, Yao

    2015-01-01

    Multidrug resistance has remained a major cause of treatment failure in chemotherapy due to the presence of P-glycoproteins (P-gp) that actively pump drugs from inside the cell to the outside. P-gp inhibitors were developed and coadministered with chemotherapeutic drugs to overcome the effect of efflux pumps thus enhancing the chemosensitivity of therapeutics. Our study aimed at developing a lipid nanoemulsion system for the coencapsulation of doxorubicin (DOX) and bromotetrandrine (W198) to reverse multidrug resistance (MDR) in breast cancer. W198 was a potent P-gp inhibitor, and DOX was selected as a model compound which is a common substrate for P-gp. Coencapsulated DOX and W198 lipid nanoemulsions (DOX/W198-LNs) displayed significantly enhanced cytotoxicity in DOX-resistant human breast cancer cells (MCF-7/ADR) compared with DOX loaded lipid nanoemulsions (DOX-LNs) (p < 0.05), which is due to the enhanced intracellular uptake of DOX in MCF-7/ADR cells. The biodistribution study was performed using a nude mice xenograft model, which demonstrates enhanced tumor uptake of DOX in the DOX/W198-LN treated group. Compared with DOX solution, DOX/W198-LNs showed reduced cardiac toxicity and gastrointestinal injury in rats. Taken together, DOX/W198-LNs represent a promising formulation for overcoming MDR in breast cancer. PMID:25469833

  1. Milk diets influence doxorubicin-induced intestinal toxicity in piglets.

    PubMed

    Shen, Rene L; Pontoppidan, Peter E L; Rathe, Mathias; Jiang, Pingping; Hansen, Carl Frederik; Buddington, Randal K; Heegaard, Peter M H; Müller, Klaus; Sangild, Per T

    2016-08-01

    Chemotherapy-induced gastrointestinal (GI) toxicity is a common adverse effect of cancer treatment. We used preweaned piglets as models to test our hypothesis that the immunomodulatory and GI trophic effects of bovine colostrum would reduce the severity of GI complications associated with doxorubicin (DOX) treatment. Five-day-old pigs were administered DOX (1 × 100 mg/m(2)) or an equivalent volume of saline (SAL) and either fed formula (DOX-Form, n = 9, or SAL-Form, n = 7) or bovine colostrum (DOX-Colos, n = 9, or SAL-Colos, n = 7). Pigs were euthanized 5 days after initiation of chemotherapy to assess markers of small intestinal function and inflammation. All DOX-treated animals developed diarrhea, growth deficits, and leukopenia. However, the intestines of DOX-Colos pigs had lower intestinal permeability, longer intestinal villi with higher activities of brush border enzymes, and lower tissue IL-8 levels compared with DOX-Form (all P < 0.05). DOX-Form pigs, but not DOX-Colos pigs, had significantly higher plasma C-reactive protein, compared with SAL-Form. Plasma citrulline was not affected by DOX treatment or diet. Thus a single dose of DOX induces intestinal toxicity in preweaned pigs and may lead to a systemic inflammatory response. The toxicity is affected by type of enteral nutrition with more pronounced GI toxicity when formula is fed compared with bovine colostrum. The results indicate that bovine colostrum may be a beneficial supplementary diet for children subjected to chemotherapy and subsequent intestinal toxicity. PMID:27445347

  2. Targeted delivery of anticancer agents via a dual function nanocarrier with an interfacial drug-interactive motif.

    PubMed

    Zhang, Xiaolan; Huang, Yixian; Zhao, Wenchen; Liu, Hao; Marquez, Rebecca; Lu, Jianqin; Zhang, Peng; Zhang, Yifei; Li, Jiang; Gao, Xiang; Venkataramanan, Raman; Xu, Liang; Li, Song

    2014-11-10

    We have developed a dual-function drug carrier, polyethylene glycol (PEG)-derivatized farnesylthiosalicylate (FTS). Here we report that incorporation of a drug-interactive motif (Fmoc) into PEG5k-FTS2 led to further improvement in both drug loading capacity and formulation stability. Doxorubicin (DOX) formulated in PEG5k-Fmoc-FTS2 showed sustained release kinetics slower than those of DOX loaded in PEG5k-FTS2. The maximum tolerated dose of DOX- or paclitaxel (PTX)-loaded PEG5k-Fmoc-FTS2 was significantly higher than that of the free drug. Pharmacokinetics and biodistribution studies showed that DOX/PEG5k-Fmoc-FTS2 mixed micelles were able to retain DOX in the bloodstream for a significant amount of time and efficiently deliver the drug to tumor sites. More importantly, drug (DOX or PTX)-loaded PEG5k-Fmoc-FTS2 led to superior antitumor activity over other treatments including drugs formulated in PEG5k-FTS2 in breast cancer and prostate cancer models. Our improved dual function carrier with a built-in drug-interactive motif represents a simple and effective system for targeted delivery of anticancer agents.

  3. Chemical and Physical Characteristics of Doxorubicin Hydrochloride Drug-Doped Salmon DNA Thin Films

    NASA Astrophysics Data System (ADS)

    Gnapareddy, Bramaramba; Reddy Dugasani, Sreekantha; Ha, Taewoo; Paulson, Bjorn; Hwang, Taehyun; Kim, Taesung; Hoon Kim, Jae; Oh, Kyunghwan; Park, Sung Ha

    2015-07-01

    Double-stranded salmon DNA (SDNA) was doped with doxorubicin hydrochloride drug molecules (DOX) to determine the binding between DOX and SDNA, and DOX optimum doping concentration in SDNA. SDNA thin films were prepared with various concentrations of DOX by drop-casting on oxygen plasma treated glass and quartz substrates. Fourier transform infrared (FTIR) spectroscopy was employed to investigate the binding sites for DOX in SDNA, and electrical and photoluminescence (PL) analyses were used to determine the optimum doping concentration of DOX. The FTIR spectra showed that up to a concentration of 30 μM of DOX, there was a tendency for binding with a periodic orientation via intercalation between nucleosides. The current and PL intensity increased as the DOX concentration increased up to 30 μM, and then as the concentration of DOX further increased, we observed a decrease in current as well as PL quenching. Finally, the optical band gap and second band onset of the transmittance spectra were analyzed to further verify the DOX binding and optimum doping concentration into SDNA thin films as a function of the DOX concentration.

  4. Chemical and Physical Characteristics of Doxorubicin Hydrochloride Drug-Doped Salmon DNA Thin Films

    PubMed Central

    Gnapareddy, Bramaramba; Reddy Dugasani, Sreekantha; Ha, Taewoo; Paulson, Bjorn; Hwang, Taehyun; Kim, Taesung; Hoon Kim, Jae; Oh, Kyunghwan; Park, Sung Ha

    2015-01-01

    Double-stranded salmon DNA (SDNA) was doped with doxorubicin hydrochloride drug molecules (DOX) to determine the binding between DOX and SDNA, and DOX optimum doping concentration in SDNA. SDNA thin films were prepared with various concentrations of DOX by drop-casting on oxygen plasma treated glass and quartz substrates. Fourier transform infrared (FTIR) spectroscopy was employed to investigate the binding sites for DOX in SDNA, and electrical and photoluminescence (PL) analyses were used to determine the optimum doping concentration of DOX. The FTIR spectra showed that up to a concentration of 30 μM of DOX, there was a tendency for binding with a periodic orientation via intercalation between nucleosides. The current and PL intensity increased as the DOX concentration increased up to 30 μM, and then as the concentration of DOX further increased, we observed a decrease in current as well as PL quenching. Finally, the optical band gap and second band onset of the transmittance spectra were analyzed to further verify the DOX binding and optimum doping concentration into SDNA thin films as a function of the DOX concentration. PMID:26228987

  5. Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles

    PubMed Central

    Cabeza, Laura; Ortiz, Raúl; Arias, José L; Prados, Jose; Ruiz Martínez, Maria Adolfina; Entrena, José M; Luque, Raquel; Melguizo, Consolación

    2015-01-01

    The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers. PMID:25709449

  6. Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles.

    PubMed

    Cabeza, Laura; Ortiz, Raúl; Arias, José L; Prados, Jose; Ruiz Martínez, Maria Adolfina; Entrena, José M; Luque, Raquel; Melguizo, Consolación

    2015-01-01

    The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers.

  7. D-limonene suppresses doxorubicin-induced oxidative stress and inflammation via repression of COX-2, iNOS, and NFκB in kidneys of Wistar rats.

    PubMed

    Rehman, Muneeb U; Tahir, Mir; Khan, Abdul Quaiyoom; Khan, Rehan; Oday-O-Hamiza; Lateef, Abdul; Hassan, Syed Kazim; Rashid, Sumaya; Ali, Nemat; Zeeshan, Mirza; Sultana, Sarwat

    2014-04-01

    D-limonene is a naturally occurring monoterpene and has been found to posses numerous therapeutic properties. In this study, we used D-limonene as a protective agent against the nephrotoxic effects of anticancer drug doxorubicin (Dox). Rats were given D-limonene at doses of 5% and 10% mixed with diet for 20 consecutive days. Dox was give at the dose of 20 mg/kg body weight intraperitoneally. The protective effects of D-limonene on Dox-induced oxidative stress and inflammation were investigated by assaying oxidative stress biomarkers, lipid peroxidation, serum toxicity markers, proinflammatory cytokines, and expression of nuclear factor kappa B (NFκB), cyclo-oxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and Nitrite levels. Administration of Dox (20 mg/kg body weight) in rats enhanced renal lipid peroxidation; depleted glutathione content and anti-oxidant enzymes; elevated levels of kidney toxicity markers viz. kidney injury molecule-1 (KIM-1), blood urea nitrogen (BUN), and creatinine; enhanced expression of NFκB, COX-2, and iNOS and nitric oxide. Treatment with D-limonene prevented oxidative stress by restoring the levels of antioxidant enzymes, further both doses of 5% and 10% showed significant decrease in inflammatory response. Both the doses of D-limonene significantly decreased the levels of kidney toxicity markers KIM-1, BUN, and creatinine. D-limonene also effectively decreased the Dox induced overexpression of NF-κB, COX-2, and iNOS and nitric oxide. Data from the present study indicate the protective role of D-limonene against Dox-induced renal damage.

  8. Multifunctional QD-based co-delivery of siRNA and doxorubicin to HeLa cells for reversal of multidrug resistance and real-time tracking.

    PubMed

    Li, Jin-Ming; Wang, Yuan-Yuan; Zhao, Mei-Xia; Tan, Cai-Ping; Li, Yi-Qun; Le, Xue-Yi; Ji, Liang-Nian; Mao, Zong-Wan

    2012-03-01

    Co-delivery of siRNA and chemotherapeutic agents has been developed to combat multidrug resistance in cancer therapy. Recently, we developed a series of quantum dots (QDs) functionalized by β-cyclodextrin (β-CD) coupled to amino acids, some of which can be used to facilitate the delivery of siRNA. In this study, two CdSe/ZnSe QDs modified with β-CD coupled to L-Arg or L-His were used to simultaneously deliver doxorubicin (Dox) and siRNA targeting the MDR1 gene to reverse the multidrug resistance of HeLa cells. In this co-delivery system, Dox was firstly encapsulated into the hydrophobic cavities of β-CD, resulting in bypass of P-glycoprotein (P-gp)-mediated drug efflux. After complex formation of the mdr1 siRNA with Dox-loaded QDs via electrostatic interaction, significant down-regulation of mdr1 mRNA levels and P-gp expression was achieved as shown by RT-PCR and Western blotting experiments, respectively. The number of apoptotic HeLa cells after treatment with the complexes substantially exceeded the number of apoptotic cells induced by free Dox only. The intrinsic fluorescence of the QDs provided an approach to track the system by laser confocal microscopy. These multifunctional QDs are promising vehicles for the co-delivery of nucleic acids and chemotherapeutics and for real-time tracking of treatment.

  9. Superoxide induces protein oxidation in plasma and TNF-α elevation in macrophage culture: Insights into mechanisms of neurotoxicity following doxorubicin chemotherapy.

    PubMed

    Keeney, Jeriel T R; Miriyala, Sumitra; Noel, Teresa; Moscow, Jeffrey A; St Clair, Daret K; Butterfield, D Allan

    2015-10-28

    Chemotherapy-induced cognitive impairment (CICI) is a quality of life-altering consequence of chemotherapy experienced by a large percentage of cancer survivors. Approximately half of FDA-approved anti-cancer drugs are known to produce ROS. Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, generates superoxide (O2(-)•) via redox cycling. Our group previously demonstrated that Dox, which does not cross the BBB, induced oxidative damage to plasma proteins leading to TNF-α elevation in the periphery and, subsequently, in brain following cancer chemotherapy. We hypothesize that such processes play a central role in CICI. The current study tested the notion that O2(-)• is involved and likely responsible for Dox-induced plasma protein oxidation and TNF-α release. Addition of O2(-)• as the potassium salt (KO2) to plasma resulted in significantly increased oxidative damage to proteins, indexed by protein carbonyl (PC) and protein-bound HNE levels. We then adapted this protocol for use in cell culture. Incubation of J774A.1 macrophage culture using this KO2-18crown6 protocol with 1 and 10 µM KO2 resulted in dramatically increased levels of TNF-α produced. These findings, together with our prior results, provide strong evidence that O2(-)• and its resulting reactive species are critically involved in Dox-induced plasma protein oxidation and TNF-α release.

  10. Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice.

    PubMed

    Schnackenberg, Laura K; Pence, Lisa; Vijay, Vikrant; Moland, Carrie L; George, Nysia; Cao, Zhijun; Yu, Li-Rong; Fuscoe, James C; Beger, Richard D; Desai, Varsha G

    2016-11-01

    The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F1 mice were dosed with 3 mg kg(-1) DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8 weeks (cumulative DOX doses of 6, 9, 12, 18 or 24 mg kg(-1) , respectively) and euthanized a week after the last dose. Mass spectrometry-based and nuclear magnetic resonance spectrometry-based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24 mg kg(-1) cumulative doses, respectively. After a cumulative dose of 6 mg kg(-1) , 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline-treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6 mg kg(-1) . A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2 weeks to repair processes with additional injury happening concurrently before myocardial injury at 8 weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  11. Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice.

    PubMed

    Schnackenberg, Laura K; Pence, Lisa; Vijay, Vikrant; Moland, Carrie L; George, Nysia; Cao, Zhijun; Yu, Li-Rong; Fuscoe, James C; Beger, Richard D; Desai, Varsha G

    2016-11-01

    The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F1 mice were dosed with 3 mg kg(-1) DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8 weeks (cumulative DOX doses of 6, 9, 12, 18 or 24 mg kg(-1) , respectively) and euthanized a week after the last dose. Mass spectrometry-based and nuclear magnetic resonance spectrometry-based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24 mg kg(-1) cumulative doses, respectively. After a cumulative dose of 6 mg kg(-1) , 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline-treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6 mg kg(-1) . A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2 weeks to repair processes with additional injury happening concurrently before myocardial injury at 8 weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID:26934058

  12. Codelivery of thioridazine and doxorubicin using nanoparticles for effective breast cancer therapy

    PubMed Central

    Jin, Xun; Zou, Bingwen; Luo, Li; Zhong, Chuanhong; Zhang, Peilan; Cheng, Hao; Guo, Yanfang; Gou, Maling

    2016-01-01

    Cancer chemotherapy can benefit from the combination of different anticancer drugs. Here, we prepared doxorubicin (Dox)- and thioridazine (Thio)-coloaded methoxy poly(ethylene glycol)-poly(l-lactic acid) (MPEG-PLA) nanoparticles (NPs) for breast cancer therapy. These NPs have an average particle size of 27 nm. The drug loading efficiencies of Thio and Dox are 4.71% and 1.98%, respectively. Compared to the treatment of Thio or Dox alone, the combination of Thio and Dox exhibited a synergistic effect in inhibiting the growth of 4T1 breast cancer cells in vitro. In addition, the Thio- and Dox-coloaded MPEG-PLA NPs could efficiently suppress the growth of breast cancer cells in vivo. This study suggests that Thio- and Dox-coloaded MPEG-PLA NPs might have potential applications in breast cancer treatment. PMID:27660446

  13. Codelivery of thioridazine and doxorubicin using nanoparticles for effective breast cancer therapy

    PubMed Central

    Jin, Xun; Zou, Bingwen; Luo, Li; Zhong, Chuanhong; Zhang, Peilan; Cheng, Hao; Guo, Yanfang; Gou, Maling

    2016-01-01

    Cancer chemotherapy can benefit from the combination of different anticancer drugs. Here, we prepared doxorubicin (Dox)- and thioridazine (Thio)-coloaded methoxy poly(ethylene glycol)-poly(l-lactic acid) (MPEG-PLA) nanoparticles (NPs) for breast cancer therapy. These NPs have an average particle size of 27 nm. The drug loading efficiencies of Thio and Dox are 4.71% and 1.98%, respectively. Compared to the treatment of Thio or Dox alone, the combination of Thio and Dox exhibited a synergistic effect in inhibiting the growth of 4T1 breast cancer cells in vitro. In addition, the Thio- and Dox-coloaded MPEG-PLA NPs could efficiently suppress the growth of breast cancer cells in vivo. This study suggests that Thio- and Dox-coloaded MPEG-PLA NPs might have potential applications in breast cancer treatment.

  14. Phytomodulatory potential of lycopene from Lycopersicum esculentum against doxorubicin induced nephrotoxicity.

    PubMed

    Koul, Ashwani; Shubrant; Gupta, Prachi

    2013-08-01

    An elevated level of serum urea and creatinine was observed in doxorubicin (DOX) treated animals indicating DOX-induced nephrotoxicity. Enhanced lipid peroxidation (LPO) in the renal tissue was accompanied by a significant decrease in the levels of reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) activities. Administration of lycopene (LycT) extracted from tomato to DOX treated mice showed a significant reduction in serum creatinine and urea levels which were associated with significantly low levels of LPO and significantly enhanced level of GSH and related antioxidant enzymes activity (GPx, GR and CAT) when compared to DOX group. Histopathological analysis revealed severe damage in the renal tissue of DOX treated animals. However, animals pretreated with LycT were observed to have reduced damage. Thus, from present results it may be inferred that lycopene may be beneficial in mitigating DOX induced nephrotoxicity in mice. PMID:24228387

  15. Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle.

    PubMed

    Kavazis, Andreas N; Smuder, Ashley J; Powers, Scott K

    2014-08-01

    Doxorubicin (DOX) is a potent antitumor agent used in cancer treatment. Unfortunately, DOX can induce myopathy in both cardiac and skeletal muscle, which limits its clinical use. Importantly, exercise training has been shown to protect against DOX-mediated cardiac and skeletal muscle myopathy. However, the mechanisms responsible for this exercise-induced muscle protection remain elusive. These experiments tested the hypothesis that short-term exercise training protects against acute DOX-induced muscle toxicity, in part, due to decreased forkhead-box O (FoxO) transcription of atrophy genes. Rats (n = 6 per group) were assigned to sedentary or endurance exercise-trained groups and paired with either placebo or DOX treatment. Gene expression and protein abundance were measured in both cardiac and skeletal muscles to determine the impact of DOX and exercise on FoxO gene targets. Our data demonstrate that DOX administration amplified FoxO1 and FoxO3 mRNA expression and increased transcription of FoxO target genes [i.e., atrogin-1/muscle atrophy F-box (MaFbx), muscle ring finger-1 (MuRF-1), and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)] in heart and soleus muscles. Importantly, exercise training protected against DOX-induced increases of FoxO1 and MuRF-1 in cardiac muscle and also prevented the rise of FoxO3, MuRF-1, and BNIP3 in soleus muscle. Furthermore, our results indicate that exercise increased peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) in both the heart and soleus muscles. This is important because increased PGC-1α expression is known to suppress FoxO activity resulting in reduced expression of FoxO target genes. Together, these results are consistent with the hypothesis that exercise training protects against DOX-induced myopathy in both heart (FoxO1 and MuRF-1) and skeletal muscles (FoxO3, MuRF-1, and BNIP3).

  16. Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells.

    PubMed

    El-Awady, Raafat A; Semreen, Mohammad H; Saber-Ayad, Maha M; Cyprian, Farhan; Menon, Varsha; Al-Tel, Taleb H

    2016-01-01

    DNA damage response machinery (DDR) is an attractive target of cancer therapy. Modulation of DDR network may alter the response of cancer cells to DNA damaging anticancer drugs such as doxorubicin. The aim of the present study is to investigate the effects of a newly developed imidazopyridine (IAZP) derivative on the DDR after induction of DNA damage in cancer cells by doxorubicin. Cytotoxicity sulphrhodamine-B assay showed a weak anti-proliferative effect of IAZP alone on six cancer cell lines (MCF7, A549, A549DOX11, HepG2, HeLa and M8) and a normal fibroblast strain. Combination of IAZP with doxorubicin resulted in synergism in lung (A549) and breast (MCF7) cancer cells but neither in the other cancer cell lines nor in normal fibroblasts. Molecular studies revealed that synergism is mediated by modulation of DNA damage response and induction of apoptosis. Using constant-field gel electrophoresis and immunofluorescence detection of γ-H2AX foci, IAZP was shown to inhibit the repair of doxorubicin-induced DNA damage in A549 and MCF7 cells. Immunoblot analysis showed that IAZP suppresses the phosphorylation of the ataxia lelangiectasia and Rad3 related (ATR) protein, which is an important player in the response of cancer cells to chemotherapy-induced DNA damage. Moreover, IAZP augmented the doxorubicin-induced degradation of p21, activation of p53, CDK2, caspase 3/7 and phosphorylation of Rb protein. These effects enhanced doxorubicin-induced apoptosis in both cell lines. Our results indicate that IAZP is a promising agent that may enhance the cytotoxic effects of doxorubicin on some cancer cells through targeting the DDR. It is a preliminary step toward the clinical application of IAZP in combination with anticancer drugs and opens the avenue for the development of compounds targeting the DDR pathway that might improve the therapeutic index of anticancer drugs and enhance their cure rate. PMID:26590797

  17. A smart tumor targeting peptide-drug conjugate, pHLIP-SS-DOX: synthesis and cellular uptake on MCF-7 and MCF-7/Adr cells.

    PubMed

    Song, Qin; Chuan, Xingxing; Chen, Binlong; He, Bing; Zhang, Hua; Dai, Wenbing; Wang, Xueqing; Zhang, Qiang

    2016-06-01

    Doxorubicin (DOX) is a potent anticancer drug for the treatment of tumors, but the poor specificity and multi-drug resistance (MDR) on tumor cells have restricted its application. Here, a pH and reduction-responsive peptide-drug conjugate (PDC), pHLIP-SS-DOX, was synthesized to overcome these drawbacks. pH low insertion peptide (pHLIP) is a cell penetrating peptide (CPP) with pH-dependent transmembrane ability. And because of the unique cell membrane insertion pattern, it might reverse the MDR. The cellular uptake study showed that on both drug-sensitive MCF-7 and drug-resistant MCF-7/Adr cells, pHLIP-SS-DOX obviously facilitated the uptake of DOX at pH 6.0 and the uptake level on MCF-7/Adr cells was similar with that on MCF-7 cells, indicating that pHLIP-SS-DOX had the ability to target acidic tumor cells and reverse MDR. In vitro cytotoxicity study mediated by GSH-OEt demonstrated that the cytotoxic effect of pHLIP-SS-DOX was reduction responsive, with obvious cytotoxicity at pH 6.0; while it had poor cytotoxicity at pH 7.4, no matter with or without GSH-OEt pretreatment. This illustrated that pHLIP could deliver DOX into tumor cells with acidic microenvironment specifically and could not deliver drugs into normal cells with neutral microenvironment. In summary, pHLIP-SS-DOX is a promising strategy to target drugs to tumors and provides a possibility to overcome MDR.

  18. Cell-penetrating peptide-doxorubicin conjugate loaded NGR-modified nanobubbles for ultrasound triggered drug delivery.

    PubMed

    Lin, Wen; Xie, Xiangyang; Deng, Jianping; Liu, Hui; Chen, Ying; Fu, Xudong; Liu, Hong; Yang, Yang

    2016-01-01

    A new drug-targeting system for CD13(+) tumors has been developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, the CPP-doxorubicin conjugate (CPP-DOX) was entrapped in the asparagine-glycine-arginine (NGR) peptide modified NB (CPP-DOX/NGR-NB) and the penetration of CPP-DOX was temporally masked; local ultrasound stimulation could trigger the CPP-DOX release from NB and activate its penetration. The CPP-DOX/NGR-NBs had particle sizes of about 200 nm and drug entrapment efficiency larger than 90%. In vitro release results showed that over 85% of the encapsulated DOX or CPP-DOX would release from NBs in the presence of ultrasound, while less than 1.5% of that (30 min) without ultrasound. Cell experiments showed the higher cellular CPP-DOX uptake of CPP-DOX/NGR-NB among the various NB formulations in Human fibrosarcoma cells (HT-1080, CD13(+)). The CPP-DOX/NGR-NB with ultrasound treatment exhibited an increased cytotoxic activity than the one without ultrasound. In nude mice xenograft of HT-1080 cells, CPP-DOX/NGR-NB with ultrasound showed a higher tumor inhibition effect (3.1% of T/C%, day 24), longer median survival time (50 days) and excellent body safety compared with the normal DOX injection group. These results indicate that the constructed vesicle would be a promising drug delivery system for specific cancer treatment.

  19. Biotin-Conjugated Multilayer Poly [D,L-lactide-co-glycolide]-Lecithin-Polyethylene Glycol Nanoparticles for Targeted Delivery of Doxorubicin.

    PubMed

    Dai, Yu; Xing, Han; Song, Fuling; Yang, Yue; Qiu, Zhixia; Lu, Xiaoyu; Liu, Qi; Ren, Shuangxia; Chen, Xijing; Li, Ning

    2016-09-01

    Multilayer nanoparticle combining the merits of liposome and polymer nanoparticle has been designed for the targeted delivery of doxorubicin (DOX) in cancer treatment. In this study, DOX-PLGA-lecithin-PEG-biotin nanoparticles (DOX-PLPB-NPs) were fabricated and functionalized with biotin for specific tumor targeting. Under the transmission electron microscopy observation, the lipid layer was found to be coated on the polymer core. The physical characteristics of PLPB-NPs were also evaluated. The confocal laser scanning microscopy confirmed the cellular uptake of nanoparticles and targeted delivery PLPB-NPs. The in vitro release experiment demonstrated a pH-depending release of DOX from drug-loaded PLPB-NPs. Cytotoxicity studies in HepG2 cells and in vivo antitumor experiment in tumor-bearing mice both proved DOX-PLPB-NPs showed the best inhibition effect of tumor proliferation. In biodistribution studies, DOX-PLPB-NPs showed a higher DOX concentration than free DOX and DOX-PLGA-lecithin-PEG nanoparticles (DOX-PLP-NPs) in tumor site, especially in 24 h, and the lowest DOX level in normal organs. The results were coincident with the strongest antitumor ability showed among in vivo antitumor experiment. Histopathology analysis demonstrated that DOX-PLPB-NPs exhibited the strongest antitumor ability and lowest cardiotoxicity. In brief, the PLPB-NPs were proved to be an efficient delivery system for tumor-targeting treatment. PMID:27209461

  20. Combination of glycosphingosomes and liposomal doxorubicin shows increased activity against dimethyl-α-benzanthracene-induced fibrosarcoma in mice

    PubMed Central

    Khan, Masood A; Aljarbou, Ahmed N; Aldebasi, Yousef H; Alorainy, Mohammed S; Khan, Arif

    2015-01-01

    The present study aimed to assess the antitumor effect of glycosphingolipid-incorporated liposomes (glycosphingosomes) in combination with liposomal doxorubicin (Lip-Dox) in a mouse model of fibrosarcoma. Glycosphingosomes were prepared by incorporating glycosphingolipids isolated from Sphingomonas paucimobilis into the liposomes of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, cholesterol, and cardiolipin. Tumors were induced by administering dimethyl-α-benzanthracene, and tumor-bearing mice were treated with various formulations of Dox, including free Dox, Lip-Dox, or glycosphingosomes + Lip-Dox. Mice were observed for 90 days to monitor their survival and tumor size. Free Dox, but not Lip-Dox or a combination of glycosphingosomes and Lip-Dox, caused the substantial depletion of leukocytes and significantly increased the levels of lactate dehydrogenase and creatinine kinase in mice. Tumor-bearing mice treated with a combination of glycosphingosomes and Lip-Dox showed restricted tumor growth and increased survival when compared to those treated with free Dox or Lip-Dox. The results of the present study suggest that a combination of glycosphingosomes and Lip-Dox may prove to be very effective in the treatment of tumors. PMID:26504383

  1. An AS1411 aptamer-conjugated liposomal system containing a bubble-generating agent for tumor-specific chemotherapy that overcomes multidrug resistance.

    PubMed

    Liao, Zi-Xian; Chuang, Er-Yuan; Lin, Chia-Chen; Ho, Yi-Cheng; Lin, Kun-Ju; Cheng, Po-Yuan; Chen, Ko-Jie; Wei, Hao-Ji; Sung, Hsing-Wen

    2015-06-28

    Recent research in chemotherapy has prioritized overcoming the multidrug resistance (MDR) of cancer cells. In this work, liposomes that contain doxorubicin (DOX) and ammonium bicarbonate (ABC, a bubble-generating agent) are prepared and functionalized with an antinucleolin aptamer (AS1411 liposomes) to target DOX-resistant breast cancer cells (MCF-7/ADR), which overexpress nucleolin receptors. Free DOX and liposomes without functionalization with AS1411 (plain liposomes) were used as controls. The results of molecular dynamic simulations suggest that AS1411 functionalization may promote the affinity and specific binding of liposomes to the nucleolin receptors, enhancing their subsequent uptake by tumor cells, whereas plain liposomes enter cells with difficulty. Upon mild heating, the decomposition of ABC that is encapsulated in the liposomes enables the immediate activation of generation of CO2 bubbles, creating permeable defects in their lipid bilayers, and ultimately facilitating the swift intracellular release of DOX. In vivo studies in nude mice that bear tumors demonstrate that the active targeting of AS1411 liposomes can substantially increase the accumulation of DOX in the tumor tissues relative to free DOX or passively targeted plain liposomes, inhibiting tumor growth and reducing systemic side effects, including cardiotoxicity. The above findings indicate that liposomes that are functionalized with AS1411 represent an attractive therapeutic alternative for overcoming the MDR effect, and support a potentially effective strategy for cancer therapy.

  2. Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity

    SciTech Connect

    Ichihara, Sahoko . E-mail: saho@gene.mie-u.ac.jp; Yamada, Yoshiji; Kawai, Yoshichika; Osawa, Toshihiko; Furuhashi, Koichi; Duan Zhiwen; Ichihara, Gaku

    2007-07-20

    Cardiotoxicity is a treatment-limiting side effect of the anticancer drug doxorubicin (DOX). We have now investigated the roles of oxidative stress and signaling by the protein kinase Akt in DOX-induced cardiotoxicity as well as the effects on such toxicity both of fenofibrate, an agonist of peroxisome proliferator-activated receptor-{alpha}, and of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), an antioxidant. Mice injected intraperitoneally with DOX were treated for 4 days with fenofibrate or PEG-SOD. Fenofibrate and PEG-SOD each prevented the induction of cardiac dysfunction by DOX. Both drugs also inhibited the activation of the transcription factor NF-{kappa}B and increase in lipid peroxidation in the left ventricle induced by DOX, whereas only PEG-SOD inhibited the DOX-induced activation of Akt and Akt-regulated gene expression. These results suggest that fenofibrate and PEG-SOD prevented cardiac dysfunction induced by DOX through normalization of oxidative stress and redox-regulated NF-{kappa}B signaling.

  3. Evaluation of Doxorubicin-loaded 3-Helix Micelles as Nanocarriers

    PubMed Central

    Dube, Nikhil; Shu, Jessica Y.; Dong, He; Seo, Jai W.; Ingham, Elizabeth; Kheirolomoom, Azadeh; Chen, Pin-Yuan; Forsayeth, John; Bankiewicz, Krystof; Ferrara, Katherine W.; Xu, Ting

    2013-01-01

    Designing stable drug nanocarriers, 10-30 nm in size, would have significant impact on their transport in circulation, tumor penetration and therapeutic efficacy. In the present study, biological properties of 3-helix micelles loaded with 8 wt% doxorubicin (DOX), ~15 nm in size, were characterized to validate their potential as a nanocarrier platform. DOX-loaded micelles exhibited high stability in terms of size and drug retention in concentrated protein environments similar to conditions after intravenous injections. DOX-loaded micelles were cytotoxic to PPC-1 and 4T1 cancer cells at levels comparable to free DOX. 3-helix micelles can be disassembled by proteolytic degradation of peptide shell to enable drug release and clearance to minimize long-term accumulation. Local administration to normal rat striatum by convection enhanced delivery (CED) showed greater extent of drug distribution and reduced toxicity relative to free drug. Intravenous administration of DOX-loaded 3-helix micelles demonstrated improved tumor half-life and reduced toxicity to healthy tissues in comparison to free DOX. In vivo delivery of DOX-loaded 3-helix micelles through two different routes clearly indicates the potential of 3-helix micelles as safe and effective nanocarriers for cancer therapeutics. PMID:24050265

  4. Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis.

    PubMed

    Yu, Caitong; Zhou, Mengjiao; Zhang, Xiujuan; Wei, Weijia; Chen, Xianfeng; Zhang, Xiaohong

    2015-03-19

    Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance.

  5. Hydrogen sulfide attenuates doxorubicin-induced cardiotoxicity by inhibiting the expression of peroxiredoxin III in H9c2 cells.

    PubMed

    Liu, Mi-Hua; Lin, Xiao-Long; Yuan, Cong; He, Jun; Tan, Tian-Ping; Wu, Shao-Jian; Yu, Shan; Chen, Li; Liu, Jun; Tian, Wei; Chen, Yu-Dan; Fu, Hong-Yun; Li, Jian; Zhang, Yuan

    2016-01-01

    Doxorubicin (DOX) is a widely used chemotherapeutic agent, which can give rise to severe cardiotoxicity, limiting its clinical use. Preliminary evidence suggests that hydrogen sulfide (H2S) may exert protective effects on DOX‑induced cardiotoxicity. Therefore, the aim of the present study was to investigate whether peroxiredoxin III is involved in the cardioprotection of H2S against DOX‑induced cardiotoxicity. The results demonstrated that DOX not only markedly induced injuries, including cytotoxicity and apoptosis, it also increased the expression levels of peroxiredoxin III. Notably, pretreatment with sodium hydrosulfide significantly attenuated the DOX‑induced decrease in cell viability and increase in apoptosis, and also reversed the increased expression levels of peroxiredoxin III in H9c2 cardiomyocytes. In addition, pretreatment of the H9c2 cells with N‑acetyl‑L‑cysteine, a scavenger of reactive oxygen species, prior to exposure to DOX markedly decreased the expression levels of peroxiredoxin III. In conclusion, the results of the present study suggested that exogenous H2S attenuates DOX‑induced cardiotoxicity by inhibiting the expression of peroxiredoxin III in H9c2 cells. In the present study, the apoptosis of H9c2 cardiomyocytes was assessed using an methyl thiazolyl tetrazolium assay and Hoechst staining. The levels of Prx III and cystathionine-γ-lyase were examined by western blotting.

  6. Preparation of hyaluronic acid micro-hydrogel by biotin-avidin-specific bonding for doxorubicin-targeted delivery.

    PubMed

    Cui, Yuan; Li, Yanhui; Duan, Qian; Kakuchi, Toyoji

    2013-01-01

    Hyaluronic acid is a naturally ionic polysaccharide with cancer cell selectivity. It is an ideal candidate material for delivery of anticancer agents. In this study, hyaluronic acid (HA) micro-hydrogel loaded with anticancer drugs was prepared by the biotin-avidin system approach. Firstly, carboxyl groups on HA were changed into amino groups with adipic acid dihydrazide (ADH) to graft with biotin by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride named as HA-biotin. When HA-biotin solution mixed with doxorubicin hydrochloride (DOX·HCl) was blended with neutravidin, the micro-hydrogels would be formed with DOX loading. If excess biotin was added into the microgel, it would be disjointed, and DOX will be released quickly. The results of the synthesis procedure were characterized by (1)H-NMR and FTIR; ADH and biotin have been demonstrated to graft on the HA molecule. A field emission scanning electron microscope was used to observe morphologies of HA micro-hydrogels. Furthermore, the in vitro DOX release results revealed that the release behaviors can be adjusted by adding biotin. Therefore, the HA micro-hydrogel can deliver anticancer drugs efficiently, and the rate of release can be controlled by biotin-specific bonding with the neutravidin. Consequently, the micro-hydrogel will perform the promising property of switching in the specific site in cancer therapy. PMID:23179277

  7. Topical Skin Cancer Therapy Using Doxorubicin-Loaded Cationic Lipid Nanoparticles and lontophoresis.

    PubMed

    Huber, Lucas A; Pereira, Tatiana A; Ramos, Danielle N; Rezende, Lucas C D; Emery, Flávio S; Sobral, Lays Martin; Leopoldino, Andréia Machado; Lopez, Renata F V

    2015-11-01

    The topical administration of chemotherapeutics is a promising approach for the treatment of skin cancer; however, different pharmaceutical strategies are required to allow large amounts of drug to penetrate tumors. This work examined the potential of the anodic iontophoresis of doxorubicin-loaded cationic solid lipid nanoparticles (DOX-SLN) to increase the distribution and tumor penetration of DOX. A double-labeled cationic DOX-SLN composed of the lipids stearic acid and monoolein and a new BODIPY dye was prepared and characterized. The skin distribution and penetration of DOX were evaluated in vitro using confocal microscopy and vertical diffusion cells, respectively. The antitumor potential was evaluated in vivo through the anodic iontophoresis of DOX-SLN in squamous cell carcinoma induced in nude BALB/c mice. The encapsulation of DOX drastically altered the DOX partition coefficient and increased the distribution of DOX in the lipid matrix of the stratum corneum (SC). The association with iontophoresis created high-concentration drug reservoir zones in the follicles of the skin. Although the iontophoresis of a DOX solution increased the penetration of DOX in the viable epidermis by approximately 4-fold, the iontophoresis of cationic DOX-SLN increased the DOX penetration by approximately 50-fold. In vivo, the DOX-SLN iontophoretic treatment was effective in inhibiting tumor cell survival and tumor growth and was accompanied by an increase in keratinization and consequent cell death. These results indicate a strong and synergic effect of iontophoresis with DOX-SLN and provide a potential strategy for the treatment of skin cancer.

  8. Doxorubicin-induced central nervous system toxicity and protection by xanthone derivative of Garcinia mangostana.

    PubMed

    Tangpong, J; Miriyala, S; Noel, T; Sinthupibulyakit, C; Jungsuwadee, P; St Clair, D K

    2011-02-23

    Doxorubicin (Dox) is a potent, broad-spectrum chemotherapeutic drug used around the world. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent pro-oxidant activity. It has been reported that Dox has toxic effects on normal tissues, including brain tissue. The present study tested the protective effect of a xanthone derivative of Garcinia Mangostana against Dox-induced neuronal toxicity. Xanthone can prevent Dox from causing mononuclear cells to increase the level of tumor necrosis factor-alpha (TNFα). We show that xanthone given to mice before Dox administration suppresses protein carbonyl, nitrotyrosine and 4-hydroxy-2'-nonenal (4HNE)-adducted proteins in brain tissue. The levels of the pro-apoptotic proteins p53 and Bax and the anti-apoptotic protein Bcl-xL were significantly increased in Dox-treated mice compared with the control group. Consistent with the increase of apoptotic markers, the levels of caspase-3 activity and TUNEL-positive cells were also increased in Dox-treated mice. Pretreatment with xanthone suppressed Dox-induced increases in all indicators of injury tested. Together, the results suggest that xanthone prevents Dox-induced central nervous system toxicity, at least in part, by suppression of Dox-mediated increases in circulating TNFα. Thus, xanthone is a good candidate for prevention of systemic effects resulting from reactive oxygen generating anticancer therapeutics.

  9. Towards the development of multifunctional chitosan-based iron oxide nanoparticles: Optimization and modelling of doxorubicin release.

    PubMed

    Soares, Paula I P; Sousa, Ana Isabel; Ferreira, Isabel M M; Novo, Carlos M M; Borges, João Paulo

    2016-11-20

    In the present work composite nanoparticles with a magnetic core and a chitosan-based shell were produced as drug delivery systems for doxorubicin (DOX). The results show that composite nanoparticles with a hydrodynamic diameter within the nanometric range are able to encapsulate more DOX than polymeric nanoparticles alone corresponding also to a higher drug release. Moreover the synthesis method of the iron oxide nanoparticles influences the total amount of DOX released and a high content of iron oxide nanoparticles inhibits DOX release. The modelling of the experimental results revealed a release mechanism dominated by Fickian diffusion. PMID:27561489

  10. Towards the development of multifunctional chitosan-based iron oxide nanoparticles: Optimization and modelling of doxorubicin release.

    PubMed

    Soares, Paula I P; Sousa, Ana Isabel; Ferreira, Isabel M M; Novo, Carlos M M; Borges, João Paulo

    2016-11-20

    In the present work composite nanoparticles with a magnetic core and a chitosan-based shell were produced as drug delivery systems for doxorubicin (DOX). The results show that composite nanoparticles with a hydrodynamic diameter within the nanometric range are able to encapsulate more DOX than polymeric nanoparticles alone corresponding also to a higher drug release. Moreover the synthesis method of the iron oxide nanoparticles influences the total amount of DOX released and a high content of iron oxide nanoparticles inhibits DOX release. The modelling of the experimental results revealed a release mechanism dominated by Fickian diffusion.

  11. Doxorubicin conjugated functionalizable carbon dots for nucleus targeted delivery and enhanced therapeutic efficacy

    NASA Astrophysics Data System (ADS)

    Yang, Lei; Wang, Zheran; Wang, Ju; Jiang, Weihua; Jiang, Xuewei; Bai, Zhaoshi; He, Yunpeng; Jiang, Jianqi; Wang, Dongkai; Yang, Li

    2016-03-01

    Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared with free DOX. Thus, the DOX-CD conjugates may be exploited as promising drug delivery vehicles in cancer therapy.Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared

  12. In Situ Lipidization as a New Approach for the Design of a Self Microemulsifying Drug Delivery System (SMEDDS) of Doxorubicin Hydrochloride for Oral Administration.

    PubMed

    Derajram M Benival, M; Devarajan, Padma V

    2015-05-01

    The present paper reports in situ lipidization as a novel approach for the design of Dox-self microemulsifying drug delivery system (SMEDDS). Dox-aerosol OT (AOT) ion pair complex (lipidized Dox), exhibited high log P value of 1.74, indicating lipophilic nature. The lipidized Dox revealed good solubility but limited stability in various oils. Rapid complex formation of Dox with AOT dissolved in oils, and the high partitioning of lipidized Dox (-90%) into the oily phase presented in situ lipidization as a strategy to overcome the limited chemical stability of lipidized Dox. SMEDDS was prepared by mixing the lipidizing agent AOT, the surfactant α-Tocopheryl-Polyethyleneglycol-1 000-Succinate (TPGS) and Capmul as the oil. Dox was suspended in the SMEDDS to obtain Dox-SMEDDS. Dox-SMEDDS on aqueous dilution, resulted in a microemulsion with globule size 196 ± 16.56 nm, and revealed slow release of Dox. Oral bioavailability study in rats revealed a 420% enhancement from Dox-SMEDDS compared to Dox solution. Dox-SMEDDS and control group revealed comparable superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) levels in heart and kidneys suggesting safety of the Dox-SMEDDS. Efficacy study (tumor size reduction) in fibrosarcoma mouse model suggested Dox-SMEDDS as a promising oral delivery system for the treatment of cancer. In situ lipidization of Dox in SMEDDS presents a novel approach for the design of an orally bioavailable and promising formulation of Dox for oral administration. PMID:26390522

  13. Choline Derivate-Modified Doxorubicin Loaded Micelle for Glioma Therapy.

    PubMed

    Li, Jianfeng; Yang, Huiying; Zhang, Yujie; Jiang, Xutao; Guo, Yubo; An, Sai; Ma, Haojun; He, Xi; Jiang, Chen

    2015-09-30

    Ligand-mediated polymeric micelles have enormous potential for improving the efficacy of glioma therapy. Linear-dendritic drug-polymer conjugates composed of doxorubicin (DOX) and polyethylene glycol (PEG) were synthesized with or without modification of choline derivate (CD). The resulting MeO-PEG-DOX8 and CD-PEG-DOX8 could self-assemble into polymeric micelles with a nanosized diameter around 30 nm and a high drug loading content up to 40.6 and 32.3%, respectively. The optimized formulation 20% CD-PEG-DOX8 micelles had superior cellular uptake and antitumor activity against MeO-PEG-DOX8 micelles. The subcellular distribution using confocal study revealed that 20% CD-PEG-DOX8 micelles preferentially accumulated in the mitochondria. Pharmacokinetic study showed area under the plasma concentration-time curve (AUC0-t) and Cmax for 20% CD-PEG-DOX8 micelles and DOX solution were 1336.58 ± 179.43 mg/L·h, 96.35 ± 3.32 mg/L and 1.40 ± 0.19 mg/L·h, 1.15 ± 0.25 mg/L, respectively. Biodistribution study showed the DOX concentration of 20% CD-PEG-DOX8 micelles treated group at 48 h was 2.37-fold higher than that of MeO-PEG-DOX8 micelles treated group at 48 h and was 24 fold-higher than that of DOX solution treated group at 24 h. CD-PEG-DOX8 micelles (20%) were well tolerated with reduced cardiotoxicity, as evaluated in the body weight change and HE staining studies, while they induced most significant antitumor activity with longest media survival time in an orthotopic mouse model of U87-luci glioblastoma model as displayed in the bioluminescence imaging and survival curve studies. Our findings consequently indicated that 20% CD-PEG-DOX8 micelles are promising drug delivery system for glioma chemotherapy. PMID:26356793

  14. Quercetin Improves Postischemic Recovery of Heart Function in Doxorubicin-Treated Rats and Prevents Doxorubicin-Induced Matrix Metalloproteinase-2 Activation and Apoptosis Induction

    PubMed Central

    Barteková, Monika; Šimončíková, Petra; Fogarassyová, Mária; Ivanová, Monika; Okruhlicová, Ľudmila; Tribulová, Narcisa; Dovinová, Ima; Barančík, Miroslav

    2015-01-01

    Quercetin (QCT) is flavonoid that possesses various biological functions including anti-oxidative and radical-scavenging activities. Moreover, QCT exerts some preventive actions in treatment of cardiovascular diseases. The aim of present study was to explore effects of prolonged administration of QCT on changes induced by repeated application of doxorubicin (DOX) in rat hearts. We focused on the ultrastructure of myocardium, matrix metalloproteinases (MMPs), biometric parameters, and apoptosis induction. Our aim was also to examine effects of QCT on ischemic tolerance in hearts exposed to chronic effects of DOX, and to determine possible mechanisms underlying effects of QCT. Our results showed that QCT prevented several negative chronic effects of DOX: (I) reversed DOX-induced blood pressure increase; (II) mediated improvement of deleterious effects of DOX on ultrastructure of left ventricle; (III) prevented DOX-induced effects on tissue MMP-2 activation; and (iv) reversed effects of DOX on apoptosis induction and superoxide dismutase inhibition. Moreover, we showed that rat hearts exposed to effects of QCT were more resistant to ischemia/reperfusion injury. Effects of QCT on modulation of ischemic tolerance were linked to Akt kinase activation and connexin-43 up-regulation. Taken together, these results demonstrate that prolonged treatment with QCT prevented negative chronic effects of DOX on blood pressure, cellular damage, MMP-2 activation, and apoptosis induction. Moreover, QCT influenced myocardial responses to acute ischemic stress. These facts bring new insights into mechanisms of QCT action on rat hearts exposed to the chronic effects of DOX. PMID:25872140

  15. Coating doxorubicin-loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmaniain hamsters by inducing Th1-type immune responses

    PubMed Central

    Kansal, S; Tandon, R; Verma, A; Misra, P; Choudhary, A K; Verma, R; Verma, P R P; Dube, A; Mishra, P R

    2014-01-01

    Background and Purpose The aim of the present study was to evaluate the immunomodulatory and chemotherapeutic potential of alginate-(SA) coated nanocapsule (NCs) loaded with doxorubicin (SA-NCs-DOX) against visceral leishmaniasis in comparison with nano-emulsions containing doxorubicin (NE-DOX). Experimental Approach NE-DOX was prepared using low-energy emulsification methods. Stepwise addition of protamine sulphate and SA in a layer-by-layer manner was used to form SA-NCs-DOX. SA-NCs-DOX, NE-DOX and Free DOX were compared for their cytotoxicity against Leishmania donovani-infected macrophages in vitro and generation of T-cell responses in infected hamsters in vivo. Key Results Size and ζ potential of the NE-DOX and SA-NCs-DOX formulations were 310 ± 2.1 nm and (−)32.6 ± 2.1 mV, 342 ± 4.1 nm and (−)29.3 ± 1.2 mV respectively. SA-NCs-DOX was better (1.5 times) taken up by J774A.1 macrophages compared with NE-DOX. SA-NCs -DOX showed greater efficacy than NE-DOX against intramacrophagic amastigotes. SA-NCs-DOX treatment exhibited enhanced apoptotic efficiency than NE-DOX and free DOX as evident by cell cycle analysis, decrease in mitochondrial membrane potential, ROS and NO production. T-cell responses, when assessed through lymphoproliferative responses, NO production along with enhanced levels of iNOS, TNF-α, IFN-γ and IL-12 were found to be up-regulated after SA-NCs-DOX, compared with responses to NE-DOX in vivo. Parasitic burden was decreased in Leishmania-infected hamsters treated with SA-NCs-DOX, compared with NE-DOX. Conclusions and Implications Our results provide insights into the development of an alternative approach to improved management of leishmaniasis through a combination of chemotherapy with stimulation of the innate immune system. PMID:24837879

  16. Cryomilling for the fabrication of doxorubicin-containing silica-nanoparticle/polycaprolactone nanocomposite films

    NASA Astrophysics Data System (ADS)

    Gao, Yu; Lim, Jing; Han, Yiyuan; Wang, Lifeng; Chong, Mark Seow Khoon; Teoh, Swee-Hin; Xu, Chenjie

    2016-01-01

    Bionanocomposites need to have a homogeneous distribution of nanomaterials in the polymeric matrix to achieve consistent mechanical and biological functions. However, a significant challenge lies in achieving the homogeneous distribution of nanomaterials, particularly through a solvent-free approach. This report introduces a technology to address this need. Specifically, cryomilling, a solvent-free, low-temperature processing method, was applied to generate a bionanocomposite film with well-dispersed nanoparticles. As a proof-of-concept, polycaprolactone (PCL) and doxorubicin-containing silica nanoparticles (Si-Dox) were processed through cryomilling and subsequently heat pressed to form the PCL/Si-Dox (cPCL/Si-Dox) film. Homogeneous distribution of Si-Dox was observed under both confocal imaging and atomic force microscopy imaging. The mechanical properties of cPCL/Si-Dox were comparable to those of the pure PCL film. Subsequent in vitro release profiles suggested that sustained release of Dox from the cPCL/Si-Dox film was achievable over 50 days. When human cervical cancer cells were seeded directly on these films, uptake of Dox was observed as early as day 1 and significant inhibition of cell growth was recorded on day 5.Bionanocomposites need to have a homogeneous distribution of nanomaterials in the polymeric matrix to achieve consistent mechanical and biological functions. However, a significant challenge lies in achieving the homogeneous distribution of nanomaterials, particularly through a solvent-free approach. This report introduces a technology to address this need. Specifically, cryomilling, a solvent-free, low-temperature processing method, was applied to generate a bionanocomposite film with well-dispersed nanoparticles. As a proof-of-concept, polycaprolactone (PCL) and doxorubicin-containing silica nanoparticles (Si-Dox) were processed through cryomilling and subsequently heat pressed to form the PCL/Si-Dox (cPCL/Si-Dox) film. Homogeneous

  17. Total Flavonoids from Clinopodium chinense (Benth.) O. Ktze Protect against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo

    PubMed Central

    Chen, Rong Chang; Xu, Xu Dong; Zhi Liu, Xue; Sun, Gui Bo; Zhu, Yin Di; Dong, Xi; Wang, Jian; Zhang, Hai Jing; Zhang, Qiang; Sun, Xiao Bo

    2015-01-01

    Doxorubicin has cardiotoxic effects that limit its clinical benefit in cancer patients. This study aims to investigate the protective effects of the total flavonoids from Clinopodium chinense (Benth.) O. Ktze (TFCC) against doxorubicin- (DOX-) induced cardiotoxicity. Male rats were intraperitoneally injected with a single dose of DOX (3 mg/kg) every 2 days for three injections. Heart samples were collected 2 weeks after the last DOX dose and then analyzed. DOX delayed body and heart growth and caused cardiac tissue injury, oxidative stress, apoptotic damage, mitochondrial dysfunction, and Bcl-2 expression disturbance. Similar experiments in H9C2 cardiomyocytes showed that doxorubicin reduced cell viability, increased ROS generation and DNA fragmentation, disrupted mitochondrial membrane potential, and induced apoptotic cell death. However, TFCC pretreatment suppressed all of these adverse effects of doxorubicin. Signal transduction studies indicated that TFCC suppressed DOX-induced overexpression of p53 and phosphorylation of JNK, p38, and ERK. Studies with LY294002 (a PI3K/AKT inhibitor) demonstrated that the mechanism of TFCC-induced cardioprotection also involves activation of PI3K/AKT. These findings indicated the potential clinical application of TFCC in preventing DOX-induced cardiac oxidative stress. PMID:25784945

  18. Total Flavonoids from Clinopodium chinense (Benth.) O. Ktze Protect against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo.

    PubMed

    Chen, Rong Chang; Xu, Xu Dong; Zhi Liu, Xue; Sun, Gui Bo; Zhu, Yin Di; Dong, Xi; Wang, Jian; Zhang, Hai Jing; Zhang, Qiang; Sun, Xiao Bo

    2015-01-01

    Doxorubicin has cardiotoxic effects that limit its clinical benefit in cancer patients. This study aims to investigate the protective effects of the total flavonoids from Clinopodium chinense (Benth.) O. Ktze (TFCC) against doxorubicin- (DOX-) induced cardiotoxicity. Male rats were intraperitoneally injected with a single dose of DOX (3 mg/kg) every 2 days for three injections. Heart samples were collected 2 weeks after the last DOX dose and then analyzed. DOX delayed body and heart growth and caused cardiac tissue injury, oxidative stress, apoptotic damage, mitochondrial dysfunction, and Bcl-2 expression disturbance. Similar experiments in H9C2 cardiomyocytes showed that doxorubicin reduced cell viability, increased ROS generation and DNA fragmentation, disrupted mitochondrial membrane potential, and induced apoptotic cell death. However, TFCC pretreatment suppressed all of these adverse effects of doxorubicin. Signal transduction studies indicated that TFCC suppressed DOX-induced overexpression of p53 and phosphorylation of JNK, p38, and ERK. Studies with LY294002 (a PI3K/AKT inhibitor) demonstrated that the mechanism of TFCC-induced cardioprotection also involves activation of PI3K/AKT. These findings indicated the potential clinical application of TFCC in preventing DOX-induced cardiac oxidative stress.

  19. Calcium modulation of doxorubicin cytotoxicity in yeast and human cells.

    PubMed

    Nguyen, Thi Thuy Trang; Lim, Ying Jun; Fan, Melanie Hui Min; Jackson, Rebecca A; Lim, Kim Kiat; Ang, Wee Han; Ban, Kenneth Hon Kim; Chen, Ee Sin

    2016-03-01

    Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar-ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes. PMID:26891792

  20. Solid lipid nanoparticles for potential doxorubicin delivery in glioblastoma treatment: preliminary in vitro studies.

    PubMed

    Battaglia, Luigi; Gallarate, Marina; Peira, Elena; Chirio, Daniela; Muntoni, Elisabetta; Biasibetti, Elena; Capucchio, Maria Teresa; Valazza, Alberto; Panciani, Pier Paolo; Lanotte, Michele; Schiffer, Davide; Annovazzi, Laura; Caldera, Valentina; Mellai, Marta; Riganti, Chiara

    2014-07-01

    The major obstacle to glioblastoma pharmacological therapy is the overcoming of the blood-brain barrier (BBB). In literature, several strategies have been proposed to overcome the BBB: in this experimental work, solid lipid nanoparticles (SLN), prepared according to fatty acid coacervation technique, are proposed as the vehicle for doxorubicin (Dox), to enhance its permeation through an artificial model of BBB. The in vitro cytotoxicity of Dox-loaded SLN has been measured on three different commercial and patient-derived glioma cell lines. Dox was entrapped within SLN thanks to hydrophobic ion pairing with negatively charged surfactants, used as counterions. Results indicate that Dox entrapped in SLN maintains its cytotoxic activity toward glioma cell lines; moreover, its permeation through hCMEC/D3 cell monolayer, assumed as a model of the BBB, was increased when the drug was entrapped in SLN. In conclusion, SLN proved to be a promising vehicle for the delivery of Dox to the brain in glioblastoma treatment.

  1. Doxorubicin-induced oxidative stress in rats is efficiently counteracted by dietary anthocyanin differently enriched strawberry (Fragaria × ananassa Duch.).

    PubMed

    Diamanti, Jacopo; Mezzetti, Bruno; Giampieri, Francesca; Alvarez-Suarez, José M; Quiles, José L; Gonzalez-Alonso, Adrian; Ramirez-Tortosa, Maria del Carmen; Granados-Principal, Sergio; Gonzáles-Paramás, Ana M; Santos-Buelga, Celestino; Battino, Maurizio

    2014-05-01

    This study investigated the effects of two different strawberry cultivars, Adria and Sveva, against doxorubicin (DOX)-induced toxicity in rats. A controlled dietary intervention was conducted over 16 weeks with four groups: (i) normal diet; (ii) normal diet + DOX injection; (iii) Adria supplementation + DOX injection; and (iv) Sveva supplementation + DOX injection. Sveva presented higher total antioxidant capacity value and phenol and and vitamin C levels than Adria, which in turn presented higher anthocyanin contents. DOX drastically increased lymphocyte DNA damage, liver biomarkers of protein and lipid oxidation, and mitochondrial ROS content and markedly decreased plasma retinol level, liver antioxidant enzymes, and mitochondrial functionality. After 2 months of strawberry supplementation, rats presented a significant reduction of DNA damage and ROS concentration and a significant improvement of oxidative stress biomarkers, antioxidant enzyme activities, and mitochondrial performance. These results suggest that strawberry supplementation can counteract DOX toxicity, confirming the potential health benefit of strawberry in vivo against oxidative stress. PMID:24580025

  2. Doxorubicin-induced oxidative stress in rats is efficiently counteracted by dietary anthocyanin differently enriched strawberry (Fragaria × ananassa Duch.).

    PubMed

    Diamanti, Jacopo; Mezzetti, Bruno; Giampieri, Francesca; Alvarez-Suarez, José M; Quiles, José L; Gonzalez-Alonso, Adrian; Ramirez-Tortosa, Maria del Carmen; Granados-Principal, Sergio; Gonzáles-Paramás, Ana M; Santos-Buelga, Celestino; Battino, Maurizio

    2014-05-01

    This study investigated the effects of two different strawberry cultivars, Adria and Sveva, against doxorubicin (DOX)-induced toxicity in rats. A controlled dietary intervention was conducted over 16 weeks with four groups: (i) normal diet; (ii) normal diet + DOX injection; (iii) Adria supplementation + DOX injection; and (iv) Sveva supplementation + DOX injection. Sveva presented higher total antioxidant capacity value and phenol and and vitamin C levels than Adria, which in turn presented higher anthocyanin contents. DOX drastically increased lymphocyte DNA damage, liver biomarkers of protein and lipid oxidation, and mitochondrial ROS content and markedly decreased plasma retinol level, liver antioxidant enzymes, and mitochondrial functionality. After 2 months of strawberry supplementation, rats presented a significant reduction of DNA damage and ROS concentration and a significant improvement of oxidative stress biomarkers, antioxidant enzyme activities, and mitochondrial performance. These results suggest that strawberry supplementation can counteract DOX toxicity, confirming the potential health benefit of strawberry in vivo against oxidative stress.

  3. Design, synthesis and evaluation of N-acetyl glucosamine (NAG)-PEG-doxorubicin targeted conjugates for anticancer delivery.

    PubMed

    Pawar, Smita K; Badhwar, Archana J; Kharas, Firuza; Khandare, Jayant J; Vavia, Pradeep R

    2012-10-15

    Efficacy of anticancer drug is limited by the severe adverse effects induced by drug; therefore the crux is in designing delivery systems targeted only to cancer cells. Toward this objectives, we propose, synthesis of poly(ethylene glycol) (PEG)-doxorubicin (DOX) prodrug conjugates consisting N-acetyl glucosamine (NAG) as a targeting moiety. Multicomponent system proposed here is characterized by (1)H NMR, UV spectroscopy, and HPLC. The multicomponent system is evaluated for in vitro cellular kinetics and anticancer activity using MCF-7 and MDA-MB-231 cells. Molecular modeling study demonstrated sterically stabilized conformations of polymeric conjugates. Interestingly, PEG-DOX conjugate with NAG ligand showed significantly higher cytotoxicity compared to drug conjugate with DOX. In addition, the polymer drug conjugate with NAG and DOX showed enhanced internalization and retention effect in cancer cells, compared to free DOX. Thus, with enhanced internalization and targeting ability of PEG conjugate of NAG-DOX has implication in targeted anticancer therapy.

  4. Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug release.

    PubMed

    Luo, Dandan; Carter, Kevin A; Razi, Aida; Geng, Jumin; Shao, Shuai; Giraldo, Daniel; Sunar, Ulas; Ortega, Joaquin; Lovell, Jonathan F

    2016-01-01

    Stealth liposomes can be used to extend the blood circulation time of encapsulated therapeutics. Inclusion of 2 molar % porphyrin-phospholipid (PoP) imparted optimal near infrared (NIR) light-triggered release of doxorubicin (Dox) from conventional sterically stabilized stealth liposomes. The type and amount of PoP affected drug loading, serum stability and drug release induced by NIR light. Cholesterol and PEGylation were required for Dox loading, but slowed light-triggered release. Dox in stealth PoP liposomes had a long circulation half-life in mice of 21.9 h and was stable in storage for months. Following intravenous injection and NIR irradiation, Dox deposition increased ∼ 7 fold in treated subcutaneous human pancreatic xenografts. Phototreatment induced mild tumor heating and complex tumor hemodynamics. A single chemophototherapy treatment with Dox-loaded stealth PoP liposomes (at 5-7 mg/kg Dox) eradicated tumors while corresponding chemo- or photodynamic therapies were ineffective. A low dose 3 mg/kg Dox phototreatment with stealth PoP liposomes was more effective than a maximum tolerated dose of free (7 mg/kg) or conventional long-circulating liposomal Dox (21 mg/kg). To our knowledge, Dox-loaded stealth PoP liposomes represent the first reported long-circulating nanoparticle capable of light-triggered drug release.

  5. TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells.

    PubMed

    Wang, Zhenyu; Zhang, Huiyuan; Shi, Minghao; Yu, Yang; Wang, Hao; Cao, Wen-Ming; Zhao, Yanling; Zhang, Hong

    2016-01-01

    Doxorubicin (Dox, Adriamycin) has been widely used in breast cancer treatment. But its severe cardio-toxic side effects limited the clinical use. Dox treatment can induce DNA damage and other accompanying effects in cancer cells, and subsequently activates nuclear factor κB (NF-κB) pathway which has a strong pro-survival role in different types of malignancy. We hypothesize that blocking NF-κB pathway may sensitize breast cancer cells to Dox chemotherapy. TGFβ-activated kinase-1 (TAK1) is a key intracellular molecule participating in genotoxic stresses-induced NF-κB activation. Targeting TAK1 as a strategy to enhance cancer treatment efficacy has been studied in several malignancies. We showed that NG25, a synthesized TAK1 inhibitor, greatly enhanced Dox treatment efficacy in a panel of breast cancer cell lines. In this pre-clinical study, we found that NG25 partially blocked Dox-induced p38 phosphorylation and IκBα degradation and enhanced Dox-induced cytotoxic effects and apoptosis in all breast cancer cell lines tested. Taken together, we provided clear evidence that NG25 sensitizes the breast cancer cells to Dox treatment in vitro. This combination may be an effective and feasible therapeutic option maximizing Dox efficacy and meanwhile minimizing Dox side effects in treating breast cancer. PMID:27599572

  6. Resveratrol inhibits doxorubicin-induced cardiotoxicity via sirtuin 1 activation in H9c2 cardiomyocytes

    PubMed Central

    Liu, Mi-Hua; Shan, Jian; Li, Jian; Zhang, Yuan; Lin, Xiao-Long

    2016-01-01

    Doxorubicin (DOX) is an efficient drug used in cancer therapy; however, it can induce severe cytotoxicity, which limits its clinical application. In the present study, the effects of resveratrol (RES) on sirtuin 1 (SIRT1) activation in mediating DOX-induced cytotoxicity in H9c2 cardiac cells was investigated. H9c2 cells were exposed to 5 µM DOX for 24 h to establish a model of DOX cardiotoxicity. Apoptosis of H9c2 cardiomyocytes was assessed using the MTT assay and Hoechst nuclear staining. The results demonstrated that pretreating H9c2 cells with RES prior to the exposure of DOX resulted in increased cell viability and a decreased quantity of apoptotic cells. Western blot analysis demonstrated that DOX decreased the expression level of SIRT1. These effects were significantly alleviated by co-treatment with RES. In addition, the results demonstrated that DOX administration amplified forkhead box O1 (FoxO1) and P53 expression levels in H9c2 cells. RES was also found to protect against DOX-induced increases of FoxO1 and P53 expression levels in H9c2 cells. Furthermore, the protective effects of RES were arrested by the SIRT1 inhibitor nicotinamide. In conclusion, the results demonstrated that RES protected H9c2 cells against DOX-induced injuries via SIRT1 activation. PMID:27446329

  7. TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells

    PubMed Central

    Wang, Zhenyu; Zhang, Huiyuan; Shi, Minghao; Yu, Yang; Wang, Hao; Cao, Wen-Ming; Zhao, Yanling; Zhang, Hong

    2016-01-01

    Doxorubicin (Dox, Adriamycin) has been widely used in breast cancer treatment. But its severe cardio-toxic side effects limited the clinical use. Dox treatment can induce DNA damage and other accompanying effects in cancer cells, and subsequently activates nuclear factor κB (NF-κB) pathway which has a strong pro-survival role in different types of malignancy. We hypothesize that blocking NF-κB pathway may sensitize breast cancer cells to Dox chemotherapy. TGFβ-activated kinase-1 (TAK1) is a key intracellular molecule participating in genotoxic stresses-induced NF-κB activation. Targeting TAK1 as a strategy to enhance cancer treatment efficacy has been studied in several malignancies. We showed that NG25, a synthesized TAK1 inhibitor, greatly enhanced Dox treatment efficacy in a panel of breast cancer cell lines. In this pre-clinical study, we found that NG25 partially blocked Dox-induced p38 phosphorylation and IκBα degradation and enhanced Dox-induced cytotoxic effects and apoptosis in all breast cancer cell lines tested. Taken together, we provided clear evidence that NG25 sensitizes the breast cancer cells to Dox treatment in vitro. This combination may be an effective and feasible therapeutic option maximizing Dox efficacy and meanwhile minimizing Dox side effects in treating breast cancer. PMID:27599572

  8. Effect of Green Tea Extract on Doxorubicin Induced Cardiovascular Abnormalities: Antioxidant Action

    PubMed Central

    Patil, Leena; Balaraman, R

    2011-01-01

    Doxorubicin (DOX) induces oxidative stress leading to cardiovascular abnormalities. Green tea extract (GTE) is reported to possess antioxidant activity mainly by means of its polyphenolic constituent, catechins. Our study was aimed to find out the effect of GTE (100 mg/kg / day p.o. for 28 days) on DOX induced (3 mg/kg, IP on days 1, 7, 14, 21, 28) cardiovascular abnormalities in rat heart. DOX treatment led to significant increase in blood pressure, ST interval, serum levels of LDH, CK, SGOT, lipid peroxidation .The antioxidant enzymes such as super oxide dismutase, catalase and reduced-glutathione were decreased considerably in the heart of DOX treated rats as compared to the normal control. A combined treatment with GTE and DOX showed a considerable decrease in serum markers of cardiotoxicity such as LDH, CK, SGOT and lipid peroxides. There was significant increase in the activities of antioxidant enzymes and also showed improvement in hemodynamic parameters and ECG changes as compared to DOX treated animals. DOX treatment caused disorganization of myocardial tissue which was restored in animals treated with GTE along with DOX. Thus it can be concluded that GTE possesses an antioxidant activity and by virtue of this action it can protect the heart from DOX induced cardiovascular abnormalities. PMID:24363686

  9. Doxorubicin-mediated Apoptosis in Glioma Cells Requires NFAT3

    PubMed Central

    Gopinath, Sreelatha; Vanamala, Sravan K.; Gujrati, Meena; Klopfenstein, Jeffrey D.; Dinh, Dzung H.; Rao, Jasti S.

    2009-01-01

    Nuclear Factor of Activated T cells (NFAT), a family of transcription factors, has been implicated in many cellular processes, including some cancers. For the first time, the present study characterizes the role of NFAT3 in doxorubicin (DOX) mediated apoptosis, migration, and invasion in SNB19 and U87 glioma cells. This study demonstrates specific knockdown of NFAT3 results in a dramatic inhibition of the apoptotic effect, induced by DOX, and favors cell survival. Inhibition of NFAT3 activation by shNFAT3 (shNF3) significantly downregulated TNF-α induction, its receptor TNFR1, caspase 10, caspase 3 and PARP, abrogating DOX-mediated apoptosis in glioma cells. DOX treatment resulted in NFAT3 translocation to the nucleus. Similarly, shNF3 treatment in SNB19 and U87 cells reversed DOX-induced inhibition of cell migration and invasion as determined by wound healing and matrigel invasion assays. Taken together, these results indicate that NFAT3 is a prerequisite for the induction of DOX-mediated apoptosis in glioma cells. PMID:19784808

  10. Combination of ultrasound and bubble liposome enhance the effect of doxorubicin and inhibit murine osteosarcoma growth.

    PubMed

    Ueno, Yoshinori; Sonoda, Shozo; Suzuki, Ryo; Yokouchi, Masahiro; Kawasoe, Yasuomi; Tachibana, Katsuro; Maruyama, Kazuo; Sakamoto, Taiji; Komiya, Setsuro

    2011-08-15

    If ultrasound (US) is applied to cells, permeability across the cell membrane temporarily increases, making it easier for drugs to be taken into the cells from around the cell membrane. Moreover, when used in combination with Bubble liposome (BL: liposomes which entrap an ultrasound imaging gas), even low-power ultrasound can facilitate drug delivery into cells. In the present study, we constructed a new drug delivery system (DDS) involving concomitant use of US and BL with doxorubicin (DOX), a key drug in the chemotherapy of osteosarcoma, and demonstrated both in vitro and in vivo that it markedly inhibited the proliferation of osteosarcoma cells. Furthermore, this system achieved an equivalent antitumor effect at about 1/5 the dose of antitumor agent employed in monotherapy with DOX. These findings suggest the possibility of reduction of adverse events. In this experiment, US and liposomes were tested, both of which are already in use in clinical practice. US and liposomes are both very safe in the body. The DDS composed of these elements we designed can be applied in simple and site-specific fashion and is therefore promising as a new, clinically feasible method of treatment.

  11. Thermosensitive Hydrogel Co-loaded with Gold Nanoparticles and Doxorubicin for Effective Chemoradiotherapy.

    PubMed

    Li, Tingting; Zhang, Mingfu; Wang, Jianzhen; Wang, Tianqi; Yao, Yao; Zhang, Xiaomei; Zhang, Cai; Zhang, Na

    2016-01-01

    Chemoradiotherapy, as a well-established paradigm to treat various cancers, still calls for novel strategies. Recently, gold nanoparticles (AuNPs) have been shown to play an important role as a radiosensitizer in cancer radiotherapy. The aim of this study was to evaluate the combination of polyethylene glycol (PEG) modified AuNPs and doxorubicin (DOX) to improve cancer chemoradiotherapy, in which the AuNPs was the radiosensitizer and the DOX was the model chemotherapeutic. A Pluronic® F127-based thermosensitive hydrogel (Au-DOX-Gel) loading AuNPs and DOX was developed by "cold method" for intratumoral injection. The formulation was optimized at a F127 concentration of 22% for Au-DOX-Gel. The release profiles compared to a control group were assessed in vitro and in vivo. Au-DOX-Gel showed sustained release of AuNPs and DOX. The cell viability and surviving fraction of mouse melanoma (B16) and Human hepatocellular liver carcinoma (HepG2) cells were significantly inhibited by the combination treatment of DOX and AuNPs under radiation. Tumor sizes of mice were significantly decreased by Au-DOX-Gel compared to controls. Interestingly, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Ki-67 staining results showed that tumor cell growth and proliferation were inhibited by AuNPs combined with DOX under radiation, suggesting that the radiosensitization activity and combination effects might be caused by inhibition of tumor cell growth and proliferation. Furthermore, the results of skin safety tests, histological observation of organs, and the body weight changes indicated in vivo safety of Au-DOX-Gel. In conclusion, the Au-DOX-Gel developed in this study could represent a promising strategy for improved cancer chemoradiotherapy.

  12. Thermosensitive Hydrogel Co-loaded with Gold Nanoparticles and Doxorubicin for Effective Chemoradiotherapy.

    PubMed

    Li, Tingting; Zhang, Mingfu; Wang, Jianzhen; Wang, Tianqi; Yao, Yao; Zhang, Xiaomei; Zhang, Cai; Zhang, Na

    2016-01-01

    Chemoradiotherapy, as a well-established paradigm to treat various cancers, still calls for novel strategies. Recently, gold nanoparticles (AuNPs) have been shown to play an important role as a radiosensitizer in cancer radiotherapy. The aim of this study was to evaluate the combination of polyethylene glycol (PEG) modified AuNPs and doxorubicin (DOX) to improve cancer chemoradiotherapy, in which the AuNPs was the radiosensitizer and the DOX was the model chemotherapeutic. A Pluronic® F127-based thermosensitive hydrogel (Au-DOX-Gel) loading AuNPs and DOX was developed by "cold method" for intratumoral injection. The formulation was optimized at a F127 concentration of 22% for Au-DOX-Gel. The release profiles compared to a control group were assessed in vitro and in vivo. Au-DOX-Gel showed sustained release of AuNPs and DOX. The cell viability and surviving fraction of mouse melanoma (B16) and Human hepatocellular liver carcinoma (HepG2) cells were significantly inhibited by the combination treatment of DOX and AuNPs under radiation. Tumor sizes of mice were significantly decreased by Au-DOX-Gel compared to controls. Interestingly, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Ki-67 staining results showed that tumor cell growth and proliferation were inhibited by AuNPs combined with DOX under radiation, suggesting that the radiosensitization activity and combination effects might be caused by inhibition of tumor cell growth and proliferation. Furthermore, the results of skin safety tests, histological observation of organs, and the body weight changes indicated in vivo safety of Au-DOX-Gel. In conclusion, the Au-DOX-Gel developed in this study could represent a promising strategy for improved cancer chemoradiotherapy. PMID:26381779

  13. Synthesis and Characterization of AICAR and DOX Conjugated Multifunctional Nanoparticles as a Platform for Synergistic Inhibition of Cancer Cell Growth.

    PubMed

    Daglioglu, Cenk; Okutucu, Burcu

    2016-04-20

    The success of cancer treatment depends on the response to chemotherapeutic agents. However, malignancies often acquire resistance to drugs if they are used frequently. Combination therapy involving both a chemotherapeutic agent and molecularly targeted therapy may have the ability to retain and enhance therapeutic efficacy. Here, we addressed this issue by examining the efficacy of a novel therapeutic strategy that combines AICAR and DOX within a multifunctional platform. In this context, we reported the bottom-up synthesis of Fe3O4@SiO2(FITC)-FA/AICAR/DOX multifunctional nanoparticles aiming to neutralize survivin (BIRC5) to potentiate the efficacy of DOX against chemoresistance. The structure of nanoparticles was characterized by dynamic light scattering (DLS), zeta-potential measurement, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), and electron microscopy (SEM and STEM with EDX) techniques. Cellular uptake and cytotoxicity experiments demonstrated preferentially targeted delivery of nanoparticles and an efficient reduction of cancer cell viability in five different tumor-derived cell lines (A549, HCT-116, HeLa, Jurkat, and MIA PaCa-2). These results indicate that the multifunctional nanoparticle system possesses high inhibitory drug association and sustained cytotoxic effect with good biocompatibility. This novel approach which combines AICAR and DOX within a single platform might be promising as an antitumor treatment for cancer. PMID:26996194

  14. Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy

    PubMed Central

    Amreddy, Narsireddy; Muralidharan, Ranganayaki; Babu, Anish; Mehta, Meghna; Johnson, Elyse V; Zhao, Yan D; Munshi, Anupama; Ramesh, Rajagopal

    2015-01-01

    Background In lung cancer, the efficacy of conventional chemotherapy is limited due to poor drug accumulation in tumors and nonspecific cytotoxicity. Resolving these issues will increase therapeutic efficacy. Methods GNR-Dox-Tf-NPs (gold nanorod-doxorubicin-transferrin-nanoparticles) were prepared by different chemical approaches. The efficacy of these nanoparticles was carried out by cell viability in lung cancer and primary coronary artery smooth muscle cells. The receptor-mediated endocytosis studies were done with human transferrin and desferrioxamine preincubation. The GNR-Dox-Tf nanoparticles induced apoptosis, and DNA damage studies were done by Western blot, H2AX foci, and comet assay. Results We developed and tested a gold nanorod-based multifunctional nanoparticle system (GNR-Dox-Tf-NP) that carries Dox conjugated to a pH-sensitive linker and is targeted to the transferrin receptor overexpressed in human lung cancer (A549, HCC827) cells. GNR-Dox-Tf-NP underwent physicochemical characterization, specificity assays, tumor uptake studies, and hyperspectral imaging. Biological studies demonstrated that transferrin receptor-mediated uptake of the GNR-Dox-Tf-NP by A549 and HCC827 cells produced increased DNA damage, apoptosis, and cell killing compared with nontargeted GNR-Dox-NP. GNR-Dox-Tf-NP-mediated cytotoxicity was greater (48% A549, 46% HCC827) than GNR-Dox-NP-mediated cytotoxicity (36% A549, 39% HCC827). Further, GNR-Dox-Tf-NP markedly reduced cytotoxicity in normal human coronary artery smooth muscle cells compared with free Dox. Conclusion Thus, GNR-Dox-Tf nanoparticles can selectively target and deliver Dox to lung tumor cells and alleviate free Dox-mediated toxicity to normal cells. PMID:26604751

  15. Exercise training in doxorubicin-induced heart failure: effects on the L-arginine-NO pathway and vascular reactivity.

    PubMed

    Matsuura, Cristiane; Brunini, Tatiana M C; Carvalho, Lenize C M M; Resende, Angela C; Carvalho, Jorge J; de Castro, João Pedro Werneck; Mendes-Ribeiro, Antonio C

    2010-01-01

    Heart failure (HF) is the end-stage of cardiovascular disease and is associated with a high incidence of thrombotic events. Nitric oxide (NO) mediates vasodilation and prevents platelet activation, providing an important antithrombotic effect. The aim of this study was to investigate the effects of aerobic training on survival, platelet L-arginine-NO pathway, and vasodilator properties in doxorubicin (DOX)-induced HF. Sprague Dawley rats were randomly assigned to saline/sedentary (SAL/SED), saline/exercise (SAL/EX), DOX/sedentary (DOX/SED), and DOX/exercise (DOX/EX) groups. Four weeks after intraperitoneal DOX injection (1mg/kg(-1)/d(-1); 10 days), shortening fraction in DOX/SED and DOX/EX was significantly reduced. Treadmill exercise was performed during 6 weeks, 5 days/week(-1), 30minutes/day(-1), 50% to 60% of maximum velocity. Survival was higher in DOX/EX (67%) than DOX/SED (33%). No differences were observed in intraplatelet L-arginine transport assessed by incubation with L- [(3)H]-arginine, nor in NOS activity measured by the conversion of L- [(3)H]-arginine into L- [(3)H]-citrulline among the groups. Vasodilation response to acetylcholine was impaired in DOX/SED and DOX/EX; in nitroglycerine, it was limited to DOX/SED. Aerobic training reduced mortality in DOX-induced HF animals and restored vascular smooth muscle relaxation properties. However, it did not ameliorate intraplatelet NO bioavailability and endothelial function during the period studied.

  16. Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin.

    PubMed

    Yokoyama, Chiharu; Aoyama, Takuma; Ido, Takahiro; Kakino, Akemi; Shiraki, Takeru; Tanaka, Toshiki; Nishigaki, Kazuhiko; Hasegawa, Aiko; Fujita, Yoshiko; Sawamura, Tatsuya; Minatoguchi, Shinya

    2016-01-01

    Oxidative stress is one of the major factors in doxorubicin (DOX)-induced cardiomyopathy. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) plays an important role to regulate cardiac remodeling and oxidative stress after ischemia-reperfusion. Therefore, we examined whether or not LOX-1 contributes to the pathogenesis of DOX-induced cardiomyopathy. Cardiomyopathy was induced by a single intraperitoneal injection of DOX into wild-type (WT) mice and LOX-1 knockout (KO) mice. Echocardiography and catheter-based hemodynamic assessment apparently revealed preserved left ventricular (LV) fractional shortening (FS) and cavity size of LOX-1 KO mice compared with those of WT mice after DOX administration. Less production of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) was observed in LOX-1 KO mice than WT mice after DOX administration. Western blotting analysis also showed lower activation of nuclear factor κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in LOX-1 KO mice treated with DOX than WT mice treated with DOX. In fact, NF-κB-dependent gene expressions of LOX-1 and vascular cell adhesion molecule-1 (VCAM-1) were suppressed in LOX-1 KO mice treated with DOX compared with WT mice treated with DOX. Therefore, histological analyses showed attenuation of leukocyte infiltration and cardiac fibrosis in LOX-1 KO mice compared with WT mice. Meanwhile, extracellular signal-regulated kinase MAPK (ERK) inactivation and decreased expression of sarcomeric proteins and related transcription factor GATA-4 in WT mice treated with DOX administration were not seen in LOX-1 KO mice treated with DOX administration and WT and LOX-1 KO mice treated with vehicle. Decreased expression of sarcometric proteins resulted in smaller diameters of cardiomyocytes in WT mice than in LOX-1 KO mice after DOX treatment. The expression of LOX-1 in cardiomyocytes was much more abundant than that in endothelial cells, fibroblasts and inflammatory

  17. Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin

    PubMed Central

    Yokoyama, Chiharu; Aoyama, Takuma; Ido, Takahiro; Kakino, Akemi; Shiraki, Takeru; Tanaka, Toshiki; Nishigaki, Kazuhiko; Hasegawa, Aiko; Fujita, Yoshiko; Sawamura, Tatsuya; Minatoguchi, Shinya

    2016-01-01

    Oxidative stress is one of the major factors in doxorubicin (DOX)-induced cardiomyopathy. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) plays an important role to regulate cardiac remodeling and oxidative stress after ischemia-reperfusion. Therefore, we examined whether or not LOX-1 contributes to the pathogenesis of DOX-induced cardiomyopathy. Cardiomyopathy was induced by a single intraperitoneal injection of DOX into wild-type (WT) mice and LOX-1 knockout (KO) mice. Echocardiography and catheter-based hemodynamic assessment apparently revealed preserved left ventricular (LV) fractional shortening (FS) and cavity size of LOX-1 KO mice compared with those of WT mice after DOX administration. Less production of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) was observed in LOX-1 KO mice than WT mice after DOX administration. Western blotting analysis also showed lower activation of nuclear factor κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in LOX-1 KO mice treated with DOX than WT mice treated with DOX. In fact, NF-κB-dependent gene expressions of LOX-1 and vascular cell adhesion molecule-1 (VCAM-1) were suppressed in LOX-1 KO mice treated with DOX compared with WT mice treated with DOX. Therefore, histological analyses showed attenuation of leukocyte infiltration and cardiac fibrosis in LOX-1 KO mice compared with WT mice. Meanwhile, extracellular signal-regulated kinase MAPK (ERK) inactivation and decreased expression of sarcomeric proteins and related transcription factor GATA-4 in WT mice treated with DOX administration were not seen in LOX-1 KO mice treated with DOX administration and WT and LOX-1 KO mice treated with vehicle. Decreased expression of sarcometric proteins resulted in smaller diameters of cardiomyocytes in WT mice than in LOX-1 KO mice after DOX treatment. The expression of LOX-1 in cardiomyocytes was much more abundant than that in endothelial cells, fibroblasts and inflammatory

  18. Novel synthesizing method of pH-dependent doxorubicin-loaded anti-CD22-labelled drug delivery nanosystem

    PubMed Central

    Sun, Mengjiao; Wang, Jun; Lu, Qin; Xia, Guohua; Zhang, Yu; Song, Lina; Fang, Yongjun

    2015-01-01

    The objective of this study was to investigate the anticancer efficacy of dimercaptosuccinic acid-modified iron oxide magnetic nanoparticles coloaded with anti-CD22 antibodies and doxorubicin (anti-CD22-MNPs-DOX) on non-Hodgkin’s lymphoma cells. The physical properties of anti-CD22-MNPs-DOX were studied and its antitumor effect on Raji cells in vitro was evaluated using the Cell Counting Kit-8 assay. Furthermore, cell apoptosis and intracellular accumulation of doxorubicin were determined by flow cytometry. The results revealed that anti-CD22-MNPs-DOX inhibited the proliferation of Raji cells, significantly increased the uptake of doxorubicin, and induced apoptosis. Therefore, it was concluded that a coloaded antibody and chemotherapeutic drug with magnetic nanoparticles might be an efficient targeted treatment strategy for non-Hodgkin’s lymphoma. PMID:26379425

  19. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line.

    PubMed

    Meng, Huan; Liong, Monty; Xia, Tian; Li, Zongxi; Ji, Zhaoxia; Zink, Jeffrey I; Nel, Andre E

    2010-08-24

    Overexpression of drug efflux transporters such as P-glycoprotein (Pgp) protein is one of the major mechanisms for multiple drug resistance (MDR) in cancer cells. A new approach to overcome MDR is to use a co-delivery strategy that utilizes a siRNA to silence the expression of efflux transporter together with an appropriate anticancer drug for drug resistant cells. In this paper, we report that mesoporous silica nanoparticles (MSNP) can be functionalized to effectively deliver a chemotherapeutic agent doxorubicin (Dox) as well as Pgp siRNA to a drug-resistant cancer cell line (KB-V1 cells) to accomplish cell killing in an additive or synergistic fashion. The functionalization of the particle surface with a phosphonate group allows electrostatic binding of Dox to the porous interior, from where the drug could be released by acidification of the medium under abiotic and biotic conditions. In addition, phosphonate modification also allows exterior coating with the cationic polymer, polyethylenimine, which endows the MSNP to contemporaneously deliver Pgp siRNA. The dual delivery of Dox and siRNA in KB-V1 cells was capable of increasing the intracellular as well as intranuclear drug concentration to levels exceeding that of free Dox or the drug being delivered by MSNP in the absence of siRNA codelivery. These results demonstrate that it is possible to use the MSNP platform to effectively deliver a siRNA that knocks down gene expression of a drug exporter that can be used to improve drug sensitivity to a chemotherapeutic agent.

  20. Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors.

    PubMed

    Koziolová, Eva; Janoušková, Olga; Cuchalová, Lucie; Hvězdová, Zuzana; Hraběta, Jan; Eckschlager, Tomáš; Sivák, Ladislav; Ulbrich, Karel; Etrych, Tomáš; Šubr, Vladimír

    2016-07-10

    Water-soluble N-(2-hydroxypropyl)methacrylamide copolymer conjugates bearing the anticancer drugs doxorubicin (Dox) or pirarubicin (THP), P-gp inhibitors derived from reversin 121 (REV) or ritonavir (RIT)), or both anticancer drug and P-gp inhibitor were designed and synthesized. All biologically active molecules were attached to the polymer carrier via pH-sensitive spacer enabling controlled release in mild acidic environment modeling endosomes and lysosomes of tumor cells. The cytotoxicity of the conjugates against three sensitive and Dox-resistant neuroblastoma (NB) cell lines, applied alone or in combination, was studied in vitro. All conjugates containing THP displayed higher cytotoxicity against all three Dox-resistant NB cell lines compared with the corresponding Dox-containing conjugates. Furthermore, the cytotoxicity of conjugates containing both drug and P-gp inhibitor was up to 10 times higher than that of the conjugate containing only drug. In general, the polymer-drug conjugates showed higher cytotoxicity when conjugates containing inhibitors were added 8 or 16h prior to treatment compared with conjugates bearing both the inhibitor and the drug. The difference in cytotoxicity was more pronounced at the 16-h time point. Moreover, higher inhibitor:drug ratios resulted in higher cytotoxicity. The cytotoxicity of the polymer-drug used in combination with polymer P-gp inhibitor was up to 84 times higher than that of the polymer-drug alone. PMID:27189135

  1. Molecular Interactions between a Novel Soybean Oil-Based Polymer and Doxorubicin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel soybean oil-based polymer, hydrolyzed polymers of epoxidized soybean oil (HPESO), was developed and investigated for drug delivery. This work was aimed at determining the molecular interactions between HPESO and doxorubicin (DOX), an anticancer drug. Powder X-ray diffraction, ATR-FTIR and ...

  2. Doxorubicin-conjugated bacteriophages carrying anti-MHC class I chain-related A for targeted cancer therapy in vitro

    PubMed Central

    Phumyen, Achara; Jantasorn, Siriporn; Jumnainsong, Amonrat; Leelayuwat, Chanvit

    2014-01-01

    Background Cancer therapy by systemic administration of anticancer drugs, besides the effectiveness shown on cancer cells, demonstrated the side effects and cytotoxicity on normal cells. The targeted drug-carrying nanoparticles may decrease the required drug concentration at the site and the distribution of drugs to normal tissues. Overexpression of major histocompatibility complex class I chain–related A (MICA) in cancer is useful as a targeted molecule for the delivery of doxorubicin to MICA-expressing cell lines. Methods The application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDC) chemistry was employed to conjugate the major coat protein of bacteriophages carrying anti-MICA and doxorubicin in a mildly acid condition. Doxorubicin (Dox) on phages was determined by double fluorescence of phage particles stained by M13-fluorescein isothiocyanate (FITC) and drug autofluorescence by flow cytometry. The ability of anti-MICA on phages to bind MICA after doxorubicin conjugation was evaluated by indirect enzyme-linked immunosorbent assay. One cervical cancer and four cholangiocarcinoma cell lines expressing MICA were used as models to evaluate targeting activity by cell cytotoxicity test. Results Flow cytometry and indirect enzyme-linked immunosorbent assay demonstrated that most of the phages (82%) could be conjugated with doxorubicin, and the Dox-carrying phage-displaying anti-MICA (Dox-phage) remained the binding activity against MICA. Dox-phage was more efficient than free drugs in killing all the cell lines tested. The half maximal inhibitory concentration (IC50) values of Dox-phage were lower than those of free drugs at approximately 1.6–6 times depending on MICA expressions and the cell lines tested. Conclusion Evidently, the application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide chemistry is effective to conjugate doxorubicin and major coat protein of bacteriophages without destroying binding activity of MICA antibodies. Dox

  3. Next-generation proteasome inhibitor MLN9708 sensitizes breast cancer cells to doxorubicin-induced apoptosis

    PubMed Central

    Wang, Hao; Yu, Yang; Jiang, Zheng; Cao, Wen-Ming; Wang, Zhenyu; Dou, Jun; Zhao, Yanling; Cui, Yunfu; Zhang, Hong

    2016-01-01

    Doxorubicin (Dox), one of the most effective chemotherapy drug for cancer treatment, is limited by its severe side effects and chemoresistance. Dox induces DNA damage and leads to significant proteomic changes in the cancer cells, which makes the ubiquitin-proteasome system a potential target to enhance the efficacy of Dox therapy. The unsuccessful clinical trials of proteasome inhibitor PS-341 (bortezomib) in solid tumors led to the invention of MLN9708 (ixazomib), an orally bioavailable next-generation proteasome inhibitor with improved pharmacokinetic and pharmacodynamic features. In this preclinical study, we used eight human breast cancer cell lines, which represent the major molecular subtypes of breast cancer, to validate the cytotoxic effects of MLN9708, alone and in combination with Dox. We found that MLN9708 had cytotoxic effects, induced autophagy and MKP-1 expression, and enhanced Dox-induced apoptosis in these cell lines. MLN9708 also enhanced Dox-induced JNK and p38 phosphorylation and inhibited Dox-induced IκBα degradation. Our in vitro results suggest that MLN9708 has antitumor effects in breast cancer and can sensitize breast cancer cells to Dox treatment. This promising combination may be an effective and feasible therapeutic option for treating breast cancer and warrants clinical validation. PMID:27217076

  4. Mesoporous silica coated gold nanorods loaded doxorubicin for combined chemo-photothermal therapy.

    PubMed

    Monem, A Soltan; Elbialy, Nihal; Mohamed, Noha

    2014-08-15

    The efficacy of the combined chemo-photothermal therapy, using a mesoporous silica-coated gold nanorods loaded DOX (pGNRs@mSiO2-DOX), was consistently tested both in vitro and in vivo. The prepared nanoparticles that were characterized using transmission electron microscopy (TEM), UV-vis absorption spectroscopy and zeta potential showed high doxorubicin loading capacity in addition to its pH-responsive release. The pGNRs@mSiO2-DOX photo-heat conversion characteristic found to be stable for several repeated NIR irradiated doses was tested in simulated body fluid. In vitro results showed that pGNRs@mSiO2-DOX causes a significant damage in breast cancer cell line MCF-7 compared to free DOX. Contrary to this, it showed low toxicity to human amnion wish cells compared to CTAB coated GNRs and free DOX. In vivo results showed that intravenous administration of pGNRs@mSiO2-DOX (1.7 mg/kg) markedly suppresses the growth of subcutaneous Ehrlich carcinoma in female Balb mice (p<0.0001). Consistently, histopathological examination revealed a complete loss of tumor cellular details for mice that received the combined treatment. Based on the obtained results, this passively targeted pGNRs@mSiO2-DOX could specifically deliver drug and excessive local heat to tumor sites achieving high combined therapeutic efficacy. PMID:24792973

  5. Cardioprotective Effect of Grape Seed Extract on Chronic Doxorubicin-Induced Cardiac Toxicity in Wistar Rats

    PubMed Central

    Razmaraii, Nasser; Babaei, Hossein; Mohajjel Nayebi, Alireza; Assadnassab, Gholamreza; Ashrafi Helan, Javad; Azarmi, Yadollah

    2016-01-01

    Purpose: The aim of the present study was to determine the ability of grape seed extract (GSE) as a powerful antioxidant in preventing adverse effect of doxorubicin (DOX) on heart function. Methods: Male rats were divided into three groups: control, DOX (2 mg/kg/48h, for 12 days) and GSE (100 mg/kg/24h, for 16 days) plus DOX. Left ventricular (LV) function and hemodynamic parameters were assessed using echocardiography, electrocardiography and a Millar pressure catheter. Histopathological analysis and in vitro antitumor activity were also evaluated. Results: DOX induced heart damage in rats through decreasing the left ventricular systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening and contractility index as demonstrated by echocardiography, electrocardiography and hemodynamic parameters relative to control group. Our data demonstrated that GSE treatment markedly attenuated DOX-induced toxicity, structural changes in myocardium and improved ventricular function. Additionally, GSE did not intervene with the antitumor effect of DOX. Conclusion: Collectively, the results suggest that GSE is potentially protective against DOX-induced toxicity in rat heart and maybe increase therapeutic index of DOX in human cancer treatment. PMID:27766227

  6. Paeoniflorin inhibits doxorubicin-induced cardiomyocyte apoptosis by downregulating microRNA-1 expression

    PubMed Central

    LI, JIAN-ZHE; TANG, XIU-NENG; LI, TING-TING; LIU, LI-JUAN; YU, SHU-YI; ZHOU, GUANG-YU; SHAO, QING-RUI; SUN, HUI-PING; WU, CHENG; YANG, YANG

    2016-01-01

    Doxorubicin (DOX) is an effective anthracycline anti-tumor antibiotic. Because of its cardiotoxicity, the clinical application of DOX is limited. Paeoniflorin (PEF), a monoterpene glucoside extracted from the dry root of Paeonia, is reported to exert multiple beneficial effects on the cardiovascular system. The present study was designed to explore the protective effect of PEF against DOX-induced cardiomyocyte apoptosis and the underlying mechanism. In cultured H9c2 cells, PEF (100 µmol/l) was added for 2 h prior to exposure to DOX (5 µmol/l) for 24 h. Cell viability, creatine kinase activity, cardiomyocyte apoptosis, intracellular reactive oxygen species (ROS) levels, and the expression of microRNA-1 (miR-1) and B-cell lymphoma 2 (Bcl-2) were measured following treatment with PEF and/or DOX. The results showed that treatment with DOX notably induced cardiomyocyte apoptosis, concomitantly with enhanced ROS generation, upregulated miR-1 expression and downregulated Bcl-2 expression. These effects of DOX were significantly inhibited by pretreatment of the cells with PEF. These results suggest that the inhibitory effect of PEF on DOX-induced cardiomyocyte apoptosis may be associated with downregulation of miR-1 expression via a reduction in ROS generation. PMID:27284328

  7. The differential effects of green tea on dose-dependent doxorubicin toxicity

    PubMed Central

    Mandziuk, Slawomir; Gieroba, Renata; Korga, Agnieszka; Matysiak, Wlodzimierz; Jodlowska-Jedrych, Barbara; Burdan, Franciszek; Poleszak, Ewa; Kowalczyk, Michał; Grzycka-Kowalczyk, Luiza; Korobowicz, Elzbieta; Jozefczyk, Aleksandra; Dudka, Jaroslaw

    2015-01-01

    Background Doxorubicin (DOX) is an anticancer drug displaying cardiac and hepatic adverse effects mostly dependent on oxidative stress. Green tea (GT) has been reported to play a protective role in diseases resulting from oxidative stress. Objective The objective of this study was to evaluate if GT protects against DOX-induced oxidative stress, heart and liver morphological changes, and metabolic disorders. Methods Male Wistar rats received intraperitoneal injection of DOX (1.0 or 2.0 mg/kg b.w.) for 7 weeks or concomitantly GT extract soluble in drinking water. Results There were multidirectional effects of GT on blood metabolic parameters changed by DOX. Among all tested biochemical parameters, statistically significant protection of GT against DOX-induced changes was revealed in case of blood fatty acid–binding protein, brain natriuretic peptide, and superoxide dismutase. Conclusion DOX caused oxidative stress in both organs. It was inhibited by GT in the heart but remained unchanged in the liver. DOX-induced general toxicity and histopathological changes in the heart and in the liver were mitigated by GT at a higher dose of DOX and augmented in rats treated with a lower dose of the drug. PMID:26699794

  8. Synthesis of pH-responsive chitosan nanocapsules for the controlled delivery of doxorubicin.

    PubMed

    Chen, Chih-Kuang; Wang, Qing; Jones, Charles H; Yu, Yun; Zhang, Hanguang; Law, Wing-Cheung; Lai, Cheng Kee; Zeng, Qinghang; Prasad, Paras N; Pfeifer, Blaine A; Cheng, Chong

    2014-04-15

    Well-defined chitosan nanocapsules (CSNCs) with tunable sizes were synthesized through the interfacial cross-linking of N-maleoyl-functionalized chitosan (MCS) in miniemulsions, and their application in the delivery of doxorubicin (Dox) was investigated. MCS was prepared by the amidation reaction of CS with maleic anhydride in water/DMSO at 65 °C for 20 h. Subsequently, thiol-ene cross-linking was conducted in oil-in-water miniemulsions at room temperature under UV irradiation for 1 h, using MCS as both a surfactant and precursor polymer, 1,4-butanediol bis(3-mercapto-propionate) as a cross-linker, and D-α-tocopheryl poly(ethylene glycol) 1000 succinate as a cosurfactant. With the increase in cosurfactant concentration in the reaction systems, the sizes of the resulting CSNCs decreased steadily. Dox-loaded CSNCs were readily prepared by in situ encapsulation of Dox during miniemulsion cross-linking. With acid-labile β-thiopropionate cross-linkages, the Dox-loaded CSNCs demonstrated a faster release rate under acidic conditions. Relative to free Dox, Dox-loaded CSNCs exhibited enhanced cytotoxicity toward MCF-7 breast cancer cells without any noticeable cytotoxicity from empty CSNCs. The effective delivery of Dox to MCF-7 breast cancer cells via Dox-loaded CSNCs was also observed.

  9. Stimulating basal mitochondrial respiration decreases doxorubicin apoptotic signaling in H9c2 cardiomyoblasts.

    PubMed

    Deus, Cláudia M; Zehowski, Cheryl; Nordgren, Kendra; Wallace, Kendall B; Skildum, Andrew; Oliveira, Paulo J

    2015-08-01

    Doxorubicin (DOX) is currently used in cancer chemotherapy, however, its use often results in adverse effects highlighted by the development of cardiomyopathy and ultimately heart failure. Interestingly, DOX cardiotoxicity is decreased by resveratrol or by physical activity, suggesting that increased mitochondrial activity may be protective. Conversely, recent studies showed that troglitazone, a PPARγ agonist, increases the cytotoxicity of DOX against breast cancer cells by up-regulating mitochondrial biogenesis. The hypothesis for the current investigation was that DOX cytotoxicity in H9c2 cardiomyoblasts is decreased when mitochondrial capacity is increased. We focused on several end-points for DOX cytotoxicity, including loss of cell mass, apoptotic signaling and alterations of autophagic-related proteins. Our results show that a galactose-based, modified cell culture medium increased H9c2 basal mitochondrial respiration, protein content, and mtDNA copy number without increasing maximal or spare respiratory capacity. H9c2 cardiomyoblasts cultured in the galactose-modified media showed lower DOX-induced activation of the apoptotic pathway, measured by decreased caspase-3 and -9 activation, and lower p53 expression, although ultimately loss of cells was not prevented. Treatment with the PPARγ agonist troglitazone had no effect on DOX toxicity in this cardiac cell line, which agrees with the fact that troglitazone did not increase mitochondrial DNA content or capacity at the concentrations and duration of exposure used in this investigation. Our results show that mitochondrial remodeling caused by stimulating basal rates of oxidative phosphorylation decreased DOX-induced apoptotic signaling and increased DOX-induced autophagy in H9c2 cardiomyoblasts. The differential effect on cytotoxicity in cardiac versus breast cancer cell lines suggests a possible overall improvement in the clinical efficacy for doxorubicin in treating cancer.

  10. Mesoporous silica nanoparticles loading doxorubicin reverse multidrug resistance: performance and mechanism

    NASA Astrophysics Data System (ADS)

    Shen, Jianan; He, Qianjun; Gao, Yu; Shi, Jianlin; Li, Yaping

    2011-10-01

    Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC50 of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.

  11. Low Intensity Ultrasound Mediated Liposomal Doxorubicin Delivery Using Polymer Microbubbles.

    PubMed

    Yu, Francois T H; Chen, Xucai; Wang, Jianjun; Qin, Bin; Villanueva, Flordeliza S

    2016-01-01

    Cardiotoxicity is the major dose-limiting factor in the chemotherapeutic use of doxorubicin (Dox). A delivery vehicle that can be triggered to release its payload in the tumoral microvasculature but not in healthy tissue would help improve the therapeutic window of the drug. Delivery strategies combining liposomal encapsulated Dox (LDox), microbubbles (MBs), and ultrasound (US) have been shown to improve therapeutic efficacy of LDox, but much remains to be known about the mechanisms and the US conditions that maximize cytotoxicity using this approach. In this study, we compared different US pulses in terms of drug release and acute toxicity. Drug uptake and proliferation rates using low-intensity US were measured in squamous cell carcinoma cells exposed to LDox conjugated to or coinjected with polymer MBs. The aims of this study were: (1) to compare the effects of low- and high-pressure US on Dox release kinetics; (2) to evaluate whether conjugating the liposome to the MB surface (DoxLPX) is an important factor for drug release and cytotoxicity; and (3) to determine which US parameters most inhibit cell proliferation and whether this inhibition is mediated by drug release or the MB/US interaction with cells. Low-pressure US (170 kPa) at high duty cycle (stable cavitation) released up to ∼ 70% of the encapsulated Dox from the DoxLPX, thus improving Dox bioavailability and cellular uptake and leading to a significant reduction in cell proliferation at 48 h. Flow cytometry showed that US generating stable oscillations of DoxLPX significantly increased cellular Dox uptake at 4 h after US exposure compared to LDox. Drug uptake was correlated with cytotoxicity at 48 h. Our results demonstrate that Dox-containing liposomes conjugated to polymer MBs can be triggered to release ∼ 70% of their payload using noninertial US. Following release, Dox became bioavailable to the cells and induced significantly higher cytotoxicity compared to nonreleased encapsulated drug. Our

  12. Doxorubicin Lipid Complex Injection

    MedlinePlus

    Doxorubicin lipid complex is used to treat ovarian cancer that has not improved or that has worsened after treatment with other medications. Doxorubicin lipid complex is also used to treat Kaposi's sarcoma (a ...

  13. Further investigation of the mechanism of Doxorubicin release from P105 micelles using kinetic models

    PubMed Central

    Stevenson-Abouelnasr, Dana; Husseini, Ghaleb A.; Pitt, William G.

    2007-01-01

    The kinetics of the release of Doxorubicin from Pluronic P105 micelles during ultrasonication and its subsequent re-encapsulation upon cessation of insonation were investigated. Four mechanisms are proposed to explain the acoustically-triggered Doxorubicin (Dox) release and re-encapsulation from Pluronic P105 micelles. The four mechanisms are: micelle destruction; destruction of cavitating nuclei; reassembly of micelles, and the re-encapsulation of Dox. The first mechanism, the destruction of micelles during insonation, causes the release of Dox into solution. The micelles are destroyed because of cavitation events produced by collapsing nuclei, or bubbles in the insonated solution. The second mechanism, the slow destruction of cavitating nuclei, results in a slow partial recovery phase, when a small amount of Dox is re-encapsulated. The third and fourth mechanisms, the reassembly of micelles and the re-encapsulatin of Dox, are independent of ultrasound. These two mechanism are responsible for maintaining the drug release at a partial level, and for recovery after insonation ceases. A normal distribution was used to describe micellar size. Parameters for the model were determined based upon the best observed fit to experimental data. The resulting model provides a good approximation to experimental data for the release of Dox from Pluronic P105 micelles. PMID:17207611

  14. Doxorubicin-loaded phosphatidylethanolamine-conjugated nanoliposomes: in vitro characterization and their accumulation in liver, kidneys, and lungs in rats

    PubMed Central

    Rudra, Anandamoy; Deepa, R Manasa; Ghosh, Miltu Kumar; Ghosh, Subhajit; Mukherjee, Biswajit

    2010-01-01

    Introduction Phosphatidylethanolamine (PE)-conjugated nanoliposomes were developed, characterized, and investigated for their accumulation in liver, kidneys, and lungs in rats. Methods Drug-excipient interaction was studied using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), surface morphology by field emission scanning electron microscopy, elemental analysis by energy dispersive X-ray (EDX) analysis, zeta potential and size distribution using a Zetasizer and particle size analyzer, and in vitro drug release by dialysis membrane. In vivo accumulation of liposomes in tissues was also studied. Results No chemical reaction was observed between drug and excipients. EDX study confirmed PE-conjugation in liposomes. Doxorubicin-loaded liposomes (DOX-L) and PE-conjugated doxorubicin-loaded liposomes (DOX-PEL) were of smooth surface and homogenously distributed in nanosize range (32–37 nm) with a negative surface charge. Loading efficiencies were 49.25% ± 1.05% and 52.98% ± 3.22% respectively, for DOX-L and DOX-PEL. In vitro drug release study showed 69.91% ± 1.05% and 77.07% ± 1.02% doxorubicin released, from DOX-L and DOX-PEL, respectively, in nine hours. Fluorescence microscopic study showed that liposomes were well distributed in liver, lungs, and kidneys. Conclusion Data suggests that PE-conjugated nanoliposomes released the drug in a sustained manner and were capable of distributing them in various organs. This may be used for cell/ tissue targeting, attaching specific antibodies to PE. PMID:21042545

  15. Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers.

    PubMed

    Matsunaga, Toshiyuki; Kezuka, Chihiro; Morikawa, Yoshifumi; Suzuki, Ayaka; Endo, Satoshi; Iguchi, Kazuhiro; Miura, Takeshi; Nishinaka, Toru; Terada, Tomoyuki; El-Kabbani, Ossama; Hara, Akira; Ikari, Akira

    2015-01-01

    Doxorubicin (DOX) is widely used for the treatment of a wide range of cancers such as breast and lung cancers, and malignant lymphomas, but is generally less efficacious in gastrointestinal cancers. The most accepted explanation for the DOX refractoriness is its resistance development. Here, we established DOX-resistant phenotypes of human gastric MKN45 and colon LoVo cells by continuous exposure to incremental concentrations of the drug. While the parental MKN45 and LoVo cells expressed carbonyl reductase 1 (CBR1) highly and moderately, respectively, the gain of DOX resistance further elevated the CBR1 expression. Additionally, the DOX-elicited cytotoxicity was lowered by overexpression of CBR1 and inversely strengthened by knockdown of the enzyme using small interfering RNA or pretreating with the specific inhibitor quercetin, which also reduced the DOX refractoriness of the two resistant cells. These suggest that CBR1 is a key enzyme responsible for the DOX resistance of gastrointestinal cancer cells and that its inhibitor is useful in the adjuvant therapy. Although CBR1 is known to metabolize DOX to a less toxic anticancer metabolite doxorubicinol, its overexpression in the parental cells hardly show significant reductase activity toward low concentration of DOX. In contrast, the overexpression of CBR1 increased the reductase activity toward an oxidative stress-derived cytotoxic aldehyde 4-oxo-2-nonenal. The sensitivity of the DOX-resistant cells to 4-oxo-2-nonenal was lower than that of the parental cells, and the resistance-elicited hyposensitivity was almost completely ameliorated by addition of the CBR1 inhibitor. Thus, CBR1 may promote development of DOX resistance through detoxification of cytotoxic aldehydes, rather than the drug's metabolism. PMID:26328486

  16. Evaluation of the pharmacokinetics and cardiotoxicity of doxorubicin in rat receiving nilotinib

    SciTech Connect

    Zhou, Zhi-yong; Wan, Li-li; Yang, Quan-jun; Han, Yong-long; Li, Yan; Yu, Qi; Guo, Cheng; Li, Xiao

    2013-10-01

    Doxorubicin (DOX) is a potent chemotherapy drug with a narrow therapeutic window. Nilotinib, a small-molecule Bcr-Abl tyrosine kinase inhibitor, was reported to reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) transmembrane transporters. The present study aimed to investigate nilotinib's affection on the steady-state pharmacokinetics, disposition and cardiotoxicity of DOX. A total of 24 male Sprague–Dawley rats were randomized into four groups (6 in each) and received the following regimens: saline, intravenous DOX (5 mg/kg) alone, and DOX co-administrated with either 20 or 40 mg/kg nilotinib. Blood was withdrawn at 12 time points till 72 h after DOX injection and the concentrations of DOX and its metabolite doxorubicinol (DOXol) in serum and cardiac tissue were assayed by LC–MS–MS method. To determine the cardiotoxicity, the following parameters were investigated: creatine kinase, lactate dehydrogenase, malondialdehyde, and superoxide dismutase. Histopathological examination of heart section was carried out to evaluate the extent of cardiotoxicity after treatments. The results showed that pretreatment of 40 mg/kg nilotinib increased the AUC{sub 0–t} and C{sub max} of DOX and DOXol. However, their accumulation in cardiac tissue was significantly decreased when compared with the group that received DOX alone. In addition, biochemical and histopathological results showed that 40 mg/kg nilotinib reduced the cardiotoxicity induced by DOX administration. In conclusion, co-administration of nilotinib increased serum exposure, but significantly decreased the accumulation of DOX in cardiac tissue. Consistent with in vitro profile, oral dose of 40 mg/kg nilotinib significantly decreased the cardiotoxicity of DOX in rat by enhancing P-gp activity in the heart.

  17. Evaluation of the pharmacokinetics and cardiotoxicity of doxorubicin in rat receiving nilotinib.

    PubMed

    Zhou, Zhi-Yong; Wan, Li-Li; Yang, Quan-Jun; Han, Yong-Long; Li, Yan; Yu, Qi; Guo, Cheng; Li, Xiao

    2013-10-01

    Doxorubicin (DOX) is a potent chemotherapy drug with a narrow therapeutic window. Nilotinib, a small-molecule Bcr-Abl tyrosine kinase inhibitor, was reported to reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) transmembrane transporters. The present study aimed to investigate nilotinib's affection on the steady-state pharmacokinetics, disposition and cardiotoxicity of DOX. A total of 24 male Sprague-Dawley rats were randomized into four groups (6 in each) and received the following regimens: saline, intravenous DOX (5mg/kg) alone, and DOX co-administrated with either 20 or 40mg/kg nilotinib. Blood was withdrawn at 12 time points till 72h after DOX injection and the concentrations of DOX and its metabolite doxorubicinol (DOXol) in serum and cardiac tissue were assayed by LC-MS-MS method. To determine the cardiotoxicity, the following parameters were investigated: creatine kinase, lactate dehydrogenase, malondialdehyde, and superoxide dismutase. Histopathological examination of heart section was carried out to evaluate the extent of cardiotoxicity after treatments. The results showed that pretreatment of 40mg/kg nilotinib increased the AUC0-t and Cmax of DOX and DOXol. However, their accumulation in cardiac tissue was significantly decreased when compared with the group that received DOX alone. In addition, biochemical and histopathological results showed that 40mg/kg nilotinib reduced the cardiotoxicity induced by DOX administration. In conclusion, co-administration of nilotinib increased serum exposure, but significantly decreased the accumulation of DOX in cardiac tissue. Consistent with in vitro profile, oral dose of 40mg/kg nilotinib significantly decreased the cardiotoxicity of DOX in rat by enhancing P-gp activity in the heart.

  18. Early biomarkers of doxorubicin-induced heart injury in a mouse model

    SciTech Connect

    Desai, Varsha G.; Kwekel, Joshua C.; Vijay, Vikrant; Moland, Carrie L.; Herman, Eugene H.; Lee, Taewon; Han, Tao; Lewis, Sherry M.; Davis, Kelly J.; Muskhelishvili, Levan; Kerr, Susan; Fuscoe, James C.

    2014-12-01

    Cardiac troponins, which are used as myocardial injury markers, are released in plasma only after tissue damage has occurred. Therefore, there is a need for identification of biomarkers of earlier events in cardiac injury to limit the extent of damage. To accomplish this, expression profiling of 1179 unique microRNAs (miRNAs) was performed in a chronic cardiotoxicity mouse model developed in our laboratory. Male B6C3F{sub 1} mice were injected intravenously with 3 mg/kg doxorubicin (DOX; an anti-cancer drug), or saline once a week for 2, 3, 4, 6, and 8 weeks, resulting in cumulative DOX doses of 6, 9, 12, 18, and 24 mg/kg, respectively. Mice were euthanized a week after the last dose. Cardiac injury was evidenced in mice exposed to 18 mg/kg and higher cumulative DOX dose whereas examination of hearts by light microscopy revealed cardiac lesions at 24 mg/kg DOX. Also, 24 miRNAs were differentially expressed in mouse hearts, with the expression of 1, 1, 2, 8, and 21 miRNAs altered at 6, 9, 12, 18, and 24 mg/kg DOX, respectively. A pro-apoptotic miR-34a was the only miRNA that was up-regulated at all cumulative DOX doses and showed a significant dose-related response. Up-regulation of miR-34a at 6 mg/kg DOX may suggest apoptosis as an early molecular change in the hearts of DOX-treated mice. At 12 mg/kg DOX, up-regulation of miR-34a was associated with down-regulation of hypertrophy-related miR-150; changes observed before cardiac injury. These findings may lead to the development of biomarkers of earlier events in DOX-induced cardiotoxicity that occur before the release of cardiac troponins. - Highlights: • Upregulation of miR-34a before doxorubicin-induced cardiac tissue injury • Apoptosis might be an early event in mouse heart during doxorubicin treatment. • Expression of miR-150 declined before doxorubicin-induced cardiac tissue injury.

  19. Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance.

    PubMed

    Kwatra, Deep; Venugopal, Anand; Standing, David; Ponnurangam, Sivapriya; Dhar, Animesh; Mitra, Ashim; Anant, Shrikant

    2013-12-01

    Recently, we demonstrated that extracts of bitter melon (BME) can be used as a preventive/therapeutic agent in colon cancers. Here, we determined BME effects on anticancer activity and bioavailability of doxorubicin (DOX) in colon cancer cells. BME enhanced the effect of DOX on cell proliferation and sensitized the cells toward DOX upon pretreatment. Furthermore, there was both increased drug uptake and reduced drug efflux. We also observed a reduction in the expression of multidrug resistance conferring proteins (MDRCP) P-glycoprotein, MRP-2, and BCRP. Further BME suppressed DOX efflux in MDCK cells overexpressing the three efflux proteins individually, suggesting that BME is a potent inhibitor of MDR function. Next, we determined the effect of BME on PXR, a xenobiotic sensing nuclear receptor and a transcription factor that controls the expression of the three MDR genes. BME suppressed PXR promoter activity thereby suppressing its expression. Finally, we determined the effect of AMPK pathway on drug efflux because we have previously demonstrated that BME affects the pathway. However, inhibiting AMPK did not affect drug resistance, suggesting that BME may use different pathways for the anticancer and MDR modulating activities. Together, these results suggest that BME can enhance the bioavailability and efficacy of conventional chemotherapy.

  20. Effect of O-4-ethoxyl-butyl-berbamine in combination with pegylated liposomal doxorubicin on advanced hepatoma in mice

    PubMed Central

    Fang, Bai-Jun; Yu, Mei-Li; Yang, Shao-Guang; Liao, Lian-Ming; Liu, Jie-Wen; Zhao, Robert -C-H

    2004-01-01

    AIM: To study the synergistic effects of calmodulin (CaM) antagonist O-4-ethoxyl-butyl-berbamine (EBB) and pegylated liposomal doxorubicin (PLD) on hepatoma-22 (H22) in vivo. METHODS: Hepatoma model was established in 50 Balb/c mice by inoculating H22 cells (2.5 × 106) subcutaneously into the right backs of the mice. These mice were divided into 5 groups, and treated with saline only, PLD only, doxorubicin (Dox) only, PLD plus EBB and Dox plus EBB, respectively. In the treatment groups, mice were given 5 intravenous of PLD or Dox on days 0, 3, 6, 9 and 12. The first dosage of PLD or Dox was 4.5 mg/kg, the other 4 injections was 1 mg/kg. EBB (5 mg/kg) was coadministered with PLD or Dox in the corresponding groups. The effect of drugs on the life spans of hepatoma-bearing mice and tumor response to the drugs were recorded. Dox levels in the hepatoma cells were measured by a fluorescence assay. Light microscopy was performed to determine the histopathological changes in the major organs of these tumor-bearing mice. The MTT method was used to analyze the effect of Dox or PLD alone, Dox in combination with EBB, or PLD in combination with EBB on the growth of H22 cells in an in vitro experiment. RESULTS: EBB (5 mg/kg) significantly augmented the antitumor activity of Dox or PLD, remarkably prolonged the median survival time. The median survival time was 18.2 d for control group, but 89.2 d for PLD + EBB group and 70.1 d for Dox + EBB group, respectively. However, Dox alone did not show any remarkable antitumor activity, and the median survival time was just 29.7 d. Addition of EBB to Dox or PLD significantly increased the level of Dox in H22 cells in vivo. Moreover, EBB diminished liver toxicity of Dox and PLD. In vitro, EBB reduced the IC50 value of Dox or PLD on H22 cells from 0.050 ± 0.006 mg/L and 0.054 ± 0.004 mg/L to 0.012 ± 0.002 mg/L and 0.013 ± 0.002 mg/L, respectively (P < 0.01). CONCLUSION: EBB and liposomization could improve the therapeutic efficacy of

  1. Remote loading of doxorubicin into liposomes by transmembrane pH gradient to reduce toxicity toward H9c2 cells.

    PubMed

    Alyane, Mohamed; Barratt, Gillian; Lahouel, Mesbah

    2016-03-01

    The use of doxorubicin (DOX) is limited by its dose-dependent cardiotoxicity. Entrapped DOX in liposome has been shown to reduce cardiotoxicity. Results showed that about 92% of the total drug was encapsulated in liposome. The release experiments showed a weak DOX leakage in both culture medium and in PBS, more than 98% and 90% of the encapsulated DOX respectively was still retained in liposomes after 24 h of incubation. When the release experiments were carried out in phosphate buffer pH5.3, the leakage of DOX from liposomes reached 37% after 24 h of incubation. Evaluation of cellular uptake of the liposomal DOX indicated the possible endocytosis of liposomes because the majority of visible fluorescence of DOX was mainly in the cytoplasm, whereas the nuclear compartment showed a weak intensity. When using unloaded fluorescent-liposomes, the fluorescence was absent in nuclei suggests that liposomes cannot cross the nuclear membrane. MTT assay and measurement of LDH release suggest that necrosis is the form of cellular death predominates in H9c2 cells exposed to high doses of DOX, while for weak doses apoptosis could be the predominate form. Entrapped DOX reduced significantly DOX toxicity after 3 and 6 h of incubation, but after 20 h entrapped DOX is more toxic than free one.

  2. Schisandrin B Prevents Doxorubicin Induced Cardiac Dysfunction by Modulation of DNA Damage, Oxidative Stress and Inflammation through Inhibition of MAPK/p53 Signaling

    PubMed Central

    Arumugam, Somasundaram; Suzuki, Kenji; Ko, Kam Ming; Krishnamurthy, Prasanna; Watanabe, Kenichi; Konishi, Tetsuya

    2015-01-01

    Doxorubicin (Dox) is a highly effective antineoplastic drug. However, Dox-induced apoptosis in cardiomyocytes leads to irreversible degenerative cardiomyopathy, which limits Dox clinical application. Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents. In current study, we investigated possible protective effects of Sch B against Dox-induced cardiomyopathy in mice. Mice received a single injection of Dox (20 mg/kg IP). Five days after Dox administration, left ventricular (LV) performance was significantly depressed and was improved by Sch B treatment. Sch B prevented the Dox-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart. In addition, the increased expression of phospho-p38 MAPK and phospho-MAPK activated mitogen kinase 2 levels by Dox were significantly suppressed by Sch B treatment. Sch B also attenuated Dox-induced higher expression of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3 positive cells and phopho-p53 levels in mice. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species were significantly less in Sch B treatment mice after Dox injection. These findings suggest that Sch B attenuates Dox-induced cardiotoxicity via antioxidative and anti-inflammatory effects. PMID:25742619

  3. In vivo distribution and antitumor activity of doxorubicin-loaded N-isopropylacrylamide-co-methacrylic acid coated mesoporous silica nanoparticles and safety evaluation.

    PubMed

    Chen, Yanzuo; Yang, Wuli; Chang, Baisong; Hu, Hangting; Fang, Xiaoling; Sha, Xianyi

    2013-11-01

    The objective of this study was to develop and evaluate the antitumor activity and the safety of a delivery system containing mesoporous silica nanoparticles (MSN) coated with pH-responsive poly (N-isopropylacrylamide-co-methacrylic acid; P NIPAM-co-MAA) for doxorubicin (DOX) delivery (P-MSN-DOX) in vitro and in vivo. We reported that P-MSN-DOX nanoparticles (190 ± 30 nm) offered a DOX-loading coefficient of more than 20%. DOX release from the P-MSN-DOX formulation was pH-dependent with enhanced antitumor effects in vitro compared with traditional MSN-DOX, which was weakly cytotoxic due to negligible drug release at tested pHs. P-MSN-DOX circulated longer, with less cardiac and renal accumulation as shown by pharmacokinetics and biodistribution studies in vivo. Also, the P-MSN-DOX delivery system had greater antitumor activity in mice bearing a murine sarcoma S-180 cell line. This finding was correlated with both in vitro and in vivo. Subacute toxicity tests revealed a low P-MSN-DOX toxicity in vivo, as well. Thus, P-MSN-DOX appears to be an efficacious and safe cancer treatment strategy.

  4. Remote loading of doxorubicin into liposomes by transmembrane pH gradient to reduce toxicity toward H9c2 cells

    PubMed Central

    Alyane, Mohamed; Barratt, Gillian; Lahouel, Mesbah

    2015-01-01

    The use of doxorubicin (DOX) is limited by its dose-dependent cardiotoxicity. Entrapped DOX in liposome has been shown to reduce cardiotoxicity. Results showed that about 92% of the total drug was encapsulated in liposome. The release experiments showed a weak DOX leakage in both culture medium and in PBS, more than 98% and 90% of the encapsulated DOX respectively was still retained in liposomes after 24 h of incubation. When the release experiments were carried out in phosphate buffer pH5.3, the leakage of DOX from liposomes reached 37% after 24 h of incubation. Evaluation of cellular uptake of the liposomal DOX indicated the possible endocytosis of liposomes because the majority of visible fluorescence of DOX was mainly in the cytoplasm, whereas the nuclear compartment showed a weak intensity. When using unloaded fluorescent-liposomes, the fluorescence was absent in nuclei suggests that liposomes cannot cross the nuclear membrane. MTT assay and measurement of LDH release suggest that necrosis is the form of cellular death predominates in H9c2 cells exposed to high doses of DOX, while for weak doses apoptosis could be the predominate form. Entrapped DOX reduced significantly DOX toxicity after 3 and 6 h of incubation, but after 20 h entrapped DOX is more toxic than free one. PMID:27013909

  5. Development and Characterization of Liposomal Doxorubicin Hydrochloride with Palm Oil

    PubMed Central

    Sabeti, Bahareh; Noordin, Mohamed Ibrahim; Mohd, Shaharuddin; Hashim, Rosnani; Akbari Javar, Hamid

    2014-01-01

    The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox). The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV) were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 ± 0.8 and 0.22 ± 1.3 and zeta potentials of about −31 and −32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4) at 37°C. Comparing cytotoxicity and cellular uptake of LUV with CaelyxR on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes. PMID:24795894

  6. Development and characterization of liposomal doxorubicin hydrochloride with palm oil.

    PubMed

    Sabeti, Bahareh; Noordin, Mohamed Ibrahim; Mohd, Shaharuddin; Hashim, Rosnani; Dahlan, Afendi; Javar, Hamid Akbari

    2014-01-01

    The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox). The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV) were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 ± 0.8 and 0.22 ± 1.3 and zeta potentials of about -31 and -32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4) at 37°C. Comparing cytotoxicity and cellular uptake of LUV with Caelyx(R) on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes.

  7. Spectroscopic study on the formation of DNA-Ag clusters and its application in temperature sensitive vehicles of DOX.

    PubMed

    Zhao, Ting-Ting; Chen, Qiu-Yun; Yang, Huan

    2015-02-25

    DNA silver nanoclusters (DNA-AgNCs) with a fluorescence emission at 610 nm were synthesized using a special hairpin DNA sequence (5'-AGCACGTAG-C3AC3AC3GC3A-CTACGTGCT-3'). Spectroscopic data demonstrate that the DNA changed from an i-motif structure containing C-quadruplexes to anti-parallel four strands structure during the formation of DNA-AgNCs. Importantly, the loose and compact four strand structure caused by the melting and hybridization of stem duplex was confirmed by the reversible fluorescence change of DNA-AgNCs in the range of 25-66°C. Herein, DNA-AgNCs were used as temperature sensitive vehicles of drug loading. The drug loading capacity is 1 Doxorubicin (Dox) molecules per CG pairs on stem-duplexes. The loaded Dox can be released by raising temperature with the melt of stem duplex. Moreover, the special DNA sequence makes it sensitive to the HepG-2 cells. PMID:25200118

  8. Doxorubicin loaded dual pH- and thermo-responsive magnetic nanocarrier for combined magnetic hyperthermia and targeted controlled drug delivery applications

    NASA Astrophysics Data System (ADS)

    Hervault, Aziliz; Dunn, Alexander E.; Lim, May; Boyer, Cyrille; Mott, Derrick; Maenosono, Shinya; Thanh, Nguyen T. K.

    2016-06-01

    Magnetic nanocarriers have attracted increasing attention for multimodal cancer therapy due to the possibility to deliver heat and drugs locally. The present study reports the development of magnetic nanocomposites (MNCs) made of an iron oxide core and a pH- and thermo-responsive polymer shell, that can be used as both hyperthermic agent and drug carrier. The conjugation of anticancer drug doxorubicin (DOX) to the pH- and thermo-responsive MNCs via acid-cleavable imine linker provides advanced features for the targeted delivery of DOX molecules via the combination of magnetic targeting, and dual pH- and thermo-responsive behaviour which offers spatial and temporal control over the release of DOX. The iron oxide cores exhibit a superparamagnetic behaviour with a saturation magnetization around 70 emu g-1. The MNCs contained 8.1 wt% of polymer and exhibit good heating properties in an alternating magnetic field. The drug release experiments confirmed that only a small amount of DOX was released at room temperature and physiological pH, while the highest drug release of 85.2% was obtained after 48 h at acidic tumour pH under hyperthermia conditions (50 °C). The drug release kinetic followed Korsmeyer-Peppas model and displayed Fickian diffusion mechanism. From the results obtained it can be concluded that this smart magnetic nanocarrier is promising for applications in multi-modal cancer therapy, to target and efficiently deliver heat and drug specifically to the tumour.Magnetic nanocarriers have attracted increasing attention for multimodal cancer therapy due to the possibility to deliver heat and drugs locally. The present study reports the development of magnetic nanocomposites (MNCs) made of an iron oxide core and a pH- and thermo-responsive polymer shell, that can be used as both hyperthermic agent and drug carrier. The conjugation of anticancer drug doxorubicin (DOX) to the pH- and thermo-responsive MNCs via acid-cleavable imine linker provides advanced

  9. The antitumor effects of tetrodotoxin and/or doxorubicin on Ehrlich ascites carcinoma-bearing female mice.

    PubMed

    El-Dayem, Samiha M Abd; Fouda, Fatma M; Ali, Elham H A; Motelp, Bosy A Abd El

    2013-06-01

    The study aimed to investigate the antitumor effect of tetrodotoxin (TTX) and/or doxorubicin (DOX) on Ehrlich ascites carcinoma (EAC)-bearing mice through the investigated biochemical parameters. TTX and/or DOX with or without N-acetylcystiene were administrated after 10 days into EAC-female mice for a period of 2 weeks in six equal doses. Treatment with TTX or DOX caused a significant decrease in the mean tumor weight and an increase in the cumulative mean survival time when compared with EAC group. All the treatments reduced the elevated liver tumor markers and increased liver antioxidant enzymes under investigation in comparison with EAC. Hepatic cells, suffered severely from degeneration and karriolysis in EAC group, revealed some improvement as appearance of healthy hepatocytes by TTX treatment. The present results suggested that TTX had a more powerful inhibitor effect on EAC growth than DOX and TTX plus DOX treatments reflected by antitumor biochemical and histological studies.

  10. Antiproliferative, antiinvasive, and proapoptotic activity of folate receptor α-targeted liposomal doxorubicin in nonfunctional pituitary adenoma cells.

    PubMed

    Liu, Xiaohai; Ma, Sihai; Dai, Congxin; Cai, Feng; Yao, Yong; Yang, Yakun; Feng, Ming; Deng, Kan; Li, Guiling; Ma, Wenbing; Xin, Bing; Lian, Wei; Xiang, Guangya; Zhang, Bo; Wang, Renzhi

    2013-04-01

    There is an urgent need for novel therapeutic strategies for the treatment of nonfunctional pituitary adenomas (NFPAs), especially those that are invasive. The folate receptor (FR)α is overexpressed in several cancers, including NFPA. The aim of this study was to determine the efficacy of FRα-targeted liposomes loaded with doxorubicin (F-L-DOX) in the treatment of NFPA. We evaluated targeting, cytotoxicity, antiinvasive, and proapoptotic activity of F-L-DOX in 25 primary cell lines derived from patients with NFPAs. We found that these liposomes effectively targeted NFPA cells through FRα and that endocytosis of the liposomes was blocked by 1mM free folic acid. F-L-DOX inhibited proliferation of NFPA cells and promoted apoptosis through activation of caspase-8, caspase-9, and caspase-3/7 more effectively than L-DOX. Furthermore, F-L-DOX also exerted greater antiinvasive ability in NFPA cells than L-DOX through suppression of the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9. Addition of 1mM free folic acid significantly reduced the pleotropic effects of F-L-DOX in NFPA cells, suggesting that FRα plays a critical role in mediating the antitumor effect of F-L-DOX. Our findings warrant further investigation of F-L-DOX as an alternative therapeutic strategy for the treatment of NFPAs that express FRα. PMID:23462961

  11. Synergistic anti-cancer effects via co-delivery of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) and doxorubicin using micellar nanoparticles.

    PubMed

    Lee, Ashlynn L Z; Dhillon, Sharon H K; Wang, Yong; Pervaiz, Shazib; Fan, Weimin; Yang, Yi Yan

    2011-05-01

    The use of small molecule drugs in cancer chemotherapy has mostly been limited by dose-dependent toxicity and development of drug resistance resulting from repeated administrations. To overcome such problems, efforts have been made to develop drug delivery systems that can bear multiple therapeutic agents in one system. The purpose of this study is to deliver human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) and doxorubicin (Dox, an anti-cancer drug) with micellar nanoparticles self-assembled from a biodegradable cationic copolymer P(MDS-co-CES) to achieve synergistic cytotoxic effects in cancer cells. Exogenously expressed TRAIL using recombinant methods shows great potential in cancer therapy as it induces cell death selectively in cancer cells with limited toxicity to normal tissues. Dox-loaded nanoparticles and TRAIL formed stable nanocomplexes with a size of ∼ 225 nm and zeta potential of ∼ 70 mV. Effects of nanocomplexes on both wild type and TRAIL-resistant SW480 colorectal carcinoma cells were investigated. The assemblies of Dox and TRAIL with P(MDS-co-CES) nanoparticles were efficiently delivered to cancer cells. Receptor-blocking studies showed that the nanocomplexes entered cells via death receptor-mediated endocytosis. Synergism in cell death induction was analysed by the isobologram method to study drug interactions. Cytotoxicity of the nanocomplexes to non-cancerous cells was significantly lower than cancerous cells. Anti-proliferative effects of nanocomplexes were retained in remaining cancer cells in long-term cultures after treatment with the nanocomplexes. In summary, this Dox and TRAIL co-delivery system can be a promising candidate for cancer treatment.

  12. Co-delivery of doxorubicin and (131)I by thermosensitive micellar-hydrogel for enhanced in situ synergetic chemoradiotherapy.

    PubMed

    Huang, Pingsheng; Zhang, Yumin; Wang, Weiwei; Zhou, Junhui; Sun, Yu; Liu, Jinjian; Kong, Deling; Liu, Jianfeng; Dong, Anjie

    2015-12-28

    Combined chemoradiotherapy is potent to defeat malignant tumor. Concurrent delivery of radioisotope with chemotherapeutic drugs, which also act as the radiosensitizer, to tumor tissues by a single vehicle is essential to achieve this objective. To this end, a macroscale injectable and thermosensitive micellar-hydrogel (MHg) depot was constructed by thermo-induced self-aggregation of poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethyleneglycol)-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) triblock copolymer micelles (Ms), which could not only serve as a micellar drug reservoir to locally deliver concentrated nano chemotherapeutic drugs, but also immobilize radioisotopes at the internal irradiation hot focus. Doxorubicin (DOX) and iodine-131 labeled hyaluronic acid ((131)I-HA) were used as the model therapeutic agents. The aqueous mixture of drug-loaded PECT micelles and (131)I-HA exhibited sol-to-gel transition around body temperature. In vitro drug release study indicated that PECT/DOX Ms were sustainedly shed from the native PECT/DOX MHg formulation, which could be internalized by tumor cells with rapid intracellular DOX release. This hydrogel formulation demonstrated considerable in vitro antitumor effect as well as remarkable radiosensitization. In vivo subcutaneous injection of PECT MHg demonstrated that (131)I isotope was immobilized stably at the injection location and no obvious indication of damage to major organs were observed as indicated by the histopathological analysis. Furthermore, the peritumoral injection of chemo-radiation therapeutic agents-encapsulated MHg formulation on tumor-bearing nude mice resulted in the desired combined treatment effect, which significantly improved the tumor growth inhibition efficiency with minimized drug-associated side effects to major organs. Consequently, such a thermosensitive MHg formulation, which enabled the precise control over the dosage and ratio of combination

  13. Analysis of proteome changes in doxorubicin-treated adult rat cardiomyocyte

    PubMed Central

    Kumar, Suresh N.; Konorev, Eugene A.; Aggarwal, Deepika; Kalyanaraman, Balaraman

    2011-01-01

    Doxorubicin-induced cardiomyopathy in cancer patients is well established. The proposed mechanism of cardiac damage includes generation of reactive oxygen species, mitochondrial dysfunction and cardiomyocyte apoptosis. Exposure of adult rat cardiomyocytes to low levels of DOX for 48 h induced apoptosis. Analysis of protein expression showed a differential regulation of several key proteins including the voltage dependent anion selective channel protein 2 and methylmalonate semialdehyde dehydrogenase. In comparison, proteomic evaluation of DOX-treated rat heart showed a slightly different set of protein changes that suggests nuclear accumulation of DOX. Using a new solubilization technique, changes in low abundant protein profiles were monitored. Altered protein expression, modification and function related to oxidative stress response may play an important role in DOX cardiotoxicity. PMID:21338723

  14. Enhanced Cytotoxicity for Colon 26 Cells Using Doxorubicin-Loaded Sorbitan Monooleate (Span 80) Vesicles

    PubMed Central

    Hayashi, Keita; Tatsui, Tsuyoshi; Shimanouchi, Toshinori; Umakoshi, Hiroshi

    2013-01-01

    Span 80 (sorbitan monooleate) vesicles behaved differently from conventional phospholipid vesicles (liposomes) because the former had a more fluid interface. After doxorubicin hydrochloride (DOX) was encapsulated into the Span 80 vesicle (loading efficiency: 63 %), DOX-loaded Span 80 vesicles (DVs) were thereafter added to Colon 26 cells. It was suggested, from the flow cytometric analysis and confocal laser microscopic observation, that DVs directly deliver DOX into the cytoplasm of Colon 26 cells. DVs showed the different delivery manner from the DOX-loaded liposomes (DLs). It is considered that the difference of delivery manner between DVs and DLs resulted in the difference of cytotoxicity (IC50); i.e. IC50 values for DVs and DLs were 5 and > 30 μM, respectively. The results obtained herein would give the fundamental findings which can contribute to the improvement of formulation of conventional liposome-based carrier and its cytotoxicity. PMID:23411680

  15. Disparate impact of butyroyloxymethyl diethylphosphate (AN-7), a histone deacetylase inhibitor, and doxorubicin in mice bearing a mammary tumor.

    PubMed

    Tarasenko, Nataly; Cutts, Suzanne M; Phillips, Don R; Inbal, Aida; Nudelman, Abraham; Kessler-Icekson, Gania; Rephaeli, Ada

    2012-01-01

    The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) synergizes the cytotoxic effect of doxorubicin (Dox) and anti-HER2 on mammary carcinoma cells while protecting normal cells against their insults. This study investigated the concomitant changes occurring in heart tissue and tumors of mice bearing a subcutaneous 4T1 mammary tumor following treatment with AN-7, Dox, or their combination. Dox or AN-7 alone led to inhibition of both tumor growth and lung metastases, whereas their combination significantly increased their anticancer efficacy and attenuated Dox- toxicity. Molecular analysis revealed that treatment with Dox, AN-7, and to a greater degree, AN-7 together with Dox increased tumor levels of γH2AX, the marker for DNA double-strand breaks and decreased the expression of Rad51, a protein needed for DNA repair. These events culminated in increased apoptosis, manifested by the appearance of cytochrome-c in the cytosol. In the myocardium, Dox-induced cardiomyopathy was associated with an increase in γH2AX expression and a reduction in Rad51 and MRE11 expression and increased apoptosis. The addition of AN-7 to the Dox treatment protected the heart from Dox insults as was manifested by a decrease in γH2AX levels, an increase in Rad51 and MRE11 expression, and a diminution of cytochrome-c release. Tumor fibrosis was high in untreated mice but diminished in Dox- and AN-7-treated mice and was almost abrogated in AN-7+Dox-treated mice. By contrast, in the myocardium, Dox alone induced a dramatic increase in fibrosis, and AN7+Dox attenuated it. The high expression levels of c-Kit, Ki-67, c-Myc, lo-FGF, and VEGF in 4T1 tumors were significantly reduced by Dox or AN-7 and further attenuated by AN-7+Dox. In the myocardium, Dox suppressed these markers, whereas AN-7+Dox restored their expression. In conclusion, the combination of AN-7 and Dox results in two beneficial effects, improved anticancer efficacy and cardioprotection.

  16. Method of hyperthermia and tumor size influence effectiveness of doxorubicin release from thermosensitive liposomes in experimental tumors.

    PubMed

    Willerding, Linus; Limmer, Simone; Hossann, Martin; Zengerle, Anja; Wachholz, Kirsten; Ten Hagen, Timo L M; Koning, Gerben A; Sroka, Ronald; Lindner, Lars H; Peller, Michael

    2016-01-28

    Systemic chemotherapy of solid tumors could be enhanced by local hyperthermia (HT) in combination with thermosensitive liposomes (TSL) as drug carriers. In such an approach, effective HT of the tumor is considered essential for successful triggering local drug release and targeting of the drug to the tumor. To investigate the effect of HT method on the effectiveness of drug delivery, a novel laser-based HT device designed for the use in magnetic resonance imaging (MRI) was compared systematically with the frequently used cold light lamp and water bath HT. Long circulating phosphatidyldiglycerol-based TSL (DPPG2-TSL) with encapsulated doxorubicin (DOX) were used as drug carrier enabling intravascular drug release. Experiments were performed in male Brown Norway rats with a syngeneic soft tissue sarcoma (BN 175) located on both hind legs. One tumor was heated while the second tumor remained unheated as a reference. Six animals were investigated per HT method. DPPG2-TSL were injected i.v. at a stable tumor temperature above 40°C. Thereafter, temperature was maintained for 60min. Total DOX concentration in plasma, tumor tissue and muscle was determined post therapy by HPLC. Finally, the new laser-based device was tested in a MRI environment at 3T using DPPG2-TSL with encapsulated Gd-based contrast agent. All methods showed effective DOX delivery by TSL with 4.5-23.1ng/mg found in the heated tumors. In contrast, DOX concentration in the non-heated tumors was 0.5±0.1ng/mg. Independent of used HT methods, higher DOX levels were found in the smaller tumors. In comparison water bath induced lowest DOX delivery but still showing fourfold higher DOX concentrations compared to the non-heated tumors. With the laser-based applicator, a 13 fold higher DOX deposition was possible for large tumors and a 15 fold higher for the small tumors, respectively. Temperature gradients in the tumor tissue were higher with the laser and cold light lamp (-0.3°C/mm to -0.5°C/mm) compared to

  17. Effect of PEG-PDLLA polymeric nanovesicles loaded with doxorubicin and hematoporphyrin monomethyl ether on human hepatocellular carcinoma HepG2 cells in vitro

    PubMed Central

    Xiang, Guang-Hua; Hong, Guo-Bin; Wang, Yong; Cheng, Du; Zhou, Jing-Xing; Shuai, Xin-Tao

    2013-01-01

    Objective To evaluate the cytotoxicity of poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-PDLLA) nanovesicles loaded with doxorubicin (DOX) and the photosensitizer hematoporphyrin monomethyl ether (HMME) on human hepatocellular carcinoma HepG2 cells and to investigate potential apoptotic mechanisms. Methods PEG-PDLLA nanovesicles were simultaneously loaded with DOX and HMME (PEG-PDLLA-DOX-HMME), and PEG-PDLLA nanovesicles were loaded with DOX (PEG-PDLLA-DOX), HMME (PEG-PDLLA-HMME), or the PEG-PDLLA nanovesicle alone as controls. The cytotoxicity of PEG-PDLLA-DOX-HMME, PEG-PDLLA-DOX, PEG-PDLLA-HMME, and PEG-PDLLA against HepG2 cells was measured, and the cellular reactive oxygen species, percentage of cells with mitochondrial membrane potential depolarization, and apoptotic rate following treatment were determined. Results Four nanovesicles (PEG-PDLLA-DOX-HMME, PEG-PDLLA-DOX, PEG-PDLLA-HMME, and PEG-PDLLA) were synthesized, and mean particle sizes were 175±18 nm, 154±3 nm, 196±2 nm, and 147±15 nm, respectively. PEG-PDLLA-DOX-HMME was more cytotoxic than PEG-PDLLA-DOX, PEG-PDLLA-HMME, and PEG-PDLLA. PEG-PDLLA-HMME-treated cells had the highest mean fluorescence intensity, followed by PEG-PDLLA-DOX-HMME-treated cells, whereas PEG-PDLLA-DOX- and PEG-PDLLA-treated cells had a similar fluorescence intensity. Mitochondrial membrane potential depolarization was observed in 54.2%, 59.4%, 13.8%, and 14.8% of the cells treated with PEG-PDLLA-DOX-HMME, PEG-PDLLA-HMME, PEG-PDLLA-DOX, and PEG-PDLLA, respectively. The apoptotic rate was significantly higher in PEG-PDLLA-DOX-HMME-treated cells compared with PEG-PDLLA-DOX- and PEG-PDLLA-HMME-treated cells. Conclusion The PEG-PDLLA nanovesicle, a drug delivery carrier, can be simultaneously loaded with two anticancer drugs (hydrophilic DOX and hydrophobic HMME). PEG-PDLLA-DOX-HMME cytotoxicity to HepG2 cells is significantly higher than the PEG-PDLLA nanovesicle loaded with DOX or HMME alone, and DOX and HMME have a

  18. Brain tumor-targeted delivery and therapy by focused ultrasound introduced doxorubicin-loaded cationic liposomes.

    PubMed

    Lin, Qian; Mao, Kai-Li; Tian, Fu-Rong; Yang, Jing-Jing; Chen, Pian-Pian; Xu, Jie; Fan, Zi-Liang; Zhao, Ya-Ping; Li, Wen-Feng; Zheng, Lei; Zhao, Ying-Zheng; Lu, Cui-Tao

    2016-02-01

    Brain tumor lacks effective delivery system for treatment. Focused ultrasound (FUS) can reversibly open BBB without impacts on normal tissues. As a potential drug carrier, cationic liposomes (CLs) have the ability to passively accumulate in tumor tissues for their positive charge. In this study, FUS introduced doxorubicin-loaded cationic liposomes (DOX-CLs) were applied to improve the efficiency of glioma-targeted delivery. Doxorubicin-loaded CLs (DOX-CLs) and quantum dot-loaded cationic liposomes (QD-CLs) were prepared using extrusion technology, and their characterizations were evaluated. With the advantage of QDs in tracing images, the glioma-targeted accumulation of FUS + CLs was evaluated by fluorescence imaging and flow cytometer. Cell survival rate, tumor volume, animal survival time, and brain histology in C6 glioma model were investigated to evaluate the glioma-targeted delivery of FUS + DOX-CLs. DOX-CLs and QD-CLs had suitable nanoscale sizes and high entrapment efficiency. The combined strategy of FUS introduced CLs significantly increased the glioma-targeted accumulation for load drugs. FUS + DOX-CLs showed the strongest inhibition on glioma based on glioma cell in vitro and glioma model in vivo experiments. From MRI and histological analysis, FUS + DOX-CLs group strongly suppressed the glioma progression and extended the animal survival time to 81.2 days. Among all the DOX treatment groups, FUS + DOX-CLs group showed the best cell viability and highest level of tumor apoptosis and necrosis. Combining the advantages of BBB reversible opening by FUS and glioma-targeted binding by CLs, ultrasound introduced cationic liposomes could achieve glioma-targeted delivery, which might be developed as a potential strategy for future brain tumor therapy.

  19. The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells.

    PubMed

    Sun, Zuyue; Schriewer, Jill; Tang, Mingxin; Marlin, Jerry; Taylor, Frederick; Shohet, Ralph V; Konorev, Eugene A

    2016-01-01

    Elevated ALK4/5 ligands including TGF-β and activins have been linked to cardiovascular remodeling and heart failure. Doxorubicin (Dox) is commonly used as a model of cardiomyopathy, a condition that often precedes cardiovascular remodeling and heart failure. In 7-8-week-old C57Bl/6 male mice treated with Dox we found decreased capillary density, increased levels of ALK4/5 ligand and Smad2/3 transcripts, and increased expression of Smad2/3 transcriptional targets. Human cardiac microvascular endothelial cells (HCMVEC) treated with Dox also showed increased levels of ALK4/5 ligands, Smad2/3 transcriptional targets, a decrease in proliferation and suppression of vascular network formation in a HCMVEC and human cardiac fibroblasts co-culture assay. Our hypothesis is that the deleterious effects of Dox on endothelial cells are mediated in part by the activation of the TGF-β pathway. We used the inhibitor of ALK4/5 kinases SB431542 (SB) in concert with Dox to ascertain the role of TGF-β pathway activation in doxorubicin induced endothelial cell defects. SB prevented the suppression of HCMVEC proliferation in the presence of TGF-β2 and activin A, and alleviated the inhibition of HCMVEC proliferation by Dox. SB also prevented the suppression of vascular network formation in co-cultures of HCMVEC and human cardiac fibroblasts treated with Dox. Our results show that the inhibition of the TGF-β pathway alleviates the detrimental effects of Dox on endothelial cells in vitro.

  20. Biomarkers for Presymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients.

    PubMed

    Todorova, Valentina K; Makhoul, Issam; Siegel, Eric R; Wei, Jeanne; Stone, Annjanette; Carter, Weleetka; Beggs, Marjorie L; Owen, Aaron; Klimberg, V Suzanne

    2016-01-01

    Cardiotoxicity of doxorubicin (DOX) remains an important health concern. DOX cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. No biomarker for presymptomatic detection of DOX cardiotoxicity has been validated. Our hypothesis is that peripheral blood cells (PBC) gene expression induced by the early doses of DOX-based chemotherapy could identify potential biomarkers for presymptomatic cardiotoxicity in cancer patients. PBC gene expression of 33 breast cancer patients was conducted before and after the first cycle of DOX-based chemotherapy. Cardiac function was evaluated before the start of chemotherapy and at its completion. Differentially expressed genes (DEG) of patients who developed DOX-associated cardiotoxicity after the completion of chemotherapy were compared with DEG of patients who did not. Ingenuity database was used for functional analysis of DEG. Sixty-sevens DEG (P<0.05) were identified in PBC of patients with DOX-cardiotoxicity. Most of DEG encode proteins secreted by activated neutrophils. The functional analysis of the DEG showed enrichment for immune- and inflammatory response. This is the first study to identify the PBC transcriptome signature associated with a single dose of DOX-based chemotherapy in cancer patients. We have shown that PBC transcriptome signature associated with one dose of DOX chemotherapy in breast cancer can predict later impairment of cardiac function. This finding may be of value in identifying patients at high or low risk for the development of DOX cardiotoxicity during the initial doses of chemotherapy and thus to avoid the accumulating toxic effects from the subsequent doses during treatment. PMID:27490685

  1. Synthesis and characterization of doxorubicin modified ZnO/PEG nanomaterials and its photodynamic action.

    PubMed

    Hariharan, R; Senthilkumar, S; Suganthi, A; Rajarajan, M

    2012-11-01

    The aim of this study is to investigate a new strategy of combined application of ZnO/PEG nanospheres with anticancer drug of doxorubicin (DOX) in photodynamic therapy (PDT). We were able to fabricate ZnO/PEG nanospheres as the drug carrier of DOX in drug delivery system. The combination of DOX-ZnO/PEG nanocomposites induced the remarkable improvement in the anti-tumor activity, which has been demonstrated by antibacterial activity, drug release and DNA cleavage study. Furthermore, the possible mechanism was explored by optical spectroscopic studies and EPR - spin trapping technique. It was noted that the photodynamic activity of the non-cytotoxic DOX loaded ZnO/PEG nanocomposite could considerably increase cancer cell injury mediated by reactive oxygen species (ROS) under UV irradiation. In our observations demonstrated that ZnO/PEG nanosphere could obviously increase the intracellular concentration of DOX and enhance its potential anti-tumor efficiency, indicating that ZnO/PEG nanosphere could act as an efficient drug delivery carrier importing DOX into target cancer cells. Nearly 91% of loaded drug was released within 26 h of incubation of conjugates in vitro in an acidic environment. It suggests that there is an efficient drug release of DOX from DOX-ZnO/PEG nanocomposite. DOX loaded on ZnO/PEG nanomaterials showed antibacterial activity was more pronounced with Gram-positive than Gram-negative bacteria under visible light. DOX-ZnO/PEG nanocomposites were effective against HeLa cell lines under in vitro condition and photocleavage of DNA. This result indicated that ZnO/PEG nanomaterials can be used as a nanocarrier for drug delivery system for PDT. PMID:22982207

  2. Biomarkers for Presymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients

    PubMed Central

    Todorova, Valentina K.; Makhoul, Issam; Siegel, Eric R.; Wei, Jeanne; Stone, Annjanette; Carter, Weleetka; Beggs, Marjorie L.; Owen, Aaron; Klimberg, V. Suzanne

    2016-01-01

    Cardiotoxicity of doxorubicin (DOX) remains an important health concern. DOX cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. No biomarker for presymptomatic detection of DOX cardiotoxicity has been validated. Our hypothesis is that peripheral blood cells (PBC) gene expression induced by the early doses of DOX-based chemotherapy could identify potential biomarkers for presymptomatic cardiotoxicity in cancer patients. PBC gene expression of 33 breast cancer patients was conducted before and after the first cycle of DOX-based chemotherapy. Cardiac function was evaluated before the start of chemotherapy and at its completion. Differentially expressed genes (DEG) of patients who developed DOX-associated cardiotoxicity after the completion of chemotherapy were compared with DEG of patients who did not. Ingenuity database was used for functional analysis of DEG. Sixty-sevens DEG (P<0.05) were identified in PBC of patients with DOX-cardiotoxicity. Most of DEG encode proteins secreted by activated neutrophils. The functional analysis of the DEG showed enrichment for immune- and inflammatory response. This is the first study to identify the PBC transcriptome signature associated with a single dose of DOX-based chemotherapy in cancer patients. We have shown that PBC transcriptome signature associated with one dose of DOX chemotherapy in breast cancer can predict later impairment of cardiac function. This finding may be of value in identifying patients at high or low risk for the development of DOX cardiotoxicity during the initial doses of chemotherapy and thus to avoid the accumulating toxic effects from the subsequent doses during treatment. PMID:27490685

  3. Biomarkers for Presymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients.

    PubMed

    Todorova, Valentina K; Makhoul, Issam; Siegel, Eric R; Wei, Jeanne; Stone, Annjanette; Carter, Weleetka; Beggs, Marjorie L; Owen, Aaron; Klimberg, V Suzanne

    2016-01-01

    Cardiotoxicity of doxorubicin (DOX) remains an important health concern. DOX cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. No biomarker for presymptomatic detection of DOX cardiotoxicity has been validated. Our hypothesis is that peripheral blood cells (PBC) gene expression induced by the early doses of DOX-based chemotherapy could identify potential biomarkers for presymptomatic cardiotoxicity in cancer patients. PBC gene expression of 33 breast cancer patients was conducted before and after the first cycle of DOX-based chemotherapy. Cardiac function was evaluated before the start of chemotherapy and at its completion. Differentially expressed genes (DEG) of patients who developed DOX-associated cardiotoxicity after the completion of chemotherapy were compared with DEG of patients who did not. Ingenuity database was used for functional analysis of DEG. Sixty-sevens DEG (P<0.05) were identified in PBC of patients with DOX-cardiotoxicity. Most of DEG encode proteins secreted by activated neutrophils. The functional analysis of the DEG showed enrichment for immune- and inflammatory response. This is the first study to identify the PBC transcriptome signature associated with a single dose of DOX-based chemotherapy in cancer patients. We have shown that PBC transcriptome signature associated with one dose of DOX chemotherapy in breast cancer can predict later impairment of cardiac function. This finding may be of value in identifying patients at high or low risk for the development of DOX cardiotoxicity during the initial doses of chemotherapy and thus to avoid the accumulating toxic effects from the subsequent doses during treatment.

  4. Early transcriptional changes in cardiac mitochondria during chronic doxorubicin exposure and mitigation by dexrazoxane in mice.

    PubMed

    Vijay, Vikrant; Moland, Carrie L; Han, Tao; Fuscoe, James C; Lee, Taewon; Herman, Eugene H; Jenkins, G Ronald; Lewis, Sherry M; Cummings, Connie A; Gao, Yuan; Cao, Zhijun; Yu, Li-Rong; Desai, Varsha G

    2016-03-15

    Identification of early biomarkers of cardiotoxicity could help initiate means to ameliorate the cardiotoxic actions of clinically useful drugs such as doxorubicin (DOX). Since DOX has been shown to target mitochondria, transcriptional levels of mitochondria-related genes were evaluated to identify early candidate biomarkers in hearts of male B6C3F1 mice given a weekly intravenous dose of 3mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice was pretreated (intraperitoneally) with the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg) 30 min before each weekly dose of DOX or SAL. At necropsy a week after the last dose, increased plasma concentrations of cardiac troponin T (cTnT) were detected at 18 and 24 mg/kg cumulative DOX doses, whereas myocardial alterations were observed only at the 24 mg/kg dose. Of 1019 genes interrogated, 185, 109, 140, 184, and 451 genes were differentially expressed at 6, 9, 12, 18, and 24 mg/kg cumulative DOX doses, respectively, compared to concurrent SAL-treated controls. Of these, expression of 61 genes associated with energy metabolism and apoptosis was significantly altered before and after occurrence of myocardial injury, suggesting these as early genomics markers of cardiotoxicity. Much of these DOX-induced transcriptional changes were attenuated by pretreatment of mice with DXZ. Also, DXZ treatment significantly reduced plasma cTnT concentration and completely ameliorated cardiac alterations induced by 24 mg/kg cumulative DOX. This information on early transcriptional changes during DOX treatment may be useful in designing cardioprotective strategies targeting mitochondria. PMID:26873546

  5. Amphiphilic Copolymeric Micelles for Doxorubicin and Curcumin Co-Delivery to Reverse Multidrug Resistance in Breast Cancer.

    PubMed

    Lv, Li; Qiu, Kaifeng; Yu, Xiaoxia; Chen, Chuxiong; Qin, Fengchao; Shi, Yonghui; Ou, Jiebin; Zhang, Tao; Zhu, Hua; Wu, Junyan; Liu, Chunxia; Li, Guocheng

    2016-05-01

    Development of multidrug resistance against chemotherapeutic drugs is one of the major obstacles to successful cancer therapy in the clinic. Thus far, amphiphilic polymeric micelles and chemosensitizers have been used to overcome multidrug resistance in cancer. The goals of this study were to prepare poly(ethylene glycol)-bock-poly(lactide) (PEG(2k)-PLA(5k)) micelles for co-delivery of the chemotherapeutic drug doxorubicin (DOX) with a chemosensitizer curcumin (CUR), investigate the potential of the dual drug-loaded micelles ((DOX+CUR)-Micelles) to reverse multidrug resistance, and explore the underlying mechanisms. (DOX + CUR)-Micelles were prepared using an emulsion solvent evaporation method. The cellular uptake, drug efflux, down-regulation of P-glycoprotein expression and inhibition of ATP activity of (DOX+ CUR)-Micelles were studied in drug-resistant MCF-7/ADR cells. In vitro analyses demonstrated that (DOX + CUR)-Micelles were superior to free DOX, free drug combination (DOX + CUR), and DOX-loaded micelles in inhibiting proliferation of MCF-7/ADR cells. This effect of (DOX + CUR)-Micelles was partially attributable to their highest cellular uptake, lowest efflux rate of DOX, and strongest effects on down-regulation of P-glycoprotein and inhibition of ATP activity. Additionally, (DOX+CUR)-Micelles showed increased tumor accumulation and strong inhibitory effect on tumor growth in the xenograft model of drug-resistant MCF-7/ADR cells compared to that of other drug formulations. These results indicate that (DOX + CUR)-Micelles display potential for application in the therapy of drug-resistant breast carcinoma. PMID:27305819

  6. The effects of onion (Allium cepa) extract on doxorubicin-induced apoptosis in aortic endothelial cells.

    PubMed

    Alpsoy, Seref; Uygur, Ramazan; Aktas, Cevat; Topcu, Birol; Kanter, Mehmet; Erboga, Mustafa; Karakaya, Osman; Gedikbasi, Asuman

    2013-05-01

    The aim of this study was to investigate the effects of onion (Allium cepa) extracts (ACE) on doxorubicin (DOX)-induced apoptosis in aortic endothelial cells. The rats in the ACE-pretreated group were given a daily dose of 1 ml ACE for 14 days. To induce aortic endothelial cell apoptosis, DOX (30 mg kg(-1) body weight) was injected intraperitoneally by a single dose and the rats were sacrificed after 48 h. To date, no such studies have been performed on antiapoptotic potential of ACE on DOX-induced apoptosis in aortic endothelial cells. Our data indicate a significant reduction in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling in aortic endothelial cells of the DOX-treated group with ACE therapy. DOX-treated with ACE groups showed a significant decrease in malondialdehyde levels and increased levels of glutathione in comparison with the DOX-treated group. Data from our study show that prevention of endothelial cell apoptosis by ACE may contribute to the restoration of aortic endothelial dysfunction that is associated with DOX treatment.

  7. In Vivo Protective Effects of Diosgenin against Doxorubicin-Induced Cardiotoxicity

    PubMed Central

    Chen, Chih-Tai; Wang, Zhi-Hong; Hsu, Cheng-Chin; Lin, Hui-Hsuan; Chen, Jing-Hsien

    2015-01-01

    Doxorubicin (DOX) induces oxidative stress leading to cardiotoxicity. Diosgenin, a steroidal saponin of Dioscorea opposita, has been reported to have antioxidant activity. Our study was aimed to find out the protective effect of diosgenin against DOX-induced cardiotoxicity in mice. DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases in the blood pressure and the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity. In the heart tissue of the DOX-treated mice, DOX reduced activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were recovered by diosgenin. Diosgenin also decreased the serum levels of cardiotoxicity markers, cardiac levels of thiobarbituric acid relative substances (TBARS) and reactive oxygen species (ROS), caspase-3 activation, and mitochondrial dysfunction, as well as the expression of nuclear factor kappa B (NF-κB), an inflammatory factor. Moreover, diosgenin had the effects of increasing the cardiac levels of cGMP via modulation of phosphodiesterase-5 (PDE5) activity, and in improving myocardial fibrosis in the DOX-treated mice. Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38. Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protect the heart from the DOX-induced cardiotoxicity. PMID:26091236

  8. Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction.

    PubMed

    Das, Anindita; Durrant, David; Mitchell, Clint; Mayton, Eric; Hoke, Nicholas N; Salloum, Fadi N; Park, Margaret A; Qureshi, Ian; Lee, Ray; Dent, Paul; Kukreja, Rakesh C

    2010-10-19

    We have shown that the potent phosphodiesterase-5 (PDE-5) inhibitor sildenafil (Viagra) induces a powerful effect on reduction of infarct size following ischemia/reperfusion injury and improvement of left ventricular dysfunction in the failing heart after myocardial infarction or doxorubicin (DOX) treatment. In the present study, we further investigated the potential effects of sildenafil on improving antitumor efficacy of DOX in prostate cancer. Cotreatment with sildenafil enhanced DOX-induced apoptosis in PC-3 and DU145 prostate cancer cells, which was mediated by enhanced generation of reactive oxygen species, up-regulation of caspase-3 and caspase-9 activities, reduced expression of Bcl-xL, and phosphorylation of Bad. Overexpression of Bcl-xL or dominant negative caspase 9 attenuated the synergistic effect of sildenafil and DOX on prostate cancer cell killing. Furthermore, treatment with sildenafil and DOX in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. The reduced tumor size was associated with amplified apoptotic cell death and increased expression of activated caspase 3. Doppler echocardiography showed that sildenafil treatment ameliorated DOX-induced left ventricular dysfunction. In conclusion, these results provide provocative evidence that sildenafil is both a powerful sensitizer of DOX-induced killing of prostate cancer while providing concurrent cardioprotective benefit. PMID:20884855

  9. In Vivo Protective Effects of Diosgenin against Doxorubicin-Induced Cardiotoxicity.

    PubMed

    Chen, Chih-Tai; Wang, Zhi-Hong; Hsu, Cheng-Chin; Lin, Hui-Hsuan; Chen, Jing-Hsien

    2015-06-01

    Doxorubicin (DOX) induces oxidative stress leading to cardiotoxicity. Diosgenin, a steroidal saponin of Dioscorea opposita, has been reported to have antioxidant activity. Our study was aimed to find out the protective effect of diosgenin against DOX-induced cardiotoxicity in mice. DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases in the blood pressure and the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity. In the heart tissue of the DOX-treated mice, DOX reduced activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were recovered by diosgenin. Diosgenin also decreased the serum levels of cardiotoxicity markers, cardiac levels of thiobarbituric acid relative substances (TBARS) and reactive oxygen species (ROS), caspase-3 activation, and mitochondrial dysfunction, as well as the expression of nuclear factor kappa B (NF-κB), an inflammatory factor. Moreover, diosgenin had the effects of increasing the cardiac levels of cGMP via modulation of phosphodiesterase-5 (PDE5) activity, and in improving myocardial fibrosis in the DOX-treated mice. Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38. Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protect the heart from the DOX-induced cardiotoxicity. PMID:26091236

  10. Stimuli-responsive lipid nanotubes in gel formulations for the delivery of doxorubicin.

    PubMed

    Ilbasmis-Tamer, Sibel; Unsal, Hande; Tugcu-Demiroz, Fatmanur; Kalaycioglu, Gokce Dicle; Degim, Ismail Tuncer; Aydogan, Nihal

    2016-07-01

    Lipid nanotubes (LNTs) are one of the most advantageous structures for drug delivery and targeting. LNTs formed by a specially designed molecule called AQUA (AQ-NH-(CH2)10COOH (AQ: anthraquinone group) is used for drug delivery, and doxorubicin (DOX) is the drug selected. DOX and AQUA have some similarities in their molecular structures, so a significant amount of DOX can be loaded to LNTs. The AQUA LNTs are pH responsive, and drug loading increased almost linearly by increasing the pH, reaching a maximum value (96%) at pH 9.0. In terms of drug release, lower pHs are preferred. Drug-loaded LNTs are also mixed with four different gels (chitosan, alginate, hydroxypropyl methylcellulose and polycarbophil) to use the advantages of these gels. The drug release efficiency is studied using a Franz diffusion cell in which sheep colon membranes and dialysis membranes are utilized. The amount of released DOX from the chitosan gel formulations was quite high. Sodium alginate gels had lower release and slower diffusion of DOX. The cytotoxic effect of DOX-loaded AQUA LNTs has also been determined on cell cultures. Our new lipid nanotubes are a non-toxic, effective, biodegradable, biocompatible, stable and promising system for drug delivery and can be used for colonic administration of DOX for the treatment of colorectal cancer (CRC).

  11. Microarray and Co-expression Network Analysis of Genes Associated with Acute Doxorubicin Cardiomyopathy in Mice.

    PubMed

    Wei, Sheng-Nan; Zhao, Wen-Jie; Zeng, Xiang-Jun; Kang, Yu-Ming; Du, Jie; Li, Hui-Hua

    2015-10-01

    Clinical use of doxorubicin (DOX) in cancer therapy is limited by its dose-dependent cardiotoxicity. But molecular mechanisms underlying this phenomenon have not been well defined. This study was to investigate the effect of DOX on the changes of global genomics in hearts. Acute cardiotoxicity was induced by giving C57BL/6J mice a single intraperitoneal injection of DOX (15 mg/kg). Cardiac function and apoptosis were monitored using echocardiography and TUNEL assay at days 1, 3 and 5. Myocardial glucose and ATP levels were measured. Microarray assays were used to screen gene expression profiles in the hearts at day 5, and the results were confirmed with qPCR analysis. DOX administration caused decreased cardiac function, increased cardiomyocyte apoptosis and decreased glucose and ATP levels. Microarrays showed 747 up-regulated genes and 438 down-regulated genes involved in seven main functional categories. Among them, metabolic pathway was the most affected by DOX. Several key genes, including 2,3-bisphosphoglycerate mutase (Bpgm), hexokinase 2, pyruvate dehydrogenase kinase, isoenzyme 4 and fructose-2,6-bisphosphate 2-phosphatase, are closely related to glucose metabolism. Gene co-expression networks suggested the core role of Bpgm in DOX cardiomyopathy. These results obtained in mice were further confirmed in cultured cardiomyocytes. In conclusion, genes involved in glucose metabolism, especially Bpgm, may play a central role in the pathogenesis of DOX-induced cardiotoxicity. PMID:25575753

  12. Enhanced doxorubicin delivery and cytotoxicity in multidrug resistant cancer cells using multifunctional magnetic nanoparticles.

    PubMed

    Pilapong, Chalermchai; Keereeta, Yanee; Munkhetkorn, Samlee; Thongtem, Somchai; Thongtem, Titipun

    2014-01-01

    Carboxymethyl modified magnetic nanoparticles (CMC-MNPs) have been designed as a vehicle for drug delivery in both drug-sensitive and drug-resistant cancer cells. We have demonstrated that the CMC-MNPs were able to load doxorubicin (DOX) with a high loading efficiency while also maintaining a good colloidal stability in an aqueous solution. According to a drug release study, DOX-loaded CMC-MNPs showed that the pH-dependent drug release property had a much higher release rate in acidic pH. Compared to free DOX, the DOX-loaded CMC-MNPs showed higher DOX accumulation in drug-sensitive cancer cells and much higher accumulation in drug-resistant cancer cells. These results indicate that our nanoplatform is highly efficient as a drug delivery system in both normal cancer cells and MDR cancer cells. In addition, the DOX-loaded CMC-MNPs can also enhance cytotoxicity against drug-resistant cancer cells in comparison to free DOX. The results obtained in this research demonstrate that our nanoplatform may be a promising approach in cancer chemotherapy and for overcoming multidrug-resistant cancer cells.

  13. Possible Protective Effect of Diacerein on Doxorubicin-Induced Nephrotoxicity in Rats

    PubMed Central

    Refaie, Marwa M. M.; Amin, Entesar F.; El-Tahawy, Nashwa F.; Abdelrahman, Aly M.

    2016-01-01

    Nephrotoxicity is one of the limiting factors for using doxorubicin (DOX). Interleukin 1 has major role in DOX-induced nephrotoxicity, so we investigated the effect of interleukin 1 receptor antagonist diacerein (DIA) on DOX-induced nephrotoxicity. DIA (25 and 50 mg/kg/day) was administered orally to rats for 15 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of DOX (15 mg/kg) at the 11th day. We measured levels of serum urea, creatinine, renal reduced glutathione (GSH), malondialdehyde (MDA), total nitrites (NOx), catalase, and superoxide dismutase (SOD). In addition, caspase-3, tumor necrosis factor alpha (TNFα), nuclear factor kappa B (NFκB) expressions, and renal histopathology were assessed. Our results showed that DOX-induced nephrotoxicity was ameliorated or reduced by both doses of DIA, but diacerein high dose (DHD) showed more improvement than diacerein low dose (DLD). This protective effect was manifested by significant improvement in all measured parameters compared to DOX treated group by using DHD. DLD showed significant improvement of creatinine, MDA, NOx, GSH, histopathology, and immunohistochemical parameters compared to DOX treated group. PMID:26904117

  14. Octreotide-modification enhances the delivery and targeting of doxorubicin-loaded liposomes to somatostatin receptors expressing tumor in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Sun, Minjie; Wang, Yu; Shen, Jie; Xiao, Yanyu; Su, Zhigui; Ping, Qineng

    2010-11-01

    Octreotide is believed to be the ligand of somatostatin receptors (SSTRs) which are widely used in tumor diagnosis and clinical therapy. In the present work, a new targeting conjugate, octreotide-polyethylene glycol-phosphatidylethanolamine (Oct-PEG-PE), was developed for the assembling of liposome, and the effect of octreotide-modification on the enhancement of the delivery and targeting of doxorubicin-loaded liposomes was investigated in vitro and in vivo. Oct-PEG-PE was synthesized by a three-step reaction involving two derivative intermediate formations of bis (p-nitrophenyl carbonate)-PEG ((pNP)2-PEG) and pNP-PEG-PE. The Oct-modified and unmodified liposomes (DOX-OL and DOX-CL) were prepared by the ammonium sulfate gradient method. Both drug uptake assay and cell apoptosis assay suggested that DOX-OL noticeably increased the uptake of DOX in SMMC-7721 cells and showed a more significant cytotoxicity, compared with DOX-CL. The effect of DOX-OL was remarkably inhibited by free octreotide. In contrast, no significant difference in drug cytotoxicty was found between DOX-OL and DOX-CL in CHO cells without obvious expression of SSTRs. The study of ex vivo fluorescence tissues imaging of BALB/c mice and in vivo tissue distribution of B16 tumor-bearing mice indicated that DOX-OL caused remarkable accumulation of DOX in melanoma tumors and the pancreas, in which the SSTRs are highly expressed.

  15. Lipoplex-Mediated Deintercalation of Doxorubicin from Calf Thymus DNA-Doxorubicin Complex.

    PubMed

    Das, Anupam; Adhikari, Chandan; Chakraborty, Anjan

    2016-09-01

    In this paper, we report the lipoplex-mediated deintercalation of anticancer drug doxorubicin (DOX) from the DOX-DNA complex under controlled experimental conditions. We used three zwitterionic liposomes, namely, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC), which are widely different in their phase transition temperatures to form a lipoplex with calf thymus DNA in the presence of Ca(2+) ions. The study revealed that DPPC being in sol-gel phase was more effective in releasing the drug from the DOX-DNA complex compared with liposomes that remain in liquid crystalline phase (DMPC and POPC). The higher extent of drug release in the case of DPPC liposomes was attributed to the stronger lipoplex formation with DNA as compared with that of other liposomes. Owing to the relatively smaller head group area, the DPPC liposomes in their sol-gel phase can absorb a larger number of Ca(2+) ions and hence offer a strong electrostatic interaction with DNA. This interaction was confirmed by time-resolved anisotropy and circular dichroism spectroscopy. Apart from the electrostatic interaction, the possible hydrophobic interaction between the liposomes and DNA was also taken into account for the observed deintercalation. The successful uptake of drug molecules by liposomes from the drug-DNA complex in the post-release period was also confirmed using confocal laser scanning microscopy (CLSM). PMID:27465781

  16. Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde.

    PubMed

    Barthel, Benjamin L; Mooz, Erin L; Wiener, Laura Elizabeth; Koch, Gary G; Koch, Tad H

    2016-03-10

    Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA cross-linker. Contrary to current dogma, we show that both efficient DNA cross-linking and potent synergy in combination with formaldehyde correlate with the anthracycline's ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better cross-linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and epirubicin, which cannot form stable oxazolidines. These results have potential clinical implications in the active field of anthracycline prodrug design and development.

  17. Chemo/Photoacoustic Dual Therapy with mRNA-Triggered DOX Release and Photoinduced Shockwave Based on a DNA-Gold Nanoplatform.

    PubMed

    Zang, Yundong; Wei, Yanchun; Shi, Yujiao; Chen, Qun; Xing, Da

    2016-02-10

    A multifunctional nanoparticle based on gold nanorod (GNR), utilizing mRNA triggered chemo-drug release and near-infrared photoacoustic effect, is developed for a combined chemo-photoacoustic therapy. The constructed nanoparticle (GNR-DNA/FA:DOX) comprises three functional components: (i) GNR as the drug delivery platform and photoacoustic effect enhancer; (ii) toehold-possessed DNA dressed on the GNR to load doxorubicin (DOX) to implement a tumor cell specific chemotherapy; and (iii) folate acid (FA) modified on GNR to guide the nanoparticle to target tumor cells. The results show that, upon an effective and specific delivery of the nanoparticles to the tumor cells with overexpressed folate receptors, the cytotoxic DOX loaded on the GNR-DNA nanoplatform can be released through DNA displacement reaction in melanoma-associated antigen gene mRNA expressed cells. With 808 nm pulse laser irradiation, the photoacoustic effect of the GNR leads to a direct physical damage to the cells. The combined treatment of the two modalities can effectively destroy tumor cells and eradicate the tumors with two distinctively different and supplementing mechanisms. With the nanoparticle, photoacoustic imaging is successfully performed in situ to monitor the drug distribution and tumor morphology for therapeutical guidance. With further in-depth investigation, the proposed nanoparticle may provide an effective and safe alternative cancer treatment modality.

  18. Synthesis and characterization of recyclable clusters of magnetic nanoparticles as doxorubicin carriers for cancer therapy

    NASA Astrophysics Data System (ADS)

    Wu, Juan; Wang, Yujiao; Jiang, Wei; Xu, Shanshan; Tian, Renbing

    2014-12-01

    This study focuses on the synthesis and characterization of recyclable clusters of magnetic nanoparticles (CMNPs) as doxorubicin carriers for cancer therapy. Fe3O4 nanoparticles were used as magnetically responsive carriers, the modified polyethylene glycol dicarboxylic acid (APS-PEG-TFEE) acted as a steady bridge between Fe3O4 and drug. The prepared CMNPs exhibited a size within 20 nm, good stability and super-paramagnetic responsibility (Ms 62.02 emu/g); doxorubicin (DOX) can be successfully loaded to CMNPs at a loading rate of 76.19% by electrostatic interaction. Moreover, the release studies in vitro showed that the drug-loaded carriers (CMNPs-DOX) had excellent pH-sensitivity, 76.16% of DOX was released within 72 h at pH 4.0, and the secondary drug loading rate was nearly 52%. WST-1 assays in model breast cancer cells (MCF-7) demonstrated that CMNPs-DOX exhibited high anti-tumor activity, while the CMNPs were practically non-toxic. Thus, our results revealed that CMNPs would be a competitive candidate for drug delivery carriers and CMNPs-DOX could be used in targeted cancer therapy in the near future.

  19. Overcoming multidrug resistance with mesoporous silica nanorods as nanocarrier of doxorubicin.

    PubMed

    Li, Linlin; Huang, Xinglu; Liu, Tianlong; Liu, Huiyu; Hao, Nanjing; Chen, Dong; Zhang, Yanqi; Li, Laifeng; Tang, Fangqiong

    2012-06-01

    Multidrug resistance (MDR) is a major obstacle to the effective chemotherapy in many human malignancies. Nanoparticulate drug delivery systems (NDDSs) have been reported to be able to bypass MDR, but the cancer therapeutic efficacy is still limited. In this study, we firstly designed the nonspherical mesoporous silica nanorods (MSNRs) with aspect ratio (AR) of 1.5 and 5 as drug delivery systems of doxorubicin to overcome multidrug resistance. For drug loading, the long-rod MSNRs (NLR, AR = 5) showed higher drug loading capacity of doxorubicin (DOX) than the short-rod MSNRs (NSR, AR = 1.5). NLR encapsulated DOX had increased intracellular DOX accumulation in drug-resistant Chinese hamster ovary (CHO) cells compared with free DOX by observablly increased cellular uptake and significantly prolonged intracellular drug retention. It further exhibited increased cytotoxicity compared with free DOX under different drug concentrations. These findings may provide a new perspective for designing high-performance nanoparticulate drug delivery systems for bypassing multidrug resistance of cancer therapy.

  20. REPEATED TREATMENTS WITH DOXORUBICIN CAUSES ELECTROCARDIOGRAM (ECG) CHANGES AND INCREASED VENTRICULAR PREMATURE BEATS IN WISTAR-KYOTO (WKY) RATS

    EPA Science Inventory

    Doxorubicin (DOX) is a widely used anthracycline anti-neoplastic drug used to treat tumors. However it has been implicated in irreversible cardiac toxicity via the generation of a proxidant semiquinone free radical, which often results in cardiomyopathy and changes in the ECG. Ac...

  1. Green Synthesis and Characterization of Monodispersed Gold Nanoparticles: Toxicity Study, Delivery of Doxorubicin and Its Bio-Distribution in Mouse Model.

    PubMed

    Mukherjee, Sudip; Sau, Samaresh; Madhuri, Durga; Bollu, Vishnu Sravan; Madhusudana, Kuncha; Sreedhar, Bojja; Banerjee, Rajkumar; Patra, Chitta Ranjan

    2016-01-01

    In the present article, we report the in vitro and in vivo delivery of doxorubicin using biosynthesized gold nanoparticles (b-Au-PP). Gold nanoparticles were synthesized by a simple, fast, efficient, environmentally friendly and economical green chemistry approach using an extract of Peltophorum pterocarpum (PP) leaves. Because the biosynthesized b-Au-PP was highly stable in various physiological buffers for several weeks and biocompatible in both in vitro and in vivo systems, we designed and developed a biosynthesized gold nanoparticle (b-Au-PP)-based drug-delivery system (DDS) using doxorubicin (Dox) (b-Au-PP-Dox). Both b-Au-PP and b-Au-PP-Dox were thoroughly characterized using several analytical tools. Administration of doxorubicin-loaded DDS (b-Au-PP-Dox) resulted in a significant inhibition of the proliferation of cancer cells (A549, B16F10) in vitro and of tumor growth in an in vivo model compared to doxorubicin alone. Furthermore, we found that the cellular uptake and release of Dox in the nanoconjugated form (b-Au-PP-Dox) were faster than the uptake and release of unconjugated Dox. The in vivo toxicity study did not show any significant changes in the hematology, serum clinical biochemistry or histopathology in the C57BL6/J female mice after consecutive intraperitoneal (IP) injections over a period of seven days. To the best of our knowledge, our study is the first to report the application of a biosynthesized gold nanoparticle-based DDS for cancer therapy in an animal model, in addition to a detailed in vivo toxicity study. Together, the results demonstrate that a biosynthesized gold nanoparticle-based drug-delivery system (b-Au-PP-Dox) could be used in the near future as an alternative cost-effective treatment strategy for cancer therapy. PMID:27301182

  2. Green Synthesis and Characterization of Monodispersed Gold Nanoparticles: Toxicity Study, Delivery of Doxorubicin and Its Bio-Distribution in Mouse Model.

    PubMed

    Mukherjee, Sudip; Sau, Samaresh; Madhuri, Durga; Bollu, Vishnu Sravan; Madhusudana, Kuncha; Sreedhar, Bojja; Banerjee, Rajkumar; Patra, Chitta Ranjan

    2016-01-01

    In the present article, we report the in vitro and in vivo delivery of doxorubicin using biosynthesized gold nanoparticles (b-Au-PP). Gold nanoparticles were synthesized by a simple, fast, efficient, environmentally friendly and economical green chemistry approach using an extract of Peltophorum pterocarpum (PP) leaves. Because the biosynthesized b-Au-PP was highly stable in various physiological buffers for several weeks and biocompatible in both in vitro and in vivo systems, we designed and developed a biosynthesized gold nanoparticle (b-Au-PP)-based drug-delivery system (DDS) using doxorubicin (Dox) (b-Au-PP-Dox). Both b-Au-PP and b-Au-PP-Dox were thoroughly characterized using several analytical tools. Administration of doxorubicin-loaded DDS (b-Au-PP-Dox) resulted in a significant inhibition of the proliferation of cancer cells (A549, B16F10) in vitro and of tumor growth in an in vivo model compared to doxorubicin alone. Furthermore, we found that the cellular uptake and release of Dox in the nanoconjugated form (b-Au-PP-Dox) were faster than the uptake and release of unconjugated Dox. The in vivo toxicity study did not show any significant changes in the hematology, serum clinical biochemistry or histopathology in the C57BL6/J female mice after consecutive intraperitoneal (IP) injections over a period of seven days. To the best of our knowledge, our study is the first to report the application of a biosynthesized gold nanoparticle-based DDS for cancer therapy in an animal model, in addition to a detailed in vivo toxicity study. Together, the results demonstrate that a biosynthesized gold nanoparticle-based drug-delivery system (b-Au-PP-Dox) could be used in the near future as an alternative cost-effective treatment strategy for cancer therapy.

  3. Antioxidant and anti-apoptotic effects of onion (Allium cepa) extract on doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Alpsoy, Seref; Aktas, Cevat; Uygur, Ramazan; Topcu, Birol; Kanter, Mehmet; Erboga, Mustafa; Karakaya, Osman; Gedikbasi, Asuman

    2013-03-01

    The aim of this study was to investigate the antioxidant and anti-apoptotic effects of onion (Allium cepa) extracts (ACE) on doxorubicin (DOX)-induced cardiotoxicity. The rats in the ACE-pretreated group were given a daily dose of 1 ml ACE for 14 days. To induce cardiotoxicity, DOX (30 mg kg(-1) body weight) was injected intraperitoneally by a single dose and the rats were sacrificed after 48 h. To date, no such studies have been performed on the cardioprotective and anti-apoptotic potential of ACE on DOX-induced cardiotoxicity. Our data indicate a significant reduction in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling in cardiomyocytes of the DOX-treated group with ACE therapy. The DOX-treated with ACE groups showed a significant decrease in malondialdehyde levels, and increased activities of superoxide dismutase, glutathione and glutathione peroxidase in comparison with the DOX-treated group. Creatine kinase, creatine kinase MB, lactate dehydrogenase activities and cardiac troponin I levels were significantly decreased in the DOX + ACE group in comparison with the DOX group. These biochemical and histological disturbances were effectively attenuated on pretreatment with ACE. The present study showed that ACE may be a suitable cardioprotector against toxic effects of DOX.

  4. Sulfated polysaccharide-protein complex sensitizes doxorubicin-induced apoptosis of breast cancer cells in vitro and in vivo

    PubMed Central

    Wang, Jie; Wu, Hua Jian; Zhou, Chao Zhu; Wang, Hao

    2016-01-01

    The present study aimed to investigate the effect of sulfated polysaccharide-protein complex (SPPC) on the antitumor effect of doxorubicin (Dox) on MDA-MB-231 breast cancer cells in vitro and in vivo. MTT and Annexin V/propidium iodide staining assays demonstrated that SPPC selectively sensitized MDA-MB-231 cells to Dox-induced cytotoxicity. The half maximal inhibitory concentration of Dox against MDA-MB-231 cells was decreased from 5.3 to 1.5 µM when it was used concomitantly with 5 µM SPPC. SPPC potentiated Dox-induced apoptosis in breast cancer cells via the mitochondrial apoptosis signaling pathway by activating caspase-3 and caspase-9. Notably, the caspase inhibitor Z-VAD-fmk diminished the effect of SPPC on Dox-mediated apoptosis. Furthermore, combination treatment with SPPC and Dox markedly reduced the growth of breast cancer xenografts in mice. The present study demonstrated that SPPC was able to enhance the antitumor effect of Dox on breast cancer cells, thus suggesting that SPCC may be used to reduce the cumulative dose of Dox and its associated toxicities in the chemotherapy of breast cancer and other types of cancer.

  5. Sulfated polysaccharide-protein complex sensitizes doxorubicin-induced apoptosis of breast cancer cells in vitro and in vivo

    PubMed Central

    Wang, Jie; Wu, Hua Jian; Zhou, Chao Zhu; Wang, Hao

    2016-01-01

    The present study aimed to investigate the effect of sulfated polysaccharide-protein complex (SPPC) on the antitumor effect of doxorubicin (Dox) on MDA-MB-231 breast cancer cells in vitro and in vivo. MTT and Annexin V/propidium iodide staining assays demonstrated that SPPC selectively sensitized MDA-MB-231 cells to Dox-induced cytotoxicity. The half maximal inhibitory concentration of Dox against MDA-MB-231 cells was decreased from 5.3 to 1.5 µM when it was used concomitantly with 5 µM SPPC. SPPC potentiated Dox-induced apoptosis in breast cancer cells via the mitochondrial apoptosis signaling pathway by activating caspase-3 and caspase-9. Notably, the caspase inhibitor Z-VAD-fmk diminished the effect of SPPC on Dox-mediated apoptosis. Furthermore, combination treatment with SPPC and Dox markedly reduced the growth of breast cancer xenografts in mice. The present study demonstrated that SPPC was able to enhance the antitumor effect of Dox on breast cancer cells, thus suggesting that SPCC may be used to reduce the cumulative dose of Dox and its associated toxicities in the chemotherapy of breast cancer and other types of cancer. PMID:27698706

  6. H-ferritin–nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection

    PubMed Central

    Liang, Minmin; Fan, Kelong; Zhou, Meng; Duan, Demin; Zheng, Jiyan; Yang, Dongling; Feng, Jing; Yan, Xiyun

    2014-01-01

    An ideal nanocarrier for efficient drug delivery must be able to target specific cells and carry high doses of therapeutic drugs and should also exhibit optimized physicochemical properties and biocompatibility. However, it is a tremendous challenge to engineer all of the above characteristics into a single carrier particle. Here, we show that natural H-ferritin (HFn) nanocages can carry high doses of doxorubicin (Dox) for tumor-specific targeting and killing without any targeting ligand functionalization or property modulation. Dox-loaded HFn (HFn-Dox) specifically bound and subsequently internalized into tumor cells via interaction with overexpressed transferrin receptor 1 and released Dox in the lysosomes. In vivo in the mouse, HFn-Dox exhibited more than 10-fold higher intratumoral drug concentration than free Dox and significantly inhibited tumor growth after a single-dose injection. Importantly, HFn-Dox displayed an excellent safety profile that significantly reduced healthy organ drug exposure and improved the maximum tolerated dose by fourfold compared with free Dox. Moreover, because the HFn nanocarrier has well-defined morphology and does not need any ligand modification or property modulation it can be easily produced with high purity and yield, which are requirements for drugs used in clinical trials. Thus, these unique properties make the HFn nanocage an ideal vehicle for efficient anticancer drug delivery. PMID:25267615

  7. Polyelectrolyte-Mediated Transport of Doxorubicin Through the Bilayer Lipid Membrane

    NASA Astrophysics Data System (ADS)

    Yaroslavov, Alexander A.; Kitaeva, Marina V.; Melik-Nubarov, Nikolay S.; Menger, Frederic M.

    A model is developed for the effect of ionic polymers on the transport of doxorubicin, an antitumor drug, through a bilayer membrane. Accordingly, a protonated (cationic) form of doxorubicin binds to an anionic polymer, poly(acrylic acid), the resulting complex being several hundred nanometers in size. Nevertheless, large complex species associate with neutral egg lecithin liposomes by means of hydrophobic attraction between the doxorubicin and the liposome bilayer. Then, the doxorubicin enters the liposome interior which has been imparted with an acidic buffer to protonate the doxorubicin. The rate of transmembrane Dox permeation decreases when elevating the polyacid-to-doxorubicin ratio. A cationic polymer, polylysine, being coupled with liposomes containing the negative lipid cardiolipin, accelerates membrane transport of doxorubicin with the maximum rate at a complete neutralization of the membrane charge by an interacting polycation. The effect of a polycation on doxorubicin transport becomes more pronounced as small negative liposomes (60-80 nm in diameter) are changed to larger ones (approx. 600 nm in diameter). An opportunity thus opens up for the manipulation of the kinetics of drug uptake by cells and, ultimately, the control of the pharmaceutical action of drugs.

  8. Dual targeted delivery of doxorubicin to cancer cells using folate-conjugated magnetic multi-walled carbon nanotubes.

    PubMed

    Lu, Yu-Jen; Wei, Kuo-Chen; Ma, Chen-Chi M; Yang, Shin-Yi; Chen, Jyh-Ping

    2012-01-01

    By combining the advantage of multi-walled carbon nanotubes (MWCNTs) and iron oxide magnetic nanoparticles (MNs), we develop a magnetic dual-targeted nanocarrier for drug delivery. MWCNTs were functionalized with poly(acrylic acid) through free radical polymerization, decorated with MNs, conjugated with a targeting ligand folic acid (FA), for loading of an anti-cancer drug doxorubicin (DOX). The proposed methodology provides dual targeted delivery of the anti-cancer drug to cancer cells under the guidance of a magnetic field and through ligand-receptor interactions. The chemico-physical properties of the nanocarrier were characterized, in addition to its drug loading efficiency and drug releasing characteristics. Doxorubicin could be loaded to MWCNTs with high efficiency via π-π stacking and hydrogen bonding and showed enhanced cytotoxicity toward U87 human glioblastoma cells compared with free DOX. From transmission electron microscopy and confocal laser scanning microscopy, we confirmed that DOX-FA-MN-MWCNT could be efficiently taken up by U87 cells with subsequent intracellular release of DOX, followed by transport of DOX into the nucleus with the nanocarrier left in the cytoplasm. These properties make the magnetic nanocarrier a potential candidate for targeted delivery of DOX for cancer treatment.

  9. Anti-tumor effect via passive anti-angiogenesis of PEGylated liposomes encapsulating doxorubicin in drug resistant tumors.

    PubMed

    Kibria, Golam; Hatakeyama, Hiroto; Sato, Yusuke; Harashima, Hideyoshi

    2016-07-25

    The PEGylated liposomal (PEG-LP) Doxorubicin, PEG-LP (DOX), with a diameter of around 100nm, accumulates in tumors via the enhanced permeability and retention (EPR) effect, and is used clinically for the treatment of several types of cancer. However, there are a number of tumor types that are resistant to DOX. We report herein on a unique anti-tumor effect of PEG-LP (DOX) in a DOX-resistant tumor xenograft model. PEG-LP (DOX) failed to suppress the growth of the DOX-resistant tumors (ex. non-small cell lung cancer, H69AR; renal cell carcinoma, OSRC-2) as observed in the xenograft model. Unexpectedly, tumor growth was suppressed in a DOX-resistant breast cancer (MDA-MB-231) xenograft model. We investigated the mechanism by which PEG-LP (DOX) responses differ in different drug resistant tumors. In hyperpermeable OSRC-2 tumors, PEG-LP was distributed to deep tumor tissues, where it delivers DOX to drug-resistant tumor cells. In contrast, extracellular matrix (ECM) molecules such as collagen, pericytes, cancer-associated fibroblasts render MDA-MB-231 tumors hypopermeable, which limits the extent of the penetration and distribution of PEG-LP, thereby enhancing the delivery of DOX to the vicinity of the tumor vasculature. Therefore, a remarkable anti-angiogenic effect with a preferential suppression in tumor growth is achieved. Based on the above findings, it appears that the response of PEG-LP (DOX) to drug-resistant tumors results from differences in the tumor microenvironment.

  10. Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading

    PubMed Central

    Leonhard, Victoria; Alasino, Roxana V; Bianco, Ismael D; Garro, Ariel G; Heredia, Valeria; Beltramo, Dante M

    2015-01-01

    Doxorubicin (Dox) is an anthracycline anticancer drug with high water solubility, whose use is limited primarily due to significant side effects. In this study it is shown that Dox interacts with monosialoglycosphingolipid (GM1) ganglioside micelles primarily through hydrophobic interactions independent of pH and ionic strength. In addition, Dox can be incorporated even into GM1 micelles already containing highly hydrophobic paclitaxel (Ptx). However, it was not possible to incorporate Ptx into Dox-containing GM1 micelles, suggesting that Dox could be occupying a more external position in the micelles. This result is in agreement with a higher hydrolysis of Dox than of Ptx when micelles were incubated at alkaline pH. The loading of Dox into GM1 micelles was observed over a broad range of temperature (4°C–55°C). Furthermore, Dox-loaded micelles were stable in aqueous solutions exhibiting no aggregation or precipitation for up to 2 months when kept at 4°C–25°C and even after freeze–thawing cycles. Upon exposure to blood components, Dox-containing micelles were observed to interact with human serum albumin. However, the amount of human serum albumin that ended up being associated to the micelles was inversely related to the amount of Dox, suggesting that both could share their binding sites. In vitro studies on Hep2 cells showed that the cellular uptake and cytotoxic activity of Dox and Ptx from the micellar complexes were similar to those of the free form of these drugs, even when the micelle was covered with albumin. These results support the idea of the existence of different nano-domains in a single micelle and the fact that this micellar model could be used as a platform for loading and delivering hydrophobic and hydrophilic active pharmaceutical ingredients. PMID:26005348

  11. Pulmonary Codelivery of Doxorubicin and siRNA by pH-Sensitive Nanoparticles for Therapy of Metastatic Lung Cancer.

    PubMed

    Xu, Caina; Wang, Ping; Zhang, Jingpeng; Tian, Huayu; Park, Kinam; Chen, Xuesi

    2015-09-01

    A pulmonary codelivery system that can simultaneously deliver doxorubicin (DOX) and Bcl2 siRNA to the lungs provides a promising local treatment strategy for lung cancers. In this study, DOX is conjugated onto polyethylenimine (PEI) by using cis-aconitic anhydride (CA, a pH-sensitive linker) to obtain PEI-CA-DOX conjugates. The PEI-CA-DOX/siRNA complex nanoparticles are formed spontaneously via electrostatic interaction between cationic PEI-CA-DOX and anionic siRNA. The drug release experiment shows that DOX releases faster at acidic pH than at pH 7.4. Moreover, PEI-CA-DOX/Bcl2 siRNA complex nanoparticles show higher cytotoxicity and apoptosis induction in B16F10 cells than those treated with either DOX or Bcl2 siRNA alone. When the codelivery systems are directly sprayed into the lungs of B16F10 melanoma-bearing mice, the PEI-CA-DOX/Bcl2 siRNA complex nanoparticles exhibit enhanced antitumor efficacy compared with the single delivery of DOX or Bcl2 siRNA. Compared with systemic delivery, most drug and siRNA show a long-term retention in the lungs via pulmonary delivery, and a considerable number of the drug and siRNA accumulate in tumor tissues of lungs, but rarely in normal lung tissues. The PEI-CA-DOX/Bcl2 siRNA complex nanoparticles are promising for the treatment of metastatic lung cancer by pulmonary delivery with low side effects on the normal tissues.

  12. Ursodeoxycholic acid inhibits overexpression of P-glycoprotein induced by doxorubicin in HepG2 cells.

    PubMed

    Komori, Yuki; Arisawa, Sakiko; Takai, Miho; Yokoyama, Kunihiro; Honda, Minako; Hayashi, Kazuhiko; Ishigami, Masatoshi; Katano, Yoshiaki; Goto, Hidemi; Ueyama, Jun; Ishikawa, Tetsuya; Wakusawa, Shinya

    2014-02-01

    The hepatoprotective action of ursodeoxycholic acid (UDCA) was previously suggested to be partially dependent on its antioxidative effect. Doxorubicin (DOX) and reactive oxygen species have also been implicated in the overexpression of P-glycoprotein (P-gp), which is encoded by the MDR1 gene and causes antitumor multidrug resistance. In the present study, we assessed the effects of UDCA on the expression of MDR1 mRNA, P-gp, and intracellular reactive oxygen species levels in DOX-treated HepG2 cells and compared them to those of other bile acids. DOX-induced increases in reactive oxygen species levels and the expression of MDR1 mRNA were inhibited by N-acetylcysteine, an antioxidant, and the DOX-induced increase in reactive oxygen species levels and DOX-induced overexpression of MDR1 mRNA and P-gp were inhibited by UDCA. Cells treated with UDCA showed improved rhodamine 123 uptake, which was decreased in cells treated with DOX alone. Moreover, cells exposed to DOX for 24h combined with UDCA accumulated more DOX than that of cells treated with DOX alone. Thus, UDCA may have inhibited the overexpression of P-gp by suppressing DOX-induced reactive oxygen species production. Chenodeoxycholic acid (CDCA) also exhibited these effects, whereas deoxycholic acid and litocholic acid were ineffective. In conclusion, UDCA and CDCA had an inhibitory effect on the induction of P-gp expression and reactive oxygen species by DOX in HepG2 cells. The administration of UDCA may be beneficial due to its ability to prevent the overexpression of reactive oxygen species and acquisition of multidrug resistance in hepatocellular carcinoma cells.

  13. Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study

    SciTech Connect

    Verret, Valentin Namur, Julien; Ghegediban, Saieda Homayra; Wassef, Michel; Moine, Laurence; Bonneau, Michel; Laurent, Alexandre

    2013-02-15

    The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques.The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process. At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 and 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration. DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models.

  14. Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells.

    PubMed

    Pramod, P S; Shah, Ruchira; Jayakannan, Manickam

    2015-04-21

    The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the administration of doxorubicin via physical loading and polymer-drug conjugation to breast cancer cells. Dextran was suitably modified with a renewable resource 3-pentadecyl phenol unit through imine and aliphatic ester chemical linkages that acted as pH and esterase enzyme stimuli, respectively. These dual responsive polysaccharide derivatives self-organized into 200 ± 10 nm diameter nano-vesicles in water. The water soluble anticancer drug doxorubicin (DOX·HCl) was encapsulated in the hydrophilic pocket to produce core-loaded polysaccharide vesicles whereas chemical conjugation produced DOX anchored at the hydrophobic layer of the dextran nano-vesicles. In vitro studies revealed that about 70-80% of the drug was retained under circulatory conditions at pH = 7.4 and 37 °C. At a low pH of 6.0 to 5.0 and in the presence of esterase; both imine and ester linkages were cleaved instantaneously to release 100% of the loaded drugs. Cytotoxicity assays on Wild Type Mouse Embryonic Fibroblasts (WTMEFs) confirmed the non-toxicity of the newly developed dextran derivatives at up to 500 μg mL(-1) in PBS. MTT assays on fibroblast cells revealed that DOX·HCl loaded nano-vesicles exhibited better killing abilities than DOX conjugated polymer nano-vesicles. Both DOX loaded and DOX conjugated nano-vesicles were found to show significant killing in breast cancer cells (MCF 7). Confocal microscopy images confirmed the uptake of DOX loaded (or conjugated) nano-vesicles by cells compared to free DOX. Thus, the newly developed pH and enzyme dual responsive polysaccharide vesicular assemblies are potential drug vectors for the administration of DOX in both loaded and chemically conjugated forms for the efficient killing of breast cancer cells. PMID:25797322

  15. Neuroprotective effects of mGluR II and III activators against staurosporine- and doxorubicin-induced cellular injury in SH-SY5Y cells: New evidence for a mechanism involving inhibition of AIF translocation.

    PubMed

    Jantas, D; Greda, A; Leskiewicz, M; Grygier, B; Pilc, A; Lason, W

    2015-09-01

    There are several experimental data sets demonstrating the neuroprotective effects of activation of group II and III metabotropic glutamate receptors (mGluR II/III), however, their effect on neuronal apoptotic processes has yet to be fully recognized. Thus, the comparison of the neuroprotective potency of the mGluR II agonist LY354740, mGluR III agonist ACPT-I, mGluR4 PAM VU0361737, mGluR8 PAM AZ12216052 and allosteric mGluR7 agonist AMN082 against staurosporine (St-) and doxorubicin (Dox)-induced cell death has been performed in undifferentiated (UN-) and retinoic acid differentiated (RA-) human neuroblastoma SH-SY5Y cells. The highest neuroprotection in UN-SH-SY5Y cells was noted for AZ12216052 (0.01-1 µM) and VU0361737 (1-10 µM), with both agents partially attenuating the St- and Dox-evoked cell death. LY354740 (0.01-10 µM) and ACPT-I (10 µM) were protective only against the St-evoked cell damage, whereas AMN082 (0.001-0.01 µM) attenuated only the Dox-induced cell death. In RA-SH-SY5Y, a moderate neuroprotective response of mGluR II/III activators was observed for LY354740 (10 µM) and AZ12216052 (0.01 and 10 µM), which afforded protection only against the St-induced cell damage. The protection mediated by mGluR II/III activators against the St- and Dox-evoked cell death in UN-SH-SY5Y cells was not related to attenuation of caspase-3 activity, however, a decrease in the number of TUNEL-positive nuclei was found. Moreover, mGluR II/III activators attenuated the cytosolic level of the apoptosis inducing factor (AIF), which was increased after St and Dox exposure. Our data point to differential neuroprotective efficacy of various mGluR II/III activators in attenuating St- and Dox-evoked cell damage in SH-SY5Y cells, and dependence of the effects on the cellular differentiation state, as well on the type of the pro-apoptotic agent that is employed. Moreover, the neuroprotection mediated by mGluR II/III activators is accompanied by inhibition of

  16. Cytotoxicity of folic acid conjugated hollow silica nanoparticles toward Caco2 and 3T3 cells, with and without encapsulated DOX.

    PubMed

    Patel, Kunal; Sundara Raj, Behin; Chen, Yan; Lou, Xia

    2016-04-01

    Hollow silica nanoparticles of two sizes with and without a folic acid targeting ligand were synthesized. Fickian diffusion of the antitumor drug doxorubicin hydrochloride (DOX) was demonstrated by the produced nanoparticles, achieving a cumulative release of 73% and 45% for 215 nm and 430 nm particles respectively over a period of 500 h. The hollow silica nanoparticles presented a time and dose dependent toxicity, selective to human epithelial colorectal adenocarcinoma (Caco2) cells, over mouse embryonic fibroblast (3T3) cells. At 24h Caco2 cell viability was reduced to 66% using pure hollow silica at a concentration of 50 μg mL(-1), while that of 3T3 cells remained at 94% under the same conditions. The selective cytotoxicity of hollow silica nanoparticles was further enhanced by conjugation of folic acid and incorporation of DOX: at 24h and an equivalent DOX concentration of 0.5 μg mL(-1), viable Caco2 cells were reduced to 45% while 3T3 cells were reduced to 83%. Interestingly the equivalent dose of free DOX was more toxic to 3T3 than to Caco2 cells, reducing the 3T3 viability to 72% and the Caco2 viability to 80%, which is likely due to the presence of the p-glycoprotein pumps in Caco2 cells. Folic acid conjugation served to enhance the viability of both cell lines in this work. Careful optimization of the folate content should further improve the cell specificity of the hollow silica nanoparticles, thus providing a viable targeting platform for cancer therapy.

  17. Protective effect of memantine against Doxorubicin toxicity in primary neuronal cell cultures: influence a development stage.

    PubMed

    Jantas, D; Lason, W

    2009-01-01

    One of the serious unwanted effects of the anthracycline anticancer drug doxorubicin (Dox, adriamycin) is its neurotoxicity, which can be evoked by the activation of extracellular (FAS/CD95/Apo-1) pathway of apoptosis in cells. Since memantine, a clinically used N-methyl-D: -aspartic acid (NMDA) receptor antagonist, shows antiapoptotic action in several models of neuronal cell damage, in this study we evaluated the effect of memantine on the cell death induced by Dox in primary neuronal cell cultures. First, we investigated the effect of different concentrations of Dox (0.1-5 microM) on mouse neocortical, hippocampal, striatal, and cerebellar neurons on 7- and 12-day in vitro (DIV). The 7 DIV neuronal cell cultures were more prone to Dox-induced cell death than 12 DIV cultures. The cerebellar neurons were the most resistant to Dox-induced apoptosis in comparison to neuronal cell cultures derived from the forebrain. Memantine (0.1-2 microM) attenuated the Dox-evoked lactate dehydrogenase release in 7 DIV neuronal cell cultures with no significant effect on 12 DIV cultures. The ameliorating effect of memantine on Dox-mediated cell death was also confirmed by an increase in cell viability measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. There was no effect of memantine on Dox-induced caspase-8 and -3 activity and Dox-evoked decrease in mitochondrial potential, although attenuation in the number of cells with apoptotic DNA fragmentation was observed. We also showed that the antiapoptotic effect of memantine in our model was NMDA receptor-independent, since two other antagonists of this receptor, MK-801 and AP-5, did not attenuate Dox-induced cell death. Furthermore, memantine did not influence the Dox-evoked increase in cytoplasmic Ca2+ level. The obtained data suggest developmental regulation of both, the Dox-mediated neurotoxicity and efficacy of memantine in alleviating the Dox-induced cell damage in neuronal cell cultures

  18. In vivo pharmacokinetics, biodistribution and the anti-tumor effect of cyclic RGD-modified doxorubicin-loaded polymers in tumor-bearing mice.

    PubMed

    Wang, Chen; Li, Yuan; Chen, Binbin; Zou, Meijuan

    2016-10-01

    In our previous study, we successfully produced and characterized a multifunctional drug delivery system with doxorubicin (RC/GO/DOX), which was based on graphene oxide (GO) and cyclic RGD-modified chitosan (RC). Its characteristics include: pH-responsiveness, active targeting of hepatocarcinoma cells, and efficient loading with controlled drug release. Here, we report the pharmacokinetics, biodistribution, and anti-tumor efficacy of RC/GO/DOX polymers in tumor-bearing nude mice. The objective of this study is to assess its targeting potential for tumors. Pharmacokinetic and biodistribution profiles demonstrated that tumor accumulation of RC/GO/DOX polymers was almost three times higher than the others, highlighting the efficacy of the active targeting strategy. Furthermore, the tumor inhibition rate of RC/GO/DOX polymers was 56.64%, 2.09 and 2.93 times higher than that of CS/GO/DOX polymers (without modification) and the DOX solution, respectively. Anti-tumor efficacy results indicated that the tumor growth was better controlled by RC/GO/DOX polymers than the others. Hematoxylin and eosin (H&E) staining showed remarkable changes in tumor histology. Compared with the saline group, the tumor section from the RC/GO/DOX group revealed a marked increase in the quantity of apoptotic and necrotic cells, and a reduction in the quantity of the blood vessels. Together, these studies show that this new system could be regarded as a suitable form of DOX-based treatment of the hepatocellular carcinoma.

  19. Hydrophilic mesoporous carbon nanospheres with high drug-loading efficiency for doxorubicin delivery and cancer therapy

    PubMed Central

    Wang, Huan; Li, Xiangui; Ma, Zhiqiang; Wang, Dan; Wang, Linzhao; Zhan, Jieqiong; She, Lan; Yang, Feng

    2016-01-01

    In this study, a highly effective transmembrane delivery vehicle based on PEGylated oxidized mesoporous carbon nanosphere (oMCN@PEG) was successfully fabricated in a facile strategy. oMCN@PEG exhibited a narrow size distribution of 90 nm, excellent hydrophilicity, good biocompatibility, and a very high loading efficiency for doxorubicin (DOX). The drug system (oMCN@DOX@PEG) exhibited excellent stability under neutral pH conditions, but with dramatic releases of DOX at reduced pH conditions. Pharmacokinetics study revealed that oMCN@DOX@PEG could prolong the circulation of DOX in the blood stream. The endocytosis, cytotoxicity, and anticancer effect in vitro and in vivo of the drug-loaded nanoparticles were also evaluated. Our results showed that the nanoparticles efficiently penetrated the membrane of tumor cells, subsequently released drugs, and efficiently inhibited the growth of cancer cells both in vitro and in vivo. Especially, oMCN@DOX@PEG also exhibited significant antimetastasis effect in advanced stage of malignant cancer, improving the survival time of tumor-bearing mice. The results suggested that oMCN@PEG might be a promising anticancer drug delivery vehicle for cancer therapy. PMID:27175077

  20. Lactoferrin-modified PEGylated liposomes loaded with doxorubicin for targeting delivery to hepatocellular carcinoma.

    PubMed

    Wei, Minyan; Guo, Xiucai; Tu, Liuxiao; Zou, Qi; Li, Qi; Tang, Chenyi; Chen, Bao; Xu, Yuehong; Wu, Chuanbin

    2015-01-01

    Lactoferrin (Lf) is a potential-targeting ligand for hepatocellular carcinoma (HCC) cells because of its specific binding with asialoglycoprotein receptor (ASGPR). In this present work, a doxorubicin (DOX)-loaded, Lf-modified, polyethylene glycol (PEG)ylated liposome (Lf-PLS) system was developed, and its targeting effect and antitumor efficacy to HCC was also explored. The DOX-loaded Lf-PLS system had spherical or oval vesicles, with mean particle size approximately 100 nm, and had an encapsulation efficiency of 97%. The confocal microscopy and flow cytometry indicated that the cellular uptake of Lf-PLS was significantly higher than that of PEGylated liposome (PLS) in ASGPR-positive cells (P<0.05) but not in ASGPR-negative cells (P>0.05). Cytotoxicity assay by MTT demonstrated that DOX-loaded Lf-PLS showed significantly stronger antiproliferative effects on ASGPR-positive HCC cells than did PLS without the Lf modification (P<0.05). The in vivo antitumor studies on male BALB/c nude mice bearing HepG2 xenografts demonstrated that DOX-loaded Lf-PLS had significantly stronger antitumor efficacy compared with PLS (P<0.05) and free DOX (P<0.05). All these results demonstrated that a DOX-loaded Lf-PLS might have great potential application for HCC-targeting therapy.

  1. Lactoferrin-modified PEGylated liposomes loaded with doxorubicin for targeting delivery to hepatocellular carcinoma

    PubMed Central

    Wei, Minyan; Guo, Xiucai; Tu, Liuxiao; Zou, Qi; Li, Qi; Tang, Chenyi; Chen, Bao; Xu, Yuehong; Wu, Chuanbin

    2015-01-01

    Lactoferrin (Lf) is a potential-targeting ligand for hepatocellular carcinoma (HCC) cells because of its specific binding with asialoglycoprotein receptor (ASGPR). In this present work, a doxorubicin (DOX)-loaded, Lf-modified, polyethylene glycol (PEG)ylated liposome (Lf-PLS) system was developed, and its targeting effect and antitumor efficacy to HCC was also explored. The DOX-loaded Lf-PLS system had spherical or oval vesicles, with mean particle size approximately 100 nm, and had an encapsulation efficiency of 97%. The confocal microscopy and flow cytometry indicated that the cellular uptake of Lf-PLS was significantly higher than that of PEGylated liposome (PLS) in ASGPR-positive cells (P<0.05) but not in ASGPR-negative cells (P>0.05). Cytotoxicity assay by MTT demonstrated that DOX-loaded Lf-PLS showed significantly stronger antiproliferative effects on ASGPR-positive HCC cells than did PLS without the Lf modification (P<0.05). The in vivo antitumor studies on male BALB/c nude mice bearing HepG2 xenografts demonstrated that DOX-loaded Lf-PLS had significantly stronger antitumor efficacy compared with PLS (P<0.05) and free DOX (P<0.05). All these results demonstrated that a DOX-loaded Lf-PLS might have great potential application for HCC-targeting therapy. PMID:26316745

  2. The engineering of doxorubicin-loaded liposome-quantum dot hybrids for cancer theranostics

    NASA Astrophysics Data System (ADS)

    Bowen, Tian; Wafa', T. Al-Jamal; Kostas, Kostarelos

    2014-08-01

    Many studies have recently attempted to develop multifunctional nanoconstructs by integrating the superior fluorescence properties of quantum dots (QD) with therapeutic capabilities into a single vesicle for cancer theranostics. Liposome-quantum dot (L-QD) hybrid vesicles have shown promising potential for the construction of multifunctional nanoconstructs for cancer imaging and therapy. To fulfil such a potential, we report here the further functionalization of L-QD hybrid vesicles with therapeutic capabilities by loading anticancer drug doxorubicin (Dox) into their aqueous core. L-QD hybrid vesicles are first engineered by the incorporation of TOPO-capped, CdSe/ZnS QD into the lipid bilayers of DSPC:Chol:DSPE-PEG2000, followed by Dox loading using the pH-gradient technique. The loading efficiency of Dox into L-QD hybrid vesicles is achieved up to 97%, comparable to liposome control. All these evidences prove that the incorporation of QD into the lipid bilayer does not affect Dox loading through the lipid membrane of liposomes using the pH-gradient technique. Moreover, the release study shows that Dox release profile can be modulated simply by changing lipid composition. In conclusion, the Dox-loaded L-QD hybrid vesicles presented here constitute a promising multifunctional nanoconstruct capable of transporting combinations of therapeutic and diagnostic modalities.

  3. Doxorubicin-Loaded Carborane-Conjugated Polymeric Nanoparticles as Delivery System for Combination Cancer Therapy.

    PubMed

    Xiong, Hejian; Zhou, Dongfang; Qi, Yanxin; Zhang, Zhiyun; Xie, Zhigang; Chen, Xuesi; Jing, Xiabin; Meng, Fanbo; Huang, Yubin

    2015-12-14

    Carborane-conjugated amphiphilic copolymer nanoparticles were designed to deliver anticancer drugs for the combination of chemotherapy and boron neutron capture therapy (BNCT). Poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2(2-dicarba-closo-dodecarborane)propyloxycarbonyl-propyne carbonate) (PLMB) was synthesized via the versatile reaction between decaborane and side alkynyl groups, and self-assembled with doxorubicin (DOX) to form drug-loaded nanoparticles. These DOX@PLMB nanoparticles could not only suppress the leakage of the boron compounds into the bloodstream due to the covalent bonds between carborane and polymer main chains, but also protect DOX from initial burst release at physiological conditions because of the dihydrogen bonds between DOX and carborane. It was demonstrated that DOX@PLMB nanoparticles could selectively deliver boron atoms and DOX to the tumor site simultaneously in vivo. Under the combination of chemotherapy and BNCT, the highest tumor suppression efficiency without reduction of body weight was achieved. This polymeric nanoparticles delivery system could be very useful in future chemoradiotherapy to obtain improved therapeutic effect with reduced systemic toxicity.

  4. Polyethylene glycol-modified arachidyl chitosan-based nanoparticles for prolonged blood circulation of doxorubicin.

    PubMed

    Termsarasab, Ubonvan; Yoon, In-Soo; Park, Ju-Hwan; Moon, Hyun Tae; Cho, Hyun-Jong; Kim, Dae-Duk

    2014-04-10

    Doxorubicin (DOX)-loaded nanoparticles based on polyethylene glycol-conjugated chitosan oligosaccharide-arachidic acid (CSOAA-PEG) were explored for potential application to leukemia therapy. PEG was conjugated with CSOAA backbone via amide bond formation and the final product was verified by (1)H NMR analysis. Using the synthesized CSOAA-PEG, nanoparticles having characteristics of a 166-nm mean diameter, positive zeta potential, and spherical shape were produced for the delivery of DOX. The mean diameter of CSOAA-PEG nanoparticles in the serum solution (50% fetal bovine serum) remained relatively constant over 72 h as compared with CSOAA nanoparticles (changes of 20.92% and 223.16%, respectively). The sustained release pattern of DOX from CSOAA-PEG nanoparticles was displayed at physiological pH, and the release rate increased under the acidic pH conditions. The cytotoxicity of the CSOAA-PEG conjugate was negligible in human leukemia cells (K562) at the concentrations tested (∼ 100 μg/ml). The uptake rate of DOX from the nanoparticles by K562 cells was higher than that from the solution. Judging from the results of pharmacokinetic studies in rats, in vivo clearance rate of DOX from the CSOAA-PEG nanoparticle group was slower than other groups, subsequently extending the circulation period. The PEGylated CSOAA-based nanoparticles could represent an effective nano-sized delivery system for DOX which has been used for the treatment of blood malignancies.

  5. Interaction of C60 fullerene complexed to doxorubicin with model bilipid membranes and its uptake by HeLa cells.

    PubMed

    Prylutskyy, Yu; Bychko, A; Sokolova, V; Prylutska, S; Evstigneev, M; Rybalchenko, V; Epple, M; Scharff, P

    2016-02-01

    With an aim to elucidate the effects of C60 fullerene complexed with antibiotic doxorubicin (Dox) on model bilipid membranes (BLM), the investigation of the electrical properties of BLM under the action of Dox and C60 fullerene, and of their complex, C60+Dox,was performed. The complex as well as its components exert a clearly detectable influence on BLM, which is concentration-dependent and also depends on phospholipid composition. The mechanism of this effect originates either from intermolecular interaction of the drug with fatty-acid residues of phospholipids, or from membranotropic effects of the drug-induced lipid peroxidation, or from the sum of these two effects. By fluorescence microscopy the entering of C60 + Dox complex into HeLa cells was directly shown.

  6. Tuning Core vs. Shell Dimensions to Adjust the Performance of Nanoscopic Containers for the Loading and Release of Doxorubicin

    PubMed Central

    Lin, Lily Yun; Lee, Nam S.; Zhu, Jiahua; Nyström, Andreas M.; Pochan, Darrin J.; Dorshow, Richard B.; Wooley, Karen L.

    2011-01-01

    Detailed studies were performed to probe the effects of the core and shell dimensions of amphiphilic, shell crosslinked, knedel-like polymer nanoparticles (SCKs) on the loading and release of doxorubicin (DOX), a widely-used chemotherapy agent, in aqueous buffer, as a function of the solution pH. Effects of the nanoparticle composition were held constant, by employing SCKs constructed from a single type of amphiphilic diblock copolymer, poly(acrylic acid)-b-polystyrene (PAA-b-PS). A series of four SCK nanoparticle samples, ranging in number-average hydrodynamic diameter from 14–30 nm, was prepared from four block copolymers having different relative block lengths and absolute degrees of polymerization. The ratios of acrylic acid to styrene block lengths ranged from 0.65 to 3.0, giving SCKs with ratios of shell to core volumes ranging from 0.44 to 2.1. Although the shell thicknesses were calculated to be similar (1.5–3.1 nm by transmission electron microscopy (TEM) calculations and 3.5–4.9 nm by small angle neutron scattering (SANS) analyses), two of the SCK nanoparticles had relatively large core diameters (19 ± 2 and 20 ± 2 nm by TEM; 17.4 and 15.3 nm by SANS), while two had similar, smaller core diameters (11 ± 2 and 13 ± 2 nm by TEM; 9.0 and 8.9 nm by SANS). The SCKs were capable of being loaded with 1500–9700 DOX molecules per each particle, with larger numbers of DOX molecules packaged within the larger core SCKs. Their shell-to-core volume ratio showed impact on the rates and extents of release of DOX, with the volume occupied by the poly(acrylic acid) shell relative to the volume occupied by the polystyrene core correlating inversely with the diffusion-based release of DOX. Given that the same amount of polymer was used to construct each SCK sample, SCKs having smaller cores and higher acrylic acid vs. styrene volume ratios were present at higher concentrations than were the larger core SCKs, and gave lower final extents of release., Higher final

  7. Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats

    SciTech Connect

    Sharkey, Leslie C.; Radin, M. Judith; Heller, Lois; Rogers, Lynette K.; Tobias, Anthony; Matise, Ilze; Wang, Qi; Apple, Fred S.; McCune, Sylvia A.

    2013-11-15

    Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12 weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure or mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity. - Highlights: • Late doxorubicin toxicity evaluated in normal, hypertensive, and cardiomyopathic rats. • Hypertension enhances the delayed toxicity of doxorubicin. • Genetic predisposition to cardiomyopathy did not further enhance toxicity. • Epoxyeicosatrienoic acids

  8. Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F{sub 1} mouse model

    SciTech Connect

    Desai, Varsha G.; Herman, Eugene H.; Moland, Carrie L.; Branham, William S.; Lewis, Sherry M.; Davis, Kelly J.; George, Nysia I.; Lee, Taewon; Kerr, Susan; Fuscoe, James C.

    2013-01-01

    Serum levels of cardiac troponins serve as biomarkers of myocardial injury. However, troponins are released into the serum only after damage to cardiac tissue has occurred. Here, we report development of a mouse model of doxorubicin (DOX)-induced chronic cardiotoxicity to aid in the identification of predictive biomarkers of early events of cardiac tissue injury. Male B6C3F{sub 1} mice were administered intravenous DOX at 3 mg/kg body weight, or an equivalent volume of saline, once a week for 4, 6, 8, 10, 12, and 14 weeks, resulting in cumulative DOX doses of 12, 18, 24, 30, 36, and 42 mg/kg, respectively. Mice were sacrificed a week following the last dose. A significant reduction in body weight gain was observed in mice following exposure to a weekly DOX dose for 1 week and longer compared to saline-treated controls. DOX treatment also resulted in declines in red blood cell count, hemoglobin level, and hematocrit compared to saline-treated controls after the 2nd weekly dose until the 8th and 9th doses, followed by a modest recovery. All DOX-treated mice had significant elevations in cardiac troponin T concentrations in plasma compared to saline-treated controls, indicating cardiac tissue injury. Also, a dose-related increase in the severity of cardiac lesions was seen in mice exposed to 24 mg/kg DOX and higher cumulative doses. Mice treated with cumulative DOX doses of 30 mg/kg and higher showed a significant decline in heart rate, suggesting drug-induced cardiac dysfunction. Altogether, these findings demonstrate the development of DOX-induced chronic cardiotoxicity in B6C3F{sub 1} mice. -- Highlights: ► 24 mg/kg was a cumulative cardiotoxic dose of doxorubicin in male B6C3F{sub 1} mice. ► Doxorubicin-induced hematological toxicity was in association with splenomegaly. ► Doxorubicin induced severe testicular toxicity in B6C3F{sub 1} male mice.

  9. Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells

    NASA Astrophysics Data System (ADS)

    Pramod, P. S.; Shah, Ruchira; Jayakannan, Manickam

    2015-04-01

    The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the administration of doxorubicin via physical loading and polymer-drug conjugation to breast cancer cells. Dextran was suitably modified with a renewable resource 3-pentadecyl phenol unit through imine and aliphatic ester chemical linkages that acted as pH and esterase enzyme stimuli, respectively. These dual responsive polysaccharide derivatives self-organized into 200 +/- 10 nm diameter nano-vesicles in water. The water soluble anticancer drug doxorubicin (DOX.HCl) was encapsulated in the hydrophilic pocket to produce core-loaded polysaccharide vesicles whereas chemical conjugation produced DOX anchored at the hydrophobic layer of the dextran nano-vesicles. In vitro studies revealed that about 70-80% of the drug was retained under circulatory conditions at pH = 7.4 and 37 °C. At a low pH of 6.0 to 5.0 and in the presence of esterase; both imine and ester linkages were cleaved instantaneously to release 100% of the loaded drugs. Cytotoxicity assays on Wild Type Mouse Embryonic Fibroblasts (WTMEFs) confirmed the non-toxicity of the newly developed dextran derivatives at up to 500 μg mL-1 in PBS. MTT assays on fibroblast cells revealed that DOX.HCl loaded nano-vesicles exhibited better killing abilities than DOX conjugated polymer nano-vesicles. Both DOX loaded and DOX conjugated nano-vesicles were found to show significant killing in breast cancer cells (MCF 7). Confocal microscopy images confirmed the uptake of DOX loaded (or conjugated) nano-vesicles by cells compared to free DOX. Thus, the newly developed pH and enzyme dual responsive polysaccharide vesicular assemblies are potential drug vectors for the administration of DOX in both loaded and chemically conjugated forms for the efficient killing of breast cancer cells.The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the

  10. Application of C60 Fullerene-Doxorubicin Complex for Tumor Cell Treatment In Vitro and In Vivo.

    PubMed

    Panchuk, R R; Prylutska, S V; Chumakl, V V; Skorokhyd, N R; Lehka, L V; Evstigneev, M P; Prylutskyy, Yu I; Berger, W; Heffeter, P; Scharff, P; Ritter, U; Stoika, R S

    2015-07-01

    Development of nanocarriers for effective drug delivery to molecular targets in tumor cells is a real problem in modern pharmaceutical chemistry. In the present work we used pristine C60 fullerene as a platform for delivery of anticancer drug doxorubicin (Dox) to its biological targets. The formation of a complex of C60 fullerene with Dox (C60 + Dox) is described and physico-chemical characteristics of such complex are presented. It was found that Dox conjugation with C60 fullerene leads to 1.5-2-fold increase in Dox toxicity towards various human tumor cell lines, compared with such effect when the drug is used alone. Cytotoxic activity of C60 + Dox complex is accompanied by an increased level of cell produced hydrogen peroxide at early time point (3 h) after its addition to cultured cells. At the same time, cellular production of superoxide radicals does not change in comparison with the effect of Dox alone. Cytomorphological studies have demonstrated that C60 + Dox complexes kill tumor cells by apoptosis induction. The results of in vivo experiments using Lewis lung carcinoma in mice confirmed the enhancement of the Dox toxicity towards tumor cells after drug complexation with C60 fullerene. The effect of such complex towards tumor-bearing mice was even more pronounced than that in the in vitro experiment with targeting human tumor cells. The tumor volume decreased by 2.5 times compared with the control, and an average life span of treated animals increased by 63% compared with control. The obtained results suggest a great perspective of application of C60 + Dox complexes for chemotherapy of malignant tumors.

  11. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice.

    PubMed

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.

  12. Aldehyde dehydrogenase 2 ameliorates doxorubicin-induced myocardial dysfunction through detoxification of 4-HNE and suppression of autophagy.

    PubMed

    Sun, Aijun; Cheng, Yong; Zhang, Yingmei; Zhang, Qian; Wang, Shijun; Tian, Shan; Zou, Yunzeng; Hu, Kai; Ren, Jun; Ge, Junbo

    2014-06-01

    Mitochondrial aldehyde dehydrogenase (ALDH2) protects against cardiac injury via reducing production of 4-hydroxynonenal (4-HNE) and ROS. This study was designed to examine the impact of ALDH2 on doxorubicin (DOX)-induced cardiomyopathy and mechanisms involved with a focus on autophagy. 4-HNE and autophagic markers were detected by Western blotting in ventricular tissues from normal donors and patients with idiopathic dilated cardiomyopathy. Cardiac function, 4-HNE and levels of autophagic markers were detected in WT, ALDH2 knockout or ALDH2 transfected mice treated with or without DOX. Autophagy regulatory signaling including PI-3K, AMPK and Akt was examined in DOX-treated cardiomyocytes incubated with or without ALDH2 activator Alda-1. DOX-induced myocardial dysfunction, upregulation of 4-HNE and autophagic proteins were further aggravated in ALDH2 knockout mice while they were ameliorated in ALDH2 transfected mice. DOX downregulated Class I and upregulated Class III PI3-kinase, the effect of which was augmented by ALDH2 deletion. Accumulation of 4-HNE and autophagic protein markers in DOX-induced cardiomyocytes was significantly reduced by Alda-1. DOX depressed phosphorylated Akt but not AMPK, the effect was augmented by ALDH2 knockout. The autophagy inhibitor 3-MA attenuated, whereas autophagy inducer rapamycin mimicked DOX-induced cardiomyocyte contractile defects. In addition, rapamycin effectively mitigated Alda-1-offered protective action against DOX-induced cardiomyocyte dysfunction. Our data further revealed downregulated ALDH2 and upregulated autophagy levels in the hearts from patients with dilated cardiomyopathy. Taken together, our findings suggest that inhibition of 4-HNE and autophagy may be a plausible mechanism underscoring ALDH2-offered protection against DOX-induced cardiac defect. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy". PMID:24434637

  13. Application of C60 Fullerene-Doxorubicin Complex for Tumor Cell Treatment In Vitro and In Vivo.

    PubMed

    Panchuk, R R; Prylutska, S V; Chumakl, V V; Skorokhyd, N R; Lehka, L V; Evstigneev, M P; Prylutskyy, Yu I; Berger, W; Heffeter, P; Scharff, P; Ritter, U; Stoika, R S

    2015-07-01

    Development of nanocarriers for effective drug delivery to molecular targets in tumor cells is a real problem in modern pharmaceutical chemistry. In the present work we used pristine C60 fullerene as a platform for delivery of anticancer drug doxorubicin (Dox) to its biological targets. The formation of a complex of C60 fullerene with Dox (C60 + Dox) is described and physico-chemical characteristics of such complex are presented. It was found that Dox conjugation with C60 fullerene leads to 1.5-2-fold increase in Dox toxicity towards various human tumor cell lines, compared with such effect when the drug is used alone. Cytotoxic activity of C60 + Dox complex is accompanied by an increased level of cell produced hydrogen peroxide at early time point (3 h) after its addition to cultured cells. At the same time, cellular production of superoxide radicals does not change in comparison with the effect of Dox alone. Cytomorphological studies have demonstrated that C60 + Dox complexes kill tumor cells by apoptosis induction. The results of in vivo experiments using Lewis lung carcinoma in mice confirmed the enhancement of the Dox toxicity towards tumor cells after drug complexation with C60 fullerene. The effect of such complex towards tumor-bearing mice was even more pronounced than that in the in vitro experiment with targeting human tumor cells. The tumor volume decreased by 2.5 times compared with the control, and an average life span of treated animals increased by 63% compared with control. The obtained results suggest a great perspective of application of C60 + Dox complexes for chemotherapy of malignant tumors. PMID:26307837

  14. TFPI1 Mediates Resistance to Doxorubicin in Breast Cancer Cells by Inducing a Hypoxic-Like Response

    PubMed Central

    Davies, Gerald F.; Berg, Arnie; Postnikoff, Spike D. L.; Wilson, Heather L.; Arnason, Terra G.; Kusalik, Anthony; Harkness, Troy A. A.

    2014-01-01

    Thrombin and hypoxia are important players in breast cancer progression. Breast cancers often develop drug resistance, but mechanisms linking thrombin and hypoxia to drug resistance remain unresolved. Our studies using Doxorubicin (DOX) resistant MCF7 breast cancer cells reveals a mechanism linking DOX exposure with hypoxic induction of DOX resistance. Global expression changes between parental and DOX resistant MCF7 cells were examined. Westerns, Northerns and immunocytochemistry were used to validate drug resistance and differentially expressed genes. A cluster of genes involved in the anticoagulation pathway, with Tissue Factor Pathway Inhibitor 1 (TFPI1) the top hit, was identified. Plasmids overexpressing TFPI1 were utilized, and 1% O2 was used to test the effects of hypoxia on drug resistance. Lastly, microarray datasets from patients with drug resistant breast tumors were interrogated for TFPI1 expression levels. TFPI1 protein levels were found elevated in 3 additional DOX resistant cells lines, from humans and rats, indicating evolutionarily conservation of the effect. Elevated TFPI1 in DOX resistant cells was active, as thrombin protein levels were coincidentally low. We observed elevated HIF1α protein in DOX resistant cells, and in cells with forced expression of TFPI1, suggesting TFPI1 induces HIF1α. TFPI1 also induced c-MYC, c-SRC, and HDAC2 protein, as well as DOX resistance in parental cells. Growth of cells in 1% O2 induced elevated HIF1α, BCRP and MDR-1 protein, and these cells were resistant to DOX. Our in vitro results were consistent with in vivo patient datasets, as tumors harboring increased BCRP and MDR-1 expression also had increased TFPI1 expression. Our observations are clinically relevant indicating that DOX treatment induces an anticoagulation cascade, leading to inhibition of thrombin and the expression of HIF1α. This in turn activates a pathway leading to drug resistance. PMID:24489651

  15. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice.

    PubMed

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. PMID:25711856

  16. Cellular uptake, intracellular trafficking, and antitumor efficacy of doxorubicin-loaded reduction-sensitive micelles.

    PubMed

    Cui, Can; Xue, Ya-Nan; Wu, Ming; Zhang, Yang; Yu, Ping; Liu, Lei; Zhuo, Ren-Xi; Huang, Shi-Wen

    2013-05-01

    Reduction-sensitive micelles were prepared from monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16), an amphiphilic poly(ethylene glycol) derivative containing a disulfide bond. The micelles were then used for the intracellular delivery of the anticancer drug doxorubicin (DOX) into tumor cells, and the cellular uptake mechanisms of the micelles were determined. To serve as a control, monomethoxy-poly(ethylene glycol)-C-C-hexadecyl (mPEG-C-C-C16) with an analogous structure but without a disulfide bond was also prepared. The polymer could self-assemble into micelles in an aqueous solution and be loaded with high-content DOX. In vitro release studies revealed that DOX-loaded mPEG-S-S-C16 micelles released DOX faster than DOX-loaded mPEG-C-C-C16 micelles in the presence of dithiothreitol (DTT), but showed similar release rates in the absence of DTT. MTT assay demonstrated significantly enhanced cytotoxicity of DOX-loaded mPEG-S-S-C16 micelles against the human cervical cancer cells (HeLa) compared with DOX-loaded mPEG-C-C-C16 micelles, but there was no significant difference in the cytotoxicity between the two DOX-loaded micelles against the african green monkey SV40-transformed kidney fibroblast cells (COS-7). Confocal laser scanning microscopy observation and flow cytometry analyses indicated that DOX-loaded mPEG-S-S-C16 micelles were efficiently internalized into HeLa cells, released DOX into the cytoplasm, and entered the nuclei. By contrast, in the case of DOX-loaded mPEG-C-C-C16 micelles, little DOX was found in the nuclei. Endocytosis inhibition results proved that both mPEG-S-S-C16 and mPEG-C-C-C16 micelles entered the HeLa cells mainly through the clathrin-mediated endocytosis pathway, and caveolae-mediated endocytosis was involved to a small extent. These results indicated that the different behaviors of cell uptake between reduction-sensitive and -insensitive micelles may occur after the micelles were internalized into the cells, but not during

  17. Electronic structure and partial charge distribution of doxorubicin under different molecular environments

    NASA Astrophysics Data System (ADS)

    Poudel, Lokendra

    Doxorubicin (trade name Adriamycin, abbreviated DOX) is a well-known an- thracyclic chemotherapeutic used in treating a variety of cancers including acute leukemia, lymphoma, multiple myeloma, and a range of stomach, lung, bladder, bone, breast, and ovarian cancers. The purpose of the present work is to study electronic structure, partial charge distribution and interaction energy of DOX under different environments. It provides a framework for better understanding of bioactivity of DOX with DNA. While in this work, we focus on DOX -- DNA interactions; the obtained knowledge could be translated to other drug -- target interactions or biomolecular interactions. The electronic structure and partial charge distribution of DOX in three dierent molecular environments: isolated, solvated, and intercalated into a DNA complex,were studied by rst principles density functional methods. It is shown that the addition of solvating water molecules to DOX and the proximity and interaction with DNA has a signicant impact on the electronic structure as well as the partial charge distribution. The calculated total partial charges for DOX in the three models are 0.0, +0.123 and -0.06 electrons for the isolated, solvated, and intercalated state, respectively. Furthermore, by using the more accurate ab initio partial charge values on every atom in the models, signicant improvement in estimating the DOX-DNA interaction energy is obtained in conjunction with the NAnoscale Molecular Dynamics (NAMD) code. The electronic structure of the DOX-DNA is further elucidated by resolving the total density of states (TDOS) into dierent functional groups of DOX, DNA, water, co-crystallized Spermine molecule, and Na ions. The surface partial charge distribution in the DOX-DNA is calculated and displayed graphically. We conclude that the presence of the solvent as well as the details of the interaction geometry matter greatly in the determination of the stability of the DOX complexion. Ab initio

  18. DNA sequence-dependent fluorescence of doxorubicin for turn-on detection of biothiols in human serum.

    PubMed

    Chen, Xing; Jiang, Guimei; Wang, Zhili; Hong, Shanni; Zhang, Yuanyuan; Guo, Yahui; Cheng, Hui; Wang, Jine; Pei, Renjun

    2016-01-01

    Doxorubicin (Dox) is a DNA-targeting anthracycline antibiotic active against a wide spectrum of cancers. The interaction between Dox and double-stranded DNA (dsDNA) was used to load Dox using DNA duplexes as carriers. More importantly, the interesting DNA sequence-dependent fluorescence response of Dox could be exploited in the design of efficient Dox release systems and efficient fluorescence sensors. In this work, we demonstrated that separate introduction of G and C bases into T-rich single-stranded DNA (ssDNA) sequences afforded the best discrimination of Dox binding between dsDNA and ssDNA. For the first time, we successfully utilized this interesting DNA sequence-dependent fluorescence response of Dox as a signal transduction mechanism for the sensitive detection of biothiols in human serum. Cysteine, homocysteine, and glutathione were detected at as low as 26 nM, 37 nM, and 29 nM, respectively. The biosensors exhibited not only good selectivity, stability, and sensitivity in aqueous solutions but also a sensitive response in human serum, demonstrating their potential for diagnosis.

  19. Carbon Nanotube-Mediated Photothermal Disruption of Endosomes/Lysosomes Reverses Doxorubicin Resistance in MCF-7/ADR Cells.

    PubMed

    Pai, Chin-Ling; Chen, Yu-Chun; Hsu, Chia-Yen; Su, Hong-Lin; Lai, Ping-Shan

    2016-04-01

    Cancer is the leading cause of human death worldwide. Although many scientists work to fight this disease, multiple drug resistance is a predominant obstacle for effective cancer therapy. In drug-resistant MCF-7/ADR cells, the acidic organelles with lower pH value than normal one can cause the protonation of anthracycline drugs, inducing drug accumulation in these organelles. In this study, single-walled carbon nanotubes with polyethylene glycol phospholipids surface modification (PEGylated SWNTs) were utilized as near infrared-activated drug carriers for doxorubicin (DOX) delivery against MCF-7/ADR cells. Our results showed that a concentration-dependent temperature increase was observed in a solution of PEGylated SWNTs with 808 nm laser irradiation, whereas a water solution showed no significant changes in temperature under a thermal camera using the same irradiation dose. Interestingly, PEGylated DOX-SWNTs enhanced the nuclear accumulation of DOX with 808 nm irradiation whereas free DOX or PEGylated DOX-SWNTs revealed discrete red spots in MCF-7/ADR cells by confocal microscopic observation. Cell viability of PEGylated DOX-SWNTs-treated cells was also significantly decreased after 808 nm laser irradiation. Thus, photothermally activated PEGylated SWNTs can be a potential nanocarrier to deliver DOX into cancer cells and successfully overcome drug-resistant behavior in MCF-7/ADR breast cancer cells. PMID:27301189

  20. Mesoporous silica nanoparticles combining Au particles as glutathione and pH dual-sensitive nanocarriers for doxorubicin.

    PubMed

    Xu, Shuang; Li, Yan; Chen, Zhenjie; Hou, Cuilan; Chen, Tong; Xu, Zhigang; Zhang, Xiaoyu; Zhang, Haixia

    2016-02-01

    Mesoporous silica nanoparticles (MSNs) combining gold particles (MSNs-Au) were synthesized as nanocarriers for glutathione (GSH) and pH dual-sensitive intracellular controlled release of the anti-cancer drug doxorubicin (DOX). The MSNs were used as an adsorbent for DOX, and the ultra-small gold nanospheres (Au NPs) partly operated as gatekeepers to control the release of DOX from the pores of MSNs and as the driver of drug release in the presence of GSH due to the association between GSH and Au particles. Under different pH conditions, DOX release changed due to different levels of dissociation between the -SH group on the MSNs and the Au particles. The composition, morphology, and properties of the as-prepared composites were characterized by elemental analysis, fluorescence spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, nitrogen adsorption-desorption, thermal gravimetric and UV-visible spectroscopy. The in vitro release experiments showed that these smart nanocarriers effectively avoided drug leakage in the neutral media. Cytotoxicity and imaging studies also indicated that DOX-loaded Au-MSNs (DOX@MSNs-Au) had a significant inhibitory effect on the growth of Tca8113 cells and sustained the release rate of DOX. PMID:26652372

  1. The flavonoid luteolin enhances doxorubicin-induced autophagy in human osteosarcoma U2OS cells

    PubMed Central

    Zhang, Baoliang; Yu, Xin; Xia, Hong

    2015-01-01

    Luteolin (LUT), a flavone, which is universally present as constituent of medicinal plants as well as some vegetables and spices, has been demonstrated display specific anti-carcinogenic effects. However, the mechanisms by which LUT inhibits human osteosarcoma growth remain unknown. The effects of LUT on cell growth in human osteosarcoma U2OS cells were measured by MTT assay and flowcytometry. The effects of LUT on morphological markers of autophagy in U2OS were analyzed by fluorescence microscopy and electron microscopy. Autophagic markers, beclin1 and LC3 were detected by western blotting. Here, we found that LUT induced autophagy in U2OS and acted as an enhancer to sensitize doxorubicin (DOX)-mediated autophagy signaling. The combined treatment of LUT and DOX greatly decreases the growth of U2OS, showing synergistic cytotoxicity. Our results indicate that LUT in combination with DOX maybe a novel strategy for the treatment of human osteosarcoma. PMID:26629003

  2. A doxorubicin delivery system: Samarium/mesoporous bioactive glass/alginate composite microspheres.

    PubMed

    Zhang, Ying; Wang, Xiang; Su, Yanli; Chen, Dongya; Zhong, Wenxing

    2016-10-01

    Samarium (Sm) incorporated mesoporous bioactive glasses (MBG) microspheres have been prepared using the method of alginate cross-linking with Ca(2+) ions. The in vitro bioactivities of Sm/MBG/alginate microspheres were studied by immersing in simulated body fluid (SBF) for various periods. The results indicated that the Sm/MBG/alginate microspheres have a faster apatite formation rate on the surface. To investigate their delivery properties further, doxorubicin (DOX) was selected as a model drug. The results showed that the Sm/MBG/alginate microspheres exhibit sustained DOX delivery, and their release mechanism is controlled by Fickian diffusion according the Higuchi model. In addition, the delivery of DOX from Sm/MBG/alginate microspheres can be dominated by changing the doping concentration of Sm and the values of pH microenvironment. These all revealed that this material is a promising candidate for the therapy of bone cancer.

  3. Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21(Cip1.).

    PubMed

    Cheng, Zhaokang; DiMichele, Laura A; Rojas, Mauricio; Vaziri, Cyrus; Mack, Christopher P; Taylor, Joan M

    2014-02-01

    Clinical application of potent anthracycline anticancer drugs, especially doxorubicin (DOX), is limited by a toxic cardiac side effect that is not fully understood and preventive strategies are yet to be established. Studies in genetically modified mice have demonstrated that focal adhesion kinase (FAK) plays a key role in regulating adaptive responses of the adult myocardium to pathological stimuli through activation of intracellular signaling cascades that facilitate cardiomyocyte growth and survival. The objective of this study was to determine if targeted myocardial FAK activation could protect the heart from DOX-induced de-compensation and to characterize the underlying mechanisms. To this end, mice with myocyte-restricted FAK knock-out (MFKO) or myocyte-specific expression of an active FAK variant (termed SuperFAK) were subjected to DOX treatment. FAK depletion enhanced susceptibility to DOX-induced myocyte apoptosis and cardiac dysfunction, while elevated FAK activity provided remarkable cardioprotection. Our mec6hanistic studies reveal a heretofore unappreciated role for the protective cyclin-dependent kinase inhibitor p21 in the repression of the pro-apoptotic BH3-only protein Bim and the maintenance of mitochondrial integrity and myocyte survival. DOX treatment induced proteasomal degradation of p21, which exacerbated mitochondrial dysfunction and cardiomyocyte apoptosis. FAK was both necessary and sufficient for maintaining p21 levels following DOX treatment and depletion of p21 compromised FAK-dependent protection from DOX. These findings identify p21 as a key determinant of DOX resistance downstream of FAK in cardiomyocytes and indicate that cardiac-restricted enhancement of the FAK/p21 signaling axis might be an effective strategy to preserve myocardial function in patients receiving anthracycline chemotherapy. PMID:24342076

  4. Promotion of initial anti-tumor effect via polydopamine modified doxorubicin-loaded electrospun fibrous membranes

    PubMed Central

    Yuan, Ziming; Zhao, Xin; Wang, Xiaohu; Qiu, Wangwang; Chen, Xinliang; Zheng, Qi; Cui, Wenguo

    2014-01-01

    Drug-loaded electrospun PLLA membranes are not conducive to adhesion between materials and tissues due to the strong hydrophobicity of PLLA, which possibly attenuate the drugs’ effect loaded on the materials. In the present work, we developed a facile method to improve the hydrophilicity of doxorubicin (DOX)-loaded electrospun PLLA fibrous membranes, which could enhance the anti-tumor effect at the early stage after implantation. A mussel protein, polydopamine (PDA), could be easily grafted on the surface of hydrophobic DOX-loaded electrospun PLLA membranes (PLLA-DOX/pDA) in water solution. The morphology analysis of PLLA-DOX/pDA fibers displayed that though the fiber diameter was slightly swollen, they still maintained a 3D fibrous structure, and the XPS analysis certified that pDA had successfully been grafted onto the surface of the fibers. The results of surface wettability analysis showed that the contact angle decreased from 136.7° to 0° after grafting. In vitro MTT assay showed that the cytotoxicity of PLLA-DOX/pDA fibers was the strongest, and the stereologic cell counting assay demonstrated that the adhesiveness of PLLA/pDA fiber was significantly better than PLLA fiber. In vivo tumor-bearing mice displayed that, after one week of implantation, the tumor apoptosis and necrosis of PLLA-DOX/pDA fibers were the most obvious from histopathology and TUNEL assay. The caspase-3 activity of PLLA-DOX/pDA group was the highest using biochemical techniques, and the Bax: Bcl-2 ratio increased significantly in PLLA-DOX/pDA group through qRT-PCR analysis. All the results demonstrated that pDA can improve the affinity of the electrospun PLLA membranes and enhance the drug effect on tumors. PMID:25337186

  5. Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy

    NASA Astrophysics Data System (ADS)

    Xiao, Yuling; Jaskula-Sztul, Renata; Javadi, Alireza; Xu, Wenjin; Eide, Jacob; Dammalapati, Ajitha; Kunnimalaiyaan, Muthusamy; Chen, Herbert; Gong, Shaoqin

    2012-10-01

    A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The Au NR was conjugated with (1) DOX, an anticancer drug, via a pH-labile hydrazone linkage to enable pH-controlled drug release, (2) polyarginine, a cationic polymer for complexing siRNA, and (3) octreotide (OCT), a tumor-targeting ligand, to specifically target NE cancer cells with overexpressed somatostatin receptors. The Au NR-based nanocarriers exhibited a uniform size distribution as well as pH-sensitive drug release. The OCT-conjugated Au NR-based nanocarriers (Au-DOX-OCT, targeted) exhibited a much higher cellular uptake in a human carcinoid cell line (BON cells) than non-targeted Au NR-based nanocarriers (Au-DOX) as measured by both flow cytometry and confocal laser scanning microscopy (CLSM). Moreover, Au-DOX-OCT-ASCL1 siRNA (Au-DOX-OCT complexed with ASCL1 siRNA) resulted in significantly higher gene silencing in NE cancer cells than Au-DOX-ASCL1 siRNA (non-targeted Au-DOX complexed with ASCL1 siRNA) as measured by an immunoblot analysis. Additionally, Au-DOX-OCT-ASCL1 siRNA was the most efficient nanocarrier at altering the NE phenotype of NE cancer cells and showed the strongest anti-proliferative effect. Thus, combined chemotherapy and RNA silencing using NE tumor-targeting Au NR-based nanocarriers could potentially enhance the therapeutic outcomes in treating NE cancers.A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The

  6. Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

    PubMed Central

    MacDiarmid, Jennifer A.; Langova, Veronika; Bailey, Dale; Pattison, Scott T.; Pattison, Stacey L.; Christensen, Neil; Armstrong, Luke R.; Brahmbhatt, Vatsala N.; Smolarczyk, Katarzyna; Harrison, Matthew T.; Costa, Marylia; Mugridge, Nancy B.; Sedliarou, Ilya; Grimes, Nicholas A.; Kiss, Debra L.; Stillman, Bruce; Hann, Christine L.; Gallia, Gary L.; Graham, Robert M.; Brahmbhatt, Himanshu

    2016-01-01

    Background Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. Methodology/Principle Findings EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Conclusions/Significance Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On

  7. Magnetically targeted delivery of DOX loaded Cu9S5@mSiO2@Fe3O4-PEG nanocomposites for combined MR imaging and chemo/photothermal synergistic therapy

    NASA Astrophysics Data System (ADS)

    Liu, Bei; Zhang, Xinyang; Li, Chunxia; He, Fei; Chen, Yinyin; Huang, Shanshan; Jin, Dayong; Yang, Piaoping; Cheng, Ziyong; Lin, Jun

    2016-06-01

    The combination of multi-theranostic modes in a controlled fashion has received tremendous attention for the construction of cooperative therapeutic systems in nanomedicine. Herein, we have synthesized a smart magnetically targeted nanocarrier system, Cu9S5@mSiO2@Fe3O4-PEG (labelled as CMF), which integrates NIR triggered photothermal therapy, pH/NIR-responsive chemotherapy and MR imaging into one nanoplatform to enhance the therapeutic efficacy. This new multifunctional paradigm has a uniform and monodisperse sesame ball-like structure by decorating tiny Fe3O4 nanoparticles on the surface of Cu9S5@mSiO2 before a further PEG modification to improve its hydrophilicity and biocompatibility. With doxorubicin (DOX) payload, the as-obtained CMF-DOX composites can simultaneously provide an intense heating effect and enhanced DOX release upon 980 nm NIR light exposure, achieving a combined chemo/photothermal therapy. Under the influence of an external magnetic field, the magnetically targeted synergistic therapeutic effect of CMF-DOX can lead to highly superior inhibition of animal H22 tumor in vivo when compared to any of the single approaches alone. The results revealed that this Cu9S5 based magnetically targeted chemo/photothermal synergistic nanocarrier system has great promise in future MR imaging assisted tumor targeted therapy of cancer.

  8. Folate-conjugated beta-cyclodextrin-based polymeric micelles with enhanced doxorubicin antitumor efficacy.

    PubMed

    Zhang, Lu; Lu, Jiafei; Jin, Yangmin; Qiu, Liyan

    2014-10-01

    In order to enhance the antitumor effects of doxorubicin (DOX), a novel micellar vector with high DOX loading and tumor targeting function based on folate-conjugated amphiphilic copolymer folate-poly(ethylene glycol)-poly(d,l-lactide)-β-cyclodextrin (FA-PEL-CD) was constructed. Cytotoxicity and cellular uptake experiments were performed in HeLa, KB, and A549 cell lines expressing different amounts of folate receptors in order to evaluate the targeting effect of the folate modification. The antitumor experiments performed in a KB cell-xenografted nude mouse model showed that the treatment with 10mg/kg DOX loaded FA-PEL-CD micelles achieved approximately 86% of tumor growth inhibition compared to the control. Ex vivo fluorescence imaging experiments and histological examination confirmed that folate modification can enhance the antitumorigenesis efficacy and reduce the cardiotoxicity of DOX. These results suggest that FA-PEL-CD copolymer-based micelles are promising nanocarriers for targeted doxorubicin delivery, with improved antitumor efficacy and reduced toxicity in normal tissues. PMID:25058857

  9. A dual pH/thermal responsive nanocarrier for combined chemo-thermotherapy based on a copper-doxorubicin complex and gold nanorods

    NASA Astrophysics Data System (ADS)

    Lei, Mingzhu; Ma, Man; Pang, Xiaojuan; Tan, Fengping; Li, Nan

    2015-09-01

    The development of treatment protocols that results in a complete response to chemotherapy has been hampered by low efficacy and systemic toxicity. Here, we created a pH sensitive copper-doxorubicin complex within the core of temperature-sensitive liposomes to maintain the stability during blood circulation and trigger Dox release in the tumor site. Synergistically, we also rationally applied gold nanorods (AuNRs) coupled with near-infrared (NIR) field strength to produce a precise and localized temperature, which not only remotely controlled the drug release but also directly destroyed the tumor, to enhance the therapeutic efficacy. As expected, the in vitro release studies showed that the drug release from CuDox-TSLs (Copper ion mediated Doxorubicin loading-Temperature Sensitive Liposomes) was both pH-dependent and temperature-dependent. Furthermore, MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assays showed that CuDox-TSLs combined with AuNRs exhibited a closer antiproliferative activity to free Dox in MCF-7 cells. The efficient intracellular Dox release from CuDox-TSLs toward the tumor cells further confirmed the anti-tumor effect. Moreover, the in vivo imaging and biodistribution studies revealed that CuDox-TSLs combined with AuNRs could actively target the tumor site. In addition, the therapeutic studies in MCF-7 nude mice exhibited CuDox-TSLs plus AuNRs in combination with NIR irradiation inhibited tumor growth to a great extent and possessed much lower side effects, which were further confirmed by systemic histological analyses. All detailed evidence suggested a considerable potential of CuDox-TSLs combined with AuNRs for treatment of metastatic cancer.The development of treatment protocols that results in a complete response to chemotherapy has been hampered by low efficacy and systemic toxicity. Here, we created a pH sensitive copper-doxorubicin complex within the core of temperature-sensitive liposomes to maintain the stability

  10. Electroporation adopting trains of biphasic pulses enhances in vitro and in vivo the cytotoxic effect of doxorubicin on multidrug resistant colon adenocarcinoma cells (LoVo).

    PubMed

    Meschini, Stefania; Condello, Maria; Lista, Pasquale; Vincenzi, Bruno; Baldi, Alfonso; Citro, Gennaro; Arancia, Giuseppe; Spugnini, Enrico P

    2012-09-01

    Few articles in the literature have focused on electroporation as a strategy to reverse multidrug resistance (MDR) of tumour cells and they are mostly limited to the improved efficacy of bleomycin. We tested the application of trains of biphasic pulses to cell suspensions and to murine xenografts as a strategy to increase the uptake of doxorubicin (DOX) and to enhance its cytotoxicity against chemoresistant cells. The human colon adenocarcinoma cell line LoVo DX, expressing MDR phenotype with high levels of P-glycoprotein (P-gp), has been used. The in vitro and in vivo studies gave the following results: (i) the application of the electric pulses to the cell suspension, immediately before DOX administration, induced a significant increase of drug retention; (ii) confocal microscopy observations showed a remarkable increase of intranuclear accumulation of DOX induced by electroporation; (iii) cell survival assay revealed a decrease of cell viability in the cultures treated with the combination of electroporation and doxorubicin; (iv) scanning electron microscopy observations revealed consistent morphological changes after the combined exposure to electroporation and doxorubicin; (v) in implanted mice the combined treatment induced an evident slowdown on the tumour growth when compared to treatment with DOX alone; (vi) histopathological analysis evidenced tumour destruction and its replacement by scar tissue in the tumours treated with the combination of doxorubicin and electroporation.

  11. Design and evaluation of a novel potential carrier for a hydrophilic antitumor drug: Auricularia auricular polysaccharide-chitosan nanoparticles as a delivery system for doxorubicin hydrochloride.

    PubMed

    Xiong, Wei; Li, Li; Wang, Yingying; Yu, Yibin; Wang, Shenxia; Gao, Yunyun; Liang, Yanyao; Zhang, Guogang; Pan, Weisan; Yang, Xinggang

    2016-09-10

    To improve the low loading content of hydrophilic drugs in nanodrug delivery systems, a natural watersoluble polysaccharide, Auricularia auricular polysaccharide (AAP), was extracted and purified as a vehicle for the hydrophilic drug doxorubicin hydrochloride (Dox·HCl). This involved the preparation of polyelectrolyte complexes nanoparticles (PEC NPs) using the electrostatic interaction between cationic chitosan (CS) and anionic AAP. The formation of AAP-CS-NPs was confirmed by FT-IR and TEM. It was found that Dox-loaded AAP-CS-NPs possessed a spherical morphology with average diameters of 237.6nm and 74.1% Dox·HCl encapsulation efficiency. The stability of Dox AAP-CS-NPs was examined by suspending the nanoparticles in PBS (pH 7.4) at room temperature. The particle size of the nanoparticle samples remained stable and exhibited no obvious variations in drug content after half a month. In addition, in vitro cytotoxicity studies showed that blank AAP-CS-NPs did not exhibit any cytotoxic effects, while Dox AAP-CS-NPs increased the Dox·HCl cytotoxicity against MCF-7 cells as the result of significantly increased cellular uptake, compared with free Dox·HCl. Hence, the overall results obtained suggest that AAP-CS-NPs are very effective in entrapping Dox·HCl and to penetrate into tumor cells, rendering them promising carriers for hydrophilic antitumor drugs. PMID:27424168

  12. A dual pH/thermal responsive nanocarrier for combined chemo-thermotherapy based on a copper-doxorubicin complex and gold nanorods.

    PubMed

    Lei, Mingzhu; Ma, Man; Pang, Xiaojuan; Tan, Fengping; Li, Nan

    2015-10-14

    The development of treatment protocols that results in a complete response to chemotherapy has been hampered by low efficacy and systemic toxicity. Here, we created a pH sensitive copper-doxorubicin complex within the core of temperature-sensitive liposomes to maintain the stability during blood circulation and trigger Dox release in the tumor site. Synergistically, we also rationally applied gold nanorods (AuNRs) coupled with near-infrared (NIR) field strength to produce a precise and localized temperature, which not only remotely controlled the drug release but also directly destroyed the tumor, to enhance the therapeutic efficacy. As expected, the in vitro release studies showed that the drug release from CuDox-TSLs (Copper ion mediated Doxorubicin loading-Temperature Sensitive Liposomes) was both pH-dependent and temperature-dependent. Furthermore, MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assays showed that CuDox-TSLs combined with AuNRs exhibited a closer antiproliferative activity to free Dox in MCF-7 cells. The efficient intracellular Dox release from CuDox-TSLs toward the tumor cells further confirmed the anti-tumor effect. Moreover, the in vivo imaging and biodistribution studies revealed that CuDox-TSLs combined with AuNRs could actively target the tumor site. In addition, the therapeutic studies in MCF-7 nude mice exhibited CuDox-TSLs plus AuNRs in combination with NIR irradiation inhibited tumor growth to a great extent and possessed much lower side effects, which were further confirmed by systemic histological analyses. All detailed evidence suggested a considerable potential of CuDox-TSLs combined with AuNRs for treatment of metastatic cancer. PMID:26370706

  13. Synthesis of Acid-Labile PEG and PEG-Doxorubicin-Conjugate Nanoparticles via Brush-First ROMP

    PubMed Central

    2015-01-01

    A panel of acid-labile bis-norbornene cross-linkers was synthesized and evaluated for the formation of acid-degradable brush-arm star polymers (BASPs) via the brush-first ring-opening metathesis polymerization (ROMP) method. An acetal-based cross-linker was identified that, when employed in conjunction with a poly(ethylene glycol) (PEG) macromonomer, provided highly controlled BASP formation reactions. A combination of this new cross-linker with a novel doxorubicin (DOX)-branch-PEG macromonomer provided BASPs that simultaneously degrade and release cytotoxic DOX in vitro. PMID:25243099

  14. Galactose engineered solid lipid nanoparticles for targeted delivery of doxorubicin.

    PubMed

    Jain, Ashay; Kesharwani, Prashant; Garg, Neeraj K; Jain, Atul; Jain, Som Akshay; Jain, Amit Kumar; Nirbhavane, Pradip; Ghanghoria, Raksha; Tyagi, Rajeev Kumar; Katare, Om Prakash

    2015-10-01

    The present investigation reports the preparation, optimization, and characterization of surface engineered solid lipid nanoparticles (SLNs) encapsulated with doxorubicin (DOX). Salient features such as biocompatibility, controlled release, target competency, potential of penetration, improved physical stability, low cost and ease of scaling-up make SLNs viable alternative to liposomes for effective drug delivery. Galactosylation of SLNs instructs some gratifying characteristic, which leads to the evolution of promising delivery vehicles. The impendence of lectin receptors on different cell surfaces makes the galactosylated carriers admirable for targeted delivery of drugs to ameliorate their therapeutic index. Active participation of some lectin receptors in immune responses to antigen overlaid the application of galactosylated carriers in delivery of antigen and immunotherapy for treatment of maladies like cancer. These advantages revealed the promising potential of galactosylated carriers in each perspective of drug delivery. The developed DOX loaded galactosylated SLNs formulation was found to have particle size 239 ± 2.40 nm, PDI 0.307 ± 0.004, entrapment efficiency 72.3 ± 0.9%. Higher cellular uptake, cytotoxicity, and nuclear localization of galactosylated SLNs against A549 cells revealed higher efficiency of the formulation. In a nutshell, the galactosylation strategy with SLNs could be a promising approach in improving the delivery of DOX for cancer therapy. PMID:26142628

  15. In vitro cytotoxicity analysis of doxorubicin-loaded/superparamagnetic iron oxide colloidal nanoassemblies on MCF7 and NIH3T3 cell lines

    PubMed Central

    Tomankova, Katerina; Polakova, Katerina; Pizova, Klara; Binder, Svatopluk; Havrdova, Marketa; Kolarova, Mary; Kriegova, Eva; Zapletalova, Jana; Malina, Lukas; Horakova, Jana; Malohlava, Jakub; Kolokithas-Ntoukas, Argiris; Bakandritsos, Aristides; Kolarova, Hana; Zboril, Radek

    2015-01-01

    One of the promising strategies for improvement of cancer treatment is based on magnetic drug delivery systems, thus avoiding side effects of standard chemotherapies. Superparamagnetic iron oxide (SPIO) nanoparticles have ideal properties to become a targeted magnetic drug delivery contrast probes, named theranostics. We worked with SPIO condensed colloidal nanocrystal clusters (MagAlg) prepared through a new soft biomineralization route in the presence of alginate as the polymeric shell and loaded with doxorubicin (DOX). The aim of this work was to study the in vitro cytotoxicity of these new MagAlg–DOX systems on mouse fibroblast and breast carcinoma cell lines. For proper analysis and understanding of cell behavior after administration of MagAlg–DOX compared with free DOX, a complex set of in vitro tests, including production of reactive oxygen species, comet assay, cell cycle determination, gene expression, and cellular uptake, were utilized. It was found that the cytotoxic effect of MagAlg–DOX system is delayed compared to free DOX in both cell lines. This was attributed to the different mechanism of internalization of DOX and MagAlg–DOX into the cells, together with the fact that the drug is strongly bound on the drug nanocarriers. We discovered that nanoparticles can attenuate or even inhibit the effect of DOX, particularly in the tumor MCF7 cell line. This is a first comprehensive study on the cytotoxic effect of DOX-loaded SPIO compared with free DOX on healthy and cancer cell lines, as well as on the induced changes in gene expression. PMID:25673990

  16. Preventive and protective effects of silymarin on doxorubicin-induced testicular damages correlate with changes in c-myc gene expression.

    PubMed

    Malekinejad, H; Janbaz-Acyabar, H; Razi, M; Varasteh, S

    2012-09-15

    This study aimed to investigate the preventive and protective effects of silymarin (SMN) on doxorubicin (DOX)-induced damages in the testis. Wistar rats were divided into six groups (n=8), including: control (C), DOX-treated (DOX, 15 mg/kg, i.p.), DOX- and SMN-treated and SMN-treated animals (SMN, 50 mg/kg, orally). Those groups, which received either compounds, were sub-grouped based on the preventive (PVT), protective (PTT) and/or therapeutic regimens (TPT) of SMN administration. The antioxidant status analyses, hormonal assay, and histopathological examinations in the testis were conducted. The expression of c-myc at mRNA level also was analyzed. SMN in preventive and protective forms significantly (p<0.05) improved the DOX-induced weight loss and lowered the alkaline phosphatase level. Pretreatment and co-treatment with SMN attenuated the DOX-induced carbonyl stress. The DOX-induced histopathological damages including negative TDI and IR were significantly (p<0.05) improved with SMN pretreatment and co-administration. SMN in preventive and protective forms prevented from DOX-induced DNA fragmentation in the testis. SMN ameliorated the DOX-reduced serum level of sexual hormones including testosterone, inhibin B, LH and FSH in PVT and PTT groups. The c-myc expression at mRNA level was completely and relatively down regulated in the testis of animals that received SMN as pretreatment and concurrent administration, respectively. Our data suggests that the DOX-induced biochemical and histopathological alterations could be prevented and/or protected by SMN. Moreover, the SMN protective and preventive effects attribute to its capacity in the reduction of DOX-induced carbonyl stress and DNA damage, which may be mediated by c-myc expression.

  17. N-acetylcysteine amide decreases oxidative stress but not cell death induced by doxorubicin in H9c2 cardiomyocytes

    PubMed Central

    Shi, Rong; Huang, Chuan-Chin; Aronstam, Robert S; Ercal, Nuran; Martin, Adam; Huang, Yue-Wern

    2009-01-01

    Background While doxorubicin (DOX) is widely used in cancer chemotherapy, long-term severe cardiotoxicity limits its use. This is the first report of the chemoprotective efficacy of a relatively new thiol antioxidant, N-acetylcysteine amide (NACA), on DOX-induced cell death in cardiomyocytes. We hypothesized that NACA would protect H9c2 cardiomyocytes from DOX-induced toxicity by reducing oxidative stress. Accordingly, we determined the ability of NACA to mitigate the cytotoxicity of DOX in H9c2 cells and correlated these effects with the production of indicators of oxidative stress. Results DOX at 5 μM induced cardiotoxicity while 1) increasing the generation of reactive oxygen species (ROS), 2) decreasing levels and activities of antioxidants and antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase) and 3) increasing lipid peroxidation. NACA at 750 μM substantially reduced the levels of ROS and lipid peroxidation, as well as increased both GSH level and GSH/GSSG ratio. However, treating H9c2 cells with NACA did little to protect H9c2 cells from DOX-induced cell death. Conclusion Although NACA effectively reduced oxidative stress in DOX-treated H9c2 cells, it had minimal effects on DOX-induced cell death. NACA prevented oxidative stress by elevation of GSH and CYS, reduction of ROS and lipid peroxidation, and restoration of antioxidant enzyme activities. Further studies to identify oxidative stress-independent pathways that lead to DOX-induced cell death in H9c2 are warranted. PMID:19368719

  18. Adipocytokine, omentin inhibits doxorubicin-induced H9c2 cardiomyoblasts apoptosis through the inhibition of mitochondrial reactive oxygen species.

    PubMed

    Kazama, Kyosuke; Okada, Muneyoshi; Yamawaki, Hideyuki

    2015-02-20

    Omentin is a relatively novel adipocyte-derived cytokine mainly expressed in visceral adipose tissues. Blood omentin level decreases in the patients with obesity, hypertension, type 2 diabetes and atherosclerosis. We have previously demonstrated that omentin inhibits key pathological processes for hypertension development, including vascular inflammatory responses, contractile reactivity and structural remodeling. In addition, there are several reports demonstrating that omentin prevents cardiac hypertrophy and myocardial ischemic injury. Doxorubicin (DOX) is an effective anti-cancer drug with cardiotoxic side effect. Here we tested the hypothesis that omentin may prevent DOX-induced cardiac cytotoxicity. H9c2 rat cardiomyoblasts were treated with DOX in the absence or presence of omentin. Omentin (300 ng/ml, 3 h pretreatment) significantly inhibited DOX (1 μM, 18 h)-induced decreases in living cell number as determined by a colorimetric cell counting assay. Omentin (300 ng/ml, 3 h) significantly inhibited DOX (1 μM, 12 h)-induced cleaved caspase-3 expression as determined by Western blotting. Omentin (300 ng/ml, 3 h) significantly inhibited DOX (1 μM, 6 h)-induced mitochondrial reactive oxygen species (ROS) production as determined by a MitoSOX Red fluorescent staining. In addition, a mitochondrial respiratory chain complex I inhibitor, rotenone (0.5 μM, 3 h pretreatment), significantly inhibited DOX (1 μM, 6-18 h)-induced decreases of living cell number, cleaved caspase-3 expression and mitochondrial ROS production. In summary, we for the first time demonstrate that omentin prevents DOX-induced H9c2 cells apoptosis through the inhibition of mitochondrial ROS production. These results indicate omentin as an attractive pharmaco-therapeautic target against DOX-induced cardiac side effect. PMID:25600813

  19. A Novel Approach to Early Detection of Doxorubicin Cardiotoxicity using Gadolinium Enhanced Cardiovascular Magnetic Resonance Imaging in an Experimental Model

    PubMed Central

    Lightfoot, James C.; D'Agostino, Ralph B.; Hamilton, Craig A; Jordan, Jennifer; Torti, Frank M.; Kock, Nancy D.; Jordan, James; Workman, Susan; Hundley, W Gregory

    2011-01-01

    Background To determine if cardiovascular magnetic resonance (CMR) measures of gadolinium (Gd) signal intensity (SI) within the left ventricular (LV) myocardium are associated with future changes in LV ejection fraction (LVEF) after receipt of doxorubicin (DOX). Methods and Results Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of: normal saline (NS) (n=7), 1.5 mg/kg DOX (n=19), or 2.5 mg/kg DOX (n=14). MR determinations of LVEF and myocardial Gd-SI were performed before and then at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were sacrificed at different time points so that histopathological assessments of the LV myocardium could be obtained. Within group analyses were performed to examine time-dependent relationships between Gd-SI and primary events (a deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg of DOX and 10/14 animals receiving 2.5 mg/kg of DOX experienced a primary event; no NS animals experienced a primary event. In animals with a primary event, histopathological evidence of myocellular vacuolization occurred (p=0.04), and the Gd-SI was elevated relative to baseline at the time of the event (p<0.0001) and during the measurement period prior to the event (p=0.0001). In all animals (including NS) without an event, measures of Gd-SI did not differ from baseline. Conclusions After DOX, low serial measures of Gd-SI predict an absence of a LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity. PMID:20622140

  20. Cardioprotective effect of green tea extract on doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Khan, Gyas; Haque, Syed Ehtaishamul; Anwer, Tarique; Ahsan, Mohd Neyaz; Safhi, Mohammad M; Alam, M F

    2014-01-01

    The in vivo antioxidant properties of green tea extract (GTE) were investigated against doxorubicin (DOX) induced cardiotoxicity in rats. In this experiment, 48 Wistar albino rats (200-250 g) were divided into eight groups (n = 6). Control group received normal saline for 30 days. Cardiotoxicity was induced by DOX (20 mg/kg ip.), once on 29th day of study and were treated with GTE (100, 200 and 400 mg/kg, p.o.) for 30 days. Aspartate aminotransferase (AST), creatinine kinase (CK), lactate dehydrogenase (LDH), lipid peroxidation (LPO), cytochrome P450 (CYP), blood glutathione, tissue glutathione, enzymatic and non-enzymatic antioxidants were evaluated along with histopathological studies. DOX treated rats showed a significant increased levels of AST, CK, LDH, LPO and CYP, which were restored by oral administration of GTE at doses 100, 200 and 400 mg/kg for 30 days. Moreover, GTE administration significantly increased the activities of glutathione peroxidase (GPX), glutathione reductase (GR), glutathione s-transferase (GST), superoxide dismutase (SOD) and catalase (CAT), in heart, which were reduced by DOX treatment. In this study, we have found that oral administration of GTE prevented DOX-induced cardiotoxicity by accelerating heart antioxidant defense mechanisms and down regulating the LPO levels to the normal levels.

  1. Vesicular gold assemblies based on host-guest inclusion and its controllable release of doxorubicin.

    PubMed

    Ha, Wei; Kang, Yang; Peng, Shu-Lin; Ding, Li-Sheng; Zhang, Sheng; Li, Bang-Jing

    2013-12-13

    We have developed a kind of gold nanoparticle (AuNP) in which polyethylene glycol (PEG) and poly(N-isopropylacrylamide) (PNIPAM) are attached on the surface of a gold nanocrystal through the host-guest inclusion between adamantane groups (ADA) and β-cyclodextrin (β-CD). The resulting AuNPs become amphiphilic in water above body temperature and self-assemble into vesicles. It is found that these vesicles can load doxorubicin (Dox) effectively. With a decrease in temperature, the PNIPAM shifted from hydrophobic to hydrophilic, causing Au vesicles to disassemble into stable small AuNPs, triggering the release of Dox. These hybrid vesicles, combining polymer functionality with the intriguing properties of AuNPs, can first release free Dox and AuNP/Dox at a site of a tumor through the application of either simple ice packs or deeply penetrating cryoprobes, then the AuNP/Dox can be taken in by tumor cells and destroy them like miniature munitions. Furthermore, these vesicles showed other therapeutic possibilities due to the presence of gold. We believe that the development of such multi-functional vesicles will provide new and therapeutically useful means for medical applications. PMID:24231410

  2. Combined Cancer Photothermal-Chemotherapy Based on Doxorubicin/Gold Nanorod-Loaded Polymersomes

    PubMed Central

    Liao, JinFeng; Li, WenTing; Peng, JinRong; Yang, Qian; Li, He; Wei, YuQuan; Zhang, XiaoNing; Qian, ZhiYong

    2015-01-01

    Gold nanorods (GNRs) are well known in photothermal therapy based on near-infrared (NIR) laser absorption of the longitudinal plasmon band. Herein, we developed an effective stimulus system -- GNRs and doxorubicin co-loaded polymersomes (P-GNRs-DOX) -- to facilitate co-therapy of photothermal and chemotherapy. DOX can be triggered to release once the polymersomes are corrupted under local hyperthermic condition of GNRs induced by NIR laser irradiation. Also, the cytotoxicity of GNRs caused by the residual cetyltrimethylacmmonium bromide (CTAB) was reduced by shielding the polymersomes. The GNRs-loaded polymersomes (P-GNRs) can be efficiently taken up by the tumor cells. The distribution of the nanomaterial was imaged by IR-820 and quantitatively analyzed by ICP-AES. We studied the ablation of tumor cells in vitro and in vivo, and found that co-therapy offers significantly improved therapeutic efficacy (tumors were eliminated without regrowth.) compared with chemotherapy or photothermal therapy alone. By TUNEL immunofluorescent staining of tumors after NIR laser irradiation, we found that the co-therapy showed more apoptotic tumor cells than the other groups. Furthermore, the toxicity study by pathologic examination of the heart tissues demonstrated a lower systematic toxicity of P-GNRs-DOX than free DOX. Thus, the chemo-photothermal treatment based on polymersomes loaded with DOX and GNRs is a useful strategy for maximizing the therapeutic efficacy and minimizing the dosage-related side effects in the treatment of solid tumors. PMID:25699095

  3. Vesicular gold assemblies based on host-guest inclusion and its controllable release of doxorubicin

    NASA Astrophysics Data System (ADS)

    Ha, Wei; Kang, Yang; Peng, Shu-Lin; Ding, Li-Sheng; Zhang, Sheng; Li, Bang-Jing

    2013-12-01

    We have developed a kind of gold nanoparticle (AuNP) in which polyethylene glycol (PEG) and poly(N-isopropylacrylamide) (PNIPAM) are attached on the surface of a gold nanocrystal through the host-guest inclusion between adamantane groups (ADA) and β-cyclodextrin (β-CD). The resulting AuNPs become amphiphilic in water above body temperature and self-assemble into vesicles. It is found that these vesicles can load doxorubicin (Dox) effectively. With a decrease in temperature, the PNIPAM shifted from hydrophobic to hydrophilic, causing Au vesicles to disassemble into stable small AuNPs, triggering the release of Dox. These hybrid vesicles, combining polymer functionality with the intriguing properties of AuNPs, can first release free Dox and AuNP/Dox at a site of a tumor through the application of either simple ice packs or deeply penetrating cryoprobes, then the AuNP/Dox can be taken in by tumor cells and destroy them like miniature munitions. Furthermore, these vesicles showed other therapeutic possibilities due to the presence of gold. We believe that the development of such multi-functional vesicles will provide new and therapeutically useful means for medical applications.

  4. Voluntary wheel running in growing rats does not protect against doxorubicin-induced osteopenia.

    PubMed

    Hayward, Reid; Iwaniec, Urszula T; Turner, Russell T; Lien, Chia-Ying; Jensen, Brock T; Hydock, David S; Schneider, Carole M

    2013-05-01

    There is growing concern regarding the long-term negative side effects of chemotherapy in childhood cancer survivors. Doxorubicin (DOX) is commonly used in the treatment of childhood cancers and has been shown to be both cardiotoxic and osteotoxic. It is unclear whether exercise can attenuate the negative skeletal effects of this chemotherapy. Rat pups were treated with saline or DOX. Animals remained sedentary or voluntarily exercised. After 10 weeks, femoral bone mineral content and bone mineral density were measured using dual-energy x-ray absorptiometry. Cortical and cancellous bone architecture was then evaluated by microcomputed tomography. DOX had a profound negative effect on all measures of bone mass and cortical and cancellous bone architecture. Treatment with DOX resulted in shorter femora and lower femoral bone mineral content and bone mineral density, lower cross-sectional volume, cortical volume, marrow volume, cortical thickness, and principal (IMAX, IMIN) and polar (IPOLAR) moments of inertia in the femur diaphysis, and lower cancellous bone volume/tissue volume, trabecular number, and trabecular thickness in the distal femur metaphysis. Exercise failed to protect bones from the damaging effects of DOX. Other modalities may be necessary to mitigate the deleterious skeletal effects that occur in juveniles undergoing treatment with anthracyclines. PMID:23211689

  5. Combined cancer photothermal-chemotherapy based on doxorubicin/gold nanorod-loaded polymersomes.

    PubMed

    Liao, JinFeng; Li, WenTing; Peng, JinRong; Yang, Qian; Li, He; Wei, YuQuan; Zhang, XiaoNing; Qian, ZhiYong

    2015-01-01

    Gold nanorods (GNRs) are well known in photothermal therapy based on near-infrared (NIR) laser absorption of the longitudinal plasmon band. Herein, we developed an effective stimulus system -- GNRs and doxorubicin co-loaded polymersomes (P-GNRs-DOX) -- to facilitate co-therapy of photothermal and chemotherapy. DOX can be triggered to release once the polymersomes are corrupted under local hyperthermic condition of GNRs induced by NIR laser irradiation. Also, the cytotoxicity of GNRs caused by the residual cetyltrimethylacmmonium bromide (CTAB) was reduced by shielding the polymersomes. The GNRs-loaded polymersomes (P-GNRs) can be efficiently taken up by the tumor cells. The distribution of the nanomaterial was imaged by IR-820 and quantitatively analyzed by ICP-AES. We studied the ablation of tumor cells in vitro and in vivo, and found that co-therapy offers significantly improved therapeutic efficacy (tumors were eliminated without regrowth.) compared with chemotherapy or photothermal therapy alone. By TUNEL immunofluorescent staining of tumors after NIR laser irradiation, we found that the co-therapy showed more apoptotic tumor cells than the other groups. Furthermore, the toxicity study by pathologic examination of the heart tissues demonstrated a lower systematic toxicity of P-GNRs-DOX than free DOX. Thus, the chemo-photothermal treatment based on polymersomes loaded with DOX and GNRs is a useful strategy for maximizing the therapeutic efficacy and minimizing the dosage-related side effects in the treatment of solid tumors.

  6. Angiopep2-functionalized polymersomes for targeted doxorubicin delivery to glioblastoma cells.

    PubMed

    Figueiredo, Patrícia; Balasubramanian, Vimalkumar; Shahbazi, Mohammad-Ali; Correia, Alexandra; Wu, Dalin; Palivan, Cornelia G; Hirvonen, Jouni T; Santos, Hélder A

    2016-09-25

    A targeted drug delivery nanosystem for glioblastoma multiforme (GBM) based on polymersomes (Ps) made of poly(dimethylsiloxane)-poly(2-methyloxazoline) (PDMS-PMOXA) diblock copolymers was developed to evaluate their potential to actively target brain cancer cells and deliver anticancer drugs. Angiopep2 was conjugated to the surface of preformed Ps to target the low density lipoprotein receptor-related protein 1 that are overexpressed in blood brain barrier (BBB) and glioma cells. The conjugation efficiency yield for angiopep2 was estimated to be 24%. The angiopep2-functionalized Ps showed no cellular toxicity after 24h and enhanced the cellular uptake around 5 times more in U87MG glioblastoma cells compared to the non-targeted Ps. The encapsulation efficiency of doxorubicin (DOX) in Ps was 13% by co-solvent method, compared to a film rehydration method (4%). The release profiles of the DOX from Ps showed a release of 42% at pH 5.5 and 40% at pH 7.4 after 24h, indicating that Ps can efficiently retain the DOX with a slow release rate. Furthermore, the in vitro antiproliferative activity of DOX-loaded Ps-Angiopep2 showed enhanced toxicity to U87MG glioblastoma cells, compared to non-targeted Ps. Overall, our in vitro results suggested that angiopep2-conjugated Ps can be used as nanocarriers for efficient targeted DOX delivery to glioblastoma cells.

  7. Doxorubicin-loaded magnetic gold nanoshells for a combination therapy of hyperthermia and drug delivery.

    PubMed

    Mohammad, Faruq; Yusof, Nor Azah

    2014-11-15

    In the present work, nanohybrid of an anticancer drug, doxorubicin (Dox) loaded gold-coated superparamagnetic iron oxide nanoparticles (SPIONs@Au) were prepared for a combination therapy of cancer by means of both hyperthermia and drug delivery. The Dox molecules were conjugated to SPIONs@Au nanoparticles with the help of cysteamine (Cyst) as a non-covalent space linker and the Dox loading efficiency was investigated to be as high as 0.32 mg/mg. Thus synthesized particles were characterized by HRTEM, UV-Vis, FT-IR, SQUID magnetic studies and further tested for heat and drug release at low frequency oscillatory magnetic fields. The hyperthermia studies investigated to be strongly influenced by the applied frequency and the solvents used. The Dox delivery studies indicated that the drug release efficacy is strongly improved by maintaining the acidic pH conditions and the oscillatory magnetic fields, i.e. an enhancement in the Dox release was observed from the oscillation of particles due to the applied frequency, and is not effected by heating of the solution. Finally, the in vitro cell viability and proliferation studies were conducted using two different immortalized cell lines containing a cancerous (MCF-7 breast cancer) and non-cancerous H9c2 cardiac cell type. PMID:25170601

  8. The anti-cancer drug, doxorubicin, causes oxidant stress-induced endothelial dysfunction.

    PubMed

    Wolf, Matthew B; Baynes, John W

    2006-02-01

    The anticancer drug doxorubicin (DOX) is toxic to target cells, but also causes endothelial dysfunction and edema, secondary to oxidative stress in the vascular wall. Thus, the mechanism of action of this drug may involve chemotoxicity to both cancer cells and to the endothelium. Indeed, we found that the permeability of monolayers of bovine pulmonary artery endothelial cells (BPAEC) to albumin was increased by approximately 10-fold above control, following 24-h exposure to clinically relevant concentrations of DOX (up to 1 microM). DOX also caused >4-fold increases in lactate dehydrogenase leakage and large decreases in ATP and reduced glutathione (GSH) in BPAECs, which paralleled the increases in endothelial permeability. A large part of the ATP loss could be attributed to DOX-induced hydrogen peroxide production which inhibited key thiol-enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate dehydrogenase (G6PDH). Depletion of reduced nicotinamide adenine dinucleotide phosphate (NADPH) appeared to be a major factor leading to DOX-induced GSH depletion. At low concentrations, the sulfhydryl reagent, iodoacetate (IA), inhibited GAPDH, caused a decrease in ATP and increased permeability, without inhibiting G6PDH or decreasing GSH. These results, coupled with those of previous work on a related quinone, menadione, suggest that depletion of either GSH or ATP may lead independently to endothelial dysfunction during chemotherapy, contributing to the cardiotoxicity and other systemic side-effects of the drug.

  9. Lipid rafts-mediated endocytosis and physiology-based cell membrane traffic models of doxorubicin liposomes.

    PubMed

    Li, Yinghuan; Gao, Lei; Tan, Xi; Li, Feiyang; Zhao, Ming; Peng, Shiqi

    2016-08-01

    The clathrin-mediated endocytosis is likely a major mechanism of liposomes' internalization. A kinetic approach was used to assess the internalization mechanism of doxorubicin (Dox) loaded cationic liposomes and to establish physiology-based cell membrane traffic mathematic models. Lipid rafts-mediated endocytosis, including dynamin-dependent or -independent endocytosis of noncaveolar structure, was a dominant process. The mathematic models divided Dox loaded liposomes binding lipid rafts (B) into saturable binding (SB) and nonsaturable binding (NSB) followed by energy-driven endocytosis. The intracellular trafficking demonstrated early endosome-late endosome-lysosome or early/late endosome-cytoplasm-nucleus pathways. The three properties of liposome structures, i.e., cationic lipid, fusogenic lipid, and pegylation, were investigated to compare their contributions to cell membrane and intracellular traffic. The results revealed great contribution of cationic lipid DOTAP and fusogenic lipid DOPE to cell membrane binding and internalization. The valid Dox in the nuclei of HepG2 and A375 cells treated with cationic liposomes containing 40mol% of DOPE were 1.2-fold and 1.5-fold higher than that in the nuclei of HepG2 and A375 cells treated with liposomes containing 20mol% of DOPE, respectively, suggesting the dependence of cell type. This tendency was proportional to the increase of cell-associated total liposomal Dox. The mathematic models would be useful to predict intracellular trafficking of liposomal Dox.

  10. Angiopep2-functionalized polymersomes for targeted doxorubicin delivery to glioblastoma cells.

    PubMed

    Figueiredo, Patrícia; Balasubramanian, Vimalkumar; Shahbazi, Mohammad-Ali; Correia, Alexandra; Wu, Dalin; Palivan, Cornelia G; Hirvonen, Jouni T; Santos, Hélder A

    2016-09-25

    A targeted drug delivery nanosystem for glioblastoma multiforme (GBM) based on polymersomes (Ps) made of poly(dimethylsiloxane)-poly(2-methyloxazoline) (PDMS-PMOXA) diblock copolymers was developed to evaluate their potential to actively target brain cancer cells and deliver anticancer drugs. Angiopep2 was conjugated to the surface of preformed Ps to target the low density lipoprotein receptor-related protein 1 that are overexpressed in blood brain barrier (BBB) and glioma cells. The conjugation efficiency yield for angiopep2 was estimated to be 24%. The angiopep2-functionalized Ps showed no cellular toxicity after 24h and enhanced the cellular uptake around 5 times more in U87MG glioblastoma cells compared to the non-targeted Ps. The encapsulation efficiency of doxorubicin (DOX) in Ps was 13% by co-solvent method, compared to a film rehydration method (4%). The release profiles of the DOX from Ps showed a release of 42% at pH 5.5 and 40% at pH 7.4 after 24h, indicating that Ps can efficiently retain the DOX with a slow release rate. Furthermore, the in vitro antiproliferative activity of DOX-loaded Ps-Angiopep2 showed enhanced toxicity to U87MG glioblastoma cells, compared to non-targeted Ps. Overall, our in vitro results suggested that angiopep2-conjugated Ps can be used as nanocarriers for efficient targeted DOX delivery to glioblastoma cells. PMID:27484836

  11. Lipid rafts-mediated endocytosis and physiology-based cell membrane traffic models of doxorubicin liposomes.

    PubMed

    Li, Yinghuan; Gao, Lei; Tan, Xi; Li, Feiyang; Zhao, Ming; Peng, Shiqi

    2016-08-01

    The clathrin-mediated endocytosis is likely a major mechanism of liposomes' internalization. A kinetic approach was used to assess the internalization mechanism of doxorubicin (Dox) loaded cationic liposomes and to establish physiology-based cell membrane traffic mathematic models. Lipid rafts-mediated endocytosis, including dynamin-dependent or -independent endocytosis of noncaveolar structure, was a dominant process. The mathematic models divided Dox loaded liposomes binding lipid rafts (B) into saturable binding (SB) and nonsaturable binding (NSB) followed by energy-driven endocytosis. The intracellular trafficking demonstrated early endosome-late endosome-lysosome or early/late endosome-cytoplasm-nucleus pathways. The three properties of liposome structures, i.e., cationic lipid, fusogenic lipid, and pegylation, were investigated to compare their contributions to cell membrane and intracellular traffic. The results revealed great contribution of cationic lipid DOTAP and fusogenic lipid DOPE to cell membrane binding and internalization. The valid Dox in the nuclei of HepG2 and A375 cells treated with cationic liposomes containing 40mol% of DOPE were 1.2-fold and 1.5-fold higher than that in the nuclei of HepG2 and A375 cells treated with liposomes containing 20mol% of DOPE, respectively, suggesting the dependence of cell type. This tendency was proportional to the increase of cell-associated total liposomal Dox. The mathematic models would be useful to predict intracellular trafficking of liposomal Dox. PMID:27117641

  12. Alginate Microspheres Containing Temperature Sensitive Liposomes (TSL) for MR-Guided Embolization and Triggered Release of Doxorubicin

    PubMed Central

    van Elk, Merel; Ozbakir, Burcin; Barten-Rijbroek, Angelique D.; Storm, Gert; Nijsen, Frank; Hennink, Wim E.; Vermonden, Tina; Deckers, Roel

    2015-01-01

    Objective The objective of this study was to develop and characterize alginate microspheres suitable for embolization with on-demand triggered doxorubicin (DOX) release and whereby the microspheres as well as the drug releasing process can be visualized in vivo using MRI. Methods and Findings For this purpose, barium crosslinked alginate microspheres were loaded with temperature sensitive liposomes (TSL/TSL-Ba-ms), which release their payload upon mild hyperthermia. These TSL contained DOX and [Gd(HPDO3A)(H2O)], a T1 MRI contrast agent, for real time visualization of the release. Empty alginate microspheres crosslinked with holmium ions (T2* MRI contrast agent, Ho-ms) were mixed with TSL-Ba-ms to allow microsphere visualization. TSL-Ba-ms and Ho-ms were prepared with a homemade spray device and sized by sieving. Encapsulation of TSL in barium crosslinked microspheres changed the triggered release properties only slightly: 95% of the loaded DOX was released from free TSL vs. 86% release for TSL-Ba-ms within 30 seconds in 50% FBS at 42°C. TSL-Ba-ms (76 ± 41 μm) and Ho-ms (64 ± 29 μm) had a comparable size, which most likely will result in a similar in vivo tissue distribution after an i.v. co-injection and therefore Ho-ms can be used as tracer for the TSL-Ba-ms. MR imaging of a TSL-Ba-ms and Ho-ms mixture (ratio 95:5) before and after hyperthermia allowed in vitro and in vivo visualization of microsphere deposition (T2*-weighted images) as well as temperature-triggered release (T1-weighted images). The [Gd(HPDO3A)(H2O)] release and clusters of microspheres containing holmium ions were visualized in a VX2 tumor model in a rabbit using MRI. Conclusions In conclusion, these TSL-Ba-ms and Ho-ms are promising systems for real-time, MR-guided embolization and triggered release of drugs in vivo. PMID:26561370

  13. Sarco“MiR” friend or foe: a perspective on the mechanisms of doxorubicin-induced cardiomyopathy

    PubMed Central

    Saddic, Louis A.

    2016-01-01

    Anthracyclines are a class of chemotherapeutics used to treat a variety of human cancers including both solid tumors such as breast, ovarian, and lung, as well as malignancies of the blood including leukemia and lymphoma. Despite being extremely effective anti-cancer agents, the application of these drugs is offset by side effects, most notably cardiotoxicity. Many patients treated with doxorubicin (DOX), one of the most common anthracyclines used in oncology, will develop radiographic signs and/or symptoms of cardiomyopathy. Since more and more patients treated with these drugs are surviving their malignancies and manifesting with heart disease, there is particular interest in understanding the mechanisms of anthracycline-induced injury and developing ways to prevent and treat its most feared complication, heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of mRNAs. Since miRNAs can regulate many mRNAs in a single network they tend to play a crucial role in the pathogenesis of several diseases, including heart failure. Here we present a perspective on a recent work by Roca-Alonso and colleagues who demonstrate a cardioprotective function of the miR-30 family members following DOX-induced cardiac injury. They provide evidence for direct targeting of these miRNAs on key elements of the β-adrenergic pathway and further show that this interaction regulates cardiac function and apoptosis. These experiments deliver fresh insights into the biology of toxin-induced cardiomyopathy and suggest the potential for novel therapeutic targets. PMID:27294099

  14. The role of doxorubicin in non-viral gene transfer in the lung.

    PubMed

    Griesenbach, Uta; Meng, Cuixiang; Farley, Raymond; Gardner, Aaron; Brake, Maresa A; Frankel, Gad M; Gruenert, Dieter C; Cheng, Seng H; Scheule, Ronald K; Alton, Eric W F W

    2009-04-01

    Proteasome inhibitors have been shown to increase adeno-associated virus (AAV)-mediated transduction in vitro and in vivo. To assess if proteasome inhibitors also increase lipid-mediated gene transfer with relevance to cystic fibrosis (CF), we first assessed the effects of doxorubicin and N-acetyl-l-leucinyl-l-leucinal-l-norleucinal in non-CF (A549) and CF (CFTE29o-) airway epithelial cell lines. CFTE29o- cells did not show a response to Dox or LLnL; however, gene transfer in A549 cells increased in a dose-related fashion (p < 0.05), up to approximately 20-fold respectively at the optimal dose (no treatment: 9.3 x 10(4) +/- 1.5 x 10(3), Dox: 1.6 x 10(6)+/-2.6 x 10(5), LLnL: 1.9 x 10(6) +/- 3.2 x 10(5)RLU/mg protein). As Dox is used clinically in cancer chemotherapy we next assessed the effect of this drug on non-viral lung gene transfer in vivo. CF knockout mice were injected intraperitoneally (IP) with Dox (25-100 mg/kg) immediately before nebulisation with plasmid DNA carrying a luciferase reporter gene under the control of a CMV promoter/enhancer (pCIKLux) complexed to the cationic lipid GL67A. Dox also significantly (p < 0.05) increased expression of a plasmid regulated by an elongation factor 1alpha promoter (hCEFI) approximately 8-fold. Although administration of Dox before lung gene transfer may not be a clinically viable option, understanding how Dox increases lung gene expression may help to shed light on intracellular bottle-necks to gene transfer, and may help to identify other adjuncts that may be more appropriate for use in man. PMID:19152975

  15. Preclinical evaluation of antitumor activity of acid-sensitive PEGylated doxorubicin.

    PubMed

    Sun, Diankui; Ding, Jianxun; Xiao, Chunsheng; Chen, Jinjin; Zhuang, Xiuli; Chen, Xuesi

    2014-12-10

    The acid-sensitive PEGylated doxorubicin (DOX) with exact chemical structure was designed and prepared as a potential tumor intracellular microenvironment-responsive drug delivery system. First, the insensitive succinic anhydride-functionalized DOX (i.e., SAD) and acid-sensitive cis-aconitic anhydride-modified DOX (i.e., CAD) were synthesized through the ring-opening reaction. Subsequently, the insensitive and acid-sensitive PEGylated DOX (i.e., mPEG-SAD and mPEG-CAD) was prepared by the condensation reaction between the terminal hydroxyl group of mPEG and the carboxyl group in SAD and CAD, respectively. The obtained mPEG-SAD and mPEG-CAD could spontaneously self-assemble into micelles in phosphate-buffered saline at pH 7.4 with diameters of about 100 nm. The DOX release of mPEG-CAD micelle could be accelerated by the decrease of pH from 7.4, 6.8, to 5.5 in relation to that of mPEG-SAD micelle. On the other hand, the result of the cellular proliferation inhibition test indicated that mPEG-CAD micelle exhibited favorable antiproliferative activity in vitro. In addition, the selective intratumoral accumulation and antitumor efficacy of mPEG-CAD micelle were significantly better than those of free DOX and mPEG-SAD. More importantly, the prodrug micelles exhibited upregulated security in vivo as compared to free DOX. Overall, the mPEG-CAD micelle with enhanced antitumor efficacy and decreased side effects was a fascinating prospect for the clinical chemotherapy of malignancy. PMID:25415351

  16. Accelerator Mass Spectrometry Allows for Cellular Quantification of Doxorubicin at Femtomolar Concentrations

    SciTech Connect

    DeGregorio, M W; Dingley, K H; Wurz, G T; Ubick, E; Turteltaub, K W

    2005-04-12

    Accelerator mass spectrometry (AMS) is a highly sensitive analytical methodology used to quantify the content of radioisotopes, such as {sup 14}C, in a sample. The primary goals of this work were to demonstrate the utility of AMS in determining cellular [{sup 14}C]doxorubicin (DOX) concentrations and to develop a sensitive assay that is superior to high performance liquid chromatography (HPLC) for the quantification of DOX at the tumor level. In order to validate the superior sensitivity of AMS versus HPLC with fluorescence detection, we performed three studies comparing the cellular accumulation of DOX: one in vitro cell line study, and two in vivo xenograft mouse studies. Using AMS, we quantified cellular DOX content up to 4 hours following in vitro exposure at concentrations ranging from 0.2 pg/ml (345 fM) to 2 {micro}g/ml (3.45 {micro}M) [{sup 14}C]DOX. The results of this study show that, compared to standard fluorescence-based HPLC, the AMS method was over five orders of magnitude more sensitive. Two in vivo studies compared the sensitivity of AMS to HPLC using a nude mouse xenograft model in which breast cancer cells were implanted subcutaneously. After sufficiently large tumors formed, DOX was administered intravenously at two dose levels. Additionally, we tested the AMS method in a nude mouse xenograft model of multidrug resistance (MDR) in which each mouse was implanted with both wild type and MDR+ cells on opposite flanks. The results of the second and third studies showed that DOX concentrations were significantly higher in the wild type tumors compared to the MDR+ tumors, consistent with the MDR model. The extreme sensitivity of AMS should facilitate similar studies in humans to establish target site drug delivery and to potentially determine the optimal treatment dose and regimen.

  17. Doxorubicin-loaded micelles of reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers as efficient "active" chemotherapeutic agents.

    PubMed

    Cambón, A; Rey-Rico, A; Mistry, D; Brea, J; Loza, M I; Attwood, D; Barbosa, S; Alvarez-Lorenzo, C; Concheiro, A; Taboada, P; Mosquera, V

    2013-03-10

    Five reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers, BOnEOmBOn, with BO ranging from 8 to 21 units and EO from 90 to 411 were synthesized and evaluated as efficient chemotherapeutic drug delivery nanocarriers and inhibitors of the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line. The copolymers were obtained by reverse polymerization of poly(butylene oxide), which avoids transfer reaction and widening of the EO block distribution, commonly found in commercial poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamers). BOnEOmBOn copolymers formed spherical micelles of 10-40 nm diameter at lower concentrations (one order of magnitude) than those of equivalent poloxamers. The influence of copolymer block lengths and BO/EO ratios on the solubilization capacity and protective environment for doxorubicin (DOXO) was investigated. Micelles showed drug loading capacity ranging from ca. 0.04% to 1.5%, more than 150 times the aqueous solubility of DOXO, and protected the cargo from hydrolysis for more than a month due to their greater colloidal stability in solution. Drug release profiles at various pHs, and the cytocompatibility and cytotoxicity of the DOXO-loaded micelles were assessed in vitro. DOXO loaded in the polymeric micelles accumulated more slowly inside the cells than free DOXO due to its sustained release. All copolymers were found to be cytocompatible, with viability extents larger than 95%. In addition, the cytotoxicity of DOXO-loaded micelles was higher than that observed for free drug solutions in a MDR ovarian NCI-ADR-RES cell line which overexpressed P-gp. The inhibition of the P-gp efflux pump by some BOnEOmBOn copolymers, similar to that measured for the common P-gp inhibitor verapamil, favored the retention of DOXO inside the cell increasing its cytotoxic activity. Therefore, poly(butylene oxide)-poly(ethylene oxide) block copolymers offer interesting features as cell

  18. Peptide dendrimer-Doxorubicin conjugate-based nanoparticles as an enzyme-responsive drug delivery system for cancer therapy.

    PubMed

    Zhang, Chengyuan; Pan, Dayi; Luo, Kui; She, Wenchuan; Guo, Chunhua; Yang, Yang; Gu, Zhongwei

    2014-08-01

    Peptide dendrimers have shown promise as an attractive platform for drug delivery. In this study, mPEGylated peptide dendrimer-doxorubicin (dendrimer-DOX) conjugate-based nanoparticle is prepared and characterized as an enzyme-responsive drug delivery vehicle. The drug DOX is conjugated to the periphery of dendrimer via an enzyme-responsive tetra-peptide linker Gly-Phe-Leu-Gly (GFLG). The dendrimer-DOX conjugate can self-assemble into nanoparticle, which is confirmed by dynamic light scattering, scanning electron microscopy, and transmission electron microscopy studies. At equal dose, mPEGylated dendrimer-DOX conjugate-based nanoparticle results in significantly high antitumor activity, and induces apoptosis on the 4T1 breast tumor model due to the evidences from tumor growth curves, an immunohistochemical analysis, and a histological assessment. The in vivo toxicity evaluation demonstrates that nanoparticle substantially avoids DOX-related toxicities and presents good biosafety without obvious side effects to normal organs of both tumor-bearing and healthy mice as measured by body weight shift, blood routine test, and a histological analysis. Thus, the mPEGylated peptide dendrimer-DOX conjugate-based nanoparticle may be a potential nanoscale drug delivery vehicle for the breast cancer therapy.

  19. Tert-butylhydroquinone ameliorates doxorubicin-induced cardiotoxicity by activating Nrf2 and inducing the expression of its target genes

    PubMed Central

    Wang, Lin-Feng; Su, Su-Wen; Wang, Lei; Zhang, Guo-Qiang; Zhang, Rong; Niu, Yu-Jie; Guo, Yan-Su; Li, Chun-Yan; Jiang, Wen-Bo; Liu, Yi; Guo, Hui-Cai

    2015-01-01

    Oxidative stress plays an important role in doxorubicin (DOX)-induced cardiotoxicity. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor that orchestrates the antioxidant and cytoprotective responses to oxidative stress. In the present study, we tested whether tert-butylhydroquinone (tBHQ) could protect against DOX-induced cardiotoxicity in vivo and, if so, whether the protection was associated with the up-regulation of the Nrf2 pathway. The results showed that treatment with tBHQ significantly decreased the DOX-induced cardiac injury in wild-type mice. Moreover, tBHQ ameliorated the DOX-induced oxidative stress and apoptosis. Further studies suggested that tBHQ increased the nuclear accumulation of Nrf2 and the Nrf2-regulated gene expression, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxido-reductase-1 (NQO-1) expression. Knocking out Nrf2 in mice abolished the protective effect of tBHQ on the DOX-induced cardiotoxicity. These results indicate that tBHQ has a beneficial effect on DOX-induced cardiotoxicity, and this effect was associated with the enhanced expression of Nrf2 and its downstream antioxidant genes, HO-1 and NQO-1. PMID:26692920

  20. Fine tuning of the pH-sensitivity of laponite-doxorubicin nanohybrids by polyelectrolyte multilayer coating.

    PubMed

    Xiao, Shili; Castro, Rita; Maciel, Dina; Gonçalves, Mara; Shi, Xiangyang; Rodrigues, João; Tomás, Helena

    2016-03-01

    Despite the wide research done in the field, the development of advanced drug delivery systems with improved drug delivery properties and effective anticancer capability still remains a great challenge. Based on previous work that showed the potentialities of the nanoclay Laponite as a pH-sensitive doxorubicin (Dox) delivery vehicle, herein we report a simple method to modulate its extent of drug release at different pH values. This was achieved by alternate deposition of cationic poly(allylamine) hydrochloride and anionic poly(sodium styrene sulfonate) (PAH/PSS) polyelectrolytes over the surface of Dox-loaded Laponite nanoparticles using the electrostatic layer-by-layer (LbL) self-assembly approach. The successful formation of polyelectrolyte multilayer-coated Dox/Laponite systems was confirmed by Dynamic Light Scattering and zeta potential measurements. Systematic studies were performed to evaluate their drug release profiles and anticancer efficiency. Our results showed that the presence of the polyelectrolyte multilayers improved the sustained release properties of Laponite and allowed a fine tuning of the extension of drug release at neutral and acidic pH values. The cytotoxicity presented by polyelectrolyte multilayer-coated Dox/Laponite systems towards MCF-7 cells was in accordance with the drug delivery profiles. Furthermore, cellular uptake studies revealed that polyelectrolyte multilayer-coated Dox/Laponite nanoparticles can be effectively internalized by cells conducting to Dox accumulation in cell nucleus. PMID:26706540

  1. Antitumor Activity of Doxorubicin-Loaded Carbon Nanotubes Incorporated Poly(Lactic-Co-Glycolic Acid) Electrospun Composite Nanofibers

    NASA Astrophysics Data System (ADS)

    Yu, Yuan; Kong, Lijun; Li, Lan; Li, Naie; Yan, Peng

    2015-08-01

    The drug-loaded composite electrospun nanofiber has attracted more attention in biomedical field, especially in cancer therapy. In this study, a composite nanofiber was fabricated by electrospinning for cancer treatment. Firstly, the carbon nanotubes (CNTs) were selected as carriers to load the anticancer drug—doxorubicin (DOX) hydrochloride. Secondly, the DOX-loaded CNTs (DOX@CNTs) were incorporated into the poly(lactic-co-glycolic acid) (PLGA) nanofibers via electrospinning. Finally, a new drug-loaded nanofibrous scaffold (PLGA/DOX@CNTs) was formed. The properties of the prepared composite nanofibrous mats were characterized by various techniques. The release profiles of the different DOX-loaded nanofibers were measured, and the in vitro antitumor efficacy against HeLa cells was also evaluated. The results showed that DOX-loaded CNTs can be readily incorporated into the nanofibers with relatively uniform distribution within the nanofibers. More importantly, the drug from the composite nanofibers can be released in a sustained and prolonged manner, and thereby, a significant antitumor efficacy in vitro is obtained. Thus, the prepared composite nanofibrous mats are a promising alternative for cancer treatment.

  2. Modulation of DNA methylation levels sensitizes doxorubicin-resistant breast adenocarcinoma cells to radiation-induced apoptosis

    SciTech Connect

    Luzhna, Lidia; Kovalchuk, Olga

    2010-02-05

    Chemoresistant tumors often fail to respond to other cytotoxic treatments such as radiation therapy. The mechanisms of chemo- and radiotherapy cross resistance are not fully understood and are believed to be epigenetic in nature. We hypothesize that MCF-7 cells and their doxorubicin-resistant variant MCF-7/DOX cells may exhibit different responses to ionizing radiation due to their dissimilar epigenetic status. Similar to previous studies, we found that MCF-7/DOX cells harbor much lower levels of global DNA methylation than MCF-7 cells. Furthermore, we found that MCF-7/DOX cells had lower background apoptosis levels and were less responsive to radiation than MCF-7 cells. Decreased radiation responsiveness correlated to significant global DNA hypomethylation in MCF-7/DOX cells. Here, for the first time, we show that the radiation resistance of MCF-7/DOX cells can be reversed by an epigenetic treatment - the application of methyl-donor SAM. SAM-mediated reversal of DNA methylation led to elevated radiation sensitivity in MCF-7/DOX cells. Contrarily, application of SAM on the radiation sensitive and higher methylated MCF-7 cells resulted in a decrease in their radiation responsiveness. This data suggests that a fine balance of DNA methylation is needed to insure proper radiation and drug responsiveness.

  3. S100A8 and S100A9 Are Associated with Doxorubicin-Induced Cardiotoxicity in the Heart of Diabetic Mice

    PubMed Central

    Pei, Xiao M.; Tam, Bjorn T.; Sin, Thomas K.; Wang, Feng F.; Yung, Benjamin Y.; Chan, Lawrence W.; Wong, Cesar S.; Ying, Michael; Lai, Christopher W.; Siu, Parco M.

    2016-01-01

    Cardiomyopathy is a clinical problem that occurs in the hearts of type 2 diabetic patients as well as cancer patients undergoing doxorubicin chemotherapy. The number of diabetic cancer patients is increasing but surprisingly the cardiac damaging effects of doxorubicin, a commonly used chemotherapeutic drug, on diabetic hearts have not been well-examined. As the signaling mechanisms of the doxorubicin-induced cardiomyopathy in type 2 diabetic heart are largely unknown, this study examined the molecular signaling pathways that are responsible for the doxorubicin-induced cardiotoxicity in type 2 diabetic hearts. Male 14- to 18-week-old db/db mice were used as the type 2 diabetic model, and age-matched non-diabetic db/+ mice served as controls. The db/+ non-diabetic and db/db diabetic mice were randomly assigned to the following groups: db/+CON, db/+DOX-5d, db/+DOX-7d, db/dbCON, db/dbDOX-5d, and db/dbDOX-7d. Mice assigned to doxorubicin (DOX) group were exposed to an intraperitoneal (i.p.) injection of DOX at a dose of 15 mg/kg to induce cardiomyopathy. Mice in control (CON) groups were i.p. injected with the same volume of saline instead of DOX. Mice were euthanized by overdose of ketamine and xylazine 5 or 7 days after the DOX injection. Microarray analysis was adopted to examine the changes of the whole transcriptional profile in response to doxorubicin exposure in diabetic hearts. Ventricular fractional shortening was examined as an indicator of cardiac function by transthoracic echocardiography. The presence of diabetic cardiomyopathy in db/db mice was evident by the reduction of fractional shortening. There was a further impairment of cardiac contractile function 7 days after the DOX administration in db/db diabetic mice. According to our microarray analysis, we identified a panel of regulatory genes associated with cardiac remodeling, inflammatory response, oxidative stress, and metabolism in the DOX-induced cardiac injury in diabetic heart. The microarray

  4. S100A8 and S100A9 Are Associated with Doxorubicin-Induced Cardiotoxicity in the Heart of Diabetic Mice.

    PubMed

    Pei, Xiao M; Tam, Bjorn T; Sin, Thomas K; Wang, Feng F; Yung, Benjamin Y; Chan, Lawrence W; Wong, Cesar S; Ying, Michael; Lai, Christopher W; Siu, Parco M

    2016-01-01

    Cardiomyopathy is a clinical problem that occurs in the hearts of type 2 diabetic patients as well as cancer patients undergoing doxorubicin chemotherapy. The number of diabetic cancer patients is increasing but surprisingly the cardiac damaging effects of doxorubicin, a commonly used chemotherapeutic drug, on diabetic hearts have not been well-examined. As the signaling mechanisms of the doxorubicin-induced cardiomyopathy in type 2 diabetic heart are largely unknown, this study examined the molecular signaling pathways that are responsible for the doxorubicin-induced cardiotoxicity in type 2 diabetic hearts. Male 14- to 18-week-old db/db mice were used as the type 2 diabetic model, and age-matched non-diabetic db/+ mice served as controls. The db/+ non-diabetic and db/db diabetic mice were randomly assigned to the following groups: db/+CON, db/+DOX-5d, db/+DOX-7d, db/dbCON, db/dbDOX-5d, and db/dbDOX-7d. Mice assigned to doxorubicin (DOX) group were exposed to an intraperitoneal (i.p.) injection of DOX at a dose of 15 mg/kg to induce cardiomyopathy. Mice in control (CON) groups were i.p. injected with the same volume of saline instead of DOX. Mice were euthanized by overdose of ketamine and xylazine 5 or 7 days after the DOX injection. Microarray analysis was adopted to examine the changes of the whole transcriptional profile in response to doxorubicin exposure in diabetic hearts. Ventricular fractional shortening was examined as an indicator of cardiac function by transthoracic echocardiography. The presence of diabetic cardiomyopathy in db/db mice was evident by the reduction of fractional shortening. There was a further impairment of cardiac contractile function 7 days after the DOX administration in db/db diabetic mice. According to our microarray analysis, we identified a panel of regulatory genes associated with cardiac remodeling, inflammatory response, oxidative stress, and metabolism in the DOX-induced cardiac injury in diabetic heart. The microarray

  5. Deposition of Doxorubicin in Rats following Administration of Three Newly Synthesized Doxorubicin Conjugates

    PubMed Central

    Huan, Menglei; Tian, Shuang; Cui, Han; Zhang, Bangle; Su, Dan; Wang, Jieping; Li, Kangchu

    2013-01-01

    We previously reported the synthesis of three DOX conjugates that represented different targeting vehicles and showed them to have antitumor activity both in vitro and in vivo. However, the relationships between the pharmacokinetics of these DOX conjugates and their chemical structures were not characterized. In the current study, free DOX derived from each of the conjugates was found at low levels in the rat circulatory system, with conjugated DOX being the major form. The two polyethylene glycol (PEG) conjugates slowly released DOX, and t1/2β for total DOX from DOX-LNA, PEG-ami-DOX, and PEG-hyd-DOX was 5.79, 10.22, and 15.18 h, respectively. All three conjugates also deposited less DOX into normal organs than did an equivalent dose of free DOX, and the Cmax value of free DOX released by DOX- LNA, PEG-ami-DOX, and PEG-hyd-DOX was 32.5, 9.5, and 4.7 μg/g, respectively. Among the conjugates, the compound with an acid-labile bond between PEG and DOX exhibited the lowest free DOX deposition in healthy tissues, which should decrease the systemic toxicity of free DOX while allowing for tumor targeting by PEG. PMID:24381947

  6. Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy.

    PubMed

    Chen, Yung-Lung; Chung, Sheng-Ying; Chai, Han-Tan; Chen, Chih-Hung; Liu, Chu-Feng; Chen, Yi-Ling; Huang, Tien-Hung; Zhen, Yen-Yi; Sung, Pei-Hsun; Sun, Cheuk-Kwan; Chua, Sarah; Lu, Hung-I; Lee, Fan-Yen; Sheu, Jiunn-Jye; Yip, Hon-Kan

    2015-12-01

    This study tested for the benefits of early administration of carvedilol as protection against doxorubicin (DOX)-induced cardiomyopathy. Thirty male, adult B6 mice were categorized into group 1 (untreated control), group 2 [DOX treatment (15 mg/every other day for 2 weeks, i.p.], and group 3 [carvedilol (15 mg/kg/d, from day 7 after DOX treatment for 28 days)], and euthanized by day 35 after DOX treatment. By day 35, the left ventricular ejection fraction (LVEF) was significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1, whereas the left ventricular (LV) end-diastolic and LV end-systolic dimensions showed an opposite pattern to the LVEF among the three groups. The protein expressions of fibrotic (Smad3, TGF-β), apoptotic (BAX, cleaved caspase 3, PARP), DNA damage (γ-H2AX), oxidative stress (oxidized protein), mitochondrial damage (cytosolic cytochrome-C), heart failure (brain natriuretic peptide), and hypertrophic (β-MHC) biomarkers of the LV myocardium showed an opposite pattern to the LVEF among the three groups. The protein expressions of antifibrotic (BMP-2, Smad1/5), α-MHC, and phosphorylated-Akt showed an identical pattern to the LVEF among the three groups. The microscopic findings of fibrotic and collagen-deposition areas and the numbers of γ-H2AX(+) and 53BP1(+) cells in the LV myocardium exhibited an opposite pattern, whereas the numbers of endothelial cell (CD31(+), vWF(+)) markers showed an identical pattern to the LVEF among the three groups. Cardiac stem cell markers (C-kit(+) and Sca-1(+) cells) were significantly and progressively increased from group 1 to group 3. Additionally, the in vitro study showed carvedilol treatment significantly inhibited DOX-induced cardiomyoblast DNA (CD90/XRCC1(+), CD90/53BP1(+), and r-H2AX(+) cells) damage. Early carvedilol therapy protected against DOX-induced DNA damage and cardiomyopathy.

  7. Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy.

    PubMed

    Chen, Yung-Lung; Chung, Sheng-Ying; Chai, Han-Tan; Chen, Chih-Hung; Liu, Chu-Feng; Chen, Yi-Ling; Huang, Tien-Hung; Zhen, Yen-Yi; Sung, Pei-Hsun; Sun, Cheuk-Kwan; Chua, Sarah; Lu, Hung-I; Lee, Fan-Yen; Sheu, Jiunn-Jye; Yip, Hon-Kan

    2015-12-01

    This study tested for the benefits of early administration of carvedilol as protection against doxorubicin (DOX)-induced cardiomyopathy. Thirty male, adult B6 mice were categorized into group 1 (untreated control), group 2 [DOX treatment (15 mg/every other day for 2 weeks, i.p.], and group 3 [carvedilol (15 mg/kg/d, from day 7 after DOX treatment for 28 days)], and euthanized by day 35 after DOX treatment. By day 35, the left ventricular ejection fraction (LVEF) was significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1, whereas the left ventricular (LV) end-diastolic and LV end-systolic dimensions showed an opposite pattern to the LVEF among the three groups. The protein expressions of fibrotic (Smad3, TGF-β), apoptotic (BAX, cleaved caspase 3, PARP), DNA damage (γ-H2AX), oxidative stress (oxidized protein), mitochondrial damage (cytosolic cytochrome-C), heart failure (brain natriuretic peptide), and hypertrophic (β-MHC) biomarkers of the LV myocardium showed an opposite pattern to the LVEF among the three groups. The protein expressions of antifibrotic (BMP-2, Smad1/5), α-MHC, and phosphorylated-Akt showed an identical pattern to the LVEF among the three groups. The microscopic findings of fibrotic and collagen-deposition areas and the numbers of γ-H2AX(+) and 53BP1(+) cells in the LV myocardium exhibited an opposite pattern, whereas the numbers of endothelial cell (CD31(+), vWF(+)) markers showed an identical pattern to the LVEF among the three groups. Cardiac stem cell markers (C-kit(+) and Sca-1(+) cells) were significantly and progressively increased from group 1 to group 3. Additionally, the in vitro study showed carvedilol treatment significantly inhibited DOX-induced cardiomyoblast DNA (CD90/XRCC1(+), CD90/53BP1(+), and r-H2AX(+) cells) damage. Early carvedilol therapy protected against DOX-induced DNA damage and cardiomyopathy. PMID:26511374

  8. Inhibition of prostate cancer growth using doxorubicin assisted by ultrasound-targeted nanobubble destruction.

    PubMed

    Fan, Xiaozhou; Wang, Luofu; Guo, Yanli; Xiong, Xingyu; Zhu, Lianhua; Fang, Kejing

    2016-01-01

    Ultrasound (US)-targeted microbubble destruction has been widely used as an effective drug-delivery system. However, nanobubbles (NBs) have better stability and stronger penetration than microbubbles, and drug delivery assisted by US-targeted NB destruction (UTND) still needs to be investigated. Our aim was to investigate the effect of doxorubicin (DOX) on the inhibition of prostate cancer growth under UTND. Contrast-enhanced US imaging of transplanted PC3 prostate cancer in mice showed that under a combination of 1 W/cm(2) US power and a 100 Hz intermittent pulse with a "5 seconds on, 5 seconds off" mode, NBs with an average size of (485.7±33) nm were effectively destroyed within 15 minutes in the tumor location. PC3 cells and 20 tumor-bearing mice were divided into four groups: a DOX group, a DOX + NB group, a DOX + US group, and a DOX + NB + US group. The cell growth-inhibition rate and DOX concentration of xenografts in the DOX + NB + US group were highest. Based on another control group and these four groups, another 25 tumor-bearing mice were used to observe the treatment effect of nine DOX injections under UTND. The xenografts in the DOX + NB + US group decreased more obviously and had more cellular apoptosis than other groups. Finally, electron microscopy was used to estimate the cavitation effect of NBs under US irradiation in the control group, NB group, US group, and NB + US group. The results of scanning electron microscopy showed that PC3 cells in the DOX + NB + US group had more holes and significantly increased cell-surface folds. Meanwhile, transmission electric microscopy confirmed that more lanthanum nitrate particles entered the parenchymal cells in xenografts in the NB + US group compared with the other groups. This study suggested that UTND technology could be an effective method to promote drugs to function in US-irradiated sites, and the underlying mechanism may be associated with a cavitation effect. PMID:27536100

  9. Keap1 redox-dependent regulation of doxorubicin-induced oxidative stress response in cardiac myoblasts

    SciTech Connect

    Nordgren, Kendra K.S. Wallace, Kendall B.

    2014-01-01

    Doxorubicin (DOX) is a widely prescribed treatment for a broad scope of cancers, but clinical utility is limited by the cumulative, dose-dependent cardiomyopathy that occurs with repeated administration. DOX-induced cardiotoxicity is associated with the production of reactive oxygen species (ROS) and oxidation of lipids, DNA and proteins. A major cellular defense mechanism against such oxidative stress is activation of the Keap1/Nrf2-antioxidant response element (ARE) signaling pathway, which transcriptionally regulates expression of antioxidant genes such as Nqo1 and Gstp1. In the present study, we address the hypothesis that an initial event associated with DOX-induced oxidative stress is activation of the Keap1/Nrf2-dependent expression of antioxidant genes and that this is regulated through drug-induced changes in redox status of the Keap1 protein. Incubation of H9c2 rat cardiac myoblasts with DOX resulted in a time- and dose-dependent decrease in non-protein sulfhydryl groups. Associated with this was a near 2-fold increase in Nrf2 protein content and enhanced transcription of several of the Nrf2-regulated down-stream genes, including Gstp1, Ugt1a1, and Nqo1; the expression of Nfe2l2 (Nrf2) itself was unaltered. Furthermore, both the redox status and the total amount of Keap1 protein were significantly decreased by DOX, with the loss of Keap1 being due to both inhibited gene expression and increased autophagic, but not proteasomal, degradation. These findings identify the Keap1/Nrf2 pathway as a potentially important initial response to acute DOX-induced oxidative injury, with the primary regulatory events being the oxidation and autophagic degradation of the redox sensor Keap1 protein. - Highlights: • DOX caused a ∼2-fold increase in Nrf2 protein content. • DOX enhanced transcription of several Nrf2-regulated down-stream genes. • Redox status and total amount of Keap1 protein were significantly decreased by DOX. • Loss of Keap1 protein was due to

  10. Inhibition of prostate cancer growth using doxorubicin assisted by ultrasound-targeted nanobubble destruction

    PubMed Central

    Fan, Xiaozhou; Wang, Luofu; Guo, Yanli; Xiong, Xingyu; Zhu, Lianhua; Fang, Kejing

    2016-01-01

    Ultrasound (US)-targeted microbubble destruction has been widely used as an effective drug-delivery system. However, nanobubbles (NBs) have better stability and stronger penetration than microbubbles, and drug delivery assisted by US-targeted NB destruction (UTND) still needs to be investigated. Our aim was to investigate the effect of doxorubicin (DOX) on the inhibition of prostate cancer growth under UTND. Contrast-enhanced US imaging of transplanted PC3 prostate cancer in mice showed that under a combination of 1 W/cm2 US power and a 100 Hz intermittent pulse with a “5 seconds on, 5 seconds off” mode, NBs with an average size of (485.7±33) nm were effectively destroyed within 15 minutes in the tumor location. PC3 cells and 20 tumor-bearing mice were divided into four groups: a DOX group, a DOX + NB group, a DOX + US group, and a DOX + NB + US group. The cell growth-inhibition rate and DOX concentration of xenografts in the DOX + NB + US group were highest. Based on another control group and these four groups, another 25 tumor-bearing mice were used to observe the treatment effect of nine DOX injections under UTND. The xenografts in the DOX + NB + US group decreased more obviously and had more cellular apoptosis than other groups. Finally, electron microscopy was used to estimate the cavitation effect of NBs under US irradiation in the control group, NB group, US group, and NB + US group. The results of scanning electron microscopy showed that PC3 cells in the DOX + NB + US group had more holes and significantly increased cell-surface folds. Meanwhile, transmission electric microscopy confirmed that more lanthanum nitrate particles entered the parenchymal cells in xenografts in the NB + US group compared with the other groups. This study suggested that UTND technology could be an effective method to promote drugs to function in US-irradiated sites, and the underlying mechanism may be associated with a cavitation effect. PMID:27536100

  11. Effect of nisin and doxorubicin on DMBA-induced skin carcinogenesis--a possible adjunct therapy.

    PubMed

    Preet, Simran; Bharati, Sanjay; Panjeta, Anshul; Tewari, Rupinder; Rishi, Praveen

    2015-11-01

    In view of the emergence of multidrug-resistant cancer cells, there is a need for therapeutic alternatives. Keeping this in mind, the present study was aimed at evaluating the synergism between nisin (an antimicrobial peptide) and doxorubicin (DOX) against DMBA-induced skin carcinogenesis. The possible tumoricidal activity of the combination was evaluated in terms of animal bioassay observations, changes in hisotological architecture of skin tissues, in situ apoptosis assay (TUNEL assay) and in terms of oxidant and antioxidant status of the skin tissues. In vivo additive effect of the combination was evidenced by larger decreases in mean tumour burden and tumour volume in mice treated with the combination than those treated with the drugs alone. Histological observations indicated that nisin-DOX therapy causes chromatin condensation and marginalisation of nuclear material in skin tissues of treated mice which correlated well with the results of TUNEL assay wherein a marked increase in the rate of apoptosis was revealed in tissues treated with the combination. A slightly increased oxidative stress in response to the adjunct therapy as compared to dox-alone-treated group was revealed by levels of lipid peroxidation (LPO) and nitrite generation in skin tissue-treated mice. An almost similar marginal enhancement in superoxide dismutase levels corresponding with a decrease in catalase activity could also be observed in nisin + DOX-treated groups as compared to nisin and dox-alone-treated groups. These results point towards the possible use of nisin as an adjunct to doxorubicin may help in developing alternate strategies to combat currently developing drug resistance in cancer cells. PMID:26002579

  12. Effect of nisin and doxorubicin on DMBA-induced skin carcinogenesis--a possible adjunct therapy.

    PubMed

    Preet, Simran; Bharati, Sanjay; Panjeta, Anshul; Tewari, Rupinder; Rishi, Praveen

    2015-11-01

    In view of the emergence of multidrug-resistant cancer cells, there is a need for therapeutic alternatives. Keeping this in mind, the present study was aimed at evaluating the synergism between nisin (an antimicrobial peptide) and doxorubicin (DOX) against DMBA-induced skin carcinogenesis. The possible tumoricidal activity of the combination was evaluated in terms of animal bioassay observations, changes in hisotological architecture of skin tissues, in situ apoptosis assay (TUNEL assay) and in terms of oxidant and antioxidant status of the skin tissues. In vivo additive effect of the combination was evidenced by larger decreases in mean tumour burden and tumour volume in mice treated with the combination than those treated with the drugs alone. Histological observations indicated that nisin-DOX therapy causes chromatin condensation and marginalisation of nuclear material in skin tissues of treated mice which correlated well with the results of TUNEL assay wherein a marked increase in the rate of apoptosis was revealed in tissues treated with the combination. A slightly increased oxidative stress in response to the adjunct therapy as compared to dox-alone-treated group was revealed by levels of lipid peroxidation (LPO) and nitrite generation in skin tissue-treated mice. An almost similar marginal enhancement in superoxide dismutase levels corresponding with a decrease in catalase activity could also be observed in nisin + DOX-treated groups as compared to nisin and dox-alone-treated groups. These results point towards the possible use of nisin as an adjunct to doxorubicin may help in developing alternate strategies to combat currently developing drug resistance in cancer cells.

  13. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

    SciTech Connect

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran–iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran–iron (15 mg/kg) for 3 weeks (D0–D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6 mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran–iron (125–1000 μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+ 22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. - Highlights: • The effects of iron on cardiomyocytes were opposite to those on cancer cell lines. • In our model, iron overload did not potentiate anthracycline cardiotoxicity. • Chronic oxidative stress induced by iron could mitigate doxorubicin cardiotoxicity. • The role of iron in

  14. Mechanisms of Doxorubicin Toxicity in Pancreatic β-Cells.

    PubMed

    Heart, Emma A; Karandrea, Shpetim; Liang, Xiaomei; Balke, Maren E; Beringer, Patrick A; Bobczynski, Elyse M; Zayas-Bazán Burgos, Delaine; Richardson, Tiffany; Gray, Joshua P

    2016-08-01

    Exposure to chemotherapeutic agents has been linked to an increased risk of type 2 diabetes (T2D), a disease characterized by both the peripheral insulin resistance and impaired glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. Using the rat β-cell line INS-1 832/13 and isolated mouse pancreatic islets, we investigated the effect of the chemotherapeutic drug doxorubicin (Adriamycin) on pancreatic β-cell survival and function. Exposure of INS-1 832/13 cells to doxorubicin caused impairment of GSIS, cellular viability, an increase in cellular toxicity, as soon as 6 h post-exposure. Doxorubicin impaired plasma membrane electron transport (PMET), a pathway dependent on reduced equivalents NADH and NADPH, but failed to redox cycle in INS-1 832/13 cells and with their lysates. Although NADPH/NADP(+ )content was unaffected, NADH/NAD(+ )content decreased at 4 h post-exposure to doxorubicin, and was followed by a reduction in ATP content. Previous studies have demonstrated that doxorubicin functions as a topoisomerase II inhibitor via induction of DNA cross-linking, resulting in apoptosis. Doxorubicin induced the expression of mRNA for mdm2, cyclin G1, and fas whereas downregulating p53, and increased the melting temperature of genomic DNA, consistent with DNA damage and induction of apoptosis. Doxorubicin also induced caspase-3 and -7 activity in INS-1 832/13 cells and mouse islets; co-treatment with the pan-caspase inhibitor Z-VAD-FMK temporarily attenuated the doxorubicin-mediated loss of viability in INS-1 832/13 cells. Together, these data suggest that DNA damage, not H2O2 produced via redox cycling, is a major mechanism of doxorubicin toxicity in pancreatic β-cells.

  15. Mechanisms of Doxorubicin Toxicity in Pancreatic β-Cells.

    PubMed

    Heart, Emma A; Karandrea, Shpetim; Liang, Xiaomei; Balke, Maren E; Beringer, Patrick A; Bobczynski, Elyse M; Zayas-Bazán Burgos, Delaine; Richardson, Tiffany; Gray, Joshua P

    2016-08-01

    Exposure to chemotherapeutic agents has been linked to an increased risk of type 2 diabetes (T2D), a disease characterized by both the peripheral insulin resistance and impaired glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. Using the rat β-cell line INS-1 832/13 and isolated mouse pancreatic islets, we investigated the effect of the chemotherapeutic drug doxorubicin (Adriamycin) on pancreatic β-cell survival and function. Exposure of INS-1 832/13 cells to doxorubicin caused impairment of GSIS, cellular viability, an increase in cellular toxicity, as soon as 6 h post-exposure. Doxorubicin impaired plasma membrane electron transport (PMET), a pathway dependent on reduced equivalents NADH and NADPH, but failed to redox cycle in INS-1 832/13 cells and with their lysates. Although NADPH/NADP(+ )content was unaffected, NADH/NAD(+ )content decreased at 4 h post-exposure to doxorubicin, and was followed by a reduction in ATP content. Previous studies have demonstrated that doxorubicin functions as a topoisomerase II inhibitor via induction of DNA cross-linking, resulting in apoptosis. Doxorubicin induced the expression of mRNA for mdm2, cyclin G1, and fas whereas downregulating p53, and increased the melting temperature of genomic DNA, consistent with DNA damage and induction of apoptosis. Doxorubicin also induced caspase-3 and -7 activity in INS-1 832/13 cells and mouse islets; co-treatment with the pan-caspase inhibitor Z-VAD-FMK temporarily attenuated the doxorubicin-mediated loss of viability in INS-1 832/13 cells. Together, these data suggest that DNA damage, not H2O2 produced via redox cycling, is a major mechanism of doxorubicin toxicity in pancreatic β-cells. PMID:27255381

  16. Electrochemically oxidized multiwalled carbon nanotube/glassy carbon electrode as a probe for simultaneous determination of dopamine and doxorubicin in biological samples.

    PubMed

    Haghshenas, Esmaeel; Madrakian, Tayyebeh; Afkhami, Abbas

    2016-04-01

    A facile and effective approach of fabricating oxidized multiwalled carbon nanotube/glassy carbon electrode (OMWCNT/GCE) is herein reported. The OMWCNT/GCE was prepared by electrochemical oxidation method in basic media (0.5 mol L(-1) NaOH solution) and used as a sensor for simultaneous determination of dopamine (DA) and doxorubicin (DOX). Scanning electron microscopy, energy dispersive X-ray spectroscopy and cyclic voltammetry were used for characterization and performance study of the OMWCNT/GCE. The modified electrode exhibited good electrocatalytic properties toward the oxidation of DA and DOX. Peaks potential difference of 240 mV between DA and DOX was large enough to determine DA and DOX individually and simultaneously. Square wave voltammetry (SWV) was used for the simultaneous determination of DA and DOX in their binary mixture. Under the optimum conditions, the linear concentration dependences of SW peak current responses were observed for DA and DOX in the concentration ranges of 0.03-55 μmol L(-1) and 0.04-90 μmol L(-1), respectively. The detection limits (S/N = 3) were 8.5 × 10(-3) μmol L(-1), and 9.4 × 10(-3) μmol L(-1) for DA and DOX, respectively. The analytical utility of OMWCNT/GCE was also successfully demonstrated for the simultaneous determination of DA and DOX in human blood serum and urine samples. Graphical Abstract Fabrication of new oxidized multiwalled carbon nanotube/glassy carbon electrode for simultaneous determination of dopamine and doxorubicin.

  17. Liposomal doxorubicin for active targeting: surface modification of the nanocarrier evaluated in vitro and in vivo — challenges and prospects

    PubMed Central

    Mentz, Susanne

    2015-01-01

    Due to the inability of classical chemotherapeutic agents to exclusively target tumor cells, these treatments are associated with severe toxicity profiles. Thus, long-circulating liposomes have been developed in the past to enhance accumulation in tumor tissue by passive targeting. Accordingly, commercially available liposomal formulations of sterically stabilized liposomal doxorubicin (Caelyx®, Doxil®, Lipodox®) are associated with improved off-target profiles. However, these preparations are still not capable to selectively bind to target cells. Thus, in an attempt to further optimize existing treatment schemes immunoliposomes have been established to enable active targeting of tumor tissues. Recently, we have provided evidence for therapeutic efficacy of anti-IGF1R-targeted, surface modified doxorubicin loaded liposomes. Our approach involved a technique, which allows specific post-modifications of the liposomal surface by primed antibody-anchor conjugates thereby facilitating personalized approaches of commercially available liposomal drugs. In the current study, post-modification of sterically stabilized liposomal Dox was thoroughly investigated including the influence of different modification techniques (PIT, SPIT, SPIT60), lipid composition (SPC/Chol, HSPC/Chol), and buffers (HBS, SH). As earlier in vivo experiments did not take into account the presence of non-integrated ab-anchor conjugates this was included in the present study. Our experiments provide evidence that post-modification of commercially available liposomal preparations for active targeting is possible. Moreover, lyophilisation represents an applicable method to obtain a storable precursor of surface modifying antibody-anchor conjugates. Thus, these findings open up new approaches in patient individualized targeting of chemotherapeutic therapies. PMID:26497207

  18. Doxorubicin Conjugated to Immunomodulatory Anticancer Lactoferrin Displays Improved Cytotoxicity Overcoming Prostate Cancer Chemo resistance and Inhibits Tumour Development in TRAMP Mice.

    PubMed

    Shankaranarayanan, Jayanth Suryanarayanan; Kanwar, Jagat R; Al-Juhaishi, Afrah Jalil Abd; Kanwar, Rupinder K

    2016-01-01

    Advanced, metastatic, castration resistant and chemo-resistant prostate cancer has triggered change in the drug development landscape against prostate cancer. Bovine lactoferrin (bLf) is currently attracting attention in clinics for its anti-cancer properties and proven safety profile. bLf internalises into cancer cells via receptor mediated endocytosis, boosts immunity and complements chemotherapy. We employed bLf as an excellent functional carrier protein for delivering doxorubicin (Dox) into DU145 cells, CD44+/EpCAM+ double positive enriched DU145 3D prostaspheres and drug resistant ADR1000-DU145 cells, thus circumventing Dox efflux, to overcome chemo-resistance. Successful bLf-Dox conjugation with iron free or iron saturated bLf forms did not affect the integrity and functionality of bLf and Dox. bLf-Dox internalised into DU145 cells within 6 h, enhanced nuclear Dox retention up to 24 h, and proved significantly effective (p < 0.001) in reducing LC50 value of Dox from 5.3 μM to 1.3 μM (4 fold). Orally fed iron saturated bLf-Dox inhibited tumour development, prolonged survival, reduced Dox induced general toxicity, cardiotoxicity, neurotoxicity in TRAMP mice and upregulated serum levels of anti-cancer molecules TNF-α, IFN-γ, CCL4 and CCL17. The study identifies promising potential of a novel and safer bLf-Dox conjugate containing a conventional cytotoxic drug along with bLf protein to target drug resistance. PMID:27576789

  19. Doxorubicin Conjugated to Immunomodulatory Anticancer Lactoferrin Displays Improved Cytotoxicity Overcoming Prostate Cancer Chemo resistance and Inhibits Tumour Development in TRAMP Mice

    PubMed Central

    Shankaranarayanan, Jayanth Suryanarayanan; Kanwar, Jagat R.; AL-Juhaishi, Afrah Jalil Abd; Kanwar, Rupinder K.

    2016-01-01

    Advanced, metastatic, castration resistant and chemo-resistant prostate cancer has triggered change in the drug development landscape against prostate cancer. Bovine lactoferrin (bLf) is currently attracting attention in clinics for its anti-cancer properties and proven safety profile. bLf internalises into cancer cells via receptor mediated endocytosis, boosts immunity and complements chemotherapy. We employed bLf as an excellent functional carrier protein for delivering doxorubicin (Dox) into DU145 cells, CD44+/EpCAM+ double positive enriched DU145 3D prostaspheres and drug resistant ADR1000-DU145 cells, thus circumventing Dox efflux, to overcome chemo-resistance. Successful bLf-Dox conjugation with iron free or iron saturated bLf forms did not affect the integrity and functionality of bLf and Dox. bLf-Dox internalised into DU145 cells within 6 h, enhanced nuclear Dox retention up to 24 h, and proved significantly effective (p < 0.001) in reducing LC50 value of Dox from 5.3 μM to 1.3 μM (4 fold). Orally fed iron saturated bLf-Dox inhibited tumour development, prolonged survival, reduced Dox induced general toxicity, cardiotoxicity, neurotoxicity in TRAMP mice and upregulated serum levels of anti-cancer molecules TNF-α, IFN-γ, CCL4 and CCL17. The study identifies promising potential of a novel and safer bLf-Dox conjugate containing a conventional cytotoxic drug along with bLf protein to target drug resistance. PMID:27576789

  20. Synergic Effects of Doxorubicin and Melatonin on Apoptosis and Mitochondrial Oxidative Stress in MCF-7 Breast Cancer Cells: Involvement of TRPV1 Channels.

    PubMed

    Koşar, Pınar Aslan; Nazıroğlu, Mustafa; Övey, İshak Suat; Çiğ, Bilal

    2016-04-01

    Transient receptor transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable channel gated by oxidative stress and capsaicin (CAP) and modulated by melatonin (MEL) and capsazepine (CPZ). A combination of doxorubicin (DOX) and MEL may offer a potential therapy for breast cancer by exerting antitumor and anti-apoptotic effects and modulating Ca(2+) influx and TRPV1 activity. We aimed to investigate the effects of MEL and DOX on the oxidative toxicity of MCF-7 human breast cancer cells, in addition to the activity of the TRPV1 channel and apoptosis. The MCF-7 cells were divided into the following six treatment groups: control, incubated with MEL (0.3 mM), incubated with 0.5 μM DOX, incubated with 1 μM DOX, incubated with MEL + 0.5 μM DOX, or incubated with MEL + 1 μM DOX. The intracellular free Ca(2+) concentration was higher in the DOX groups than in the control, and the concentration was decreased by MEL. The intracellular free Ca(2+) concentration was further increased by treatment with the TRPV1 channel activator CAP (0.01 mM), and it was decreased by the CPZ (0.1 mM). The intracellular production of reactive oxygen species, mitochondrial membrane depolarization, apoptosis level, procaspase 9 and PARP activities, and caspase 3 and caspase 9 activities were higher in the DOX and MEL groups than in the control. Apoptosis and the activity of caspase 9 were further increased in the DOX plus MEL groups. Taken together, the findings indicate that MEL supported the effects of DOX by activation of TRPV1 and apoptosis, as well as by inducing MCF-7 cell death. As the apoptosis and caspase activity of cancer cells increase because of their elevated metabolism, MEL may be useful in supporting their apoptotic capacity. PMID:26525975

  1. Protective effects of fractions from Artemisia biennis hydro-ethanolic extract against doxorubicin-induced oxidative stress and apoptosis in PC12 cells

    PubMed Central

    Mojarrab, Mahdi; Mehrabi, Mehran; Ahmadi, Farahnaz; Hosseinzadeh, Leila

    2016-01-01

    Objective(s): This study was designed to indicate whether different fractions from Artemisia biennis hydroethanolic extract could provide cytoprotection against oxidative stress and apoptosis induced by doxorubicin (DOX) in rat pheochromocytoma cell line (PC12). Material and Methods: Cell viability was determined by MTT assay. Also, activation of caspase-3 and superoxide dismutase were evaluated by spectrophotometry. Detection of reactive oxygen species (ROS) and measurement of mitochondrial membrane potential (MMP) were performed by flowcytometry. Results: Treatment of PC12 cells with DOX reduced viability dose dependently. For evaluation of the effect of fractions (A-G) on DOX-induced cytotoxicity, PC12 cells were pretreated for 24 hr with the A. biennis fractions and then cells were treated with DOX. The fractions C and D increased PC12 cells viability significantly compared to DOX treated cells. Moreover, pretreatment with fractions C and D for 24 hr attenuated DOX-mediated apoptosis and the anti-apoptotic action of A. biennis fractions was partially dependent on inhibition of caspase 3 activity and also increasing the mitochondrial membrane potential (MMP). Selected A. biennis fractions also suppressed the generation of ROS and increased superoxide dismutase (SOD) activity. Conclusion: Taken together our observation indicated that subtoxic concentration of aforementioned fractions of A. biennis hydroetanolic extract has protective effect against apoptosis induced by DOX in PC12 cell. The results highlighted that fractions C and D may exert cytoprotective effects through their antioxidant actions. PMID:27403257

  2. Micelles of d-α-Tocopheryl Polyethylene Glycol 2000 Succinate (TPGS 2K) for Doxorubicin Delivery with Reversal of Multidrug Resistance.

    PubMed

    Hao, Tangna; Chen, Dawei; Liu, Kexin; Qi, Yan; Tian, Yan; Sun, Pengyuan; Liu, Yuanhong; Li, Zhen

    2015-08-19

    The purpose of this study is to investigate the ability of doxorubicin (DOX)-loaded d-α-tocopheryl polyethylene glycol 2000 succinate (TPGS 2K) micelles to overcome MDR in breast cancer treatment. The DOX-loaded TPGS 2K micelles exhibited an average size of around 23 nm, a near neutral zeta potential of around 4 mv and high encapsulation efficiency (85.22 ± 1.89%). The TPGS 2K conjugate did not have significant influences on the reduction of mitochondrial membrane potential (MMP) and the depletion of intracellular ATP level of MCF-7/ADR cells but had an evident effect on the inhibition of Verapamil-induced P-gp ATPase activity. In vitro cell culture experiments demonstrated the DOX-loaded TPGS 2K micelles, resulting in higher cellular uptake and more significant cytotoxicity effect against MCF-7/MDR cells than the free DOX solution. Additionally, the in vivo imaging study revealed DiR-loaded TPGS 2K micelles distributed selectively in MCF-7/ADR tumor-bearing nude mice and had a sufficient residence time. In the anticancer efficacy test with MCF-7/ADR tumor bearing nude mice, the DOX-loaded TPGS 2K micelles displayed significantly higher antitumor activity compared with free DOX solution at the same DOX dosage but less toxicity evaluated by the change of body weight and histological examination. Therefore, this drug delivery micellar system based on TPGS 2K conjugates can serve as a potential nanomedicine for reversing MDR. PMID:26214761

  3. Self-assembled mPEG-PCL-g-PEI micelles for multifunctional nanoprobes of doxorubicin delivery and magnetic resonance imaging and optical imaging.

    PubMed

    Guo, Qingfa; Kuang, Lei; Cao, Hui; Li, Weizhong; Wei, Jing

    2015-12-01

    In this paper, a novel bifunctional nanoprobe based on polyethylene glycol(MPEG)-poly(ϵ-caprolactone)(ϵ-CL)-polyethylenimine(PEI) labeled with FITC (MPEG-PCL-PEI-FITC, PCIF) were prepared to provide tumor therapy and simultaneous diagnostic information via magnetic resonance imaging (MRI) and optical imaging. Superparamagnetic iron oxide (SPIO) and doxorubicin (DOX) loaded PCIF (PCIF/SPIO/DOX) nanoprobes were prepared by self-assembling into micelles, which had uniformly distributed particle size of 130 ± 5 nm and a zeta potential of +35 ± 2 mV. Transmission electronic microscopy(TEM) showed that SPIO NPs were loaded into PCIF micelles. The PCIF/SPIO/DOX nanoprobes were superparamagnetic at 300 K with saturated magnetization of 20.5 emu/g Fe by vibrating-sample-magnetomete (VSM). Studies on cellular uptake of PCIF/SPIO/DOX nanoprobes demonstrated that SPIO NPs, DOX and FITC labeled MPEG-PCL-PEI were simultaneously taken up by the breast cancer (4T1) cells. After intravenous injection of PCIF/SPIO/DOX nanoprobes in 4T1 tumor-bearing mice, SPIO NPs, DOX and FITC labeled MPEG-PCL-PEI micelles were simultaneously delivered into tumor tissue by histochemisty. This work is important for the applications to multimodal diagnostic and theragnosis as nanomedicine. PMID:26513751

  4. A preloaded amorphous calcium carbonate/doxorubicin@silica nanoreactor for pH-responsive delivery of an anticancer drug.

    PubMed

    Zhao, Yang; Luo, Zhong; Li, Menghuan; Qu, Qiuyu; Ma, Xing; Yu, Shu-Hong; Zhao, Yanli

    2015-01-12

    Biomedical applications of nontoxic amorphous calcium carbonate (ACC) nanoparticles have mainly been restricted because of their aqueous instability. To improve their stability in physiological environments while retaining their pH-responsiveness, a novel nanoreactor of ACC-doxorubicin (DOX)@silica was developed for drug delivery for use in cancer therapy. As a result of its rationally engineered structure, this nanoreactor maintains a low drug leakage in physiological and lysosomal/endosomal environments, and responds specifically to pH 6.5 to release the drug. This unique ACC-DOX@silica nanoreactor releases DOX precisely in the weakly acidic microenvironment of cancer cells and results in efficient cell death, thus showing its great potential as a desirable chemotherapeutic nanosystem for cancer therapy.

  5. Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration.

    PubMed

    Molyneux, Gemma; Andrews, Michael; Sones, William; York, Malcolm; Barnett, Anne; Quirk, Edel; Yeung, Wing; Turton, John

    2011-02-01

    Many anticancer drugs are myelotoxic and cause bone marrow depression; however, generally, the marrow/blood returns to normal after treatment. Nevertheless, after the administration of some anti-neoplastic agents (e.g. busulphan, BU) under conditions as yet undefined, the marrow may begin a return towards normal, but normality may not be achieved, and late-stage/residual marrow injury may be evident. The present studies were conducted to develop a short-term mouse model (a 'screen') to identify late-stage/residual marrow injury using a brief regimen of drug administration. Female BALB/c mice were treated with BU, doxorubicin (DOX), cisplatin (CISPLAT) or cyclophosphamide (CYCLOPHOS) on days 1, 3 and 5. In 'preliminary studies', a maximum tolerated dose (MTD) for each drug was determined for use in 'main studies'. In main studies, mice were treated with vehicle (control), low and high (the MTD) dose levels of each agent. Necropsies were performed, and blood parameters and femoral/humeral nucleated marrow cell counts (FNCC/HNCC) were assessed on six occasions (from days 1 to 60/61 post-dosing). Late-stage/residual changes were apparent in BU-treated mice at day 61 post-dosing: RBC, Hb and haematocrit were reduced, mean cell volume/mean cell haemoglobin were increased and platelet and FNCC counts were decreased. Mice given DOX, CISPLAT and CYCLOPHOS, in general, showed no clear late-stage/residual effects (day 60/61). It was concluded that a brief regimen of drug administration, at an MTD, with assessment at day 60/61 post-dosing was a suitable short-term method/screen in the mouse for detecting late-stage/residual marrow injury for BU, a drug shown to exhibit these effects in man.

  6. NLRP3 Deficiency Reduces Macrophage Interleukin-10 Production and Enhances the Susceptibility to Doxorubicin-induced Cardiotoxicity

    PubMed Central

    Kobayashi, Motoi; Usui, Fumitake; Karasawa, Tadayoshi; Kawashima, Akira; Kimura, Hiroaki; Mizushina, Yoshiko; Shirasuna, Koumei; Mizukami, Hiroaki; Kasahara, Tadashi; Hasebe, Naoyuki; Takahashi, Masafumi

    2016-01-01

    NLRP3 inflammasomes recognize non-microbial danger signals and induce release of proinflammatory cytokine interleukin (IL)-1β, leading to sterile inflammation in cardiovascular disease. Because sterile inflammation is involved in doxorubicin (Dox)-induced cardiotoxicity, we investigated the role of NLRP3 inflammasomes in Dox-induced cardiotoxicity. Cardiac dysfunction and injury were induced by low-dose Dox (15 mg/kg) administration in NLRP3-deficient (NLRP3−/−) mice but not in wild-type (WT) and IL-1β−/− mice, indicating that NLRP3 deficiency enhanced the susceptibility to Dox-induced cardiotoxicity independent of IL-1β. Although the hearts of WT and NLRP3−/− mice showed no significant difference in inflammatory cell infiltration, macrophages were the predominant inflammatory cells in the hearts, and cardiac IL-10 production was decreased in Dox-treated NLRP3−/− mice. Bone marrow transplantation experiments showed that bone marrow-derived cells contributed to the exacerbation of Dox-induced cardiotoxicity in NLRP3−/− mice. In vitro experiments revealed that NLRP3 deficiency decreased IL-10 production in macrophages. Furthermore, adeno-associated virus-mediated IL-10 overexpression restored the exacerbation of cardiotoxicity in the NLRP3−/− mice. These results demonstrated that NLRP3 regulates macrophage IL-10 production and contributes to the pathophysiology of Dox-induced cardiotoxicity, which is independent of IL-1β. Our findings identify a novel role of NLRP3 and provided new insights into the mechanisms underlying Dox-induced cardiotoxicity. PMID:27225830

  7. The protective effects of ω-3 fatty acids on doxorubicin-induced hepatotoxicity and nephrotoxicity in rats.

    PubMed

    Tulubas, Feti; Gurel, Ahmet; Oran, Mustafa; Topcu, Birol; Caglar, Veli; Uygur, Emine

    2015-07-01

    This study aims to evaluate the protective effects of ω-3 fatty acids (FAs) on doxorubicin (DOX)-induced hepatotoxicity and nephrotoxicity in rats. A total of 24 adult male Sprague Dawley rats were divided into three groups. Control group was given only saline by intragastric gavage. DOX group received DOX at the dose of 30 mg/kg intraperitoneally on day 28. DOX-ω-3 FA group was given as ω-3 FAs at the dose of 400 mg/kg daily by intragastric gavage for 30 days and received DOX at the dose of 30 mg/kg intraperitoneally on day 28. At the end of the 30-day experimental period, the serum, liver and kidney tissue specimens were taken from the animals by giving a general anesthesia. Glutathione (GSH) and malondialdehyde (MDA) levels in serum and GSH and MDA levels and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in liver and kidney tissues were measured spectrophotometrically. In our study, a significant increase in MDA levels was observed in rats when given a dose of DOX and a significant decrease in the levels of GSH, SOD and GSH-Px activities in serum, liver and kidney tissues was determined when compared with control group. In addition, a significant decrease in MDA levels was observed in rats when a dose of ω-3 FAs was given with DOX and a significant increase was determined in the levels of GSH, SOD and GSH-Px activities in serum, liver and kidney tissues, when compared with DOX group. We concluded that ω-3 FA had favorable effects in rat liver and kidney tissues by preventing oxidative damage.

  8. Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in β-adrenergic signaling and enhances apoptosis.

    PubMed

    Roca-Alonso, L; Castellano, L; Mills, A; Dabrowska, A F; Sikkel, M B; Pellegrino, L; Jacob, J; Frampton, A E; Krell, J; Coombes, R C; Harding, S E; Lyon, A R; Stebbing, J

    2015-01-01

    The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks of cardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typically progresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development of cardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles in both cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellular processes downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application to isolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts following myocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating the β-adrenergic pathway, where preferential β1- and β2-adrenoceptor (β1AR and β2AR) direct inhibition is combined with Giα-2 targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, we demonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygen species generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. In conclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30 overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotective and anti-tumorigenic strategy for anthracyclines. PMID:25950484

  9. Transactivation of bad by vorinostat-induced acetylated p53 enhances doxorubicin-induced cytotoxicity in cervical cancer cells.

    PubMed

    Lee, Sook-Jeong; Hwang, Sung-Ook; Noh, Eun Joo; Kim, Dong-Uk; Nam, Miyoung; Kim, Jong Hyeok; Nam, Joo Hyun; Hoe, Kwang-Lae

    2014-02-14

    Vorinostat (VOR) has been reported to enhance the cytotoxic effects of doxorubicin (DOX) with fewer side effects because of the lower DOX dosage in breast cancer cells. In this study, we investigated the novel mechanism underlying the synergistic cytotoxic effects of VOR and DOX co-treatment in cervical cancer cells HeLa, CaSki and SiHa cells. Co-treatment with VOR and DOX at marginal doses led to the induction of apoptosis through caspase-3 activation, poly (ADP-ribose) polymerase cleavage and DNA micronuclei. Notably, the synergistic growth inhibition induced by the co-treatment was attributed to the upregulation of the pro-apoptotic protein Bad, as the silencing of Bad expression using small interfering RNA (siRNA) abolished the phenomenon. As siRNA against p53 did not result in an increase in acetylated p53 and the consequent upregulation of Bad, the observed Bad upregulation was mediated by acetylated p53. Moreover, a chromatin immunoprecipitation analysis showed that the co-treatment of HeLa cells with VOR and DOX increased the recruitment of acetylated p53 to the bad promoter, with consequent bad transactivation. Conversely, C33A cervical cancer cells containing mutant p53 co-treated with VOR and DOX did not exhibit Bad upregulation, acetylated p53 induction or consequent synergistic growth inhibition. Together, the synergistic growth inhibition of cervical cancer cell lines induced by co-treatment with VOR and DOX can be attributed to the upregulation of Bad, which is induced by acetylated p53. These results show for the first time that the acetylation of p53, rather than histones, is a mechanism for the synergistic growth inhibition induced by VOR and DOX co-treatments.

  10. Construction of near-infrared light-triggered reactive oxygen species-sensitive (UCN/SiO2-RB + DOX)@PPADT nanoparticles for simultaneous chemotherapy and photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Zhou, Fang; Zheng, Bin; Zhang, Ying; Wu, Yudong; Wang, Hanjie; Chang, Jin

    2016-06-01

    Combined therapy now plays a major role in cancer therapy due to the outcome of huge amounts of scientific experiments in recent years. However, all systems designed previously have been unable to simultaneously deliver therapy effects using several methods to produce a greater overall therapeutic effect. To solve the problem, we constructed a delivery system of near-infrared light (NIR)-triggered reactive oxygen species (ROS)-sensitive nanoparticles (NPs) for simultaneous chemotherapy and photodynamic therapy (PDT). The inner NP was assembled from a hydrophobic upconverting nanoparticle (UCN) core, with a thin silica shell linked with rose bengal (RB). Finally, a type of ROS-induced biodegradable polymer named poly-(1, 4-phenyleneacetone dimethylenethioketal) (PPADT) was self-assembled to form the NP as an outer shell to load the inner NP and doxorubicin (DOX). As the results show, the UCN core works as a transducer to convert deeply penetrating NIR to visible light for activating the photosensitizer RB for PDT under NIR excitation. In the meantime, the redundant ROS caused PPADT to biodegrade to release the loaded DOX, realizing simultaneous chemotherapy and PDT. Properties such as structure, size distribution, morphology, Fourier transform infrared spectroscopy, ROS production test, cell uptake test and combined therapy treatment effect in vitro were evaluated to prove NIR triggered ROS-sensitive (UCN/SiO2-RB + DOX)@PPADT NPs. Based on our data, this delivery system could provide an effective means to realize simultaneous chemotherapy and PDT through external NIR-triggered ROS sensitivity.

  11. Construction of near-infrared light-triggered reactive oxygen species-sensitive (UCN/SiO2-RB + DOX)@PPADT nanoparticles for simultaneous chemotherapy and photodynamic therapy.

    PubMed

    Zhou, Fang; Zheng, Bin; Zhang, Ying; Wu, Yudong; Wang, Hanjie; Chang, Jin

    2016-06-10

    Combined therapy now plays a major role in cancer therapy due to the outcome of huge amounts of scientific experiments in recent years. However, all systems designed previously have been unable to simultaneously deliver therapy effects using several methods to produce a greater overall therapeutic effect. To solve the problem, we constructed a delivery system of near-infrared light (NIR)-triggered reactive oxygen species (ROS)-sensitive nanoparticles (NPs) for simultaneous chemotherapy and photodynamic therapy (PDT). The inner NP was assembled from a hydrophobic upconverting nanoparticle (UCN) core, with a thin silica shell linked with rose bengal (RB). Finally, a type of ROS-induced biodegradable polymer named poly-(1, 4-phenyleneacetone dimethylenethioketal) (PPADT) was self-assembled to form the NP as an outer shell to load the inner NP and doxorubicin (DOX). As the results show, the UCN core works as a transducer to convert deeply penetrating NIR to visible light for activating the photosensitizer RB for PDT under NIR excitation. In the meantime, the redundant ROS caused PPADT to biodegrade to release the loaded DOX, realizing simultaneous chemotherapy and PDT. Properties such as structure, size distribution, morphology, Fourier transform infrared spectroscopy, ROS production test, cell uptake test and combined therapy treatment effect in vitro were evaluated to prove NIR triggered ROS-sensitive (UCN/SiO2-RB + DOX)@PPADT NPs. Based on our data, this delivery system could provide an effective means to realize simultaneous chemotherapy and PDT through external NIR-triggered ROS sensitivity.

  12. MiR-133a Is Functionally Involved in Doxorubicin-Resistance in Breast Cancer Cells MCF-7 via Its Regulation of the Expression of Uncoupling Protein 2

    PubMed Central

    Yuan, Yuan; Yao, Yu Feng; Hu, Sai Nan; Gao, Jin; Zhang, Li-Li

    2015-01-01

    The development of novel targeted therapies holds promise for conquering chemotherapy resistance, which is one of the major hurdles in current breast cancer treatment. Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells. In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7. We postulated that miR133a might play a functional role in the development of Doxorubicin-resistant in breast cancer cells. In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2. These findings provided direct evidences that the miR133a/UCP-2 axis might play an essential role in the development of Doxorubicin-resistance in breast cancer cells, suggesting that the miR133a/UCP-2 signaling cohort could be served as a novel therapeutic target for the treatment of chemotherapy resistant in breast cancer. PMID:26107945

  13. Hyaluronic acid-modified multiwalled carbon nanotubes for targeted delivery of doxorubicin into cancer cells.

    PubMed

    Cao, Xueyan; Tao, Lei; Wen, Shihui; Hou, Wenxiu; Shi, Xiangyang

    2015-03-20

    Development of novel drug carriers for targeted cancer therapy with high efficiency and specificity is of paramount importance and has been one of the major topics in current nanomedicine. Here we report a general approach to using multifunctional multiwalled carbon nanotubes (MWCNTs) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for targeted cancer therapy. In this approach, polyethyleneimine (PEI)-modified MWCNTs were covalently conjugated with fluorescein isothiocyanate (FI) and hyaluronic acid (HA). The formed MWCNT/PEI-FI-HA conjugates were characterized via different techniques and were used as a new carrier system to encapsulate the anticancer drug doxorubicin for targeted delivery to cancer cells overexpressing CD44 receptors. We show that the formed MWCNT/PEI-FI-HA/DOX complexes with a drug loading percentage of 72% are water soluble and stable. In vitro release studies show that the drug release rate under an acidic condition (pH 5.8, tumor cell microenvironment) is higher than that under physiological condition (pH 7.4). Cell viability assay demonstrates that the carrier material has good biocompatibility in the tested concentration range, and the MWCNT/PEI-FI-HA/DOX complexes can specifically target cancer cells overexpressing CD44 receptors and exert growth inhibition effect to the cancer cells. The developed HA-modified MWCNTs hold a great promise to be used as an efficient anticancer drug carrier for tumor-targeted chemotherapy.

  14. Dual responsive nanogels for intracellular doxorubicin delivery.

    PubMed

    Asadi, Hamed; Khoee, Sepideh

    2016-09-10

    Nanosized polymeric delivery systems that encapsulate drug molecules and release them in response to a specific intracellular stimulus are of promising interest for cancer therapy. Here, we demonstrated a simple and fast synthetic protocol of redox-responsive nanogels with high drug encapsulation efficiency and stability. The prepared nanogels displayed narrow size distributions and versatility of surface modification. The polymer precursor of these nanogels is based on a random copolymer that contains oligoethyleneglycol (OEG) and pyridyldisulfide (PDS) units as side-chain functionalities. The nanogels were prepared through a lock-in strategy in aqueous media via self cross-linking of PDS groups. By changing polymer concentration, we could control the size of nanogels in range of 80-115nm. The formed nanogels presented high doxorubicin (DOX) encapsulation efficiency (70% (w/w)) and displayed pH and redox-controlled drug release triggered by conditions mimicking the reducible intracellular environment. The nanogels displayed an excellent cytocompatibility and were effectively endocytosed by A2780CP ovarian cancer cells, which make them promising nanomaterials for the efficient intracellular delivery of anticancer drugs. PMID:27444549

  15. Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats

    SciTech Connect

    Zordoky, Beshay N.M.; Anwar-Mohamed, Anwar; Aboutabl, Mona E.

    2010-01-01

    Doxorubicin (DOX) is a potent anti-neoplastic antibiotic used to treat a variety of malignancies; however, its use is limited by dose-dependent cardiotoxicity. Moreover, there is a strong correlation between cytochrome P450 (CYP)-mediated arachidonic acid metabolites and the pathogenesis of many cardiovascular diseases. Therefore, in the current study, we have investigated the effect of acute DOX toxicity on the expression of several CYP enzymes and their associated arachidonic acid metabolites in the heart of male Sprague-Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection of 15 mg/kg of the drug. Our results showed that DOX treatment for 24 h caused a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A1, CYP4A3, CYP4F1, CYP4F4, and EPHX2 gene expression in the heart of DOX-treated rats as compared to the control. Similarly, there was a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A, and sEH proteins after 24 h of DOX administration. In the heart microsomes, acute DOX toxicity significantly increased the formation of 20-HETE which is consistent with the induction of the major CYP omega-hydroxylases: CYP4A1, CYP4A3, CYP4F1, and CYP4F4. On the other hand, the formation of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) was significantly reduced, whereas the formation of their corresponding dihydroxyeicosatrienoic acids was significantly increased. The decrease in the cardioprotective EETs can be attributed to the increase of sEH activity parallel to the induction of the EPHX2 gene expression in the heart of DOX-treated rats. In conclusion, acute DOX toxicity alters the expression of several CYP and sEH enzymes with a consequent alteration in arachidonic acid metabolism. These results may represent a novel mechanism by which this drug causes progressive cardiotoxicity.

  16. Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity.

    PubMed

    Fouad, Amr A; Albuali, Waleed H; Al-Mulhim, Abdulruhman S; Jresat, Iyad

    2013-09-01

    The potential protective effect of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated against doxorubicin cardiotoxicity in rats. Cardiotoxicity was induced by six equal doses of doxorubicin (2.5mgkg(-1) i.p., each) given at 48h intervals over two weeks to achieve a total dose of 15mgkg(-1). Cannabidiol treatment (5mgkg(-1)/day, i.p.) was started on the same day of doxorubicin administration and continued for four weeks. Cannabidiol significantly reduced the elevations of serum creatine kinase-MB and troponin T, and cardiac malondialdehyde, tumor necrosis factor-α, nitric oxide and calcium ion levels, and attenuated the decreases in cardiac reduced glutathione, selenium and zinc ions. Histopathological examination sh