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Sample records for liposomes preventing tumor

  1. Current trends in the use of liposomes for tumor targeting

    PubMed Central

    Deshpande, Pranali P; Biswas, Swati; Torchilin, Vladimir P

    2013-01-01

    The use of liposomes for drug delivery began early in the history of pharmaceutical nanocarriers. These nanosized, lipid bilayered vesicles have become popular as drug delivery systems owing to their efficiency, biocompatibility, nonimmunogenicity, enhanced solubility of chemotherapeutic agents and their ability to encapsulate a wide array of drugs. Passive and ligand-mediated active targeting promote tumor specificity with diminished adverse off-target effects. The current field of liposomes focuses on both clinical and diagnostic applications. Recent efforts have concentrated on the development of multifunctional liposomes that target cells and cellular organelles with a single delivery system. This review discusses the recent advances in liposome research in tumor targeting. PMID:23914966

  2. Binding and interstitial penetration of liposomes within avascular tumor spheroids.

    PubMed

    Kostarelos, Kostas; Emfietzoglou, Dimitris; Papakostas, Alexandros; Yang, Wei-Hong; Ballangrud, Ase; Sgouros, George

    2004-11-20

    The liposomal delivery of cancer therapeutics, including gene therapy vectors, is an area of intense study. Poor penetration of liposomes into interstitial tumor spaces remains a problem, however. In this work, the penetration of different liposomal formulations into prostate carcinoma spheroids was examined. Spheroid penetration was assessed by confocal microscopy of fluorescently labeled liposomes. The impact of liposomal surface charge, mean diameter, lipid bilayer fluidity and fusogenicity on spheroid penetration was examined. A variety of different liposome systems relevant to clinical or preclinical protocols have been studied, including classical zwitterionic (DMPC:chol) and sterically stabilized liposomes (DMPC:chol:DOPE-PEG2000), both used clinically, and cationic liposomes (DMPC:DOPE:DC-chol and DOTAP), forming the basis of the vast majority of nonviral gene transfer vectors tested in various cancer trials. Surface interactions between strongly cationic vesicles and the tumor cells led to an electrostatically derived binding-site barrier effect, inhibiting further association of the delivery systems with the tumor spheroids (DMPC:DC-chol). However, inclusion of the fusogenic lipid DOPE and use of a cationic lipid of lower surface charge density (DOTAP instead of DC-chol) led to improvements in the observed intratumoral distribution characteristics. Sterically stabilized liposomes did not interact with the tumor spheroids, whereas small unilamellar classical liposomes exhibit extensive distribution deeper into the tumor volume. Engineering liposomal delivery systems with a relatively low charge molar ratio and enhanced fusogenicity, or electrostatically neutral liposomes with fluid bilayers, offered enhanced intratumoral penetration. This study shows that a delicate balance exists between the strong affinity of delivery systems for the tumor cells and the efficient penetration and distribution within the tumor mass, similar to previous work studying

  3. Improved Tumor Uptake by Optimizing Liposome Based RES Blockade Strategy

    PubMed Central

    Sun, Xiaolian; Yan, Xuefeng; Jacobson, Orit; Sun, Wenjing; Wang, Zhantong; Tong, Xiao; Xia, Yuqiong; Ling, Daishun; Chen, Xiaoyuan

    2017-01-01

    Minimizing the sequestration of nanomaterials (NMs) by the reticuloendothelial system (RES) can enhance the circulation time of NMs, and thus increase their tumor-specific accumulation. Liposomes are generally regarded as safe (GRAS) agents that can block the RES reversibly and temporarily. With the help of positron emission tomography (PET), we monitored the in vivo tissue distribution of 64Cu-labeled 40 × 10 nm gold nanorods (Au NRs) after pretreatment with liposomes. We systematically studied the effectiveness of liposome administration by comparing (1) differently charged liposomes; (2) different liposome doses; and (3) varying time intervals between liposome dose and NR dose. By pre-injecting 400 μmol/kg positively charged liposomes into mice 5 h before the Au NRs, the liver and spleen uptakes of Au NRs decreased by 30% and 53%, respectively. Significantly, U87MG tumor uptake of Au NRs increased from 11.5 ± 1.1 %ID/g to 16.1 ± 1.3 %ID/g at 27 h post-injection. Quantitative PET imaging is a valuable tool to understand the fate of NMs in vivo and cationic liposomal pretreatment is a viable approach to reduce RES clearance, prolong circulation, and improve tumor uptake. PMID:28042337

  4. Recent Trends in Multifunctional Liposomal Nanocarriers for Enhanced Tumor Targeting

    PubMed Central

    Perche, Federico; Torchilin, Vladimir P.

    2013-01-01

    Liposomes are delivery systems that have been used to formulate a vast variety of therapeutic and imaging agents for the past several decades. They have significant advantages over their free forms in terms of pharmacokinetics, sensitivity for cancer diagnosis and therapeutic efficacy. The multifactorial nature of cancer and the complex physiology of the tumor microenvironment require the development of multifunctional nanocarriers. Multifunctional liposomal nanocarriers should combine long blood circulation to improve pharmacokinetics of the loaded agent and selective distribution to the tumor lesion relative to healthy tissues, remote-controlled or tumor stimuli-sensitive extravasation from blood at the tumor's vicinity, internalization motifs to move from tumor bounds and/or tumor intercellular space to the cytoplasm of cancer cells for effective tumor cell killing. This review will focus on current strategies used for cancer detection and therapy using liposomes with special attention to combination therapies. PMID:23533772

  5. Tumor specific ultrasound enhanced gene transfer in vivo with novel liposomal bubbles.

    PubMed

    Suzuki, Ryo; Takizawa, Tomoko; Negishi, Yoichi; Utoguchi, Naoki; Sawamura, Kaori; Tanaka, Kumiko; Namai, Eisuke; Oda, Yusuke; Matsumura, Yasuhiro; Maruyama, Kazuo

    2008-01-22

    Bubble liposomes (liposomes which entrap an ultrasound imaging gas) may constitute a unique system for delivering various molecules efficiently into mammalian cells in vitro. In this study, Bubble liposomes were compared with cationic lipid (CL)-DNA complexes as potential gene delivery carriers into tumor in vivo. The delivery of genes by Bubble liposomes depended on the intensity of the applied ultrasound. Transfection efficiency plateaued at 0.7 W/cm(2) ultrasound intensity. Bubble liposomes efficiently transferred genes into cultured cells even when the cells were exposed to ultrasound for only 1 s. In addition, Bubble liposomes could introduce the luciferase gene more effectively than CL-DNA complexes into mouse ascites tumor cells and solid tumor tissue. We conclude that the combination of Bubble liposomes and ultrasound is a minimally-invasive and tumor specific gene transfer method in vivo.

  6. The intra-tumoral relationship between microcirculation, interstitial fluid pressure and liposome accumulation.

    PubMed

    Stapleton, Shawn; Milosevic, Michael; Tannock, Ian F; Allen, Christine; Jaffray, David A

    2015-08-10

    The heterogeneous intra-tumoral accumulation of liposomes has been linked to both the chaotic tumor microcirculation and to elevated interstitial fluid pressure (IFP). Here, we explored the relationship between tumor microcirculation, IFP, and the intra-tumoral accumulation of liposomes. Measurements of the tumor microcirculation using perfusion imaging, IFP using a novel image-guided robotic needle positioning system, and the intra-tumoral distribution of liposomes using volumetric micro-CT imaging were performed in mice bearing subcutaneous and orthotopic MDA-MB-231 tumors. Intra-tumoral perfusion and IFP were substantially different between the two tumor implantation sites. Tumor perfusion and not vascular permeability was found to be the primary mediator of the intra-tumoral accumulation of CT-liposomes. A strong relationship was observed between the radial distribution of IFP, metrics of tumor perfusion, and the intra-tumoral accumulation of liposomes. Tumors with elevated central IFP that decreased at the periphery had low perfusion and low levels of CT-liposome accumulation that increased towards the periphery. Conversely, tumors with low and radially uniform IFP exhibited higher levels of tumor perfusion and CT-liposome accumulation. Both tumor perfusion and elevated IFP exhibit substantial intra-tumoral heterogeneity and both play an integral role in mediating the intra-tumoral accumulation of liposomes through a complex interactive effect. Measuring IFP in the clinical setting remains challenging and these results demonstrate that tumor perfusion imaging alone provides a robust non-invasive method to identify factors that contribute to poor liposome accumulation and may allow for pre-selection of patients that are more likely to respond to nanoparticle therapy.

  7. An evaluation of anti-tumor effect and toxicity of PEGylated ursolic acid liposomes

    NASA Astrophysics Data System (ADS)

    Wang, Qianqian; Zhao, Tingting; Liu, Yanping; Xing, Shanshan; Li, Lei; Gao, Dawei

    2016-02-01

    Therapy of solid tumors mediated by nano-drug delivery has attracted considerable interest. In our previous study, ursolic acid (UA) was successfully encapsulated into PEGylated liposomes. The study aimed to evaluate the tumor inhibition effect and cytotoxicity of the PEGylated UA liposomes by U14 cervical carcinoma-bearing mice. The liposomes were spherical particles with mean particle diameters of 127.2 nm. The tumor inhibition rate of PEGylated UA liposomes was 53.60 % on U14 cervical carcinoma-bearing mice, which was greater than those of the UA solution (18.25 %) and traditional UA liposome groups (40.75 %). The tumor cells apoptosis rate of PEGylated UA liposomes was 25.81 %, which was significantly higher than that of the traditional UA liposomes (13.37 %). Moreover, the kidney and liver did not emerge the pathological changes in UA therapeutic mice by histopathological analysis, while there were significant differences on tumor tissues among three UA formulation groups. The PEGylated UA liposomes exhibited higher anti-tumor activity and lower cytotoxicity, and the main reason was that the coating PEG layer improved UA liposome properties, such as enhancing the stability of liposomes, promoting the effect of slow release, and prolonging the time of blood circulation. This may shed light on the development of PEGylated nano-vehicles.

  8. A mathematical model of the enhanced permeability and retention effect for liposome transport in solid tumors.

    PubMed

    Stapleton, Shawn; Milosevic, Michael; Allen, Christine; Zheng, Jinzi; Dunne, Michael; Yeung, Ivan; Jaffray, David A

    2013-01-01

    The discovery of the enhanced permeability and retention (EPR) effect has resulted in the development of nanomedicines, including liposome-based formulations of drugs, as cancer therapies. The use of liposomes has resulted in substantial increases in accumulation of drugs in solid tumors; yet, significant improvements in therapeutic efficacy have yet to be achieved. Imaging of the tumor accumulation of liposomes has revealed that this poor or variable performance is in part due to heterogeneous inter-subject and intra-tumoral liposome accumulation, which occurs as a result of an abnormal transport microenvironment. A mathematical model that relates liposome accumulation to the underlying transport properties in solid tumors could provide insight into inter and intra-tumoral variations in the EPR effect. In this paper, we present a theoretical framework to describe liposome transport in solid tumors. The mathematical model is based on biophysical transport equations that describe pressure driven fluid flow across blood vessels and through the tumor interstitium. The model was validated by direct comparison with computed tomography measurements of tumor accumulation of liposomes in three preclinical tumor models. The mathematical model was fit to liposome accumulation curves producing predictions of transport parameters that reflect the tumor microenvironment. Notably, all fits had a high coefficient of determination and predictions of interstitial fluid pressure agreed with previously published independent measurements made in the same tumor type. Furthermore, it was demonstrated that the model attributed inter-subject heterogeneity in liposome accumulation to variations in peak interstitial fluid pressure. These findings highlight the relationship between transvascular and interstitial flow dynamics and variations in the EPR effect. In conclusion, we have presented a theoretical framework that predicts inter-subject and intra-tumoral variations in the EPR effect

  9. A Mathematical Model of the Enhanced Permeability and Retention Effect for Liposome Transport in Solid Tumors

    PubMed Central

    Stapleton, Shawn; Milosevic, Michael; Allen, Christine; Zheng, Jinzi; Dunne, Michael; Yeung, Ivan; Jaffray, David A.

    2013-01-01

    The discovery of the enhanced permeability and retention (EPR) effect has resulted in the development of nanomedicines, including liposome-based formulations of drugs, as cancer therapies. The use of liposomes has resulted in substantial increases in accumulation of drugs in solid tumors; yet, significant improvements in therapeutic efficacy have yet to be achieved. Imaging of the tumor accumulation of liposomes has revealed that this poor or variable performance is in part due to heterogeneous inter-subject and intra-tumoral liposome accumulation, which occurs as a result of an abnormal transport microenvironment. A mathematical model that relates liposome accumulation to the underlying transport properties in solid tumors could provide insight into inter and intra-tumoral variations in the EPR effect. In this paper, we present a theoretical framework to describe liposome transport in solid tumors. The mathematical model is based on biophysical transport equations that describe pressure driven fluid flow across blood vessels and through the tumor interstitium. The model was validated by direct comparison with computed tomography measurements of tumor accumulation of liposomes in three preclinical tumor models. The mathematical model was fit to liposome accumulation curves producing predictions of transport parameters that reflect the tumor microenvironment. Notably, all fits had a high coefficient of determination and predictions of interstitial fluid pressure agreed with previously published independent measurements made in the same tumor type. Furthermore, it was demonstrated that the model attributed inter-subject heterogeneity in liposome accumulation to variations in peak interstitial fluid pressure. These findings highlight the relationship between transvascular and interstitial flow dynamics and variations in the EPR effect. In conclusion, we have presented a theoretical framework that predicts inter-subject and intra-tumoral variations in the EPR effect

  10. All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells.

    PubMed

    Li, Ruo-Jing; Ying, Xue; Zhang, Yan; Ju, Rui-Jun; Wang, Xiao-Xing; Yao, Hong-Juan; Men, Ying; Tian, Wei; Yu, Yang; Zhang, Liang; Huang, Ren-Jie; Lu, Wan-Liang

    2011-02-10

    The relapse of cancer is mostly due to the proliferation of cancer stem cells which could not be eliminated by a standard chemotherapy. A new kind of all-trans retinoic acid stealth liposomes was developed for preventing the relapse of breast cancer and for treating the cancer in combination with a cytotoxic agent, vinorelbine stealth liposomes. In vitro studies were performed on the human breast cancer MCF-7 and MDA-MB-231 cells. In vivo evaluations were performed on the newly established relapse model with breast cancer stem cells. Results showed that the particle size of all-trans retinoic acid stealth liposomes was approximately 80nm, and the encapsulation efficiency was >90%. Breast cancer stem cells were identified with the CD44(+)/CD24(-) phenotype and characterized with properties: resistant to cytotoxic agent, stronger capability of proliferation, and stronger capability of differentiation. Inhibitory effect of all-trans retinoic acid stealth liposomes was more potent in cancer stem cells than in cancer cells. The mechanisms were defined to be two aspects: arresting breast cancer stem cells at the G(0)/G(1) phase in mitosis, and inducing the differentiation of breast cancer stem cells. The cancer relapse model was successfully established by xenografting breast cancer stem cells into NOD/SCID mice, and the formation and growth of the xenografted tumors were significantly inhibited by all-trans retinoic acid stealth liposomes. The combination therapy of all-trans retinoic acid stealth liposomes with vinorelbine stealth liposomes produced the strongest inhibitory effect to the relapse tumor model. It could be concluded that all-trans retinoic acid stealth liposomes could be used for preventing the relapse of breast cancer by differentiating cancer stem cells and arresting the cell-cycle, and for treating breast cancer as a co-therapy, thus providing a novel strategy for treating breast cancer and preventing relapse derived from breast cancer stem cells.

  11. Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose.

    PubMed

    Nakamura, Hiroyuki; Abu Lila, Amr S; Nishio, Miho; Tanaka, Masao; Ando, Hidenori; Kiwada, Hiroshi; Ishida, Tatsuhiro

    2015-12-28

    Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems.

  12. Improved Efficacy of Liposomal Doxorubicin Treatment of Superficial Tumors by Thermotherapy.

    PubMed

    Ping, Xiong; Angang, Ding; Xia, Gong; Yinzhu, Zhao; Jia, Li; Guofeng, Shen; Yazhu, Chen

    2016-04-01

    Our study aimed to investigate the effect of ultrasonic thermotherapy on the targeted delivery of liposomal doxorubicin to superficial tumors, local drug concentrations in tumor tissue, and the curative effect of chemotherapy. Twenty rabbits with VX2 tumors transplanted into the superficial muscle of the hind limb were randomly assigned to the following 4 treatment groups: (1) free doxorubicin, (2) liposomal doxorubicin hydrochloride, (3) liposomal doxorubicin hydrochloride plus 41 °C thermotherapy, and (4) liposomal doxorubicin hydrochloride plus 43 °C thermotherapy. Ultrasonic thermotherapy was delivered at 41 °C to 43 °C. Plasma, tumor, and organ/tissue homogenates were analyzed by high-pressure liquid chromatography to determine doxorubicin concentrations. The drug concentration in plasma and tumor tissue was significantly higher in the liposomal doxorubicin hydrochloride plus thermotherapy group than in the liposomal doxorubicin hydrochloride and free doxorubicin groups, but there were no significant differences among the 4 groups in the concentration in heart or kidney tissue. Combining thermotherapy with liposomal doxorubicin hydrochloride chemotherapy significantly increased the concentration of the drug in tumor tissue. The doxorubicin concentration was significantly higher in the liposomal doxorubicin hydrochloride plus 41 °C thermotherapy group.

  13. Anti-Tumor Effects From Dendritic Cell-Based Cancer Immunotherapy Using Liposomal Bubbles and Ultrasound

    NASA Astrophysics Data System (ADS)

    Oda, Yusuke; Suzuki, Ryo; Hirata, Keiichi; Nomura, Tetsuya; Utoguchi, Naoki; Maruyama, Kazuo

    2011-09-01

    Dendritic cell (DC)-based cancer immunotherapy has the potential to be a minimally invasive therapy that could prevent cancer metastasis and recurrence. Recently, in order to induce effective anti-tumor immunity, we developed a novel antigen delivery system for DCs by the combination of ultrasound (US) and liposomal bubbles (Bubble Liposomes: BLs) with entrapped perfluoropropane gas. In this study, we investigated the induction of antigen specific immune responses in vivo and the anti-tumor effect caused by immunization of DCs treated with BLs and US. For the immunization of DCs which had delivered antigen, using BLs and US, the mice induced antigen specific cytotoxic T lymphocytes (CTLs) were found to be the main effector cells in DC-based cancer immunotherapy. In addition, immunization with DCs that had been pulsed with antigen using BLs and US completely suppressed tumor growth Therefore, immunization of DCs with this antigen delivery system has promise for the efficient induction of anti-tumor immune responses.

  14. Predicting diffusive transport of cationic liposomes in 3-dimensional tumor spheroids.

    PubMed

    Wientjes, Michael G; Yeung, Bertrand Z; Lu, Ze; Wientjes, M Guillaume; Au, Jessie L S

    2014-10-28

    Nanotechnology is widely used in cancer research. Models that predict nanoparticle transport and delivery in tumors (including subcellular compartments) would be useful tools. This study tested the hypothesis that diffusive transport of cationic liposomes in 3-dimensional (3D) systems can be predicted based on liposome-cell biointerface parameters (binding, uptake, retention) and liposome diffusivity. Liposomes comprising different amounts of cationic and fusogenic lipids (10-30mol% DOTAP or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1-20mol% DOPE or 1,2-dioleoyl-3-trimethylammonium-propane, +25 to +44mV zeta potential) were studied. We (a) measured liposome-cell biointerface parameters in monolayer cultures, and (b) calculated effective diffusivity based on liposome size and spheroid composition. The resulting parameters were used to simulate the liposome concentration-depth profiles in 3D spheroids. The simulated results agreed with the experimental results for liposomes comprising 10-30mol% DOTAP and ≤10mol% DOPE, but not for liposomes with higher DOPE content. For the latter, model modifications to account for time-dependent extracellular concentration decrease and liposome size increase did not improve the predictions. The difference among low- and high-DOPE liposomes suggests concentration-dependent DOPE properties in 3D systems that were not captured in monolayers. Taken together, our earlier and present studies indicate the diffusive transport of neutral, anionic and cationic nanoparticles (polystyrene beads and liposomes, 20-135nm diameter, -49 to +44mV) in 3D spheroids, with the exception of liposomes comprising >10mol% DOPE, can be predicted based on the nanoparticle-cell biointerface and nanoparticle diffusivity. Applying the model to low-DOPE liposomes showed that changes in surface charge affected the liposome localization in intratumoral subcompartments within spheroids.

  15. Gold nanoparticles decorated liposomes and their SERS performance in tumor cells

    NASA Astrophysics Data System (ADS)

    Zhu, D.; Wang, Z. Y.; Zong, S. F.; Chen, H.; Chen, P.; Li, M. Y.; Wu, L.; Cui, Y. P.

    2015-05-01

    Due to their unique properties, liposomes have been widely used as drug nanocarriers. Herein a liposome-Au nanohybrid has been demonstrated as a SERS active intracellular drug nanocarrier. In this study, cationic Raman reporter tagged gold nanoparticles (Au@4MBA@PAH) were anchored onto the surfaces of anionic liposomes via electrostatic interactions. Using SKBR3 cells as model cells, we revealed that the hybrid formulation can be effectively taken up by tumor cells and tracked by the SERS signals. Collectively, the liposome-Au nanohybrids hold great promise in biomedical applications.

  16. RGD-fatty alcohol-modified docetaxel liposomes improve tumor selectivity in vivo.

    PubMed

    Li, Yinghuan; Zheng, Xuelian; Sun, Yi; Ren, Zhao; Li, Xuemei; Cui, Guohui

    2014-07-01

    The tripeptide arginine-glycine-aspartate (RGD) was conjugated with various fatty alcohols to obtain RGDOCnH2n+1 (n=8, 10, 12, 14, 16, 18), which were incorporated into the bilayer of docetaxel liposomes to improve their tumor specificity. The fatty alcohols were accepted as linking groups to insert the tetrapeptide RGDX (X=amino acid) into the bilayer of liposomes. RGDX was previously shown to be a potent ligand to target tumor cell-surface integrin receptors, whereas RGD was not shown to have this ability. We hypothesized that RGD-fatty alcohol conjugates lacking the fourth amine X can guide liposomes to tumors without reducing their binding affinity to integrins. Antitumor activity, pharmacokinetics and biodistribution studies were evaluated in mice inoculated with S180 sarcoma. Compared with unmodified liposomes, RGD-fatty alcohol-modified liposomes successfully delivered significantly more docetaxel to tumors, which led to significant tumor weight loss and increased tumor docetaxel concentrations accompanied by reduced liver accumulation. Improved affinity of RGD-fatty alcohols to integrins was also confirmed on A375 cell model. Further comparisons among the tumor-targeting capacities of liposomes containing RGD-fatty alcohols, RGDF-fatty alcohols and RGDV-fatty acids demonstrated that RGD-fatty alcohols were as effective as the other two tetrapeptide derivatives. Therefore, a simplified tumor-targeting delivery system using RGD-fatty alcohols was developed.

  17. Effects of surface displayed targeting ligand GE11 on liposome distribution and extravasation in tumor.

    PubMed

    Tang, Hailing; Chen, Xiaojing; Rui, Mengjie; Sun, Wenqiang; Chen, Jian; Peng, Jinliang; Xu, Yuhong

    2014-10-06

    Targeting ligands displayed on liposome surface had been used to mediate specific interactions and drug delivery to target cells. However, they also affect liposome distribution in vivo, as well as the tissue extravasation processes after IV injection. In this study, we incorporated an EGFR targeting peptide GE11 on liposome surfaces in addition to PEG at different densities and evaluated their targeting properties and antitumor effects. We found that the densities of surface ligand and PEG were critical to target cell binding in vitro as well as pharmacokinetic profiles in vivo. The inclusion of GE11-PEG-DSPE and PEG-DSPE at 2% and 4% mol ratios in the liposome formulation mediated a rapid accumulation of liposomes within 1 h after IV injection in the tumor tissues surrounding neovascular structures. This is in addition to the EPR effect that was most prominently described for surface PEG modified liposomes. Therefore, despite the fact that the distribution of liposomes into interior tumor tissues was still limited by diffusion, GE11 targeted doxorubicin loaded liposomes showed significantly better antitumor activity in tumor bearing mice as a result of the fast active-targeting efficiency. We anticipate these understandings can benefit further optimization of targeted drug delivery systems for improving efficacy in vivo.

  18. Multiscale Kinetic Modeling of Liposomal Doxorubicin Delivery Quantifies the Role of Tumor and Drug-Specific Parameters in Local Delivery to Tumors

    PubMed Central

    Hendriks, B S; Reynolds, J G; Klinz, S G; Geretti, E; Lee, H; Leonard, S C; Gaddy, D F; Espelin, C W; Nielsen, U B; Wickham, T J

    2012-01-01

    Nanoparticle encapsulation has been used as a means to manipulate the pharmacokinetic (PK) and safety profile of drugs in oncology. Using pegylated liposomal doxorubicin (PLD) vs. conventional doxorubicin as a model system, we developed and experimentally validated a multiscale computational model of liposomal drug delivery. We demonstrated that, for varying tumor transport properties, there is a regimen where liposomal and conventional doxorubicin deliver identical amounts of doxorubicin to tumor cell nuclei. In mice, typical tumor properties consistently favor improved delivery via liposomes relative to free drug. However, in humans, we predict that some tumors will have properties wherein liposomal delivery delivers the identical amount of drug to its target relative to dosing with free drug. The ability to identify tumor types and/or individual patient tumors with high degree of liposome deposition may be critical for optimizing the success of nanoparticle and liposomal anticancer therapeutics. PMID:23835797

  19. Hepatic Tumor Metastases Cause Enhanced PEGylated Liposome Uptake by Kupffer Cells.

    PubMed

    Ukawa, Masami; Fujiwara, Yukako; Ando, Hidenori; Shimizu, Taro; Ishida, Tatsuhiro

    2016-01-01

    Kupffer cells in livers bearing tumor metastases were found to have promoted tumor invasion and exacerbated the metastasis. This implies that the function of Kupffer cells might differ between animals bearing hepatic metastases and those that are healthy. Kupffer cells are considered responsible for the accumulation of liposomes in the liver. In this study, we hypothesized that the alteration in the function of Kupffer cells by hepatic metastasis would also affect the biodistribution of liposomes following intravenous administration. The hepatic accumulation and the blood concentration of PEGylated liposomes were compared between healthy mice and tumor-bearing mice. We noted that hepatic accumulation and elimination from the blood were significantly accelerated in tumor-bearing mice, indicating that our hypothesis was correct. In the tumor-bearing mice, the proportion of Kupffer cells taking up liposomes was significantly increased. Intravenous injection of oxaliplatin (l-OHP) containing PEGylated liposomes decreased the fraction of Kupffer cells, but this administration caused no injury to the hepatocytes. These results suggest that PEGylated liposomes containing l-OHP may have the potential to treat metastatic hepatic cancer-not only via the direct killing of the cancer cells but also via a reduction in tumor-supportive Kupffer cells.

  20. Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region.

    PubMed

    Amin, Mohamadreza; Mansourian, Mercedeh; Koning, Gerben A; Badiee, Ali; Jaafari, Mahmoud Reza; ten Hagen, Timo L M

    2015-12-28

    Liposomes containing cytotoxic agents and targeted with Arg-Gly-Asp based peptides have frequently been used against αvβ3 integrin on tumor neovasculature. However, like many other ligand modified liposomes these preparations suffered from enhanced uptake by the reticulo endothelial system (RES) and off-targeted interaction with integrin receptors vastly expressed in normal organs causing poor biodistribution and toxic effects. Here we mainly focus on development of a RGD-modified liposomal delivery system to enhance both targeting selectivity and tumor uptake. First, sterically stabilized liposomal doxorubicin (SSLD) prepared and decorated with cRGDfK and RGDyC peptides differ in their physical properties. Stability assessments as well as in vitro and in vivo studies revealed that increasing the peptide hydrophobicity promotes the therapeutic efficacy of RGD-SSLD in a C-26 tumor model due to decreased recognition by RES and opsonization and limited off-targeted interactions. Then a novel N-methylated RGD peptide was designed and its capability in targeting integrin presenting cells was comprehensively assessed both in vitro and in vivo. RGDf[N-methyl]C promotes the liposome internalization by HUVEC via integrin mediated endocytosis. Intravital microscopy in window chamber bearing mice illustrated the capability of RGDf[N-methyl]C-liposomes in targeting both tumor vasculature and tumor cells in murine B16F0 and human BLM tumor models. Quantitative biodistribution in mice bearing B16F0 tumor revealed its high affinity to tumor with no considerable affinity to normal organs. Treatment by high dose of RGDf[N-methyl]C-SSLD was found more effective than non-targeted SSLD and no toxic side effect was observed. In conclusion, the RGDf[N-methyl]C-liposome was found promising in targeting tumor vasculature as well as other cells inside the tumor.

  1. Baicalin loaded in folate-PEG modified liposomes for enhanced stability and tumor targeting.

    PubMed

    Chen, Yiyin; Minh, Le Van; Liu, Jianwen; Angelov, Borislav; Drechsler, Markus; Garamus, Vasil M; Willumeit-Römer, Regine; Zou, Aihua

    2016-04-01

    Bioavailability of baicalin (BAI), an example of traditional Chinese medicine, has been modified by loading into liposome. Several liposome systems of different composition i.e., lipid/cholesterol (L), long-circulating stealth liposome (L-PEG) and folate receptor (FR)-targeted liposome (L-FA) have been used as the drug carrier for BAI. The obtained liposomes were around 80 nm in diameter with proper zeta potentials about -25 mV and sufficient physical stability in 3 months. The entrapment efficiency and loading efficiency of BAI in the liposomes were 41.0-46.4% and 8.8-10.0%, respectively. The morphology details of BAI lipsosome systems i.e., formation of small unilamellar vesicles, have been determined by cryogenic transmission electron microscopy (cryo-TEM) and small angle X-ray scattering (SAXS). In vitro cytotoxicity of BAI liposomes against HeLa cells was evaluated by MTT assay. BAI loaded FR-targeted liposomes showed higher cytotoxicity and cellular uptake compared with non-targeted liposomes. The results suggested that L-FA-BAI could enhance anti-tumor efficiency and should be an effective FR-targeted carrier system for BAI delivery.

  2. Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects.

    PubMed

    Maruyama, Kazuo

    2011-03-18

    The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200 nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.

  3. An evaluation of the anti-tumor efficacy of oleanolic acid-loaded PEGylated liposomes

    NASA Astrophysics Data System (ADS)

    Tang, Shengnan; Gao, Dawei; Zhao, Tingting; Zhou, Jing; Zhao, Xiaoning

    2013-06-01

    The effective delivery of oleanolic acid (OA) to the target site has several benefits in therapy for different pathologies. However, the delivery of OA is challenging due to its poor aqueous solubility. The study aims to evaluate the tumor inhibition effect of the PEGylated OA nanoliposome on the U14 cervical carcinoma cell line. In our previous study, OA was successfully encapsulated into PEGylated liposome with the modified ethanol injection method. Oral administration of PEGylated OA liposome was demonstrated to be more efficient in inhibiting xenograft tumors. The results of organ index indicated that PEG liposome exhibited higher anti-tumor activity and lower cytotoxicity. It was also found that OA and OA liposomes induced tumor cell apoptosis detected by flow cytometry. Furthermore, effects of OA on the morphology of tumor and other tissues were observed by hematoxylin and eosin staining. The histopathology sections did not show pathological changes in kidney or liver in tested mice. In contrast, there was a significant difference in tumor tissues between treatment groups and the negative control group. These observations imply that PEGylated liposomes seem to have advantages for cancer therapy in terms of effective delivery of OA.

  4. 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.

  5. Improvement of intratumor microdistribution of PEGylated liposome via tumor priming by metronomic S-1 dosing

    PubMed Central

    Doi, Yusuke; Abu Lila, Amr S; Matsumoto, Haruna; Okada, Tomoko; Shimizu, Taro; Ishida, Tatsuhiro

    2016-01-01

    The efficient delivery of nanocarrier-based cancer therapeutics into tumor tissue is problematic. Structural abnormalities, tumor vasculature heterogeneity, and elevated intratumor pressure impose barriers against the preferential accumulation of nanocarrier-based cancer therapeutics within tumor tissues and, consequently, compromise their therapeutic efficacy. Recently, we have reported that metronomic S-1, orally available tegafur formulation, dosing synergistically augmented the therapeutic efficacy of oxaliplatin (l-OHP)-containing PEGylated liposome without increasing the toxicity in animal model. However, the exact mechanism behind such synergistic effect was not fully elucidated. In this study, therefore, we tried to shed the light on the contributions of metronomic S-1 dosing to the enhanced accumulation and/or spatial distribution of PEGylated liposome within tumor tissue. Tumor priming with metronomic S-1 treatment induced a potent apoptotic response against both angiogenic endothelial cells and tumor cells adjacent to tumor blood vessels, resulting in enhanced tumor blood flow via transient normalization of tumor vasculature, along with alleviation of intratumor pressure. Such a change in the tumor microenvironment imparted by S-1 treatment allows efficient delivery of PEGylated liposome to tumor tissue and permits their deep penetration/distribution into the tumor mass. Such a priming effect of S-1 dosing can be exploited as a promising strategy to enhance the therapeutic efficacy of nanocarrier-based cancer therapeutics suffering from inadequate/heterogeneous delivery to tumor tissues. PMID:27822036

  6. Anti-tumor mechanism in IL-12 Gene therapy using liposomal bubbles and ultrasound

    NASA Astrophysics Data System (ADS)

    Suzuki, Ryo; Oda, Yusuke; Koshima, Risa; Hirata, Keiichi; Nomura, Tetsuya; Negishi, Yoichi; Utoguchi, Naoki; Nakagawa, Shinsaku; Maruyama, Kazuo

    2011-09-01

    Sonoporation combined with nano/microbubbles is an attractive technique for developing non-invasive and non-viral gene delivery systems. Previously, we developed novel ultrasound sensitive liposomes (Bubble liposomes) which contain the ultrasound imaging gas perfluoropropane. IL-12 corded plasmid DNA delivery into tumor tissue by sonoporation combined with Bubble liposomes was found to suppress tumor growth. In this study, we examined the mechanism of the anti-tumor effect in this IL-12 gene delivery. This therapeutic effect was T-cell dependent, requiring mainly CD8+ T lymphocytes in the effector phase, as confirmed by a mouse in vivo depletion assay. In addition, migration of CD8+ T cells was observed in the mice. These results suggest that CD8+ T lymphocytes play an important role in the anti-tumor effects of this IL-12 gene therapy.

  7. A diaCEST MRI approach for monitoring liposomal accumulation in tumors.

    PubMed

    Chan, Kannie W Y; Yu, Tao; Qiao, Yuan; Liu, Qiang; Yang, Ming; Patel, Himatkumar; Liu, Guanshu; Kinzler, Kenneth W; Vogelstein, Bert; Bulte, Jeff W M; van Zijl, Peter C M; Hanes, Justin; Zhou, Shibin; McMahon, Michael T

    2014-04-28

    Nanocarrier-based chemotherapy allows preferential delivery of therapeutics to tumors and has been found to improve the efficacy of cancer treatment. However, difficulties in tracking nanocarriers and evaluating their pharmacological fates in patients have limited judicious selection of patients to those who might most benefit from nanotherapeutics. To enable the monitoring of nanocarriers in vivo, we developed MRI-traceable diamagnetic Chemical Exchange Saturation Transfer (diaCEST) liposomes. The diaCEST liposomes were based on the clinical formulation of liposomal doxorubicin (i.e. DOXIL®) and were loaded with barbituric acid (BA), a small, organic, biocompatible diaCEST contrast agent. The optimized diaCEST liposomal formulation with a BA-to-lipid ratio of 25% exhibited 30% contrast enhancement at B1=4.7μT in vitro. The contrast was stable, with ~80% of the initial CEST signal sustained over 8h in vitro. We used the diaCEST liposomes to monitor the response to tumor necrosis factor-alpha (TNF-α), an agent in clinical trials that increases vascular permeability and uptake of nanocarriers into tumors. After systemic administration of diaCEST liposomes to mice bearing CT26 tumors, we found an average diaCEST contrast at the BA frequency (5ppm) of 0.4% at B1=4.7μT while if TNF-α was co-administered the contrast increased to 1.5%. This novel approach provides a non-radioactive, non-metallic, biocompatible, semi-quantitative, and clinically translatable approach to evaluate the tumor targeting of stealth liposomes in vivo, which may enable personalized nanomedicine.

  8. MRI-visible liposome nanovehicles for potential tumor-targeted delivery of multimodal therapies

    NASA Astrophysics Data System (ADS)

    Ren, Lili; Chen, Shizhen; Li, Haidong; Zhang, Zhiying; Ye, Chaohui; Liu, Maili; Zhou, Xin

    2015-07-01

    Real-time diagnosis and monitoring of disease development, and therapeutic responses to treatment, are possible by theranostic magnetic resonance imaging (MRI). Here we report the synthesis of a multifunctional liposome, which contains Gd-DOTA (an MRI probe), paclitaxel and c(RGDyk) (a targeted peptide). This nanoparticle overcame the insolubility of paclitaxel, reduced the side effects of FDA-approved formulation of PTX-Cre (Taxol®) and improved drug delivery efficiency to the tumor. c(RGDyk) modification greatly enhanced the cytotoxicity of the drug in tumor cells A549. The T1 relaxivity in tumor cells treated with the targeted liposome formulation was increased 16-fold when compared with the non-targeted group. In vivo, the tumors in mice were visualized using T1-weighted imaging after administration of the liposome. Also the tumor growth could be inhibited well after the treatment. Fluorescence images in vitro and ex vivo also showed the targeting effect of this liposome in tumor cells, indicating that this nanovehicle could limit the off-target side effects of anticancer drugs and contrast agents. These findings lay the foundation for further tumor inhibition study and application of this delivery vehicle in cancer therapy settings.

  9. Spatial and temporal mapping of heterogeneity in liposome uptake and microvascular distribution in an orthotopic tumor xenograft model.

    PubMed

    Ekdawi, Sandra N; Stewart, James M P; Dunne, Michael; Stapleton, Shawn; Mitsakakis, Nicholas; Dou, Yannan N; Jaffray, David A; Allen, Christine

    2015-06-10

    Existing paradigms in nano-based drug delivery are currently being challenged. Assessment of bulk tumor accumulation has been routinely considered an indicative measure of nanomedicine potency. However, it is now recognized that the intratumoral distribution of nanomedicines also impacts their therapeutic effect. At this time, our understanding of the relationship between the bulk (i.e., macro-) tumor accumulation of nanocarriers and their intratumoral (i.e., micro-) distribution remains limited. Liposome-based drug formulations, in particular, suffer from diminished efficacy in vivo as a result of transport-limiting properties, combined with the heterogeneous nature of the tumor microenvironment. In this report, we perform a quantitative image-based assessment of macro- and microdistribution of liposomes. Multi-scalar assessment of liposome distribution was enabled by a stable formulation which co-encapsulates an iodinated contrast agent and a near-infrared fluorescence probe, for computed tomography (CT) and optical microscopy, respectively. Spatio-temporal quantification of tumor uptake in orthotopic xenografts was performed using CT at the bulk tissue level, and within defined sub-volumes of the tumor (i.e., rim, periphery and core). Tumor penetration and relative distribution of liposomes were assessed by fluorescence microscopy of whole tumor sections. Microdistribution analysis of whole tumor images exposed a heterogeneous distribution of both liposomes and tumor vasculature. Highest levels of liposome uptake were achieved and maintained in the well-vascularized tumor rim over the study period, corresponding to a positive correlation between liposome and microvascular density. Tumor penetration of liposomes was found to be time-dependent in all regions of the tumor however independent of location in the tumor. Importantly, a multi-scalar comparison of liposome distribution reveals that macro-accumulation in tissues (e.g., blood, whole tumor) may not reflect

  10. Liposomes As Carriers Of Hydrophobic Photosensitizers In Vivo: Increased Selectivity Of Tumor Targeting

    NASA Astrophysics Data System (ADS)

    Ricchelli, Fernanda; Biolo, Roberta; Reddi, Elena; Tognon, Giuseppe; Jori, Giulio

    1988-02-01

    Unilamellar liposomes of dipalmitoyl-phosphatidylcholine (DPPC) incorporate a variety of hydrophobic photosensitizers (e.g. hematoporphyrin dimethylester, unsubstituted phthalo-cyanines, porphycene) into the phospholipid bilayer. The physico-chemical properties of the liposome-bound photosensitizers in the ground and electronically excited states can be characterized by steady-state and time-resolved fluorescence spectroscopy. The liposome-drug system is stable under physiological conditions and, once injected into tumor-bearing animals, selectively delivers the photosensitizer to serum lipoproteins. As a consequence, the tumor uptake of the drug via receptor-mediated endocytosis of low-density lipoproteins (LDL) is favoured. This leads to a larger ratio between the photosensitizer concentration in the tumor and adjacent normal tissues, hence to an increased efficacy of the photodynamic therapy (PDT).

  11. Galactosylated liposome as a dendritic cell-targeted mucosal vaccine for inducing protective anti-tumor immunity.

    PubMed

    Jiang, Ping-Lun; Lin, Hung-Jun; Wang, Hsiao-Wen; Tsai, Wen-Yu; Lin, Shen-Fu; Chien, Mei-Yin; Liang, Pi-Hui; Huang, Yi-You; Liu, Der-Zen

    2015-01-01

    Mucosal surfaces contain specialized dendritic cells (DCs) that are able to recognize foreign pathogens and mount protective immunity. We previously demonstrated that intranasal administration of targeted galactosylated liposomes can elicit mucosal and systemic antibody responses. In the present study, we assessed whether galactosylated liposomes could act as an effective DC-targeted mucosal vaccine that would be capable of inducing systemic anti-tumor immunity as well as antibody responses. We show that targeted galactosylated liposomes effectively facilitated antigen uptake by DCs beyond that mediated by unmodified liposomes both in vitro and in vivo. Targeted galactosylated liposomes induced higher levels of pro-inflammatory cytokines than unmodified liposomes in vitro. C57BL/6 mice thrice immunized intranasally with ovalbumin (OVA)-encapsulated galactosylated liposomes produced high levels of OVA-specific IgG antibodies in their serum. Spleen cells from mice receiving galactosylated liposomes were restimulated with OVA and showed significantly augmented levels of IFN-γ, IL-4, IL-5 and IL-6. In addition, intranasal administration of OVA-encapsulated beta-galactosylated liposomes resulted in complete protection against EG7 tumor challenge in C57BL/6 mice. Taken together, these results indicate that nasal administration of a galactosylated liposome vaccine mediates the development of an effective immunity against tumors and might be useful for further clinical anti-tumoral applications.

  12. Liposomes.

    PubMed

    Posner, Robert

    2002-09-01

    Robert Posner has 40 years of experience in skin care bench chemistry, product development, and sales and marketing. Working closely with dermatologists and plastic surgeons, Posner is a former member of the NY State Hospital Pharmacists Association, the American Pharmaceutical Association, and the American Association of Hospital Pharmacists. Currently, Posner sits on the Board of Directors of EMDA (Esthetic Manufacturers and Distributors Association). Posner has written numerous articles for Les Nouvelles Esthetiques Magazine, is presently a consultant for Day Spa Magazine, and had been one of only two non-dermatologists on a consultant basis with Cosmetic Dermatology Journal. Posner's company--ABBE Cosmetic Group International in Farmingdale, NY--formulates and manufactures skin care products for many well-known companies in the beauty industry. For many years, both the bench chemist and the dermatologist have been concerned with developing an ideal base for deliverance of 'actives' to the human epidermis. As is common knowledge, the skin is a protective organ which allows very few materials to penetrate. Some bases are unable to work effectively because of their relative inability to penetrate the stratum corneum; for example, some notable actives such as collagen and elastin are molecules too large to penetrate effectively. With the liposome at our command however, we can carry and then release an active into several layers of epidermis. We can release both oil- and water-soluble actives, and at the same time control the feel and effectiveness of a topical application. This article will examine the liposome: what it is, how it works, and how products made with liposomes can benefit dermatology.

  13. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.

    PubMed Central

    Gabizon, A; Papahadjopoulos, D

    1988-01-01

    The rapid clearance of circulating liposomes from the bloodstream, coupled with their high uptake by liver and spleen, has thus far been an obstacle to any attempts at targeting to tumors. We have assessed the impact of liposome composition on their clearance from the circulation in normal and tumor-bearing mice and on their uptake by tumors and various normal tissues. By selective changes in lipid composition, while maintaining a mean particle diameter of approximately equal to 100 nm, we have achieved up to a 60-fold increase in the fraction of recovered dose present in blood 24 hr after i.v. injection. Concomitantly, there was a decrease by a factor of 4 of the recovered dose localizing in the liver and spleen, the major organs of the reticuloendothelial system. Parallel experiments in tumor-bearing mice demonstrated a 25-fold increase of the liposome concentration in the tumor when formulations with long and short blood residence time were compared. The most favorable results were obtained with liposomes containing a small molar fraction of a negatively charged glycolipid, such as monosialoganglioside or phosphatidylinositol, and a solid-phase neutral phospholipid as the bulk component. The bio-distribution of such formulations is of considerable therapeutic potential in cancer for increasing the concentration of cytotoxic agents in tumors while minimizing the likelihood of toxicity to the reticuloendothelial system. PMID:3413128

  14. Liposomally formulated phospholipid-conjugated indocyanine green for intra-operative brain tumor detection and resection.

    PubMed

    Suganami, Akiko; Iwadate, Yasuo; Shibata, Sayaka; Yamashita, Masamichi; Tanaka, Tsutomu; Shinozaki, Natsuki; Aoki, Ichio; Saeki, Naokatsu; Shirasawa, Hiroshi; Okamoto, Yoshiharu; Tamura, Yutaka

    2015-12-30

    Some tumor-specific near-infrared (NIR) fluorescent dyes such as indocyanine green (ICG), IDRye800CW, and 5-aminolevulinic acid have been used clinically for detecting tumor margins or micro-cancer lesions. In this study, we evaluated the physicochemical properties of liposomally formulated phospholipid-conjugated ICG, denoted by LP-iDOPE, as a clinically translatable NIR imaging nanoparticle for brain tumors. We also confirmed its brain-tumor-specific biodistribution and its characteristics as the intra-operative NIR imaging nanoparticles for brain tumor surgery. These properties of LP-iDOPE may enable neurosurgeons to achieve more accurate identification and more complete resection of brain tumor.

  15. Improved drug delivery and therapeutic efficacy of PEgylated liposomal doxorubicin by targeting anti-HER2 peptide in murine breast tumor model.

    PubMed

    Zahmatkeshan, Masoumeh; Gheybi, Fatemeh; Rezayat, Seyed Mahdi; Jaafari, Mahmoud Reza

    2016-04-30

    Targeted cancer therapy is a powerful therapeutic strategy to management of cancer. HER2 as an anticancer target has long been studied. Its overexpression plays an important role in the pathogenesis and progressiveness of breast and other cancers. To establish efficient and reliable drug delivery to HER2-overexpressing cells, the authors of this study have developed anti-HER2 (ErbB2) peptide-liposomal formulations of doxorubicin (DOX) by an engineered breast tumor-targeting peptide ligand, AHNP, Anti-HER2/neu peptide, (FCDGFYACYADV) with three glycine amino acids as spacer before its original sequencing. Towards this goal, PEGylated liposome doxorubicin (PLD) bearing different ligand densities of AHNP was prepared and characterized for their size, zeta potential and peptide conjugation. The AHNP functionalization and density effects on breast tumor cell uptake, selective cytotoxicity, prevention of tumor growth and the tissue biodistribution of encapsulated DOX were studied in mice bearing TUBO breast cancer tumor model. The findings demonstrated that increasing the ligand density of AHNP increases cytotoxicity and cell-uptake in SKBR3 and TUBO cells which overexpress HER2 but not in MDA-MB-231with low HER2 expression profile. The anticancer activity was also superior for targeted liposomal DOX with more AHNP densities. Overall, the results showed that optimum AHNP density functionalization of PLD can significantly improve selectivity and the therapeutic index of liposomal DOX in the treatment of HER2 positive breast cancer and merits further investigation.

  16. Overcoming cellular and tissue barriers to improve liposomal drug delivery

    NASA Astrophysics Data System (ADS)

    Kohli, Aditya G.

    Forty years of liposome research have demonstrated that the anti-tumor efficacy of liposomal therapies is, in part, driven by three parameters: 1) liposome formulation and lipid biophysics, 2) accumulation and distribution in the tumor, and 3) release of the payload at the site of interest. This thesis outlines three studies that improve on each of these delivery steps. In the first study, we engineer a novel class of zwitterlipids with an inverted headgroup architecture that have remarkable biophysical properties and may be useful for drug delivery applications. After intravenous administration, liposomes accumulate in the tumor by the enhanced permeability and retention effect. However, the tumor stroma often limits liposome efficacy by preventing distribution into the tumor. In the second study, we demonstrate that depletion of hyaluronan in the tumor stroma improves the distribution and efficacy of DoxilRTM in murine 4T1 tumors. Once a liposome has distributed to the therapeutic site, it must release its payload over the correct timescale. Few facile methods exist to quantify the release of liposome therapeutics in vivo. In the third study, we outline and validate a simple, robust, and quantitative method for tracking the rate and extent of release of liposome contents in vivo. This tool should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals. This work highlights aspects of liposome behavior that have prevented successful clinical translation and proposes alternative approaches to improve liposome drug delivery.

  17. Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide

    PubMed Central

    Li, Chong; Wang, Yixin; Zhang, Xiaolin; Deng, Li; Zhang, Yan; Chen, Zhangbao

    2013-01-01

    Peptide ligands have played an important role in tumor-targeted drug delivery as targeting moieties. The in vivo fate of peptide-mediated drug delivery systems and the following antitumor effects may greatly depend on the stability of the peptide ligand. In the current study, a tumor-targeting cyclic peptide screened by phage display, Lyp-1 (a peptide that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors), was structurally modified by replacement of the original intramolecular disulfide bond with a diseleno bond. The produced analog Syp-1 (seleno derivative of Lyp-1) maintained specific binding ability to the target protein p32 (Kd = 18.54 nM), which is similar to that of Lyp-1 (Kd = 10.59 nM), indicated by surface plasmon resonance assay. Compared with Lyp-1, Syp-1 showed significantly improved stability against serum. After the peptide attached onto the surface of fluorophore-encapsulating liposomes, the more efficient tumor uptake of liposomal fluorophore mediated by Syp-1 was observed. Furthermore, Syp-1 modified liposomal doxorubicin presented the most potent tumor growth inhibitory ability among all the therapeutic groups, with a low half maximal inhibitory concentration of 588 nM against MDA-MB-435 cells in vitro and a high tumor inhibition rate of 73.5% in vivo. These findings clearly indicated that Syp-1 was a stable and effective tumor targeting ligand and suggest that the sulfur-to-selenium replacement strategy may help stabilize the phage-displayed cyclic peptide containing disulfide-bond under physiological conditions and strongly support the validity of peptide-mediated drug targeting. PMID:23515368

  18. Liposomal chemotherapeutics.

    PubMed

    Gentile, Emanuela; Cilurzo, Felisa; Di Marzio, Luisa; Carafa, Maria; Ventura, Cinzia Anna; Wolfram, Joy; Paolino, Donatella; Celia, Christian

    2013-12-01

    Currently, six liposomal chemotherapeutics have received clinical approval and many more are in clinical trials or undergoing preclinical evaluation. Liposomes exhibit low toxicity and improve the biopharmaceutical features and therapeutic index of drugs, thereby increasing efficacy and reducing side effects. In this review we discuss the advantages of using liposomes for the delivery of chemotherapeutics. Gemcitabine and paclitaxel have been chosen as examples to illustrate how the performance of a metabolically unstable or poorly water-soluble drug can be greatly improved by liposomal incorporation. We look at the beneficial effects of liposomes in a variety of solid and blood-borne tumors, including thyroid cancer, pancreatic cancer, breast cancer and multiple myeloma.

  19. Multi-functional liposomes showing radiofrequency-triggered release and magnetic resonance imaging for tumor multi-mechanism therapy

    NASA Astrophysics Data System (ADS)

    Du, Bin; Han, Shuping; Li, Hongyan; Zhao, Feifei; Su, Xiangjie; Cao, Xiaohui; Zhang, Zhenzhong

    2015-03-01

    Recently, nanoplatforms with multiple functions, such as tumor-targeting drug carriers, MRI, optical imaging, thermal therapy etc., have become popular in the field of cancer research. The present study reports a novel multi-functional liposome for cancer theranostics. A dual targeted drug delivery with radiofrequency-triggered drug release and imaging based on the magnetic field influence was used advantageously for tumor multi-mechanism therapy. In this system, the surface of fullerene (C60) was decorated with iron oxide nanoparticles, and PEGylation formed a hybrid nanosystem (C60-Fe3O4-PEG2000). Thermosensitive liposomes (dipalmitoylphosphatidylcholine, DPPC) with DSPE-PEG2000-folate wrapped up the hybrid nanosystem and docetaxel (DTX), which were designed to combine features of biological and physical (magnetic) drug targeting for fullerene radiofrequency-triggered drug release. The magnetic liposomes not only served as powerful tumor diagnostic magnetic resonance imaging (MRI) contrast agents, but also as powerful agents for photothermal ablation of tumors. Furthermore, a remarkable thermal therapy combined chemotherapy multi-functional liposome nanoplatform converted radiofrequency energy into thermal energy to release drugs from thermosensitive liposomes, which was also observed during both in vitro and in vivo treatment. The multi-functional liposomes also could selectively kill cancer cells in highly localized regions via their excellent active tumor targeting and magnetic targeted abilities.

  20. In vitro study of novel gadolinium-loaded liposomes guided by GBI-10 aptamer for promising tumor targeting and tumor diagnosis by magnetic resonance imaging.

    PubMed

    Gu, Meng-Jie; Li, Kun-Feng; Zhang, Lan-Xin; Wang, Huan; Liu, Li-Si; Zheng, Zhuo-Zhao; Han, Nan-Yin; Yang, Zhen-Jun; Fan, Tian-Yuan

    2015-01-01

    Novel gadolinium-loaded liposomes guided by GBI-10 aptamer were developed and evaluated in vitro to enhance magnetic resonance imaging (MRI) diagnosis of tumor. Nontargeted gadolinium-loaded liposomes were achieved by incorporating amphipathic material, Gd (III) [N,N-bis-stearylamidomethyl-N'-amidomethyl] diethylenetriamine tetraacetic acid, into the liposome membrane using lipid film hydration method. GBI-10, as the targeting ligand, was then conjugated onto the liposome surface to get GBI-10-targeted gadolinium-loaded liposomes (GTLs). Both nontargeted gadolinium-loaded liposomes and GTLs displayed good dispersion stability, optimal size, and zeta potential for tumor targeting, as well as favorable imaging properties with enhanced relaxivity compared with a commercial MRI contrast agent (CA), gadopentetate dimeglumine. The use of GBI-10 aptamer in this liposomal system was intended to result in increased accumulation of gadolinium at the periphery of C6 glioma cells, where the targeting extracellular matrix protein tenascin-C is overexpressed. Increased cellular binding of GTLs to C6 cells was confirmed by confocal microscopy, flow cytometry, and MRI, demonstrating the promise of this novel delivery system as a carrier of MRI contrast agent for the diagnosis of tumor. These studies provide a new strategy furthering the development of nanomedicine for both diagnosis and therapy of tumor.

  1. Boron-Containing Compounds for Liposome-Mediated Tumor Localization and Application to Neutron Capture Therapy

    SciTech Connect

    Hawthorne, M. Frederick

    2005-04-07

    Medical application of boron neutron capture therapy (BNCT) has been significantly hindered by the slow development of boron drug-targeting methodologies for the selective delivery of high boron concentration sto malignant cells. We have successfully sought to fill this need by creating liposomes suitable as in vivo boron delivery vehicles for BNCT. Delivery of therapeutic quantities of boron to tumors in murine models has been achieved with small unilamellar boron-rich liposomes. Subsequently, attempts have been made to improve delivery efficiency of liposomes encapsulating boron-containing water-soluble species into their hollow core by incorporating lipophilic boron compounds as addenda to the liposome bilayer, incorporating boron compounds as structural components of the bilayer (which however, poses the risk of sacrificing some stability), and combinations thereof. Regardless of the method, approximately 90% of the total liposome mass remains therapeutically inactive and comprised of the vehicle's construction materials, while less than 5% is boron for neutron targeting. Following this laboratory's intensive study, the observed tumor specificity of certain liposomes has been attributed to their diminutive size of these liposomes (30-150 nm), which enables these small vesicles to pass through the porous, immature vasculature of rapidly growing tumor tissue. We surmised that any amphiphilic nanoparticle of suitable size could possess some tumor selectivity. Consequently, the discovery of a very boron-rich nanoparticle delivery agent with biodistribution performance similar to unilamellar liposomes became one of our goals. Closomers, a new class of polyhedral borane derivatives, attracted us as an alternative BNCT drug-delivery system. We specifically envisioned dodeca (nido-carboranyl)-substituted closomers as possibly having a great potential role in BNCT drug delivery. They could function as extraordinarily boron-rich BNCT drugs since they are amphiphilic

  2. Different Efficiency of Liposomal Forms with Hydrophilic and Hydrophobic Antitumor Agents in Relation to Solid Transplants of Mouse Tumor and Its Metastases in the Liver.

    PubMed

    Popova, N A; Kaledin, V I; Nikolin, V P; Bogdanova, L A; Morozkova, T S; Tornuev, Yu V

    2016-10-01

    Experiments were performed on the model of transplanted mouse tumor with high incidence of liver metastases. Hydrophilic drug cycloplatam (injected intravenously in liposomes) was more potent than "free cycloplatam" (injected intravenously or intraperitoneally in physiological saline) in inhibiting the growth of natural and experimental metastases in the liver. By contrast, liposomal cycloplatam had lower efficiency than free cycloplatam in suppressing the growth of solid tumor. Liposomal and free cortifen (hydrophobic hormonal cytostatic) produced nearly the same effects on solid tumor growth. Our results suggest that liposomal forms of hydrophobic compounds producing nonselective effect on tumor cells (e.g., actinomycin D or Cosmegen), should not have advantages over free forms.

  3. Improvement in the drug delivery and anti-tumor efficacy of PEGylated liposomal doxorubicin by targeting RNA aptamers in mice bearing breast tumor model.

    PubMed

    Moosavian, Seyedeh Alia; Abnous, Khalil; Badiee, Ali; Jaafari, Mahmoud Reza

    2016-03-01

    Targeted delivery by ligands such as aptamers, is a promising method to increase the efficiency of PEGylated-liposomal doxorubicin (PL-Dox). In this study, we have successfully conjugated our recently developed anti-breast cancer RNA aptamer (TSA14) to the surface of PL-Dox and characterized for their size, zeta potential, Dox percent encapsulation and release properties in the presence of fetal bovine serum. In vitro experiments showed that aptamer could improve cellular uptake and cytotoxicity of PL-Dox in TUBO breast cell line. In mice bearing TUBO breast tumor, although, the doxorubicin plasma level of liposomal doxorubicin did not significantly change after modification of nanoparticles with aptamer, however, much higher tumor accumulation of Dox as compared with non-targeted liposomes proved the tumor-targeting capability of aptamers. In the same way, aptamer-PL-Dox improved anti-tumor efficiency of liposomes in TUBO breast tumor in mice compared to non-targeted liposomes. Overall, the results showed that aptamer decoration of PL-Dox could significantly improve selectivity and the therapeutic efficacy of liposomal DOX and merits further investigation.

  4. Combination radiofrequency (RF) ablation and IV liposomal heat shock protein suppression: Reduced tumor growth and increased animal endpoint survival in a small animal tumor model

    PubMed Central

    Yang, Wei; Ahmed, Muneeb; Tasawwar, Beenish; Levchenko, Tatynana; Sawant, Rupa R.; Torchilin, Vladimir; Goldberg, S. Nahum

    2012-01-01

    Background To investigate the effect of IV liposomal quercetin (a known down-regulator of heat shock proteins) alone and with liposomal doxorubicin on tumor growth and end-point survival when combined with radiofrequency (RF) tumor ablation in a rat tumor model. Methods Solitary subcutaneous R3230 mammary adenocarcinoma tumors (1.3–1.5 cm) were implanted in 48 female Fischer rats. Initially, 32 tumors (n=8, each group) were randomized into four experimental groups: (a) conventional monopolar RF alone (70°C for 5 min), (b) IV liposomal quercetin alone (1 mg/kg), (c) IV liposomal quercetin followed 24hr later with RF, and (d) no treatment. Next, 16 additional tumors were randomized into two groups (n=8, each) that received a combined RF and liposomal doxorubicin (15 min post-RF, 8 mg/kg) either with or without liposomal quercetin. Kaplan-Meier survival analysis was performed using a tumor diameter of 3.0 cm as the defined survival endpoint. Results Differences in endpoint survival and tumor doubling time among the groups were highly significant (P<0.001). Endpoint survivals were 12.5±2.2 days for the control group, 16.6±2.9 days for tumors treated with RF alone, 15.5±2.1days for tumors treated with liposomal quercetin alone, and 22.0±3.9 days with combined RF and quercetin. Additionally, combination quercetin/RF/doxorubicin therapy resulted in the longest survival (48.3±20.4 days), followed by RF/doxorubicin (29.9±3.8 days). Conclusions IV liposomal quercetin in combination with RF ablation reduces tumor growth rates and improves animal endpoint survival. Further increases in endpoint survival can be seen by adding an additional anti-tumor adjuvant agent liposomal doxorubicin. This suggests that targeting several post-ablation processes with multi-drug nanotherapies can increase overall ablation efficacy. PMID:22230341

  5. Optimizing tumor targeting of the lipophilic EGFR-binding radiotracer SKI 243 using a liposomal nanoparticle delivery system.

    PubMed

    Medina, Oula Penate; Pillarsetty, Nagavarakishore; Glekas, Athanasios; Punzalan, Blesida; Longo, Valerie; Gönen, Mithat; Zanzonico, Pat; Smith-Jones, Peter; Larson, Steven M

    2011-02-10

    Positron emission tomography (PET) of epidermal growth factor receptor (EGFR) kinase-specific radiolabeled tracers could provide a means for non-invasively characterizing EGFR expression and signaling activity in patients' tumors before, during, and after therapy with EGFR inhibitors. Towards this goal, our group has developed PET tracers which irreversibly bind to EGFR. However, tumor uptake is relatively low because of both the lipophilicity of such tracers (e.g. the morpholino-[124I]-IPQA [SKI 212243]), with octanol-to-water partition coefficients of up to 4, and a short dwell time in the blood and significant hepatobiliary clearance and intestinal reuptake. Liposomal nanoparticle delivery systems may favorably alter the pharmacokinetic profile and improve tumor targeting of highly lipophilic but otherwise promising cancer imaging tracers, such as the EGFR inhibitor SKI 243. SKI 243 is therefore an interesting model molecule for incorporation into lipid-based nanoparticles, as it would not only improve their solubility but also increase the circulation time, availability and, potentially, targeting of tumors. In the current study, we compared the pharmacokinetics and tumor targeting of the bare EGFR kinase-targeting radiotracer SKI 212243 (SKI 243) with that of the same tracer embedded in liposomes. SKI 243 and liposomal SKI 243 are both taken up by tumor xenografts but liposomal SKI 243 remained in the blood longer and consequently exhibited a 3- to 6-fold increase in uptake in the tumor among several other organs.

  6. Vincristine-sulphate-loaded liposome-templated calcium phosphate nanoshell as potential tumor-targeting delivery system.

    PubMed

    Thakkar, Hetal Paresh; Baser, Amit Kumar; Parmar, Mayur Prakashbhai; Patel, Ketul Harshadbhai; Ramachandra Murthy, Rayasa

    2012-06-01

    Vincristine-sulfate-loaded liposomes were prepared with an aim to improve stability, reduce drug leakage during systemic circulation, and increase intracellular uptake. Liposomes were prepared by the thin-film hydration method, followed by coating with calcium phosphate, using the sequential addition approach. Prepared formulations were characterized for size, zeta potential, drug-entrapment efficiency, morphology by transmission electron microscopy (TEM), in vitro drug-release profile, and in vitro cell cytotoxicity study. Effect of formulation variables, such as drug:lipid ratio as well as nature and volume of hydration media, were found to affect drug entrapment, and the concentration of calcium chloride in coating was found to affect size and coating efficiency. Size, zeta potential, and TEM images confirmed that the liposomes were effectively coated with calcium phosphate. The calcium phosphate nanoshell exhibited pH-dependent drug release, showing significantly lower release at pH 7.4, compared to the release at pH 4.5, which is the pH of the tumor interstitium. The in vitro cytotoxicity study done on the lung cancer cell line indicated that coated liposomes are more cytotoxic than plain liposomes and drug solution, indicating their potential for intracellular drug delivery. The cell-uptake study done on the lung cancer cell line indicated that calcium-phosphate-coated liposomes show higher cell uptake than uncoated liposomes.

  7. 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.

  8. Lipophilic prodrugs of a triazole-containing colchicine analogue in liposomes: biological effects on human tumor cells.

    PubMed

    Kuznetsova, N R; Svirshchevskaya, E V; Sitnikov, N S; Abodo, L; Sutorius, H; Zapke, J; Velder, J; Thomopoulou, P; Oschkinat, H; Prokop, A; Schmalz, H G; Fedorov, A Yu; Vodovozova, E L

    2013-01-01

    Colchicine site binders--blockers of tubulin polymerization--are potential antimitotic agents for anticancer therapy. To reduce their systemic toxicity and improve biodistribution, encapsulation in nanosized liposomes may be employed. Liposomes present a convenient means for preparation of injectable formulations of hydrophobic compounds, however colchicine as such is known to leak through the lipid bilayer. In this study, newly synthesized triazole-containing analogues of colchicine and allocolchicine, and their palmitic and oleic esters (lipophilic prodrugs) were tested for anti-proliferative activity and apoptosis-inducing potential. In contrast to colchicine conjugates, whose activities ranged with those of colchicine, allocolchicine derivatives exhibited drastically lower effects and were discarded. Liposomes of about 100 nm in diameter composed of egg phosphatidylcholine--yeast phosphatidylinositol--palmitic or oleic prodrug, 8 : 1: 1, by mol, were prepared by standard extrusion technique and tested in a panel of four human tumor cell lines. Liposome formulations preserved the biological activities of the parent colchicinoid the most towards human epithelial tumor cells. Moreover, liposomal form of the oleoyl bearing colchicinoid inhibited cell proliferation more efficiently than free lipophilic prodrug. Due to substantial loading capacity of the liposomes, the dispersions contain sufficient concentration of the active agent to test wide dose range in experiments on systemic administration to animals.

  9. Improved in vitro anti-tumoral activity, intracellular uptake and apoptotic induction of gemcitabine-loaded pegylated unilamellar liposomes.

    PubMed

    Celia, Christian; Calvagno, Maria Grazia; Paolino, Donatella; Bulotta, Stefania; Ventura, Cinzia Anna; Russo, Diego; Fresta, Massimo

    2008-04-01

    Anaplastic thyroid carcinoma is one of the most aggressive and lethal solid carcinomas affecting humans. A major limit of the chemotherapeutic agents is represented by their low therapeutic index. In this work, we investigated the possibility of improving the anti-tumoral activity of gemcitabine by using pegylated unilamellar liposomes. Liposomes were made up of 1,2-dipalmitoyl-sn-glycero-3-phospocholine monohydrate/cholesterol/N-(carbonyl-methoxypolyethylene glycol-2000)-1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (6:3:1 molar ratio) and they were prepared with a pH gradient to improve the gemcitabine loading capacity. The anti-tumoral efficacy of the liposomal formulation was tested in vitro on human anaplastic thyroid carcinoma cells (ARO) in culture, comparing the effects with those of the free drug. Gemcitabine-loaded unilamellar liposomes had a mean size approximately 200 nm with a zeta potential approximately -2 mV. The liposomal carrier noticeably improved the anti-tumoral activity of gemcitabine against ARO cells in terms of both dose-dependent cytotoxic effect and of drug exposition effect. Namely, gemcitabine-loaded liposomes showed a cytotoxic effect (58.2% increase of cell mortality at 1 microM with respect to free drug) after 12 h incubation, while the free drug showed a significant activity only after 72 h incubation. Moreover, a significant effect on the cell mortality appeared at 0.1 microM and 100% mortality was detected at a concentration of 1 microM of gemcitabine-loaded liposomes, while the free drug elicited the same effect at a concentration of 100 microM. The improved anti-tumoral activity of gemcitabine determined by the liposomal carrier was due to a greater intracellular uptake. The intracellular gemcitabine levels as a function of time showed a sinusoidal profile with peaks after 2 h, 6 h and 11 h, related to the cellular cycle of ARO. PARP cleavage and DNA fragmentation analysis provided clear evidence of the apoptosis induction in

  10. Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improves outcomes in a rat glioma model

    PubMed Central

    Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi; Park, Juyoung; McDannold, Nathan

    2013-01-01

    The blood-brain-barrier (BBB) prevents the transport of most anticancer agents to the central nervous system and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels, along with several other factors, creates additional barriers for drug treatment for brain tumors. Focused ultrasound (FUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and the “blood-tumor barrier”. Here, we tested the impact of three weekly sessions of FUS and liposomal doxorubicin (DOX) in 9L rat glioma tumors. Animals that received FUS + DOX (N = 8) had a median survival time that was increased significantly (P < 0.001) compared to animals who received DOX only (N = 6), FUS only (N = 8), or no treatment (N = 7). Median survival for animals that received FUS + DOX was increased by 100% relative to untreated controls, whereas animals who received DOX alone had only a 16% improvement. Animals who received only FUS showed no improvement. No tumor cells were found in histology in 4/8 animals in the FUS + DOX group, and in two animals, only a few tumor cells were detected. Adverse events in the treatment group included skin toxicity, impaired activity, damage to surrounding brain tissue, and tissue loss at the tumor site. In one animal, intratumoral hemorrhage was observed. These events are largely consistent with known side effects of doxorubicin and with an extensive tumor burden. Overall this work demonstrates that multiple sessions using this FUS technique to enhance the delivery of liposomal doxorubicin has a pronounced therapeutic effect in this rat glioma model. PMID:23603615

  11. Concurrent intrathecal methotrexate and liposomal cytarabine for leptomeningeal metastasis from solid tumors: a retrospective cohort study.

    PubMed

    Scott, Brian J; van Vugt, Vincent A; Rush, Toni; Brown, Tiffany; Chen, Clark C; Carter, Bob S; Schwab, Richard; Fanta, Paul; Helsten, Teresa; Bazhenova, Lyudmila; Parker, Barbara; Pingle, Sandeep; Saria, Marlon G; Brown, Bradley D; Piccioni, David E; Kesari, Santosh

    2014-09-01

    Leptomeningeal metastasis (LM) from solid tumors is typically a late manifestation of systemic cancer with limited survival. Randomized trials comparing single agent intrathecal methotrexate to liposomal cytarabine have shown similar efficacy and tolerability. We hypothesized that combination intrathecal chemotherapy would be a safe and tolerable option in solid tumor LM. We conducted a retrospective cohort study of combination IT chemotherapy in solid tumor LM at a single institution between April 2010 and July 2012. In addition to therapies directed at active systemic disease, each subject received IT liposomal cytarabine plus IT methotrexate with dexamethasone premedication. Patient characteristics, survival outcomes and toxicities were determined by systematic chart review. Thirty subjects were treated during the study period. The most common cancer types were breast 15 (50 %), glioblastoma 6 (20 %), and lung 5 (17 %). Cytologic clearance was achieved in 6 (33 %). Median non-glioblastoma overall survival was 30.2 weeks (n = 18; range 3.9-73.4), and did not differ significantly by tumor type. Median time to neurologic progression was 7 weeks (n = 8; range 0.9-57), with 10 subjects (56 %) experiencing death from systemic disease without progression of LM. Age less than 60 was associated with longer overall survival (p = 0.01). Six (21 %) experienced grade III toxicities during treatment, most commonly meningitis 2 (7 %). Combination IT chemotherapy was feasible in this small retrospective cohort. Prospective evaluation is necessary to determine tolerability, the impact on quality of life and neurocognitive outcomes or any survival benefit when compared to single agent IT chemotherapy.

  12. Thermosensitive liposomes for the delivery of gemcitabine and oxaliplatin to tumors.

    PubMed

    May, Jonathan P; Ernsting, Mark J; Undzys, Elijus; Li, Shyh-Dar

    2013-12-02

    The majority of ultrafast temperature sensitive liposome (uTSL) formulations reported in the literature deliver the highly membrane permeable drug, doxorubicin (DOX). Here we report on the study of the uTSL formulation, HaT (Heat activated cytoToxic, composed of the phospholipid DPPC and the surfactant Brij78) loaded with the water-soluble, but poorly membrane permeable anticancer drugs, gemcitabine (GEM) and oxaliplatin (OXA). The HaT formulation displayed ultrafast release of these drugs in response to temperature, whereas attempts with LTSL (Lyso-lipid Temperature Sensitive Liposome, composed of DPPC, MSPC, and DSPE-PEG) were unsuccessful. HaT-GEM and HaT-OXA both released >80% of the encapsulated drug within 2 min at 40-42 °C, with <5% drug leakage at 37 °C after 30 min in serum. The pharmacokinetic profile of both drugs was improved by formulating with HaT relative to the free drug, with clearance reduced by 50-fold for GEM and 3-fold for OXA. HaT-GEM and HaT-OXA both displayed improved drug uptake in the heated tumor relative to the unheated tumor (by 9-fold and 3-fold, respectively). In particular, HaT-GEM showed 25-fold improved delivery to the heated tumor relative to free GEM and significantly enhanced antitumor efficacy with complete tumor regression after a single dose of HaT-GEM. These data suggest that uTSL technology can also be used to deliver nonmembrane permeable drugs via an intravascular ultrafast release mechanism to great effect.

  13. [Anionic long circulation liposomes mediated antisense scintigraphy in tumor-bearing rats].

    PubMed

    Ma, Chao; Kuang, Anren; Huang, Rui; Tang, Gongshun

    2011-04-01

    This paper was aimed to investigate the biodistribution and ability of free 131-bcl-2/bcl-xl ASON (FA) and anionic long circulation liposomes encapsulated with 131I-bcl-2/bcl-xlASON (NA), in tumor-bearing rats, to image breast cancer. We investigated the tissue distribution of NA in virgin female Sprague-Dawley (SD) rats with n-methyl nitrosourea (MNU)-induced breast cancers in situ. The percentage of the injected dose per gram (%ID/g) was calculated, with the maximum ratios of tumor to blood and tumor to muscle, after injections of NA and FA for 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 12 h and 24 h, respectively. The ability of NA to image breast cancer in tumor-bearing rats was determined using emission computed tomography (ECT). Seventy percent (90/130) SD rats in the study developed mammary tumors after MNU injection with the average latency (NA) (96 +/- 1.2)days. The %ID/g of NA in breast cancer tissue, tumor bearing rats in liver and spleen tumor tissues after 10 hours were (6.23 +/- 0.23) %ID/g, (12.00 +/- 0.26) %ID/g and (18.25 +/- 1.33)% ID/g, respectively. The ratios of tumor to blood 6.29 +/- 0.76 and tumor to muscle 10.55 +/- 0.68 in tumor bearing rats slowly maximized at 10 h post injection of NA, most probably due to the enhanced permeability and retention effect. Hence in radionuclide antisense scintigraphy, the breast cancer in rat was clearly displayed at 10h after iv administration of NA-D. However, tumors were not visualized in rats with the iv injection of NS and NN even at the delayed time. Due to the inhibition of rapid uptake of NA by the reticulo-endothelial system, NA displays valuable pharmacologic properties characterized by the enhanced accumulation in tumor.

  14. Dual-functionalized liposomal delivery system for solid tumors based on RGD and a pH-responsive antimicrobial peptide

    PubMed Central

    Zhang, Qianyu; Lu, Libao; Zhang, Li; Shi, Kairong; Cun, Xingli; Yang, Yuting; Liu, Yayuan; Gao, Huile; He, Qin

    2016-01-01

    [D]-H6L9, as a pH-responsive anti-microbial peptide (AMP), has been evidenced by us to be an excellent choice in tumor microenvironment-responsive delivery as it could render liposomes responsive to the acidified tumor microenvironment. However, [D]-H6L9-modified liposomes could not actively target to tumor area. Therefore, integrin αvβ3-targeted peptide RGD was co-modified with [D]-H6L9 onto liposomes [(R + D)-Lip] for improved tumor delivery efficiency. Under pH 6.3, (R + D)-Lip could be taken up by C26 cells and C26 tumor spheroids (integrin αvβ3-positive) with significantly improved efficiency compared with other groups, which was contributed by both RGD and [D]-H6L9, while RGD did not increase the cellular uptake performance on MCF-7 cells (integrin αvβ3-negative). Results showed that RGD could decrease cellular uptake of (R + D)-Lip while [D]-H6L9 could increase it, implying the role of both RGD and [D]-H6L9 in cellular internalization of (R + D)-Lip. On the other hand, (R + D)-Lip could escape the entrapment of lysosomes. PTX-loaded (R + D)-Lip could further increase the cellular toxicity against C26 cells compared with liposomes modified only with RGD and [D]-H6L9 respectively, and achieve remarkable tumor inhibition effect on C26 tumor models. PMID:26842655

  15. Adjuvant Cationic Liposomes Presenting MPL and IL-12 Induce Cell Death, Suppress Tumor Growth, and Alter the Cellular Phenotype of Tumors in a Murine Model of Breast Cancer

    PubMed Central

    2015-01-01

    Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80+ macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response. PMID:25179345

  16. Characterization of 9-nitrocamptothecin-in-cyclodextrin-in-liposomes modified with transferrin for the treating of tumor.

    PubMed

    Chen, Jun; Lu, Shanshan; Gu, Wei; Peng, Pei; Dong, Jie; Xu, Fei; Yang, Xueqin; Xiong, Zheyun; Yang, Xixiong

    2015-07-25

    Encapsulation of hydrophobic drugs in the form of drug-cyclodextrin (CD) complex in liposomes has been applied as a novel strategy to combine the relative advantages of CDs and liposomes into one system, naming drug-in-CD-in-liposome (DCL). In the present study, soluble 9-NC/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complexes were prepared using the freeze-drying technique. Then 9-NC inclusion complexes were further encapsulated into liposomes by ethanol injection method and transferrin (Tf) was conjugated to the surface of 9-NC DCL to obtain Tf modified 9-NC DCL (Tf-9-NC-CL). Compared to PEGylated 9-NC DCL (P-9-NC-CL), the lactone stability and vesicle stability of Tf-9-NC-CL were significantly increased. Both 9-NC and HP-β-CD were found to release from the DCL and Tf modification resulted in reduced release of them. The enhanced targeting efficiency of the Tf-modified liposomes was demonstrated by flow cytometry and confocal microscopy. In vivo pharmacokinetics in rats showed improved lactone stability of 9-NC following intravenous injection of Tf-9-NC-CL. The cytotoxicity of Tf-9-NC-CL against tumor cells and normal cells was investigated in vitro and the antitumor efficacy was evaluated in S180 tumor-bearing mice in vivo. Compared with free 9-NC, 9-NC inclusion complexes and P-9-NC-CL, Tf-9-NC-CL demonstrated the strongest cytotoxicity to tumor cells. And the inhibitory rate of tumor (IRT) values were determined to be 43.08%, 56.92%, 67.69% and 80.00% for 9-NC solution, inclusion complexes, P-9-NC-CL and Tf-9-NC-CL, respectively. In conclusion, Tf modification can be useful in increasing vesicle stability, targeting drug delivery efficiency and antitumor efficacy of DCL containing hydrophobic antitumor drugs, such as 9-NC.

  17. LyP-1-conjugated doxorubicin-loaded liposomes suppress lymphatic metastasis by inhibiting lymph node metastases and destroying tumor lymphatics

    NASA Astrophysics Data System (ADS)

    Yan, Zhiqiang; Zhan, Changyou; Wen, Ziyi; Feng, Linglin; Wang, Fei; Liu, Yu; Yang, Xiangkun; Dong, Qing; Liu, Min; Lu, Weiyue

    2011-10-01

    Lymphatic metastasis can be greatly promoted by metastases growth and lymphangiogenesis in lymph nodes (LNs). LyP-1, a cyclic peptide, is able to specifically bind with tumor cells and tumor lymphatics in metastatic LNs. This work aimed to use LyP-1-conjugated liposomes (L-LS) loaded with doxorubicin (DOX) (L-LS/DOX) to suppress lymphatic metastasis by inhibiting both metastases and tumor lymphatics in LNs. L-LS were prepared and exhibited sizes around 90 nm and spherical morphology as characterized by transmission electron microscopy. The in vitro cellular studies showed that LyP-1 modification obviously increased liposome uptake by MDA-MB-435 tumor cells and enhanced the cytotoxicity of liposomal DOX. A popliteal and iliac LN metastases model was successfully established by subcutaneous inoculation of tumor cells to nude mice. The immunofluorescence staining analysis indicated that LyP-1 modification enabled specific binding of liposome with tumor lymphatics and enhanced the destroying effect of liposomal DOX on tumor lymphatics. The in vivo fluorescence imaging and pharmacodynamic studies showed that LyP-1 modification increased liposome uptake by metastatic LNs and that L-LS/DOX significantly decreased metastatic LN growth and LN metastasis rate. These results suggested that L-LS/DOX were an effective delivery system for suppressing lymphatic metastasis by simultaneously inhibiting LN metastases and tumor lymphatics.

  18. Photo activation of HPPH encapsulated in “Pocket” liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts

    PubMed Central

    Sine, Jessica; Urban, Cordula; Thayer, Derek; Charron, Heather; Valim, Niksa; Tata, Darrell B; Schiff, Rachel; Blumenthal, Robert; Joshi, Amit; Puri, Anu

    2015-01-01

    We recently reported laser-triggered release of photosensitive compounds from liposomes containing dipalmitoylphosphatidylcholine (DPPC) and 1,2 bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8,9PC). We hypothesized that the permeation of photoactivated compounds occurs through domains of enhanced fluidity in the liposome membrane and have thus called them “Pocket” liposomes. In this study we have encapsulated the red light activatable anticancer photodynamic therapy drug 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) (Ex/Em410/670 nm) together with calcein (Ex/Em490/517 nm) as a marker for drug release in Pocket liposomes. A mole ratio of 7.6:1 lipid:HPPH was found to be optimal, with >80% of HPPH being included in the liposomes. Exposure of liposomes with a cw-diode 660 nm laser (90 mW, 0–5 minutes) resulted in calcein release only when HPPH was included in the liposomes. Further analysis of the quenching ratios of liposome-entrapped calcein in the laser treated samples indicated that the laser-triggered release occurred via the graded mechanism. In vitro studies with MDA-MB-231-LM2 breast cancer cell line showed significant cell killing upon treatment of cell-liposome suspensions with the laser. To assess in vivo efficacy, we implanted MDA-MB-231-LM2 cells containing the luciferase gene along the mammary fat pads on the ribcage of mice. For biodistribution experiments, trace amounts of a near infrared lipid probe DiR (Ex/Em745/840 nm) were included in the liposomes. Liposomes were injected intravenously and laser treatments (90 mW, 0.9 cm diameter, for an exposure duration ranging from 5–8 minutes) were done 4 hours postinjection (only one tumor per mouse was treated, keeping the second flank tumor as control). Calcein release occurred as indicated by an increase in calcein fluorescence from laser treated tumors only. The animals were observed for up to 15 days postinjection and tumor volume and luciferase expression was measured. A

  19. New generation of liposomal drugs for cancer.

    PubMed

    Minko, Tamara; Pakunlu, Refika I; Wang, Yang; Khandare, Jayant J; Saad, Maha

    2006-11-01

    This review is focused on liposomes as a delivery system for anticancer agents and more specifically on the advantages of using liposomes as drug nanocarrier in cancer chemotherapy. The main advantages of liposomal drugs over the non-encapsulated drugs include: (1) improved pharmacokinetics and drug release, (2) enhanced intracellular penetration, (3) tumor targeting and preventing adverse side effects and (4) ability to include several active ingredients in one complex liposomal drug delivery system (DDS). The review also includes our recent data on advanced liposomal anticancer drug delivery systems. As a conclusion we propose a novel liposomal DDS which includes inhibitors of pump resistance combined in one liposomal drug delivery system with an inhibitor of antiapoptotic cellular defense, an apoptosis inducer (a traditional anticancer drug) and a targeting moiety. The proposed drug delivery system utilizes a novel three tier approach, simultaneously targeting three molecular targets: (1) extracellular receptors or antigen expressed on the surface of plasma membrane of cancer cells in order to direct the whole system specifically to the tumor, preventing adverse side effects on healthy tissues; (2) drug efflux pumps in order to inhibit them and enhance drug retention by cancer cells, increasing intracellular drug accumulation and thereby limiting the need for prescribed high drug doses that cause adverse drug side effects; and (3) intracellular controlling mechanisms of apoptosis in order to suppress cellular antiapoptotic defense.

  20. Prevention of peroxidation of cardiolipin liposomes by quinol-based antioxidants.

    PubMed

    Lokhmatikov, A V; Voskoboynikova, N E; Cherepanov, D A; Sumbatyan, N V; Korshunova, G A; Skulachev, M V; Steinhoff, H-J; Skulachev, V P; Mulkidjanian, A Y

    2014-10-01

    In mammalian mitochondria, cardiolipin molecules are the primary targets of oxidation by reactive oxygen species. The interaction of oxidized cardiolipin molecules with the constituents of the apoptotic cascade may lead to cell death. In the present study, we compared the effects of quinol-containing synthetic and natural amphiphilic antioxidants on cardiolipin peroxidation in a model system (liposomes of bovine cardiolipin). We found that both natural ubiquinol and synthetic antioxidants, even being introduced in micro- and submicromolar concentrations, fully protected the liposomal cardiolipin from peroxidation. The duration of their action, however, varied; it increased with the presence of either methoxy groups of ubiquinol or additional reduced redox groups (in the cases of rhodamine and berberine derivates). The concentration of ubiquinol in the mitochondrial membrane substantially exceeds the concentrations of antioxidants we used and would seem to fully prevent peroxidation of membrane cardiolipin. In fact, this does not happen: cardiolipin in mitochondria is oxidized, and this process can be blocked by amphiphilic cationic antioxidants (Y. N. Antonenko et al. (2008) Biochemistry (Moscow), 73, 1273-1287). We suppose that a fraction of mitochondrial cardiolipin could not be protected by natural ubiquinol; in vivo, peroxidation most likely threatens those cardiolipin molecules that, being bound within complexes of membrane proteins, are inaccessible to the bulky hydrophobic ubiquinol molecules diffusing in the lipid bilayer of the inner mitochondrial membrane. The ability to protect these occluded cardiolipin molecules from peroxidation may explain the beneficial therapeutic action of cationic antioxidants, which accumulate electrophoretically within mitochondria under the action of membrane potential.

  1. Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts

    PubMed Central

    Krauze, Michal T.; Noble, Charles O.; Kawaguchi, Tomohiro; Drummond, Daryl; Kirpotin, Dmitri B.; Yamashita, Yoji; Kullberg, Erika; Forsayeth, John; Park, John W.; Bankiewicz, Krystof S.

    2007-01-01

    We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts. In this study, we have evaluated the combination of a newly developed nanoparticle/liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin. Both drugs were detectable in the CNS for more than 36 days after a single CED application. Tissue half-life was 16.7 days for nLs-CPT-11 and 10.9 days for Doxil. The combination of the two agents produced synergistic cytotoxicity in vitro. In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly. Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed. These findings have implications for further clinical applications of CED-based treatment of brain tumors. PMID:17652269

  2. Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts.

    PubMed

    Krauze, Michal T; Noble, Charles O; Kawaguchi, Tomohiro; Drummond, Daryl; Kirpotin, Dmitri B; Yamashita, Yoji; Kullberg, Erika; Forsayeth, John; Park, John W; Bankiewicz, Krystof S

    2007-10-01

    We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts. In this study, we have evaluated the combination of a newly developed nanoparticle/liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin. Both drugs were detectable in the CNS for more than 36 days after a single CED application. Tissue half-life was 16.7 days for nLs-CPT-11 and 10.9 days for Doxil. The combination of the two agents produced synergistic cytotoxicity in vitro. In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly. Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed. These findings have implications for further clinical applications of CED-based treatment of brain tumors.

  3. Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

    PubMed Central

    Kueffer, Peter J.; Maitz, Charles A.; Khan, Aslam A.; Schuster, Seth A.; Shlyakhtina, Natalia I.; Jalisatgi, Satish S.; Brockman, John D.; Nigg, David W.; Hawthorne, M. Frederick

    2013-01-01

    The application of boron neutron capture therapy (BNCT) following liposomal delivery of a 10B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine and incorporating Na3[1-(2′-B10H9)-2-NH3B10H8] in the aqueous interior and K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h—with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)—following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 1012 neutrons per cm2 (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study. PMID:23536304

  4. Tumor priming by Apo2L/TRAIL reduces interstitial fluid pressure and enhances efficacy of liposomal gemcitabine in a patient derived xenograft tumor model.

    PubMed

    Hylander, Bonnie L; Sen, Arindam; Beachy, Sarah H; Pitoniak, Rose; Ullas, Soumya; Gibbs, John F; Qiu, Jingxin; Prey, Joshua D; Fetterly, Gerald J; Repasky, Elizabeth A

    2015-11-10

    Interstitial fluid pressure (IFP) is elevated in tumors and high IFP, a negative cancer prognosticator, is known to limit the uptake and efficacy of anti-tumor therapeutics. Approaches that alter the tumor microenvironment and enhance uptake of therapeutics are collectively referred to as tumor "priming". Here we show that the cytotoxic biological therapy Apo2L/TRAIL can prime the tumor microenvironment and significantly lower IFP in three different human tumor xenograft models (Colo205, MiaPaca-2 and a patient gastrointestinal adenocarcinoma tumor xenograft). We found that a single dose of Apo2L/TRAIL resulted in a wave of apoptosis which reached a maximum at 8h post-treatment. Apoptotic debris subsequently disappeared concurrent with an increase in macrophage infiltration. By 24h post-treatment, treated tumors appeared less condensed with widening of the stromal areas which increased at 48 and 72h. Analysis of tumor vasculature demonstrated a significant increase in overall vessel size at 48 and 72h although the number of vessels did not change. Notably, IFP was significantly reduced in these tumors by 48h after Apo2L/TRAIL treatment. Administration of gemcitabine at this time resulted in increased tumor uptake of both gemcitabine and liposomal gemcitabine and significantly improved anti-tumor efficacy of liposomal gemcitabine. These results suggest that Apo2L/TRAIL has a potential as a tumor priming agent and provides a rationale for developing a sequencing schema for combination therapy such that an initial dose of Apo2L/TRAIL would precede administration of gemcitabine or other therapies.

  5. Tumor growth suppression by gadolinium-neutron capture therapy using gadolinium-entrapped liposome as gadolinium delivery agent.

    PubMed

    Dewi, Novriana; Yanagie, Hironobu; Zhu, Haito; Demachi, Kazuyuki; Shinohara, Atsuko; Yokoyama, Kazuhito; Sekino, Masaki; Sakurai, Yuriko; Morishita, Yasuyuki; Iyomoto, Naoko; Nagasaki, Takeshi; Horiguchi, Yukichi; Nagasaki, Yukio; Nakajima, Jun; Ono, Minoru; Kakimi, Kazuhiro; Takahashi, Hiroyuki

    2013-07-01

    Neutron capture therapy (NCT) is a promising non-invasive cancer therapy approach and some recent NCT research has focused on using compounds containing gadolinium as an alternative to currently used boron-10 considering several advantages that gadolinium offers compared to those of boron. In this study, we evaluated gadolinium-entrapped liposome compound as neutron capture therapy agent by in vivo experiment on colon-26 tumor-bearing mice. Gadolinium compound were injected intravenously via tail vein and allowed to accumulate into tumor site. Tumor samples were taken for quantitative analysis by ICP-MS at 2, 12, and 24 h after gadolinium compound injection. Highest gadolinium concentration was observed at about 2 h after gadolinium compound injection with an average of 40.3 μg/g of wet tumor tissue. We performed neutron irradiation at JRR-4 reactor facility of Japan Atomic Energy Research Institute in Tokaimura with average neutron fluence of 2×10¹² n/cm². The experimental results showed that the tumor growth suppression of gadolinium-injected irradiated group was revealed until about four times higher compared to the control group, and no significant weight loss were observed after treatment suggesting low systemic toxicity of this compound. The gadolinium-entrapped liposome will become one of the candidates for Gd delivery system on NCT.

  6. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

    PubMed Central

    Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

    2015-01-01

    Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the “blood tumor barrier” (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced MRI (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and Definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg/kg. This chemotherapy agent was shown previously to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823±600, 1817±732 and 2432±448 ng/g) in the control tumors at 9, 14 and 17 days. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P<0.05, P<0.01, and P<0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222±784, 3687±796 and 5658±821 ng/g) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (p<0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can

  7. Design and synthesis of fluorescence-labeled closo-dodecaborate lipid: its liposome formation and in vivo imaging targeting of tumors for boron neutron capture therapy.

    PubMed

    Nakamura, Hiroyuki; Ueda, Noriko; Ban, Hyun Seung; Ueno, Manabu; Tachikawa, Shoji

    2012-02-21

    The fluorescence-labeled closo-dodecaborane lipid (FL-SBL) was synthesized from (S)-(+)-1,2-isopropylideneglycerol as a chiral starting material. FL-SBL was readily accumulated into the PEGylated DSPC liposomes prepared from DSPC, CH, and DSPE-PEG-OMe by the post insertion protocol. The boron concentrations and the fluorescent intensities of the FL-SBL-labeled DSPC liposomes increased with the increase of the additive FL-SBL, and the maximum emission wavelength of the liposomes appeared at 531 nm. A preliminary in vivo imaging study of tumor-bearing mice revealed that the FL-SBL-labeled DSPC liposomes were delivered to the tumor tissue but not distributed to hypoxic regions.

  8. Liposome encapsulated of temozolomide for the treatment of glioma tumor: preparation, characterization and evaluation.

    PubMed

    Gao, Jinhua; Wang, Zhonglan; Liu, Honghai; Wang, Longmei; Huang, Guihua

    2015-06-01

    Temozolomide plays a critical role in curing glioma at present. The purpose of this work was to develop a suitable drug delivery system which could prolong the half-life, improve the brain targeting, and reduce the systemic effect of the drug. Temozolomide-liposomes were formulated by the method of proliposomes. They were found to be relatively uniform in size of 156.70 ± 11.40 nm with a narrow polydispersity index (PI) of 0.29 ± 0.04. The average drug entrapment efficiency and loading capacity were 35.45 ± 1.48% and 2.81 ± 0.20%, respectively. The pH of temozolomide-liposomes was 6.46. In vitro release studies were conducted by a dynamic dialysis. The results showed that temozolomide released slowly from liposomes compared with the solution group. The release behavior of temozolomide-liposomes was in line with First-order kinetics and Weibull equation. The pharmacokinetics study was evaluated by pharmacokinetics parameters. The t(1/2β) and MRT of temozolomide-liposomes were 3.57 times and 1.27 times greater than that of temozolomide solution. The Cmax and AUC values of temozolomide-liposomes were 1.10 times and 1.55 times greater than that of temozolomide solution. The results of pharmacokinetics study showed temozolomide-liposomes prolonged the in vivo circulation time and increased AUC. Furthermore, the biodistribution in mice showed that temozolomide-liposomes preferentially decreased the accumulation of temozolomide in heart and lung and increased the drug concentration in brain after i.v. injection, which implied that temozolomide-liposomes improved the therapeutic effect in the brain and reduced the toxicity in lung and heart.

  9. Loading mitomycin C inside long circulating hyaluronan targeted nano-liposomes increases its antitumor activity in three mice tumor models.

    PubMed

    Peer, Dan; Margalit, Rimona

    2004-02-20

    The frequent overexpression of the hyaluronan receptors CD44 and RHAMM in cancer cells opens the door for targeting by the naturally-occurring high-M(r) hyaluronan. This is the first time effective in vivo tumor targeting is reported for mitomycin C (MMC) loaded inside nano-sized hyaluronan-liposomes (denoted tHA-LIP). The severe adverse effects of free MMC made it a rational candidate for an effective targeted carrier. In vitro, loading MMC inside tHA-LIP increased drug potency 100-fold, in cells overexpressing, but not in cells underexpressing, hyaluronan receptors. Both types of liposomes were non-toxic and reduced MMC-related toxicity in healthy C57BL/6 mice. In 3 tumor models, BALB/c bearing C-26 solid tumors; C57BL/6 bearing B16F10.9 or (separately) D122 lung metastasis, tHA-LIP were long-circulating, 7-fold and 70-fold longer than nt-LIP and free MMC, respectively. tHA-LIP-mediated MMC accumulation in tumor-bearing lungs was 20% of injected dose, compared to 0.6% and 4% with free drug and nt-LIP, respectively. Tumor-free lungs showed low accumulation, irrespective of drug formulation. Key indicators of therapeutic responses, tumor progression, metastatic burden and survival, were superior (p < 0.001) in animals receiving MMC-loaded tHA-LIP, no treatment, MMC-loaded nt-LIP and free drug. In conclusion, tHA-LIP perform as tumor-targeted carriers, with promising prospects for treatment of tumors overexpressing hyaluronan receptors.

  10. Safety and toxicity of intrathecal liposomal cytarabine (Depocyte) in children and adolescents with recurrent or refractory brain tumors: a multi-institutional retrospective study.

    PubMed

    Benesch, Martin; Siegler, Nele; Hoff, Katja von; Lassay, Lisa; Kropshofer, Gabriele; Müller, Hermann; Sommer, Constanze; Rutkowski, Stefan; Fleischhack, Gudrun; Urban, Christian

    2009-10-01

    This retrospective study aimed to evaluate the safety and toxicity of intrathecal liposomal cytarabine (Depocyte) in children and adolescents with refractory or recurrent brain tumors. Nineteen heavily pretreated patients (males, n = 14; females, n = 5; median age at diagnosis 8.5 years; range, 1.4-22 years) were given intrathecal liposomal cytarabine on a compassionate use basis for recurrent refractory medulloblastoma (n = 12), mixed germ cell tumor (n = 2), central nervous system primitive neuroectodermal tumors of the pons (n = 1), anaplastic ependymoma (n = 1), anaplastic oligodendroglioma (n = 1), atypical teratoid rhabdoid tumor (n = 1), or rhabdoid papillary meningioma (n = 1). Eighteen patients received concomitant systemic radiochemotherapy. A total of 88 intrathecal injections of liposomal cytarabine (dose range, 20-50 mg) were administered with concomitant dexamethasone prophylaxis. The median number of doses per patient was four (range, 1-10). Duration of treatment ranged from (1/2) to 10 months. Eleven patients (57.9%) did not show any side effects, whereas eight patients (42.1%) developed side effects related to either chemical arachnoiditis (n = 4) or neurological progression (n = 2). Less typical treatment-related symptoms (e.g. lethargy, ataxia, and slurred speech) were observed in two patients. Treatment with intrathecal liposomal cytarabine was discontinued twice because of side effects. In conclusion, although intrathecal liposomal cytarabine was generally well tolerated, it should be used cautiously and only with dexamethasone prophylaxis in extensively pretreated patients with recurrent brain tumors. Proof of efficacy requires a prospective single-agent phase II study.

  11. Imaging Features of Radiofrequency Ablation with Heat-Deployed Liposomal Doxorubicin in Hepatic Tumors

    SciTech Connect

    Hong, Cheng William Chow, Lucy; Turkbey, Evrim B.; Lencioni, Riccardo; Libutti, Steven K.; Wood, Bradford J.

    2016-03-15

    IntroductionThe imaging features of unresectable hepatic malignancies in patients who underwent radiofrequency ablation (RFA) in combination with lyso-thermosensitive liposomal doxorubicin (LTLD) were determined.Materials and MethodsA phase I dose escalation study combining RFA with LTLD was performed with peri- and post- procedural CT and MRI. Imaging features were analyzed and measured in terms of ablative zone size and surrounding penumbra size. The dynamic imaging appearance was described qualitatively immediately following the procedure and at 1-month follow-up. The control group receiving liver RFA without LTLD was compared to the study group in terms of imaging features and post-ablative zone size dynamics at follow-up.ResultsPost-treatment scans of hepatic lesions treated with RFA and LTLD have distinctive imaging characteristics when compared to those treated with RFA alone. The addition of LTLD resulted in a regular or smooth enhancing rim on T1W MRI which often correlated with increased attenuation on CT. The LTLD-treated ablation zones were stable or enlarged at follow-up four weeks later in 69 % of study subjects as opposed to conventional RFA where the ablation zone underwent involution compared to imaging acquired immediately after the procedure.ConclusionThe imaging features following RFA with LTLD were different from those after standard RFA and can mimic residual or recurrent tumor. Knowledge of the subtle findings between the two groups can help avoid misinterpretation and proper identification of treatment failure in this setting. Increased size of the LTLD-treated ablation zone after RFA suggests the ongoing drug-induced biological effects.

  12. 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.

  13. Development of a liposome microbicide formulation for vaginal delivery of octylglycerol for HIV prevention.

    PubMed

    Wang, Lin; Sassi, Alexandra Beumer; Patton, Dorothy; Isaacs, Charles; Moncla, B J; Gupta, Phalguni; Rohan, Lisa Cencia

    2012-08-01

    The feasibility of using a liposome drug delivery system to formulate octylglycerol (OG) as a vaginal microbicide product was explored. A liposome formulation was developed containing 1% OG and phosphatidyl choline in a ratio that demonstrated in vitro activity against Neisseria gonorrhoeae, HSV-1, HSV-2 and HIV-1 while sparing the innate vaginal flora, Lactobacillus. Two conventional gel formulations were prepared for comparison. The OG liposome formulation with the appropriate OG/lipid ratio and dosing level had greater efficacy than either conventional gel formulation and maintained this efficacy for at least 2 months. No toxicity was observed for the liposome formulation in ex vivo testing in a human ectocervical tissue model or in vivo testing in the macaque safety model. Furthermore, minimal toxicity was observed to lactobacilli in vitro or in vivo safety testing. The OG liposome formulation offers a promising microbicide product with efficacy against HSV, HIV and N. gonorrhoeae.

  14. Development of a liposome microbicide formulation for vaginal delivery of octylglycerol for HIV prevention

    PubMed Central

    Wang, Lin; Sassi, Alexandra Beumer; Patton, Dorothy; Isaacs, Charles; Moncla, B. J.; Gupta, Phalguni; Rohan, Lisa Cencia

    2015-01-01

    The feasibility of using a liposome drug delivery system to formulate octylglycerol (OG) as a vaginal microbicide product was explored. A liposome formulation was developed containing 1% OG and phosphatidyl choline in a ratio that demonstrated in vitro activity against Neisseria gonorrhoeae, HSV-1, HSV-2 and HIV-1 while sparing the innate vaginal flora, Lactobacillus. Two conventional gel formulations were prepared for comparison. The OG liposome formulation with the appropriate OG/lipid ratio and dosing level had greater efficacy than either conventional gel formulation and maintained this efficacy for at least 2 months. No toxicity was observed for the liposome formulation in ex vivo testing in a human ectocervical tissue model or in vivo testing in the macaque safety model. Furthermore, minimal toxicity was observed to lactobacilli in vitro or in vivo safety testing. The OG liposome formulation offers a promising microbicide product with efficacy against HSV, HIV and N. gonorrhoeae. PMID:22149387

  15. Thermosensitive liposomal cisplatin in combination with local hyperthermia results in tumor growth delay and changes in tumor microenvironment in xenograft models of lung carcinoma.

    PubMed

    Dou, Yannan Nancy; Dunne, Michael; Huang, Huang; Mckee, Trevor; Chang, Martin C; Jaffray, David A; Allen, Christine

    2016-11-01

    Treatment efficacy of a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, was determined in xenograft models of non-small-cell lung carcinoma. The short-term impact of local hyperthermia (HT) on tumor morphology, microvessel density and local inflammatory response was also evaluated. The HTLC formulation in combination with local HT resulted in a significant advantage in therapeutic effect in comparison with free drug and a non-thermosensitive liposome formulation of CDDP (i.e. Lipoplatin(TM)) when administered at their maximum tolerated doses. Local HT-induced widespread cell necrosis and a significant reduction in microvessel density in the necrotic regions of tumors. CD11b-expressing innate leukocytes were demonstrated to infiltrate and reside preferentially at the necrotic rim of tumors, likely as a means to phagocytose-damaged tissue. Colocalization of CD11b with a marker of DNA damage (i.e. γH2AX) revealed a small portion of CD11b-expressing leukocytes that were possibly undergoing apoptosis as a result of HT-induced damage and/or the short lifespan of leukocytes. Overall, HT-induced tissue damage (i.e. at 24-h post-treatment) alone did not result in significant improvements in treatment effect, rather, the enhancement in tumor drug availability was correlated with improved therapeutic outcomes.

  16. Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides

    PubMed Central

    Sun, Jiawei; Jiang, Lei; Lin, Yi; Gerhard, Ethan Michael; Jiang, Xuehua; Li, Li; Yang, Jian; Gu, Zhongwei

    2017-01-01

    Mitochondria serve as both “energy factories” and “suicide weapon stores” of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Here, multistage tumor-targeting liposomes containing two targeted peptide-modified lipids, cRGD-PEG2000-DSPE and KLA-PEG2000-DSPE, were developed for encapsulation of the anticancer drug paclitaxel (PTX, RGD-KLA/PTX-Lips). Compared with Taxol (free PTX), RGD/PTX-Lips and KLA/PTX-Lips, the half-maximal inhibitory concentration (IC50) value of RGD-KLA/PTX-Lips in vitro was 1.9-, 36.7- and 22.7-fold lower with 4T1 cells, respectively, because of higher levels of cellular uptake. Similar results were also observed with human umbilical vascular endothelial cells (HUVECs). An apoptosis assay showed that the total apoptotic ratio of RGD-KLA/PTX-Lips was the highest because of the mitochondria-targeted drug delivery and the activation of mitochondrial apoptosis pathways, as evidenced by visible mitochondrial localization, decreased mitochondrial membrane potential, release of cytochrome c and increased activities of caspase-9 and caspase-3. The strongest tumor growth inhibition (TGI; 80.6%) and antiangiogenesis effects without systemic toxicity were also observed in RGD-KLA/PTX-Lip-treated 4T1 tumor xenograft BALB/c mice. In conclusion, these multistage tumor-targeting liposomes represent a promising anticancer drug delivery system (DDS) capable of maximizing anticancer therapeutic efficacy and minimizing systemic toxicity. PMID:28280323

  17. NIR-Laser-Controlled Drug Release from DOX/IR-780-Loaded Temperature-Sensitive-Liposomes for Chemo-Photothermal Synergistic Tumor Therapy

    PubMed Central

    Yan, Fei; Duan, Wanlu; Li, Yekuo; Wu, Hao; Zhou, Yuli; Pan, Min; Liu, Hongmei; Liu, Xin; Zheng, Hairong

    2016-01-01

    NIR laser-induced photothermal therapy (PTT) through near-infrared agents has demonstrated the great potential in solid tumor ablation. However, the nonuniform heat distribution over tumors from PTT makes it insufficient to kill all tumor cells, resulting in tumor recurrence and inferior outcomes. To improve the tumor treatment efficacy, it is highly desirable to develop the combinational treatment of PTT with other modalities, especially with chemotherapeutic agents. Here we report a smart DOX/IR-780-loaded temperature-sensitive-liposome (DITSL) which can achieve NIR-laser-controlled drug release for chemo-photothermal synergistic tumor therapy. In this system, the liposoluble IR-780 was incorporated into the temperature-sensitive lipid bilayer and the soluble chemotherapeutic doxorubicin (DOX) was encapsulated in the hydrophilic core. The resulting DITSL is proved to be physiologically stable and can provide a fast and laser irradiation-controllable DOX release in the PBS and cellular conditions. We further employed this nanoparticle for tumor treatment, demonstrating significantly higher tumor inhibition efficacy than that of DOX-loaded temperature-sensitive-liposome (DTSL) or IR780-loaded temperature-sensitive-liposome (ITSL) in the in vitro cells and in vivo animals. Histological analysis further revealed much more apoptotic cells, confirming the advantageous anti-tumor effect of DITSL over DTSL or ITSL. Our study provides a promising strategy to realize chemo-photothermal synergistic combination therapy for breast tumors. PMID:27877239

  18. [Importance of the conjugated antibody for the induction of selective effect of adriamycin conjugated with anti AFP monoclonal antibody and entrapped in liposomes against AFP producing tumors].

    PubMed

    Konno, H; Kumai, K; Tsubouchi, T; Ishibiki, K; Abe, O; Tadakuma, T; Yasuda, T; Nagaike, K; Hosokawa, S; Sakaguchi, S

    1989-06-01

    We investigated experimentally the effect of adriamycin (ADM) conjugated with anti alpha-fetoprotein (AFP) monoclonal antibodies and entrapped in liposomes (Lip-ADM = AbAFP) in vitro or in vivo. In the present study, we examined the importance of the conjugated antibody for the induction of selective therapeutic effect of Lip-ADM = AbAFP against AFP producing tumors. As the target tumors, AFP producing human hepatoma strain, Li-7, and AFP non-producing human breast cancer strain, MX-1 maintained in BALB/c nu/nu male mice were used. In order to evaluate the importance of the conjugated antibody, we prepared also ADM conjugated with normal mouse IgG, and entrapped in liposomes Lip-ADM = NIgG, of which therapeutic effects were compared with that of Lip-ADM = AbAFP. Judging from the tumor growth curve and the tumor weight, the therapeutic effect of Lip-ADM = AbAFP was greater against Li-7 than that of Lip-ADM = NIgG. On the other hand, both conjugates showed similar effects against MX-1. As the results it is suggested that the antibody which recognizes the antigen expressed on the target tumor cells can solely increase the therapeutic effect of ADM entrapped in liposomes (Lip-ADM) and that the main factors which contribute to the efficient therapeutic effect of the conjugate were the sensitibility to ADM, the affinity of the tumor cells to liposomes and the superiority of the conjugated antibody.

  19. Thermo-sensitive liposomes loaded with doxorubicin and lysine modified single-walled carbon nanotubes as tumor-targeting drug delivery system.

    PubMed

    Zhu, Xiali; Xie, Yingxia; Zhang, Yingjie; Huang, Heqing; Huang, Shengnan; Hou, Lin; Zhang, Huijuan; Li, Zhi; Shi, Jinjin; Zhang, Zhenzhong

    2014-11-01

    This report focuses on the thermo-sensitive liposomes loaded with doxorubicin and lysine-modified single-walled carbon nanotube drug delivery system, which was designed to enhance the anti-tumor effect and reduce the side effects of doxorubicin. Doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes was prepared by reverse-phase evaporation method, the mean particle size was 232.0 ± 5.6 nm, and drug entrapment efficiency was 86.5 ± 3.7%. The drug release test showed that doxorubicin released more quickly at 42℃ than at 37℃. Compared with free doxorubicin, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes could efficiently cross the cell membranes and afford higher anti-tumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) cells in vitro. For in vivo experiments, the relative tumor volumes of the sarcomaia 180-bearing mice in thermo-sensitive liposomes group and doxorubicin group were significantly smaller than those of N.S. group. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced the tumor growth inhibition both on SMMC-7721 cells and the sarcomaia 180-bearing mice. The quality of life such as body weight, mental state, food and water intake of sarcomaia 180 tumor-bearing mice treated with doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes were much higher than those treated with doxorubicin. In conclusion, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes combined with near-infrared laser irradiation at 808 nm may potentially provide viable clinical strategies for targeting delivery of anti-cancer drugs.

  20. Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and a topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts1

    PubMed Central

    Yamashita, Yoji; Krauze, Michal T.; Kawaguchi, Tomohiro; Noble, Charles O.; Drummond, Daryl C.; Park, John W.; Bankiewicz, Krystof S.

    2007-01-01

    Despite multimodal treatment options, the response and survival rates for patients with malignant gliomas remain dismal. Clinical trials with convection-enhanced delivery (CED) have recently opened a new window in neuro-oncology to the direct delivery of chemotherapeutics to the CNS, circumventing the blood-brain barrier and reducing systemic side effects. Our previous CED studies with liposomal chemotherapeutics have shown promising antitumor activity in rodent brain tumor models. In this study, we evaluated a combination of nanoliposomal topotecan (nLs-TPT) and pegylated liposomal doxorubicin (PLD) to enhance efficacy in our brain tumor models, and to establish a CED treatment capable of improving survival from malignant brain tumors. Both liposomal drugs decreased key enzymes involved in tumor cell replication in vitro. Synergistic effects of nLs-TPT and PLD on U87MG cell death were found. The combination displayed excellent efficacy in a CED-based survival study 10 days after tumor cell implantation. Animals in the control group and those in single-agent groups had a median survival of less than 30 days, whereas the combination group experienced a median survival of more than 90 days. We conclude that CED of two liposomal chemotherapeutics (nLs-TPT and PLD) may be an effective treatment option for malignant gliomas. PMID:17018695

  1. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

    NASA Astrophysics Data System (ADS)

    Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

    2015-03-01

    Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P < 0.05, P < 0.01, and P < 0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222  ±  784, 3687  ±  796 and 5658  ±  821 ng g-1) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P < 0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are

  2. The influence of phospholipid on the physicochemical properties and anti-tumor efficacy of liposomes encapsulating cisplatin in mice bearing C26 colon carcinoma.

    PubMed

    Alavizadeh, Seyedeh Hoda; Badiee, Ali; Golmohammadzadeh, Shiva; Jaafari, Mahmoud Reza

    2014-10-01

    SPI-077, cisplatin stealth liposome, is the best illustration of poor cisplatin release from liposomes and the subsequent negligible therapeutic activity. For this reason, optimizing drug release kinetics is desirable. In this report, cisplatin was encapsulated in liposomes composed of different phosphatidylcholines with various phase transition temperatures (Tm) (HSPC, DPPC, DMPC, soy phosphatidylcholine (SPC)), cholesterol and mPEG2000-DSPE. In vitro cytotoxicity studies indicated that lowering Tm of lipids increases cisplatin release; the highest cytotoxicity was observed in SPCs. Cisplatin plasma concentration was also sensitive to the transition temperature. The highest platinum concentration observed after treatment with HSPC and DPPC liposomes, whilst the lowest was observed with SPC. HSPC and DPPC containing liposomes showed the highest therapeutic efficacy and survival with DPPC exhibited better efficacy in mouse model of C26. It seems that DPPC with Tm (41.5°C) nearly, or close to body temperature maintains good drug retention in blood circulation. Upon extravasation through permeable tumor microvasculature, it gradually releases its payload in the tumor area better than HSPC, with a greater Tm of 55°C. Our data suggests, the choice of Tm for lipid mixture directed to a considerable extent the rate of cisplatin elimination from plasma and therapeutic effects.

  3. Efficient tumor regression by a single and low dose treatment with a novel and enhanced formulation of thermosensitive liposomal doxorubicin.

    PubMed

    Tagami, Tatsuaki; Ernsting, Mark J; Li, Shyh-Dar

    2011-06-10

    We have developed a novel and simplified thermosensitive liposomal formulation (HaT: Hyperthermia-activated cytoToxic) composed of DPPC lipid and Brij78 (96:4, molar ratio). The HaT nanoparticles were loaded with doxorubicin (DOX) with >95% efficiency when a pH gradient method and a drug/lipid ratio of 1/20 (w/w) were applied. Drug release from the HaT formulation was significantly faster at 40-41°C (100% release in 2-3min) with 3.4-fold increased membrane permeability compared to the LTSL (lyso-lipid temperature sensitive liposomes; DPPC: MSPC: DSPE-PEG(2000)=86:10:4, molar ratio), a formulation that is currently in clinical trials. Both formulations displayed similar stability at 37°C in serum (10-20% release in 30min), which corresponds to their comparable pharmacokinetics in the unheated mice. An approximately 1.4-fold increased drug delivery to the locally heated tumor (~43°C) was detected with HaT-DOX compared to LTSL-DOX. Moreover, when compared with free DOX, HaT enhanced drug uptake in the heated tumor by 5.2-fold and reduced drug delivery to the heart by 15-fold. A single i.v. treatment with HaT-DOX at 3mg DOX/kg in combination with localized hyperthermia demonstrated enhanced tumor regression compared to LTSL-DOX and free DOX, and exhibited little toxicity.

  4. Study of the pH-sensitive mechanism of tumor-targeting liposomes.

    PubMed

    Fan, Yang; Chen, Cong; Huang, Yiheng; Zhang, Fang; Lin, Guimei

    2017-03-01

    Currently, the phosphatidylethanolamine-based, pH-sensitive, liposome drug-delivery system has been widely developed for efficient, targeted cancer therapy. However, the mechanism of pH sensitivity was unclear; it is a main obstacle in controlling the preparation of pH-sensitive liposomes (PSLs).Therefore, our research is aimed at clarifying the pH-response mechanism of the various molecules that compose liposomes. We chose the small pH-sensitive molecules oleic acid (OA), linoleic acid (LA) and cholesteryl hemisuccinate (CHEMS) and the fundamental lipids cholesterol and phosphatidylethanolamine (PE) as test molecules. The PSLs were prepared using the thin-film hydration method and characterized in detail at various pH values (pH 5.0, 6.0 and 7.4), including particle size, ζ-potential, drug encapsulation efficiency and drug loading. The surface structure was observed by transmission electron microscopy (TEM), and the electrical conductivity of the liposome dispersion was also tested. The calorimetric analysis was conducted by Nano-differential scanning calorimetry (Nano-DSC). The in vitro drug release profile showed that PSLs exhibit good pH sensitivity. At neutral pH, the particle size was approximately 150nm, and it dramatically increased at pH 5.0. The ζ-potential increased as the pH decreased. The Nano-DSC results showed that cholesterol and CHEMS can both increase the stability and phase transfer temperature of PSLs. Conductivity increased to a maximum at pH 5.0 and was rather low at pH 7.4. In conclusion, results show that the three kinds of liposomes have pH responsive release characteristics in acidic pH. The OA-PSLs have a pH sensitive point of 5. Since CHEMS has a cholesterol-like structure, it can stabilizes the phospholipid bilayer under neutral conditions as shown in the Nano-DSC data, and because it has a special steroidal rigid structure, it exhibits better pH response characteristics under acidic conditions.

  5. Pharmacokinetics, brain delivery, and efficacy in brain tumor-bearing mice of glutathione pegylated liposomal doxorubicin (2B3-101).

    PubMed

    Gaillard, Pieter J; Appeldoorn, Chantal C M; Dorland, Rick; van Kregten, Joan; Manca, Francesca; Vugts, Danielle J; Windhorst, Bert; van Dongen, Guus A M S; de Vries, Helga E; Maussang, David; van Tellingen, Olaf

    2014-01-01

    Brain cancer is a devastating disease affecting many people worldwide. Effective treatment with chemotherapeutics is limited due to the presence of the blood-brain barrier (BBB) that tightly regulates the diffusion of endogenous molecules but also xenobiotics. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is based on already marketed pegylated liposomal doxorubicin (Doxil®/Caelyx®), with an additional glutathione coating that safely enhances drug delivery across the BBB. Uptake of 2B3-101 by human brain capillary endothelial cells in vitro was time-, concentration- and temperature-dependent, while pegylated liposomal doxorubicin mainly remained bound to the cells. In vivo, 2B3-101 and pegylated liposomal doxorubicin had a comparable plasma exposure in mice, yet brain retention 4 days after administration was higher for 2B3-101. 2B3-101 was overall well tolerated by athymic FVB mice with experimental human glioblastoma (luciferase transfected U87MG). In 2 independent experiments a strong inhibition of brain tumor growth was observed for 2B3-101 as measured by bioluminescence intensity. The effect of weekly administration of 5 mg/kg 2B3-101 was more pronounced compared to pegylated liposomal doxorubicin (p<0.05) and saline (p<0.01). Two out of 9 animals receiving 2B3-101 showed a complete tumor regression. Twice-weekly injections of 5 mg/kg 2B3-101 again had a significant effect in inhibiting brain tumor growth (p<0.001) compared to pegylated liposomal doxorubicin and saline, and a complete regression was observed in 1 animal treated with 2B3-101. In addition, twice-weekly dosing of 2B3-101 significantly increased the median survival time by 38.5% (p<0.001) and 16.1% (p<0.05) compared to saline and pegylated liposomal doxorubicin, respectively. Overall, these data demonstrate that glutathione pegylated liposomal doxorubicin enhances the effective delivery of doxorubicin to brain

  6. The effect of photoimmunotherapy (PIT) followed by liposomal daunorubicin in a mixed tumor model: A demonstration of the super enhanced permeability and retention (SUPR) effect after PIT

    PubMed Central

    Sano, Kohei; Nakajima, Takahito; Choyke, Peter L.; Kobayashi, Hisataka

    2014-01-01

    In general, de novo solid tumors are composed of phenotypically and functionally heterogeneous malignant cells. This heterogeneity interferes with the effectiveness of targeted molecular cancer therapies. Even if most of the tumor is killed by a targeted treatment, recurrences are common and can be lethal. In this study, a mixed tumor model, which is predominantly a population of epidermal growth factor receptor (EGFR)-positive A431 cells combined with a smaller population of EGFR-negative Balb3T3/deRed cells, was established. This mixed tumor was then treated with photoimmunotherapy (PIT), a newly developed target-cell selective cancer therapy using a monoclonal antibody (mAb)-photosensitizer (IR700 fluorescence dye) conjugate and exposure of near infrared light. While PIT successfully treated EGFR-positive A431 cells in the mixed tumor, EGFR negative Balb/DsRed cells were not responsive. However, PIT also induced a large increase in tumor permeability known as the SUPR effect, which allowed a 5-fold increase in the accumulation of a liposomal chemotherapy (DaunoXome) and resulted in more effective therapy than either PIT or liposomal daunorubicin alone. The liposomal daunorubicin, administered 1 h after EGFR-targeted PIT, was homogeneously distributed allowing delivery to tiny surviving nests of EGFR-negative Balb3T3/DsRed cells resulting in prolonged survival of mice. PMID:24356818

  7. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    PubMed Central

    Ding, Yuan; Sun, Dan; Wang, Gui-Ling; Yang, Hong-Ge; Xu, Hai-Feng; Chen, Jian-Hua; Xie, Ying; Wang, Zhi-Qiang

    2015-01-01

    Cell-penetrating peptides (CPPs) as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG) and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL) to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR) to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS) was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into targeted subcellular compartments while remaining inactive and free from opsonins at a maximum extent in systemic circulation. The 4% CPPL as a drug delivery system will have great potential in the clinical application of anticancer drugs in future. PMID:26491292

  8. Effect of low-dose tumor necrosis factor-alpha in combination with STEALTH liposomal cisplatin (SPI-077) on soft-tissue- and osteosarcoma-bearing rats.

    PubMed

    Hoving, Saske; van Tiel, Sandra T; Eggermont, Alexander M M; ten Hagen, Timo L M

    2005-01-01

    Cisplatin is a widely used agent for treatment of solid tumors, but its clinical utility is limited by toxicity. Preclinical studies have shown less acute toxicity when STEALTH liposomal cisplatin (SPI-077) is used, with antitumor effects equivalent to those of intravenously administered free cisplatin. We previously reported that systemic treatment with low-dose tumor necrosis factor-alpha (TNF) augments the activity of STEALTH liposomal doxorubicin (Doxil). In this study, we examined the effect of repeated systemic applications of low-dose TNF on the antitumor activity of SPI-077 in rats with soft-tissue sarcoma or osteosarcoma. Addition of TNF to SPI-077 treatment showed an improved tumor growth delay of the soft-tissue sarcoma. The combined SPI-077/TNF treatment resulted in a more prolonged antitumor activity, whereas free cisplatin showed a better tumor response, however with a rapid outgrowth a few days after the end of therapy. In the osteosarcoma, free cisplatin did not have an antitumor effect, but addition of TNF caused a clear tumor growth delay. SPI-077 alone resulted in a tumor growth delay, but combination with TNF had no additive effect. SPI-077 yielded less systemic toxicity than cisplatin. Depending on the type of tumor, the addition of TNF to SPI-077 results in a better tumor growth delay with a prolonged antitumor effect and, in combination with the reduced toxicity of SPI-077, this combination may be preferable to cisplatin.

  9. Prevention of Organophosphorus Lethality with Anhydrolase (OPA-2) Containing Stealth Liposomes

    DTIC Science & Technology

    2002-10-01

    alternative method was to encapsulate the enzymes organophosphorus acid anhydrolase, OPAA, and organophosphorus hydrolase, OPH, into liposomes and lastly to...102 Table of Contents I) Pyridinium appended Cyclodextrin Derivatives 4 A. Introduction 5 B. Body 7 C. Key Research Accomplished 15 D. Reportable...Outcomes 16 E. Conclusion 16 II) Nanobiotechnology of OP antagonism with nanostructural encapsulation of OPAA and OPH 17 A. Introduction 17 B. Body 20 C

  10. Nanosystem composed with MSNs, gadolinium, liposome and cytotoxic peptides for tumor theranostics.

    PubMed

    Jin, Yaqing; Zhang, Nengpan; Li, Chunlin; Pu, Kefeng; Ding, Chen; Zhu, Yimin

    2017-03-01

    A dual-functional delivery system, based on mesoporous silica nanoparticles (MSNs) with the integration of Magnetic Resonance (MR) imaging and therapeutic peptide delivery, is reported in this paper. A lipid bilayer is attached onto the surface of the nanoparticles, following the doping of Gadolinium (Gd), a paramagnetic lanthanide ion. The liposome-coated GdMSNs exhibit improved colloidal stability, better biocompatibility and more efficient cellular uptake. The Gd renders the nano carrier a potential T1 contrast agent, confirmed by the MR imaging. A pro-apoptotic peptide, KLA (HGGKLAKLAKKLAKLAK), is encapsulated into the GdMSNs-LP and enters into the cells successfully to induce mitochondrial swelling and apoptosis, while it is nontoxic outside the cells. The synthesis procedure is convenient and free of toxic organic reagents. The nanosystem we construct may contribute to a promising theranostic platform for therapeutic peptide delivery in cancer treatment.

  11. Liposomes derivatized with multimeric copies of KCCYSL peptide as targeting agents for HER-2-overexpressing tumor cells

    PubMed Central

    Ringhieri, Paola; Mannucci, Silvia; Conti, Giamaica; Nicolato, Elena; Fracasso, Giulio; Marzola, Pasquina; Morelli, Giancarlo; Accardo, Antonella

    2017-01-01

    Mixed liposomes, obtained by coaggregation of 1,2-dioleoyl-sn-glycero-3-phosphocholine and of the synthetic monomer containing a gadolinium complex ([C18]2DTPA[Gd]) have been prepared. Liposomes externally decorated with KCCYSL (P6.1 peptide) sequence in its monomeric, dimeric, and tetrameric forms are studied as target-selective delivery systems toward cancer cells overexpressing human epidermal growth factor receptor-2 (HER-2) receptors. Derivatization of liposomal surface with targeting peptides is achieved using the postmodification method: the alkyne-peptide derivative Pra-KCCYSL reacts, through click chemistry procedures, with a synthetic surfactant modified with 1, 2, or 4 azido moieties previously inserted in liposome formulation. Preliminary in vitro data on MDA-MB-231 and BT-474 cells indicated that liposomes functionalized with P6.1 peptide in its tetrameric form had better binding to and uptake into BT-474 cells compared to liposomes decorated with monomeric or dimeric versions of the P6.1 peptide. BT-474 cells treated with liposomes functionalized with the tetrameric form of P6.1 showed high degree of liposome uptake, which was comparable with the uptake of anti-HER-2 antibodies such as Herceptin. Moreover, magnetic MRI experiments have demonstrated the potential of liposomes to act as MRI contrast agents. PMID:28144135

  12. Prostate tumor attenuation in the nu/nu murine model due to anti-sarcosine antibodies in folate-targeted liposomes

    PubMed Central

    Heger, Zbynek; Polanska, Hana; Merlos Rodrigo, Miguel Angel; Guran, Roman; Kulich, Pavel; Kopel, Pavel; Masarik, Michal; Eckschlager, Tomas; Stiborova, Marie; Kizek, Rene; Adam, Vojtech

    2016-01-01

    Herein, we describe the preparation of liposomes with folate-targeting properties for the encapsulation of anti-sarcosine antibodies (antisarAbs@LIP) and sarcosine (sar@LIP). The competitive inhibitory effects of exogenously added folic acid supported the role of folate targeting in liposome internalization. We examined the effects of repeated administration on mice PC-3 xenografts. Sar@LIP treatment significantly increased tumor volume and weight compared to controls treated with empty liposomes. Moreover, antisarAbs@LIP administration exhibited a mild antitumor effect. We also identified differences in gene expression patterns post-treatment. Furthermore, Sar@LIP treatment resulted in decreased amounts of tumor zinc ions and total metallothioneins. Examination of the spatial distribution across the tumor sections revealed a sarcosine-related decline of the MT1X isoform within the marginal regions but an elevation after antisarAbs@LIP administration. Our exploratory results demonstrate the importance of sarcosine as an oncometabolite in PCa. Moreover, we have shown that sarcosine can be a potential target for anticancer strategies in management of PCa. PMID:27646588

  13. Boronated liposome development and evaluation

    SciTech Connect

    Hawthorne, M.F.

    1995-11-01

    The boronated liposome development and evaluation effort consists of two separate tasks. The first is the development of new boron compounds and the synthesis of known boron species with BNCT potential. These compounds are then encapsulated within liposomes for the second task, biodistribution testing in tumor-bearing mice, which examines the potential for the liposomes and their contents to concentrate boron in cancerous tissues.

  14. Liposomal paclitaxel formulations.

    PubMed

    Koudelka, Stěpán; Turánek, Jaroslav

    2012-11-10

    Over the past three decades, taxanes represent one of the most important new classes of drugs approved in oncology. Paclitaxel (PTX), the prototype of this class, is an anti-cancer drug approved for the treatment of breast and ovarian cancer. However, notwithstanding a suitable premedication, present-day chemotherapy employing a commercial preparation of PTX (Taxol®) is associated with serious side effects and hypersensitivity reactions. Liposomes represent advanced and versatile delivery systems for drugs. Generally, both in vivo mice tumor models and human clinical trials demonstrated that liposomal PTX formulations significantly increase a maximum tolerated dose (MTD) of PTX which outperform that for Taxol®. Liposomal PTX formulations are in various stages of clinical trials. LEP-ETU (NeoPharm) and EndoTAG®-1 (Medigene) have reached the phase II of the clinical trials; Lipusu® (Luye Pharma Group) has already been commercialized. Present achievements in the preparation of various liposomal formulations of PTX, the development of targeted liposomal PTX systems and the progress in clinical testing of liposomal PTX are discussed in this review summarizing about 30 years of liposomal PTX development.

  15. Potential of Diallyl Sulfide Bearing pH-Sensitive Liposomes in Chemoprevention Against DMBA-Induced Skin Papilloma

    PubMed Central

    Khan, Arif; Shukla, Yogeshwer; Kalra, Neetu; Alam, Maroof; Ahmad, Manzoor Gatoo; Hakim, Seema Rashid; Owais, Mohammad

    2007-01-01

    Diallyl sulfide (DAS), an active component of garlic, possesses strong anti-neoplastic properties against various forms of cancer. In the present study, we have evaluated chemo-preventive effects of liposomized DAS (conventional egg PC and pH-sensitive liposomes) against DMBA-induced skin papilloma. Various liposome-based novel formulations of DAS (250 μg/mouse) were applied topically, after one hour of exposure to DMBA (52 μg/mouse/dose), to the animals. The animals were treated thrice weekly for the total period of 12 weeks. The efficacy of the various liposomal formulations of DAS was evaluated on the basis of parameters such as incidence of tumorogenesis and total numbers and sizes of induced tumor nodules. The liposomized DAS formulations also were assessed for their effect on the expression of p53wt, p53mut, and p21/Waf1. The results of the present study showed that liposomized DAS could effectively delay the onset of tumorogenesis and reduce the cumulative numbers and sizes of tumor papillomas in treated mice. Treatment of DMBA-exposed animals with the liposomal formulation of DAS ensued in upregulation of p53wt and p21/Waf1, while levels of p53mut expression reduced down. The promising chemo-preventive nature of liposomal DAS may form the basis for establishing effective means of controlling various forms of cancer, including skin papilloma. PMID:17622315

  16. Effective induction of anti-tumor immunity using p5 HER-2/neu derived peptide encapsulated in fusogenic DOTAP cationic liposomes co-administrated with CpG-ODN.

    PubMed

    Mansourian, Mercedeh; Badiee, Ali; Jalali, Seyed Amir; Shariat, Sheida; Yazdani, Mona; Amin, Mohamdreza; Jaafari, Mahmoud Reza

    2014-11-01

    Cationic liposomes have been used as efficient antigen delivery systems for cancer vaccination. The current study has investigated whether the incorporation of the helper-fusogenic lipid dioleoylphosphatidylethanolamine (DOPE) in cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-cholesterol enhances the cytosolic delivery of p5 HER-2/neu derived peptide (p5) and promotes cytotoxic T lymphocytes (CTL) response. The p5, which is a very hydrophobic peptide, was encapsulated into liposomes by using three different methods and characterized for their colloidal properties. A chaotropic loading method using 7 M urea provided the highest encapsulation yields. Mice were first immunized with encapsulated p5 in liposomes composed of either DOTAP-cholesterol or DOTAP-cholesterol-DOPE, alone or co-administered with CpG-ODN, as an immunoadjuvant, then, inoculated with a subcutaneous injection of TUBO tumor cells. Results obtained from enzyme-linked immunospot, cytotoxicity and intracellular cytokine assays as well as tumor sizes and animal survival analysis demonstrated that p5 encapsulated in DOTAP-cholesterol-DOPE liposomes co-administered with CpG-ODN greatly enhanced the cytotoxic T lymphocytes response and highly inhibited the tumor progression. The outperformance of DOTAP-cholesterol-DOPE liposomes+CpG-ODN was found to be attributed to its capability in induction of both CD8+ and CD4+ responses. This formulation could be a suitable vaccine candidate against Her2 positive cancers and merits further investigations.

  17. Apples prevent mammary tumors in rats.

    PubMed

    Liu, Rui Hai; Liu, Jiaren; Chen, Bingqing

    2005-03-23

    Regular consumption of fruits and vegetables has been consistently shown to be associated with reduced risk of developing chronic diseases such as cancer and cardiovascular disease. Apples are commonly consumed and are the major contributors of phytochemicals in human diets. It was previously reported that apple extracts exhibit strong antioxidant and antiproliferative activities and that the major part of total antioxidant activity is from the combination of phytochemicals. Phytochemicals, including phenolics and flavonoids, are suggested to be the bioactive compounds contributing to the health benefits of apples. Here it is shown that whole apple extracts prevent mammary cancer in a rat model in a dose-dependent manner at doses comparable to human consumption of one, three, and six apples a day. This study demonstrated that whole apple extracts effectively inhibited mammary cancer growth in the rat model; thus, consumption of apples may be an effective strategy for cancer protection.

  18. Pegylated liposomal mitomycin C prodrug enhances tolerance of mitomycin C: a phase 1 study in advanced solid tumor patients.

    PubMed

    Golan, Talia; Grenader, Tal; Ohana, Patricia; Amitay, Yasmine; Shmeeda, Hilary; La-Beck, Ninh M; Tahover, Esther; Berger, Raanan; Gabizon, Alberto A

    2015-10-01

    Mitomycin C (MMC) has potent cytotoxicity but cumulative toxicity limits widespread use. In animals, pegylated liposomal mitomycin C lipid-based prodrug (PL-MLP) was well tolerated and more effective than free MMC. We evaluated PL-MLP in patients with advanced cancer. Twenty-seven patients were treated in escalating dose cohorts of 0.5-3.5 mg/kg (equivalent to 0.15-1.03 mg/kg MMC) every 4 weeks for up to 12 cycles, unless disease progression or unacceptable toxicity occurred. Pharmacokinetics were assessed during cycles 1 and 3. Per protocol maximum tolerated dose was not reached at 3.5 mg/kg. However, prolonged thrombocytopenia developed after repeated doses of 3 mg/kg or cumulative doses of 10-12 mg/kg. Dose-related grade 3 or higher adverse events included fatigue, anemia, and decreased platelets. Cmax and AUC0-∞ increased linearly over the dose range 0.5-2.0 mg/kg, and greater than linearly from 2.5 to 3.5 mg/kg; there were no significant differences in clearance of MLP between cycles 1 and 3. Median t1/2 was 23 h among dose cohorts, with no trend by dose or cycle. One patient had a partial response. Stable disease was observed in 10 patients across all dose levels. PL-MLP has a long circulation time, was well tolerated, and can be administered to heavily pretreated patients at a single dose of 3.0 mg/kg and cumulative dose of 10-12 mg/kg before development of prolonged thrombocytopenia; this is nearly threefold the equivalent dose of MMC tolerated historically. This formulation may be active in a variety of tumor types and is better tolerated than free MMC.

  19. Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model

    PubMed Central

    Ranjan, Ashish; Jacobs, Genevieve; Woods, David L.; Negussie, Ayele H.; Partanen, Ari; Yarmolenko, Pavel S.; Gacchina, Carmen E.; Sharma, Karun V.; Frenkel, Victor; Wood, Bradford J.; Dreher, Matthew R.

    2012-01-01

    Clinical-grade Doxorubicin encapsulated low temperature sensitive liposomes (LTSLs) were combined with a clinical magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) platform to investigate in-vivo image-guided drug delivery. Plasma pharmacokinetics were determined in 3 rabbits. Fifteen rabbits with Vx2 tumors within superficial thigh muscle were randomly assigned into three treatment groups: 1) free doxorubicin, 2) LTSL and 3) LTSL+MR-HIFU. For the LTSL+MR-HIFU group, mild hyperthermia (40–41°C) was applied to the tumors using an MR-HIFU system. Image-guided non-invasive hyperthermia was applied for a total of 30 min, completed within 1 hour after LTSL infusion. High-pressure liquid chromatography (HPLC) analysis of the harvested tumor and organ/tissue homogenates was performed to determine doxorubicin concentration. Fluorescence microscopy was performed to determine doxorubicin spatial distribution in the tumors. Sonication of Vx2 tumors resulted in accurate (mean=40.5±0.1°C) and spatially homogenous (SD=1.0°C) temperature control in the target region. LTSL+MR-HIFU resulted in significantly higher tumor doxorubicin concentrations (7.6- and 3.4-fold greater compared to free doxorubicin and LTSL respectively, p<0.05, Newman-Keuls). This improved tumor concentration was achieved despite heating <25% of the tumor volume. Free doxorubicin and LTSL treatments appeared to deliver more drug in the tumor periphery as compared to the tumor core. In contrast, LTSL+MR-HIFU treatment suggested an improved distribution with doxorubicin found in both the tumor periphery and core. Doxorubicin bio-distribution in non-tumor organs/tissues was fairly similar between treatment groups. This technique has potential for clinical translation as an image-guided method to deliver drug to a solid tumor. PMID:22210162

  20. Localized immunotherapy via liposome-anchored Anti-CD137 + IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity.

    PubMed

    Kwong, Brandon; Gai, S Annie; Elkhader, Jamal; Wittrup, K Dane; Irvine, Darrell J

    2013-03-01

    Immunostimulatory agonists such as anti-CD137 and interleukin (IL)-2 have elicited potent antitumor immune responses in preclinical studies, but their clinical use is limited by inflammatory toxicities that result upon systemic administration. We hypothesized that by rigorously restricting the biodistribution of immunotherapeutic agents to a locally accessible lesion and draining lymph node(s), effective local and systemic antitumor immunity could be achieved in the absence of systemic toxicity. We anchored anti-CD137 and an engineered IL-2Fc fusion protein to the surfaces of PEGylated liposomes, whose physical size permitted dissemination in the tumor parenchyma and tumor-draining lymph nodes but blocked entry into the systemic circulation following intratumoral injection. In the B16F10 melanoma model, intratumoral liposome-coupled anti-CD137 + IL-2Fc therapy cured a majority of established primary tumors while avoiding the lethal inflammatory toxicities caused by equivalent intratumoral doses of soluble immunotherapy. Immunoliposome therapy induced protective antitumor memory and elicited systemic antitumor immunity that significantly inhibited the growth of simultaneously established distal tumors. Tumor inhibition was CD8(+) T-cell-dependent and was associated with increased CD8(+) T-cell infiltration in both treated and distal tumors, enhanced activation of tumor antigen-specific T cells in draining lymph nodes, and a reduction in regulatory T cells in treated tumors. These data suggest that local nanoparticle-anchored delivery of immuno-agonists represents a promising strategy to improve the therapeutic window and clinical applicability of highly potent but otherwise intolerable regimens of cancer immunotherapy. Cancer Res; 73(5); 1547-58. ©2012 AACR.

  1. Tolerability and outcome of once weekly liposomal amphotericin B for the prevention of invasive fungal infections in hematopoietic stem cell transplant patients with graft-versus-host disease

    PubMed Central

    Tran, H. Luu; Mahmoudjafari, Zahra; Rockey, Michelle; Henry, Dave; Grauer, Dennis; Aljitawi, Omar; Abhyankar, Sunil; Ganguly, Siddhartha; Lin, Tara; McGuirk, Joseph

    2015-01-01

    Background Invasive fungal infections remain problematic in immunosuppressed allogeneic stem cell transplant recipients and the use of corticosteroids for the treatment of graft-versus-host-disease can increase the risk three-fold. Although antifungal prophylaxis has been shown to decrease the incidence of infection, the optimal antifungal prophylactic regimen in this patient population has yet to be identified. Since early diagnosis of fungal infections might not be possible and the treatment of established fungal infections might be difficult and associated with high infection related mortality, prevention has become an important strategy in reducing overall morbidity and mortality. While triazoles are the preferred agents, some patients are unable to tolerate them and an alternative drug is warranted. Objectives To assess the tolerability of once weekly liposomal amphotericin B as a prophylactic strategy in patients undergoing stem cell transplantation by evaluating any adverse events leading to its discontinuation. In terms of efficacy, to also compare the outcome and incidence of invasive fungal infections in patients who received amphotericin B, triazoles, and echinocandins. Results A total of 101 allogeneic transplant recipients receiving corticosteroids for the treatment of graft-versus-host-disease and antifungal prophylaxis were evaluated from August 2009 to September 2012. Liposomal amphotericin B 3 mg/kg intravenous once weekly was found to be well-tolerated. The incidence of invasive fungal infections was 19%, 17%, and 7% in the liposomal amphotericin B, echinocandin, and triazole groups, respectively. Two deaths occurred in the liposomal amphotericin B group and one death occurred in the echinocandin group. None of the deaths were fungal infection-related. Conclusion Antifungal prophylaxis with liposomal amphotericin B was well-tolerated but the incidence of invasive fungal infections in patients receiving liposomal amphotericin B was higher than

  2. Preparation and characterization of gemcitabine liposome injections.

    PubMed

    Zhou, Qinmei; Liu, Liucheng; Zhang, Dengshan; Fan, Xingfeng

    2012-10-01

    Gemcitabine liposome injection (stealth liposomes) has facilitated the targeting of gemcitabine for cancer treatment. We systemically review liposome-based drug-delivery systems, which can improve pharmacokinetics, reduce side effects and potentially increase tumor uptake, for pancreatic cancer therapy. A novel liposomal formulation, which allows for higher tumor targeting efficiencies and can be used in current clinical trials to treat this challenging disease, has gained great popularity and attention. In this study, since extrusion technology was used to make sterile preparation of liposomes, the process included aseptic production process and sterile filtration. During the preparation, it has been found that the lipid concentration, emulsification speed and time, the homogenization times and pattern, the lipid solution temperature are all critical parameters for the character of the gemcitabine liposome injection. The particle size method and zeta potential method to characterize a PEGylated liposomal drug formulation of the anti-cancer agent gemcitabine was developed. The methods are specific, precise, reproducible and sensitive, therefore they are suitable for the determination of particle size and zeta potential of gemcitabine liposome injection. Negative staining technology of transmission electron microscopy revealed that gemcitabine liposome injection has a typical morphology, which enables liposomal surfaces could be seen so additional visual information on the stealth liposome can be routinely obtained in a fast and reliable manner. Moreover, the above three methods are simple, fast and would be used for continuous quality control of gemcitabine liposome injection when it moves to cGMP production scale.

  3. Combination between Taxol-Encapsulated Liposomes and Eruca sativa Seed Extract Suppresses Mammary Tumors in Female Rats Induced by 7,12 Dimethylbenz(α)anthracene.

    PubMed

    Shaban, Nadia; Abdel-Rahman, Salah; Haggag, Amany; Awad, Doaa; Bassiouny, Ahmad; Talaat, Iman

    2016-01-01

    Taxol (paclitaxel) is a powerful anti-cancer drug widely used against several types of malignant tumors. Because Taxol may exert several side effects, a variety of formulations have been developed. One of these features liposomes, regarded as one of the most promising drug carriers, biocompatible and best able to reduce drug toxicity without changing efficacy against tumor cells. Eruca sativa seed extract (SE) is considered a promising natural product from cruciferous vegetables against breast cancer, increasing chemotherapeutic and eliminating harmful side effects. The effects of Taxol-encapsulated liposomes (T) alone and in combination between Eruca sativa seed extract on nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels were investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(α) anthracene (DMBA) using qRT-PCR. The results showed that DMBA increased NF-κB, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while decreasing glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. T and T-SE treatment reduced NF-κB, COX-2 and Bcl-2 gene expression levels and LP. Hence, T and T-SE treatment appeared to reduce inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC.

  4. Effects of the protein corona on liposome-liposome and liposome-cell interactions.

    PubMed

    Corbo, Claudia; Molinaro, Roberto; Taraballi, Francesca; Toledano Furman, Naama E; Sherman, Michael B; Parodi, Alessandro; Salvatore, Francesco; Tasciotti, Ennio

    2016-01-01

    A thorough understanding of interactions occurring at the interface between nanocarriers and biological systems is crucial to predict and interpret their biodistribution, targeting, and efficacy, and thus design more effective drug delivery systems. Upon intravenous injection, nanoparticles are coated by a protein corona (PC). This confers a new biological identity on the particles that largely determines their biological fate. Liposomes have great pharmaceutical versatility, so, as proof of concept, their PC has recently been implicated in the mechanism and efficiency of their internalization into the cell. In an attempt to better understand the interactions between nanocarriers and biological systems, we analyzed the plasma proteins adsorbed on the surface of multicomponent liposomes. Specifically, we analyzed the physical properties and ultrastructure of liposome/PC complexes and the aggregation process that occurs when liposomes are dispersed in plasma. The results of combined confocal microscopy and flow cytometry experiments demonstrated that the PC favors liposome internalization by both macrophages and tumor cells. This work provides insights into the effects of the PC on liposomes' physical properties and, consequently, liposome-liposome and liposome-cell interactions.

  5. Analysis of the photodynamic therapy effects by using chloroaluminum phthalocyanine incorporated into liposomes and fractionation energy in colon tumors of rats

    NASA Astrophysics Data System (ADS)

    Duarte, Janaina; Hage, Raduan; Tedesco, Antonio C.; Pazos, Marcelo; Martin, Airton A.; Plapler, Helio

    2006-02-01

    Photodynamic therapy (PDT) has been widely studied in the last decades and it is becoming a promising tool in the treatment of tumors of many kinds. PDT is based on photoactivation of a sensitized drug that is restrained in the tumor cells, producing highly reactive species that can destroy tumoral cells with minimum collateral effect. This study aimed to evaluate the effect of the PDT in induced neoplasias of the colon by 1,2-dimetilhidrazine in rats, using as photosensitizing drug the chloroaluminum phthalocyanine incorporated to the liposomes and to compare the methods of irradiation using continuous or fractionated energy in PDT. Ten Wistar rats were distributed randomly in 3 groups (G1, G2 and C), anaesthetized and submitted to PDT with of fractionated (G1) or continuum (G2) irradiation energy using as a source of excitement an InGaAl laser. After 3 hours of the laser irradiation, 2 animals of the G1 group, 2 animals of the G2 group and 1 animal of C group were sacrificed and samples of tumoral tissue were collected for histological analysis; the same procedure was carried through 24 hours after irradiation. There were no significant differences between the extensions of the induced areas of necrosis for PDT in the groups under fractionated or continuous irradiation for the parameters used in this study. New studies must be carried through, using different parameters and intervals of laser irradiation, aiming to maximize the effect of the PDT for the treatment of colon tumors.

  6. Aerosolised liposomal amphotericin B to prevent aspergillosis in acute myeloid leukaemia: Efficacy and cost effectiveness in real-life.

    PubMed

    Chong, Ga-Lai M; Broekman, Fleur; Polinder, Suzanne; Doorduijn, Jeanette K; Lugtenburg, Pieternella J; Verbon, Annelies; Cornelissen, Jan J; Rijnders, Bart J A

    2015-07-01

    Chemotherapy-induced neutropenia can be complicated by invasive pulmonary aspergillosis (IPA). In 2008, liposomal amphotericin B (L-AmB) inhalation was shown to prevent IPA in a placebo-controlled trial. Patients with acute myeloid leukaemia (AML) are the subset of haematology patients at high risk for IPA. In 2008, L-AmB inhalation prophylaxis became the standard of care for all AML patients in Erasmus MC. In this study, the efficacy and cost effectiveness of L-AmB inhalation were evaluated in a prospective cohort of AML patients. In total, 127 consecutive AML patients received chemotherapy and prophylactically inhaled L-AmB during their first and second chemotherapy cycles; 108 patients treated for AML at the same sites from 2005-2008 served as controls. A standardised diagnostic protocol was used and probable/proven IPA served as the primary endpoint. Diagnostic and therapeutic costs were also comprehensively analysed and compared. A significant decrease in probable/proven IPA in the L-AmB inhalation group was observed (L-AmB 9.5% vs. controls 23.4%; P=0.0064). Systemic antifungal therapy given at any time during the entire AML therapy decreased from 52.8% to 29.9%. Per-patient equipment and drug costs for L-AmB inhalation (1292 €/patient) were more than compensated for by a decrease in costs for diagnostics and therapeutic voriconazole use (-1816 €/patient). No serious adverse events related to L-AmB inhalation were observed. In an unselected AML patient group, L-AmB inhalation resulted in a significant and substantial decrease in IPA and was cost saving. Now that azole resistance is more frequent, non-azole-based prophylaxis may become an attractive strategy.

  7. Liposome-encapsulated actinomycin for cancer chemotherapy

    DOEpatents

    Rahman, Yueh-Erh; Cerny, Elizabeth A.

    1976-01-01

    An improved method is provided for chemotherapy of malignant tumors by injection of antitumor drugs. The antitumor drug is encapsulated within liposomes and the liposomes containing the encapsulated drug are injected into the body. The encapsulated drug penetrates into the tumor cells where the drug is slowly released and induces degeneration and death of the tumor cells, while any toxicity to the host body is reduced. Liposome encapsulation of actinomycin D has been found to be particularly effective in treating cancerous abdominal tumors, while drastically reducing the toxicity of actinomycin D to the host.

  8. Liposomal Indocyanine Green for Enhanced Photothermal Therapy.

    PubMed

    Yoon, Hwan-Jun; Lee, Hye-Seong; Lim, Ji-Young; Park, Ji-Ho

    2017-02-22

    In this study, we engineered liposomal indocyanine green (ICG) to maximize its photothermal effects while maintaining the fluorescence intensity. Various liposomal formulations of ICG were prepared by varying the lipid composition and the molar ratio between total lipid and ICG, and their photothermal characteristics were evaluated under near-infrared irradiation. We showed that the ICG dispersity in the liposomal membrane and its physical interaction with phospholipids were the main factors determining the photothermal conversion efficiency. In phototherapeutic studies, the optimized formulation of liposomal ICG showed greater anticancer effects in a mouse tumor model compared with other liposomal formulations and the free form of ICG. Furthermore, we utilized liposomal ICG to visualize the metastatic lymph node around the primary tumor under fluorescence imaging guidance and ablate the lymph node with the enhanced photothermal effect, indicating the potential for selective treatment of metastatic lymph node.

  9. Anti-cancer activity of doxorubicin-loaded liposomes co-modified with transferrin and folic acid.

    PubMed

    Sriraman, Shravan Kumar; Salzano, Giusseppina; Sarisozen, Can; Torchilin, Vladimir

    2016-08-01

    Cancer-specific drug delivery represents an attractive approach to prevent undesirable side-effects and increase the accumulation of the drug in the tumor. Surface modification of nanoparticles such as liposomes with targeting moieties specific to the up-regulated receptors on the surface of tumor cells thus represents an effective strategy. Furthermore, since this receptor expression can be heterogeneous, using a dual-combination of targeting moieties may prove advantageous. With this in mind, the anti-cancer activity of PEGylated doxorubicin-loaded liposomes targeted with folic acid (F), transferrin (Tf) or both (F+Tf) was evaluated. The dual-targeted liposomes showed a 7-fold increase in cell association compared to either of the single-ligand targeted ones in human cervical carcinoma (HeLa) cell monolayers. The increased penetration and cell association of the dual-targeted liposomes were also demonstrated using HeLa cell spheroids. The in vitro cytotoxicity of the doxorubicin liposomes (LD) was then evaluated using HeLa and A2780-ADR ovarian carcinoma cell monolayers. In both these cell lines, the (F+Tf) LD showed significantly higher cytotoxic effects than the untargeted, or single-ligand targeted liposomes. In a HeLa xenograft model in nude mice, compared to the untreated group, though the untargeted LD showed 42% tumor growth inhibition, both the (F) LD and (F+Tf) LD showed 75% and 79% tumor growth inhibition respectively. These results thus highlight that though the dual-targeted liposomes represent an effective cytotoxic formulation in the in vitro setting, they were equally effective as the folic acid-targeted liposomes in reducing tumor burden in the more complex in vivo setting in this particular model.

  10. Effect of calcium antagonists and metabolic inhibitors on the retention of adriamycin, in both free and liposomal form, in a number of tumor cells lines

    SciTech Connect

    Radel, S.

    1987-01-01

    Adriamycin (ADR) encapsulated in liposomes (MLV-ADR) accumulated at a lower rate, with a concomitant reduced cytotoxicity, in comparison to the free drug form (F-ADR) in all murine tumors tested. However, inhibition of (/sup 3/H) thymidine incorporation into DNA appeared nearly equal between F-ADR and MLV-ADR treated tumor cells suggesting that the concentration necessary to inhibit DNA synthesis is only a fraction of the total drug content within the cells. Electrophoretic mobility of tumor cells was unaffected by exposure to either F-ADR or MLV-ADR. The metabolic inhibitor N-ethylmaleimide (NEM) when coincubated with F-ADR in P388 adriamycin-resistant leukemia cells (P388-ADR) resulted in a marked increase in intracellular drug accumulation. Use of the calcium channel blockers verapamil (VRP) and N-3,4-dimethoxyphenethyl)-N-methyl-2-(2-napthyl)-m-dithane-2-propylamine hydrochloride, (DMDP), a derivative of verapamil, in conjunction with adriamycin treatment demonstrated a near reversal of resistance in P388/ADR. Retention of drug increased 4-5 fold in the presence of each of the calcium antagonists in vitro studies with a concomitant drop in viability which surpassed that observed in P388/O. P388/ADR tumor bearing mice treated with the combination of VRP or DMDP and F-ADR exhibited no increase in mean survival times (MST) over F-ADR therapy alone. Scanning electron microscopy (SEM) studies of P388/O tumor cells demonstrated numerous, small villi-like processes, whereas P388/ADR cells possessed many large membraneous folds. Transmission electron microscopy (TEM) demonstrated not only the membrane folding seem by SEM, but also the presence of large numbers of C type viral particles in P388/ADR cells in comparison to the small amounts detected in P388/O cells.

  11. A systemic administration of liposomal curcumin inhibits radiation pneumonitis and sensitizes lung carcinoma to radiation

    PubMed Central

    Shi, Hua-shan; Gao, Xiang; Li, Dan; Zhang, Qiong-wen; Wang, Yong-sheng; Zheng, Yu; Cai, Lu-Lu; Zhong, Ren-ming; Rui, Ao; Li, Zhi-yong; Zheng, Hao; Chen, Xian-cheng; Chen, Li-juan

    2012-01-01

    Radiation pneumonitis (RP) is an important dose-limiting toxicity during thoracic radiotherapy. Previous investigations have shown that curcumin is used for the treatment of inflammatory conditions and cancer, suggesting that curcumin may prevent RP and sensitize cancer cells to irradiation. However, the clinical advancement of curcumin is limited by its poor water solubility and low bioavailability after oral administration. Here, a water-soluble liposomal curcumin system was developed to investigate its prevention and sensitizing effects by an intravenous administration manner in mice models. The results showed that liposomal curcumin inhibited nuclear factor-κB pathway and downregulated inflammatory factors including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and transforming growth factor-β induced by thoracic irradiation. Furthermore, the combined treatment with liposomal curcumin and radiotherapy increased intratumoral apoptosis and microvessel responses to irradiation in vivo. The significantly enhanced inhibition of tumor growth also was observed in a murine lung carcinoma (LL/2) model. There were no obvious toxicities observed in mice. The current results indicate that liposomal curcumin can effectively mitigate RP, reduce the fibrosis of lung, and sensitize LL/2 cells to irradiation. This study also suggests that the systemic administration of liposomal curcumin is safe and deserves to be investigated for further clinical application. PMID:22679371

  12. Nanocomposite liposomes containing quantum dots and anticancer drugs for bioimaging and therapeutic delivery: a comparison of cationic, PEGylated and deformable liposomes

    NASA Astrophysics Data System (ADS)

    Wen, Chih-Jen; Sung, Calvin T.; Aljuffali, Ibrahim A.; Huang, Yu-Jie; Fang, Jia-You

    2013-08-01

    Multifunctional liposomes loaded with quantum dots (QDs) and anticancer drugs were prepared for simultaneous bioimaging and drug delivery. Different formulations, including cationic, PEGylated and deformable liposomes, were compared for their theranostic efficiency. We had evaluated the physicochemical characteristics of these liposomes. The developed liposomes were examined using experimental platforms of cytotoxicity, cell migration, cellular uptake, in vivo melanoma imaging and drug accumulation in tumors. The average size of various nanocomposite liposomes was found to be 92-134 nm. Transmission electron microscopy confirmed the presence of QDs within liposomal bilayers. The incorporation of polyethylene glycol (PEG) and Span 20 into the liposomes greatly increased the fluidity of the bilayers. The liposomes provided sustained release of camptothecin and irinotecan. The cytotoxicity and cell migration assay demonstrated superior activity of cationic liposomes compared with other carriers. Cationic liposomes also showed a significant fluorescence signal in melanoma cells after internalization. The liposomes were intratumorally administered to a melanoma-bearing mouse. Cationic liposomes showed the brightest fluorescence in tumors, followed by classical liposomes. This signal could last for up to 24 h for cationic nanosystems. Intratumoral accumulation of camptothecin from free control was 35 nmol g-1 it could be increased to 50 nmol g-1 after loading with cationic liposomes. However, encapsulation of irinotecan into liposomes did not further increase intratumoral drug accumulation. Cationic liposomes were preferable to other liposomes as nanocarriers in both bioimaging and therapeutic approaches.

  13. WE-EF-BRA-09: Microbeam Radiation Therapy Enhances Tumor Drug Uptake of PEGylated Liposomal Doxorubicin (PLD) in a Triple Negative Breast Cancer GEM Model

    SciTech Connect

    Chang, SX; Madden, AJ; Rivera, JN; Santos, CM; Hunter, LM; Darr, DB; Zamboni, WC

    2015-06-15

    Purpose: Overcoming low anti-cancer drug uptake in tumors is a key challenge limiting its clinical use. We propose to enhance the drug delivery using upfront Microbeam Radiation Therapy (MRT). MRT is a preclinical cancer therapy that utilizes microplanar beams to deliver spatially oscillating planes of high and low doses. Animal studies have demonstrated that ultrahigh dose (100s Gy) MRT eradicates tumors without damaging the function of normal tissue exposed to the same radiation. Our previous study indicated that MRT induces intense angiogenesis in tumor rim and surrounding normal tissue 1–2 days post radiation. We hypothesize that the tumor microenvironment modulation induced by MRT may enhance carrier-mediated agent drug delivery to tumors with inherent poor drug uptake. We thus investigated MRT-induced pharmacokinetics (PK) of PEGylated liposomal doxorubicin (PLD), a nano-scale doxorubicin, in T11 genetically engineered mouse model of triple negative breast cancer. Methods: A research irradiator (160kVp, RadSource Technologies) with a customized collimator was used to produce the MRT microbeam of in average 390µm width and 1190µm peak-to-peak distance. The peak dose rate of 1–2Gy/min. Dosimetry is by EBT3 film cross-calibrated with ion chamber at large fields. All mice were administered PLD at 6mg/kg IV x1 at 16h post MRT and sacrificed at 5min, 6h, 24h, and 96h post PLD administration (n=3 or 4 per group). Results: The MRT(28Gy)+PLD group mice had a total doxorubicin tumor concentration (area-under-the concentration-curve, AUC) of 206,040ng/mL•h, 3.71 times the concentration of the PLD-alone group. The MRT(34Gy)+PLD group had a higher mean total doxorubicin concentration in tumor (20,779ng/ml) than the MRT(28Gy)+PLD group (10,665ng/ml). Conclusion: Our preliminary results indicate that microbeam radiation therapy (MRT) can enhance nano-scale anti-cancer drug delivery to tumors approximately 4-fold. The exact working mechanism, the comparison with

  14. Pharmacokinetic, biodistribution and therapeutic efficacy of 5-fluorouracil-loaded pH-sensitive PEGylated liposomal nanoparticles in HCT-116 tumor bearing mouse

    PubMed Central

    Udofot, Ofonime; Affram, Kevin; Smith, Taylor; Tshabe, Bulumko; Krishnan, Sunil; Sachdeva, Mandip; Agyare, Edward

    2016-01-01

    The objective of the study was to investigate the pharmacokinetics and efficacy of 5-FU entrapped pH-sensitive liposomal nanoparticles with surface-modified anti-epidermal growth factor receptor (EGFR) antibody (pHLNps-5-FU) delivery system. Cytotoxicity of 5-FU and pHLNps-5-FU was determined in vitro against HCT-116 cells. The biodistribution and pharmacokinetic parameters of the administered 5-FU and pHLNps-5-FU as well as efficacy of 5-FU and pHLNps-5-FU were determined in HCT-116 subcutaneous mouse model. Mean size of pHLNp-5-FU was 164.3 ± 8.4 nm with entrapment efficiency (E.E) of 54.17%. While cytotoxicity of 5-FU and pHLNps-5-FU showed a strong dose-dependent, pHLNps-5-FU proved to be more effective (2–3 fold high) than that of 5-FU against HCT-116 cells. Pharmacokinetic study showed a prolonged plasma circulation of pHLNps-5-FU and a more significant body exposure while accumulation of pHLNps-5-FU in tumor was significantly higher than that of free 5-FU. Further, the efficacy of pHLNps-5-FU, was greater than free 5-FU at equivalent 5-FU dose. The study suggests that pHLNps may be an effective drug delivery system to enhance the anticancer activity of 5-FU against colorectal tumor growth. PMID:27200415

  15. Tumor Expression of CD200 Inhibits IL-10 Production by Tumor-Associated Myeloid Cells and Prevents Tumor Immune Evasion of CTL Therapy

    PubMed Central

    Wang, Lixin; Liu, Jin-Qing; Talebian, Fatemeh; El-Omrani, Hani Y.; Khattabi, Mazin; Yu, Li; Bai, Xue-Feng

    2010-01-01

    CD200 is a cell-surface glycoprotein that functions through interaction with the CD200 receptor (CD200R) on myeloid lineage cells to regulate myeloid cell functions. Expression of CD200 has been implicated in multiple types of human cancer, however the impact of tumor expression of CD200 on tumor immunity remains poorly understood. To evaluate this issue, we generated CD200-positive mouse plasmacytoma J558 and mastocytoma P815 cells. We found that established CD200-positive tumors were often completely rejected by adoptively transferred CTL without tumor recurrence; in contrast, CD200-negative tumors were initially rejected by adoptively transferred CTL but the majority of tumors recurred. Tumor expression of CD200 significantly inhibited suppressive activity and IL-10 production by tumor-associated myeloid cells (TAMC), and as a result, more CTL accumulated in the tumor and exhibited a greater capacity to produce IFN-γ in CD200-positive tumors than in CD200-negative tumors. Neutralization of IL-10 significantly inhibited the suppressor activity of TAMC, and IL-10-deficiency allowed TAMC to kill cancer cells and their antigenic variants, which prevented tumor recurrence during CTL therapy. Thus, tumor expression of CD200 prevents tumor recurrence via inhibiting IL-10 production by TAMC. PMID:20662098

  16. Environment-Responsive Multifunctional Liposomes

    PubMed Central

    Kale, Amit A.; Torchilin, Vladimir P.

    2012-01-01

    Liposomal nanocarriers modified with cell-penetrating peptide and a pH-sensitive PEG shield demonstrate simultaneously a better systemic circulation and site-specific exposure of the cell-penetrating peptide. PEG chains were incorporated into the liposome membrane via the PEG-attached phosphatidylethanolamine (PE) residue with PEG and PE being conjugated with the lowered pH-degradable hydrazone bond (PEG-HZ-PE), while cell-penetrating peptide (TATp) was added as TATp-PEG-PE conjugate. Under normal conditions, liposome-grafted PEG “shielded” liposome-attached TATp moieties, since the PEG spacer for TATp attachment (PEG(1000)) was shorter than protective PEG(2000). PEGylated liposomes accumulate in targets via the EPR effect, but inside the “acidified” tumor or ischemic tissues lose their PEG coating because of the lowered pH-induced hydrolysis of HZ and penetrate inside cells via the now-exposed TATp moieties. pH-responsive behavior of these constructs is successfully tested in cell cultures in vitro as well as in tumors in experimental mice in vivo. These nanocarriers also showed enhanced pGFP transfection efficiency upon intratumoral administration in mice, compared to control pH nonsensitive counterpart. These results can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems. PMID:20072884

  17. Clinical developments of chemotherapeutic nanomedicines: polymers and liposomes for delivery of camptothecins and platinum (II) drugs.

    PubMed

    Kieler-Ferguson, Heidi M; Fréchet, Jean M J; Szoka, Francis C

    2013-01-01

    For the past 40 years, liposomal and polymeric delivery vehicles have been studied as systems capable of modulating the cytotoxicity of small molecule chemotherapeutics, increasing tumor bearing animal survival times, and improving drug targeting. Although a number of macromolecular-drug conjugates have progressed to clinical trials, tuning drug release to maintain efficacy in conjunction with controlling drug toxicity has prevented the clinical adoption of many vehicles. In this article, we review the motivations for and approaches to polymer and liposomal delivery with regard to camptothecin and cisplatin delivery.

  18. Optimizing long-circulating liposomes for delivery of simvastatin to C26 colon carcinoma cells.

    PubMed

    Porfire, Alina; Tomuta, Ioan; Muntean, Dana; Luca, Lavinia; Licarete, Emilia; Alupei, Marius Costel; Achim, Marcela; Vlase, Laurian; Banciu, Manuela

    2015-01-01

    Simvastatin (SIM) is a lipophilic statin that has potential benefits for prevention and treatment of several types of malignancies. However, its low water solubility and the toxicity associated with administration of high doses recommend it for encapsulation in carriers able to deliver the therapeutic dose in the tumor. In this work, liposomes with long-circulating properties were proposed as delivery systems for SIM. The objective of this study was to optimize the formulation of SIM-loaded long-circulating liposomes (LCL-SIM) by using D-optimal experimental design. The influence of phospholipids concentration, phospholipids to cholesterol molar ratio and SIM concentration was studied on SIM liposomal concentration, encapsulation efficiency and liposomal size. The optimized formulation had liposomal SIM concentration 6238 µg/ml, EE % of 83.4% and vesicle size of 190.5 nm. Additionally we evaluated the in vitro cytotoxicity of the optimized liposomal SIM (LCL-SIM-OPT) on C26 murine colon carcinoma cells cultivated in monoculture as well as in co-culture with murine peritoneal macrophages at a cell density ratio that provides an approximation of physiological conditions of colon carcinoma development in vivo. Our preliminary studies suggested that LCL-SIM-OPT exerted cytotoxicity on C26 cells probably via enhancement of oxidative stress in co-culture environment.

  19. Capacious and programmable multi-liposomal carriers

    NASA Astrophysics Data System (ADS)

    Yaroslavov, Alexander A.; Sybachin, Andrey V.; Zaborova, Olga V.; Migulin, Vasiliy A.; Samoshin, Vyacheslav V.; Ballauff, Matthias; Kesselman, Ellina; Schmidt, Judith; Talmon, Yeshayahu; Menger, Fredric M.

    2015-01-01

    Spherical polycationic brushes (SPBs) were synthesized by grafting polycationic chains onto 100 nm polystyrene particles. These particles were exposed to unilamellar egg-lecithin (EL) liposomes with a mean diameter of 40 nm that had been rendered anionic via the presence of 10 molar% of phosphatidylserine (PS1-). The liposomes also contained 30 mole% of a morpholinocyclohexanol-based lipid (MOCH) that undergoes a conformational flip when the pH is decreased from 7.0 to 5.0. Mixtures of SPBs and liposomes at pH 7 gave an electrostatically-driven complex possessing, on average, about 40 liposomes for each SPB particle. It was found that the bound liposomes rapidly release much of their contents when the pH is reduced from 7.0 to 5.0 owing mostly to a MOCH conformational change that creates defects in the bilayer membrane. The drop in pH does not, however, induce a separation of the liposomes from the SPBs. Around 50-60% of the liposome contents escape before, it is reasoned, lateral and transmembrane motion of the membrane components heals the defects and prevents further release. Remarkably, the liposomes complexed with SPB release their cargo much faster than the identical but non-complexed liposomes.Spherical polycationic brushes (SPBs) were synthesized by grafting polycationic chains onto 100 nm polystyrene particles. These particles were exposed to unilamellar egg-lecithin (EL) liposomes with a mean diameter of 40 nm that had been rendered anionic via the presence of 10 molar% of phosphatidylserine (PS1-). The liposomes also contained 30 mole% of a morpholinocyclohexanol-based lipid (MOCH) that undergoes a conformational flip when the pH is decreased from 7.0 to 5.0. Mixtures of SPBs and liposomes at pH 7 gave an electrostatically-driven complex possessing, on average, about 40 liposomes for each SPB particle. It was found that the bound liposomes rapidly release much of their contents when the pH is reduced from 7.0 to 5.0 owing mostly to a MOCH conformational

  20. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors.

    PubMed

    Beg, Muhammad S; Brenner, Andrew J; Sachdev, Jasgit; Borad, Mitesh; Kang, Yoon-Koo; Stoudemire, Jay; Smith, Susan; Bader, Andreas G; Kim, Sinil; Hong, David S

    2017-04-01

    Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1-12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m(2), with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m(2). The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m(2) for non-HCC and 93 mg/m2 for HCC

  1. Are PEGylated liposomes better than conventional liposomes? A special case for vincristine.

    PubMed

    Wang, Xuling; Song, Yanzhi; Su, Yuqing; Tian, Qingjing; Li, Boqun; Quan, Jingjing; Deng, Yihui

    2016-05-01

    Cancer poses a significant threat to human health worldwide, and many therapies have been used for its palliative and curative treatments. Vincristine has been extensively used in chemotherapy. However, there are two major challenges concerning its applications in various tumors: (1) Vincristine's antitumor mechanism is cell-cycle-specific, and the duration of its exposure to tumor cells can significantly affect its antitumor activity and (2) Vincristine is widely bio-distributed and can be rapidly eliminated. One solution to these challenges is the encapsulation of vincristine into liposomes. Vincristine can be loaded into conventional liposomes, but it quickly leak out owing to its high membrane permeability. Numerous approaches have been attempted to overcome this problem. Vincristine has been loaded into PEGylated liposomes to prolong circulation time and improve tumor accumulation. These liposomes indeed prolong circulation time, but the payout characteristic of vincristine is severer, resulting in a compromised outcome rather than a better efficacy compared to conventional sphingomyelin (SM)/cholesterol (Chol) liposomes. In 2012, the USA Food and Drug Administration (FDA) approved SM/Chol liposomal vincristine (Marqibo®) for commercial use. In this review, we mainly focus on the drug's rapid leakage problem and the potentially relevant solutions that can be applied during the development of liposomal vincristine and the reason for conventional liposomal vincristine rather than PEGylated liposomes has access to the market.

  2. Super natural killer cells that target metastases in the tumor draining lymph nodes.

    PubMed

    Chandrasekaran, Siddarth; Chan, Maxine F; Li, Jiahe; King, Michael R

    2016-01-01

    Tumor draining lymph nodes are the first site of metastasis in most types of cancer. The extent of metastasis in the lymph nodes is often used in staging cancer progression. We previously showed that nanoscale TRAIL liposomes conjugated to human natural killer cells enhance their endogenous therapeutic potential in killing cancer cells cultured in engineered lymph node microenvironments. In this work, it is shown that liposomes decorated with apoptosis-inducing ligand TRAIL and an antibody against a mouse natural killer cell marker are carried to the tumor draining inguinal lymph nodes and prevent the lymphatic spread of a subcutaneous tumor in mice. It is shown that targeting natural killer cells with TRAIL liposomes enhances their retention time within the tumor draining lymph nodes to induce apoptosis in cancer cells. It is concluded that this approach can be used to kill cancer cells within the tumor draining lymph nodes to prevent the lymphatic spread of cancer.

  3. Doped colorimetric assay liposomes

    DOEpatents

    Charych, Deborah; Stevens, Raymond C.

    2001-01-01

    The present invention provides compositions comprising colorimetric assay liposomes. The present invention also provides methods for producing colorimetric liposomes and calorimetric liposome assay systems. In preferred embodiments, these calorimetric liposome systems provide high levels of sensitivity through the use of dopant molecules. As these dopants allow the controlled destabilization of the liposome structure, upon exposure of the doped liposomes to analyte(s) of interest, the indicator color change is facilitated and more easily recognized.

  4. Application of long-circulating liposomes to cancer photodynamic therapy.

    PubMed

    Oku, N; Saito, N; Namba, Y; Tsukada, H; Dolphin, D; Okada, S

    1997-06-01

    Photodynamic therapy (PDT) as a cancer treatment is notable for its quite low side effects in comparison with those of chemotherapy and radiotherapy. However, the accumulation of porphyrin derivatives used in PDT into tumor tissues is rather low. Since long-circulating liposomes are known to accumulate passively into tumor tissues, we liposomalized a porphyrin derivative, benzoporphyrin derivative monoacid ring A (BPD-MA), and used these liposomes to investigate the usefulness of PDT for tumor-bearing mice. BPD-MA was liposomalized into glucuronate-modified liposomes, which are known to be long-circulating. These liposomes were injected i.v. into Balb/c mice bearing Meth A sarcoma, and tumor regression and survival time were monitored after irradiation with laser light. Tumor regression and complete curing of tumor (80% cure rate by the treatment with 6 mg/kg BPD-MA) were observed when long circulating liposomalized BPD-MA was injected and laser-irradiated. In contrast, only a 20% cure rate was obtained when the animals were treated with BPD-MA solution or BPD-MA entrapped in conventional liposomes. These results suggest that a long-circulating liposomal formulation of photo-sensitive agents is useful for PDT.

  5. Novel antisense therapeutics delivery systems: In vitro and in vivo studies of liposomes targeted with anti-CD20 antibody.

    PubMed

    Meissner, Justyna M; Toporkiewicz, Monika; Czogalla, Aleksander; Matusewicz, Lucyna; Kuliczkowski, Kazimierz; Sikorski, Aleksander F

    2015-12-28

    Antisense gene therapy using molecules such as antisense oligodeoxynucleotides, siRNA or miRNA is a very promising strategy for the treatment of neoplastic diseases. It can be combined with other treatment strategies to enhance therapeutic effect. In acute leukemias, overexpression of the antiapoptotic gene BCL2 is observed in more than 70% of cases. Therefore, reduction of the Bcl-2 protein level could, in itself, prevent the development of cancer or could possibly help sensitize cancer cells to apoptosis inducers. The main objective of our work is to develop therapeutic liposome formulations characterized by high transfection efficiency, stability in the presence of serum, as well as specificity and toxicity for target (leukemic) cells. Each of our liposomal formulations consists of a core composed of antisense oligonucleotides complexed by either cationic lipid, DOTAP, or a synthetic polycation, polyethyleneimine, encapsulated within liposomes modified with polyethylenoglycol. In addition, the liposomal shells are enriched with covalently-bound antibodies recognizing a well characterized bio-marker, CD20, exposed on the surface of leukemia cells. The resulting immunoliposomes selectively and effectively reduced the expression of BCL2 in target cells. Model animal experiments carried out on mice-engrafted tumors expressing the specific marker showed high efficiency of the liposome formulations against specific tumor development. In conclusion, we show that lipid formulations based on a polyplex or lipoplex backbone additionally equipped with antibodies are promising non-viral vectors for specific oligonucleotide transfer into human tumor cells.

  6. Biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomal cisplatin administered in Ehrlich tumor-bearing mice.

    PubMed

    Araújo, José Geraldo Coimbra; Mota, Luciene das Graças; Leite, Elaine Amaral; Maroni, Laís de Carvalho; Wainstein, Alberto Julius Alves; Coelho, Luiz Gonzaga Vaz; Savassi-Rocha, Paulo Roberto; Pereira, Márcio Tadeu; de Carvalho, Andréa Teixeira; Cardoso, Valbert Nascimento; De Oliveira, Mônica Cristina

    2011-07-01

    Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL-CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal

  7. Sequential treatment of oxaliplatin-containing PEGylated liposome together with S-1 improves intratumor distribution of subsequent doses of oxaliplatin-containing PEGylated liposome.

    PubMed

    Nakamura, Hiroyuki; Doi, Yusuke; Abu Lila, Amr S; Nagao, Ai; Ishida, Tatsuhiro; Kiwada, Hiroshi

    2014-05-01

    We recently reported that combination therapy with metronomic S-1 dosing and oxaliplatin (l-OHP)-containing PEGylated liposomes improved antitumor activity in a murine colorectal tumor model. However, little is known about the mechanism underlying such improved therapeutic efficacy. Here we investigated the impact of combined treatment on biodistribution, tumor accumulation and intratumor distribution of test PEGylated liposomes and on the structure of tumor vasculature in a solid tumor. The combined treatment clearly enhanced tumor accumulation and intratumor distribution of a subsequent test dose of PEGylated liposome as a result of on the one hand prolonging blood circulation of test liposome and on the other hand the alteration in tumor microenvironment. The l-OHP-containing PEGylated liposomes contributed predominantly to the enhanced tumor accumulation and altered tumor distribution of test liposome. On the other hand, metronomic S-1 dosing contributed to the altered tumor distribution but not the tumor accumulation of test liposome. The antitumor effect of the combined treatment, reflected by the proportion of apoptotic cells in the tumor, was approximately equally accounted for by each of the two treatments, leading to a roughly additive effect. In conclusion, 1-OHP-containing PEGylated liposome together with S-1 enhanced intratumor influx, leading to improved antitumor activity of subsequently injected 1-OHP-containing PEGylated liposomes and/or S-1. This strategy we propose, which is clinically applicable, may overcome the problems related to the use of EPR effect-based nanocarrier systems.

  8. Cardiac safety of liposomal anthracyclines.

    PubMed

    Ewer, Michael S; Martin, Francis J; Henderson, Craig; Shapiro, Charles L; Benjamin, Robert S; Gabizon, Alberto A

    2004-12-01

    Conventional anthracyclines are active against many tumor types, but cardiotoxicity related to the cumulative dose may limit their use; this is particularly problematic for patients with risk factors for increased toxicity, for those who have received any anthracycline in the past, or for those who are to receive other cardiotoxic agents. Preclinical studies determined that encapsulating conventional anthracyclines in liposomes reduced the incidence and severity of cumulative dose-related cardiomyopathy while preserving antitumor activity. In controlled clinical trials, the risk of cardiotoxicity was significantly lower when nonpegylated liposomal doxorubicin (Myocet [NPLD]) was substituted for conventional doxorubicin, but the risk was not significantly different when NPLD was used in place of conventional epirubicin. Direct comparisons to conventional doxorubicin therapy showed comparable efficacy but significantly lower risk of cardiotoxicity with pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) therapy. Retrospective and prospective trials have not identified a maximum "cardiac safe" dose of PLD, despite use of cumulative doses exceeding 2,000 mg/m2 in some patients. Liposomal daunorubicin (DaunoXome [DNX]) may be associated with a lower risk of cardiotoxicity than conventional anthracyclines, but comparative trials are not available. With respect to combination chemotherapy, early results of clinical trials suggest that combining trastuzumab or a taxane with NPLD or PLD instead of a conventional anthracycline significantly reduces cardiotoxicity risk without reducing chemotherapeutic efficacy. Further results are eagerly awaited from ongoing controlled trials of cardiac safety with long-term liposomal anthracycline therapy, either alone or in combination with other potentially cardiotoxic agents.

  9. Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy

    PubMed Central

    Crittenden, Marka R.; Baird, Jason; Friedman, David; Savage, Talicia; Uhde, Lauren; Alice, Alejandro; Cottam, Benjamin; Young, Kristina; Newell, Pippa; Nguyen, Cynthia; Bambina, Shelly; Kramer, Gwen; Akporiaye, Emmanuel; Malecka, Anna; Jackson, Andrew; Gough, Michael J.

    2016-01-01

    Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFb inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy. PMID:27602953

  10. Use of liposomes as injectable-drug delivery systems.

    PubMed

    Ostro, M J; Cullis, P R

    1989-08-01

    The formation of liposomes and their application as delivery systems for injectable drugs are described. Liposomes are microscopic vesicles composed of one or more lipid membranes surrounding discrete aqueous compartments. These vesicles can encapsulate water-soluble drugs in their aqueous spaces and lipid-soluble drugs within the membrane itself. Liposomes release their contents by interacting with cells in one of four ways: adsorption, endocytosis, lipid exchange, or fusion. Liposome-entrapped drugs are distributed within the body much differently than free drugs; when administered intravenously to healthy animals and humans, most of the injected vesicles accumulate in the liver, spleen, lungs, bone marrow, and lymph nodes. Liposomes also accumulate preferentially at the sites of inflammation and infection and in some solid tumors; however, the reason for this accumulation is not clear. Four major factors influence liposomes' in vivo behavior and biodistribution: (1) liposomes tend to leak if cholesterol is not included in the vesicle membrane, (2) small liposomes are cleared more slowly than large liposomes, (3) the half-life of a liposome increases as the lipid dose increases, and (4) charged liposomal systems are cleared more rapidly than uncharged systems. The most advanced application of liposome-based therapy is in the treatment of systemic fungal infections, especially with amphotericin B. Liposomes are also under investigation for treatment of neoplastic disorders. Liposomes' uses in cancer therapy include encapsulation of known antineoplastic agents such as doxorubicin and methotrexate, delivery of immune modulators such as N-acetylmuramyl-L-alanine-D-isoglutamine, and encapsulation of new chemical entities that are synthesized with lipophilic segments tailored for insertion into lipid bilayers. Liposomal formulations of injectable antimicrobial agents and antineoplastic agents already are undergoing clinical testing, and most probably will receive

  11. Targeted Magnetic Liposomes Loaded with Doxorubicin.

    PubMed

    Pradhan, Pallab; Banerjee, Rinti; Bahadur, Dhirendra; Koch, Christian; Mykhaylyk, Olga; Plank, Christian

    2017-01-01

    Targeted delivery systems for anticancer drugs are urgently needed to achieve maximum therapeutic efficacy by site-specific accumulation and thereby minimizing adverse effects resulting from systemic distribution of many potent anticancer drugs. We have prepared folate receptor-targeted magnetic liposomes loaded with doxorubicin, which are designed for tumor targeting through a combination of magnetic and biological targeting. Furthermore, these liposomes are designed for hyperthermia-induced drug release to be mediated by an alternating magnetic field and to be traceable by magnetic resonance imaging (MRI). Here, detailed preparation and relevant characterization techniques of targeted magnetic liposomes encapsulating doxorubicin are described.

  12. Etoposide incorporated into camel milk phospholipids liposomes shows increased activity against fibrosarcoma in a mouse model.

    PubMed

    Maswadeh, Hamzah M; Aljarbou, Ahmad N; Alorainy, Mohammed S; Alsharidah, Mansour S; Khan, Masood A

    2015-01-01

    Phospholipids were isolated from camel milk and identified by using high performance liquid chromatography and gas chromatography-mass spectrometry (GC/MS). Anticancer drug etoposide (ETP) was entrapped in liposomes, prepared from camel milk phospholipids, to determine its activity against fibrosarcoma in a murine model. Fibrosarcoma was induced in mice by injecting benzopyrene (BAP) and tumor-bearing mice were treated with various formulations of etoposide, including etoposide entrapped camel milk phospholipids liposomes (ETP-Cam-liposomes) and etoposide-loaded DPPC-liposomes (ETP-DPPC-liposomes). The tumor-bearing mice treated with ETP-Cam-liposomes showed slow progression of tumors and increased survival compared to free ETP or ETP-DPPC-liposomes. These results suggest that ETP-Cam-liposomes may prove to be a better drug delivery system for anticancer drugs.

  13. Radioprotective effect of transferrin targeted citicoline liposomes.

    PubMed

    Suresh Reddy, Jannapally; Venkateswarlu, Vobalaboina; Koning, Gerben A

    2006-01-01

    The high level of expression of transferrin receptors (Tf-R) on the surface of endothelial cells of the blood-brain-barrier (BBB) had been widely utilized to deliver drugs to the brain. The primary aim of this study was to use transferrin receptor mediated endocytosis as a pathway for the rational development of holo-transferrin coupled liposomes for drug targeting to the brain. Citicoline is a neuroprotective agent used clinically to treat for instance Parkinson disease, stroke, Alzheimer's disease and brain ischemia. Citicoline does not readily cross the BBB because of its strong polar nature. Hence, citicoline was used as a model drug. (Citicoline liposomes have been prepared using dipalmitoylphosphatidylcholine (DPPC) or distearoylphosphatidylcholine (DSPC) by dry lipid film hydration-extrusion method). The effect of the use of liposomes composed of DPPC or DSPC on their citicoline encapsulation efficiency and their stability in vitro were studied. Transferrin was coupled to liposomes by a technique which involves the prevention of scavenging diferric iron atoms of transferrin. The coupling efficiency of transferrin to the liposomes was studied. In vitro evaluation of transferrin-coupled liposomes was performed for their radioprotective effect in radiation treated cell cultures. In this study, OVCAR-3 cells were used as a model cell type over-expressing the Tf-R and human umbilical vein endothelial cells (HUVEC) as BBB endothelial cell model. The average diameter of DPPC and DSPC liposomes were 138 +/- 6.3 and 79.0 +/- 3.2 nm, respectively. The citicoline encapsulation capacity of DPPC and DSPC liposomes was 81.8 +/- 12.8 and 54.9 +/- 0.04 microg/micromol of phospholipid, respectively. Liposomes prepared from DSPC showed relatively better stability than DPPC liposomes at 37 degrees C and in the presence of serum. Hence, DSPC liposomes were used for transferrin coupling and an average of 46-55 molecules of transferrin were present per liposome. Free citicoline

  14. Tumor Angiogenesis as a Target for Dietary Cancer Prevention

    PubMed Central

    Li, William W.; Li, Vincent W.; Hutnik, Michelle; Chiou, Albert S.

    2012-01-01

    Between 2000 and 2050, the number of new cancer patients diagnosed annually is expected to double, with an accompanying increase in treatment costs of more than $80 billion over just the next decade. Efficacious strategies for cancer prevention will therefore be vital for improving patients' quality of life and reducing healthcare costs. Judah Folkman first proposed antiangiogenesis as a strategy for preventing dormant microtumors from progressing to invasive cancer. Although antiangiogenic drugs are now available for many advanced malignancies (colorectal, lung, breast, kidney, liver, brain, thyroid, neuroendocrine, multiple myeloma, myelodysplastic syndrome), cost and toxicity considerations preclude their broad use for cancer prevention. Potent antiangiogenic molecules have now been identified in dietary sources, suggesting that a rationally designed antiangiogenic diet could provide a safe, widely available, and novel strategy for preventing cancer. This paper presents the scientific, epidemiologic, and clinical evidence supporting the role of an antiangiogenic diet for cancer prevention. PMID:21977033

  15. Randomized trial of dietary fiber and Lactobacillus casei administration for prevention of colorectal tumors.

    PubMed

    Ishikawa, Hideki; Akedo, Ikuko; Otani, Toru; Suzuki, Takaichiro; Nakamura, Tomiyo; Takeyama, Ikuko; Ishiguro, Shingo; Miyaoka, Etsuo; Sobue, Tomotaka; Kakizoe, Tadao

    2005-09-20

    The epidemiologic evidence that dietary fiber protects against colorectal cancer is equivocal. No large-scale clinical study of the administration of Lactobacillus casei has been reported. We examined whether dietary fiber and L. casei prevented the occurrence of colorectal tumors. Subjects were 398 men and women presently free from tumor who had had at least 2 colorectal tumors removed. Subjects were randomly assigned to 4 groups administered wheat bran, L. casei, both or neither. The primary end point was the presence or absence of new colorectal tumor(s) diagnosed by colonoscopy after 2 and 4 years. Among 380 subjects who completed the study, 95, 96, 96 and 93 were assigned to the wheat bran, L. casei, both and no treatment groups, respectively. Multivariate adjusted ORs for occurrence of tumors were 1.31 (95% CI 0.87-1.98) in the wheat bran group and 0.76 (0.50-1.15) in the L. casei group compared to the control group. There was a significantly higher number of large tumors after 4 years in the wheat bran group. The occurrence rate of tumors with a grade of moderate atypia or higher was significantly lower in the group administered L. casei. No significant difference in the development of new colorectal tumors was observed with administration of either wheat bran or L. casei. However, our results suggest that L. casei prevented atypia of colorectal tumors.

  16. Glioblastoma Treatment: Bypassing the Toxicity of Platinum Compounds by Using Liposomal Formulation and Increasing Treatment Efficiency With Concomitant Radiotherapy

    SciTech Connect

    Charest, Gabriel; Sanche, Leon; Fortin, David; Mathieu, David; Paquette, Benoit

    2012-09-01

    Purpose: Treatments of glioblastoma with cisplatin or oxaliplatin only marginally improve the overall survival of patients and cause important side effects. To prevent adverse effects, improve delivery, and optimize the tumor response to treatment in combination with radiotherapy, a potential approach consists of incorporating the platinum agent in a liposome. Methods and Materials: In this study, cisplatin, oxaliplatin, carboplatin, Lipoplatin (the liposomal formulation of cisplatin), and Lipoxal (the liposomal formulation of oxaliplatin) were tested on F98 glioma orthotopically implanted in Fischer rats. The platinum compounds were administered by intracarotid infusion and were assessed for the ability to reduce toxicity, improve cancer cell uptake, and increase survival of animals when combined or not combined with radiotherapy. Results: The tumor uptake was 2.4-fold more important for Lipoxal than the liposome-free oxaliplatin. Lipoxal also improved the specificity of oxaliplatin as shown by a higher ratio of tumor to right hemisphere uptake. Surprisingly, Lipoplatin led to lower tumor uptake compared with cisplatin. However, Lipoplatin had the advantage of largely reducing the toxicity of cisplatin and allowed us to capitalize on the anticancer activity of this agent. Conclusion: Among the five platinum compounds tested, carboplatin showed the best increase in survival when combined with radiation for treatment of glioma implanted in Fischer rats.

  17. Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes.

    PubMed

    Coimbra, Maria; Isacchi, Benedetta; van Bloois, Louis; Torano, Javier Sastre; Ket, Aldo; Wu, Xiaojie; Broere, Femke; Metselaar, Josbert M; Rijcken, Cristianne J F; Storm, Gert; Bilia, Rita; Schiffelers, Raymond M

    2011-09-20

    Natural bioactive compounds have been studied for a long time for their chemopreventive and therapeutic potential in several chronic inflammatory diseases, including cancer. However, their physicochemical properties generally result in poor chemical stability and lack of in vivo bioavailability. Very few human clinical trials have addressed absorption, distribution, metabolism, and excretion of these compounds in relation to efficacy. This limits the use of these valuable natural compounds in the clinic. In this study, we examined caffeic acid (derivatives), carvacrol (derivatives), thymol, pterostilbene (derivatives), and N-(3-oxo-dodecanoyl)-l-homoserine lactone. These are natural compounds with strong anti-inflammatory properties derived from plants and bacteria. However, these compounds have poor water solubility or are chemically unstable. To overcome these limitations we have prepared liposomal formulations. Our results show that lipophilic 3-oxo-C(12)-homoserine lactone and stilbene derivatives can be loaded into liposomal lipid bilayer with efficiencies of 50-70%. Thereby, the liposomes solubilize these compounds, allowing intravenous administration without use of solvents. When compounds could not be loaded into the lipid bilayer (carvacrol and thymol) or are rapidly extracted from the liposomes in the presence of serum albumin (3-oxo-C(12)-homoserine lactone and pterostilbene derivatives), derivatization of the compound into a water-soluble prodrug was shown to improve loading efficiency and encapsulation stability. The phosphate forms of carvacrol and pterostilbene were loaded into the aqueous interior of the liposomes and encapsulation was unaffected by the presence of serum albumin. Chemical instability of resveratrol was improved by liposome-encapsulation, preventing inactivating cis-trans isomerization. For caffeic acid, liposomal encapsulation did not prevent oxidation into a variety of products. Still, by derivatization into a phenyl ester, the

  18. Multifunctional liposomes for enhanced anti-cancer therapy

    NASA Astrophysics Data System (ADS)

    Falcao, Claudio Borges

    2011-12-01

    Macromolecular drugs have great promises for cancer treatment, such as the pro-apoptotic peptide D-(KLAKLAK)2 and the bcl-2 antisense oligodeoxynucleotide G3139. However, these macromolecules require efficient drug carriers, like liposomes, to deliver them inside cells. Also, if these macromolecules can be combined in a single liposome, the cancer cell killing will be greater than using just one. With this possibility in mind, cationic liposomes (CLs) were elaborated to encapsulate both macromolecules and deliver them inside cells. Later, surface modification of CLs was investigated through the addition of polyethylene glycol (PEG) to obtain long-circulating liposomes. CLs were prepared through charge alternation among D-(KLAKLAK)2 , G3139 and DOTAP. These liposomes were characterized with particle size and zeta-potential measurements, antisense entrapment and peptide loading efficiency. The in vitro effects of CL formulations were tested with B16(F10) cells through viability studies, uptake assay and detection of apoptosis. CL formulations were also applied in vivo in B16(F10) tumor-bearing mice through intratumoral injections, and tumor growth inhibition and detection of apoptosis were evaluated. Next, the mechanism of action of the CL formulations was investigated by Western blotting. Later, PEG was incorporated at increasing amounts to the liposomes to determine which concentration can better prevent interactions between PEG-cationic liposomes (PCL) and B16(F10) cells. Next, pH-cleavable PEG was prepared and then added to the liposomes in the same amount that PEG in PCL could decrease interaction with cells. Finally, cell viability studies were performed with CL, PCL and pH-sensitive PCL (pH-PCL) formulations after pre-incubation at pH 7.4 or at pH 5.0. Positively charged CL particles were obtained after encapsulation of negatively charged D-(KLAKLAK)2/G3139 complexes. In vitro , CLs containing D-(KLAKLAK)2/G3139 complexes could reduce B16(F10) cell viability

  19. The impact of a chlorotoxin-modified liposome system on receptor MMP-2 and the receptor-associated protein ClC-3.

    PubMed

    Qin, Chao; He, Bing; Dai, Wenbing; Lin, Zhiqiang; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Wang, Guangji; Yin, Lifang; Zhang, Qiang

    2014-07-01

    Currently, it is unknown whether a receptor-associated protein will be affected when a ligand modified delivery system interacts with its receptor. Besides, chlorotoxin (ClTx)-modified liposomes can target to glioma cells, but the target molecule is not clear: MMP-2, ClC-3 or both? Here a comparative study of ClTx-conjugated liposomes was conducted on two types of tumor cells: U87, a human glioma cell line with high expression of both MMP-2 and ClC-3, and A549, a human lung cancer cell line with expression of only MMP-2. ClTx-modified liposomes behaved similarly in these two cancer cells in terms of in vitro cell uptake, endocytosis pathway, intracellular trafficking and in vivo targeting efficacy, though the two tested cell lines were very different in ClC-3 expression. These results revealed that the targeted delivery of ClTx modified liposomes to U87 tumor was MMP-2-mediated and not correlated with the chloride channel ClC-3. On the other hand, ClTx modified on the liposomes did activate the receptor-associated protein ClC-3 via the binding with MMP-2, leading to the inhibition on cell migration and chloride currents. This is significant because cell migration is a key step in tumor metastasis. Interestingly, higher in vitro cellular uptake and lower in vivo tumor accumulation of liposomal systems was found in U87 compared to the A549 model, possibly due to the biological differences between in vitro and in vivo models. In general, ClTx-modified delivery systems may potentially target to tumors other than glioma that express a high level of MMP-2, and its effect on ClC-3 may help prevent tumor metastasis.

  20. Composite implants coated with biodegradable polymers prevent stimulating tumor progression

    NASA Astrophysics Data System (ADS)

    Litviakov, N. V.; Tverdokhlebov, S. I.; Perelmuter, V. M.; Kulbakin, D. E.; Bolbasov, E. N.; Tsyganov, M. M.; Zheravin, A. A.; Svetlichnyi, V. A.; Cherdyntseva, N. V.

    2016-08-01

    In this experiment we studied oncologic safety of model implants created using the solution blow spinning method with the use of the PURASORB PL-38 polylactic acid polymer and organic mineral filler which was obtained via laser ablation of a solid target made of dibasic calcium phosphate dihydrate. For this purpose the implant was introduced into the area of Wistar rats' iliums, and on day 17 after the surgery the Walker sarcoma was transplanted into the area of the implant. We evaluated the implant's influence on the primary tumor growth, hematogenous and lymphogenous metastasis of the Walker sarcoma. In comparison with sham operated animals the implant group demonstrated significant inhibition of hematogenous metastasis on day 34 after the surgery. The metastasis inhibition index (MII) equaled 94% and the metastases growth inhibition index (MGII) equaled 83%. The metastasis frequency of the Walker sarcoma in para aortic lymph nodes in the implant group was not statistically different from the control frequency; there was also no influence of the implant on the primary tumor growth noted. In case of the Walker sarcoma transplantation into the calf and the palmar pad of the ipsilateral limb to the one with the implant in the ilium, we could not note any attraction of tumor cells to the implant area, i.e. stimulation of the Walker sarcoma relapse by the implant. Thus, the research concluded that the studied implant meets the requirements of oncologic safety.

  1. Pros and cons of the liposome platform in cancer drug targeting.

    PubMed

    Gabizon, Alberto A; Shmeeda, Hilary; Zalipsky, Samuel

    2006-01-01

    Coating of liposomes with polyethylene-glycol (PEG) by incorporation in the liposome bilayer of PEG-derivatized lipids results in inhibition of liposome uptake by the reticulo-endothelial system and significant prolongation of liposome residence time in the blood stream. Parallel developments in drug loading technology have improved the efficiency and stability of drug entrapment in liposomes, particularly with regard to cationic amphiphiles such as anthracyclines. An example of this new generation of liposomes is a formulation of pegylated liposomal doxorubicin known as Doxil or Caelyx, whose clinical pharmacokinetic profile is characterized by slow plasma clearance and small volume of distribution. A hallmark of these long-circulating liposomal drug carriers is their enhanced accumulation in tumors. The mechanism underlying this passive targeting effect is the phenomenon known as enhanced permeability and retention (EPR) which has been described in a broad variety of experimental tumor types. Further to the passive targeting effect, the liposome drug delivery platform offers the possibility of grafting tumor-specific ligands on the liposome membrane for active targeting to tumor cells, and potentially intracellular drug delivery. The pros and cons of the liposome platform in cancer targeting are discussed vis-à-vis nontargeted drugs, using as an example a liposome drug delivery system targeted to the folate receptor.

  2. Amphotericin B Liposomal Injection

    MedlinePlus

    Amphotericin B liposomal injection is used to treat fungal infections such as cryptococcal meningitis (a fungal infection of the ... infections in people who cannot receive conventional amphotericin B therapy. Amphotericin B liposomal injection is in a ...

  3. Archaebacterial tetraetherlipid liposomes.

    PubMed

    Ozcetin, Aybike; Mutlu, Samet; Bakowsky, Udo

    2010-01-01

    Liposomes are widely investigated for their applicability as drug delivery systems. However, the unstable liposomal constitution is one of the greatest limitations, because the liposomes undergo fast elimination after application to the human body. In the presented study, novel archeal lipids were used to prepare liposomal formulations which were tested for their stability at elevated temperatures, at different pH-values and after heat sterilization.

  4. Effects of lipid composition and preparation conditions on physical-chemical properties, technological parameters and in vitro biological activity of gemcitabine-loaded liposomes.

    PubMed

    Calvagno, Maria Grazia; Celia, Christian; Paolino, Donatella; Cosco, Donato; Iannone, Michelangelo; Castelli, Francesco; Doldo, Patrizia; Frest, Massimo

    2007-01-01

    The effects of lipid composition and preparation conditions on the physicochemical and technological properties of gemcitabine-loaded liposomes, as well as the in vitro anti-tumoral activity of various liposome formulations were investigated. Three liposome formulations were investigated: DPPC/Chol/Oleic acid (8:3:1 molar ratio, liposomes A), DPPC/Chol/DPPS (6:3:1 molar ratio, liposomes B) and DPPC/Chol/DSPE-MPEG (6:3:1 molar ratio, liposomes C). Multilamellar liposomes were prepared by using the TLE, FAT and DRV methods, while small unilamellar liposomes were obtained by extrusion through polycarbonate filters. Light scattering techniques were used to characterize liposome formulations. Loading capacity and release profiles of gemcitabine from various liposome formulations were also investigated. Caco-2 cells were used to evaluate in vitro the antitumoral activity of gemcitabine-loaded liposomes with respect to the free drug and also the intracellular drug uptake. Preparation methods and liposome lipid composition influenced both physicochemical parameters and drug delivery features. Liposomes with a size ranging from 200 nm to 7 microm were obtained. The gemcitabine entrapment was higher than that expected probably due to an interaction with the liposome lipid components. The following decreasing loading capacity order was observed: liposome B>liposome C>liposome A. Gemcitabine release from various liposome formulations is modulated by two different processes, i.e. desorption from and permeation through liposomal bilayers. MTT assay showed a greater cytotoxic effect of gemcitabine-loaded liposomes with respect to the free drug. The following decreasing anticancer activity order was observed between the various liposome formulations: liposome C>liposome A>liposome B. The increased anticancer activity is correlated to the ability of the colloidal carrier to increase the intracellular drug uptake. Due to the encouraging results and to the high liposome modularity

  5. Liposome technology. Volume I: Preparation of liposomes

    SciTech Connect

    Gregoriadis, G.

    1984-01-01

    These three volumes cover liposome technology in pharmacology and medicine. Contributors emphasize methodology used in their own laboratories, and include a brief introduction, coverage of relevant literature, applications and critical evaluations for the methods they describe. Volume I examine methods for the preparation of liposomes and auxiliary techniques.

  6. From conventional to stealth liposomes: a new frontier in cancer chemotherapy.

    PubMed

    Cattel, Luigi; Ceruti, Maurizio; Dosio, Franco

    2003-01-01

    Many attempts have been made to achieve good selectivity to targeted tumor cells by preparing specialized carrier agents that are therapeutically profitable for anticancer therapy. Among these, liposomes are the most studied colloidal particles thus far applied in medicine and in particular in antitumor therapy. Although they were first described in the 1960s, only at the beginning of 1990s did the first therapeutic liposomes appear on the market. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome (Nexstar, Boulder, CO, USA), used as an antifungal drug, and Myocet (Elan Pharma Int, Princeton, NJ, USA), a doxorubicin-containing liposome, used in clinical trials to treat metastatic breast cancer. The second-generation liposomes ("pure lipid approach") were long-circulating liposomes, such as Daunoxome, a daunorubicin-containing liposome approved in the US and Europe to treat AIDS-related Kaposi's sarcoma. The third-generation liposomes were surface-modified liposomes with gangliosides or sialic acid, which can evade the immune system responsible for removing liposomes from circulation. The fourth-generation liposomes, pegylated liposomal doxorubicin, were called "stealth liposomes" because of their ability to evade interception by the immune system, in the same way as the stealth bomber was able to evade radar. Actually, the only stealth liposome on the market is Caelyx/Doxil (Schering-Plough, Madison NJ, USA), used to cure AIDS-related Kaposi's sarcoma, resistant ovarian cancer and metastatic breast cancer. Pegylated liposomal doxorubicin is characterized by a very long-circulation half-life, favorable pharmacokinetic behavior and specific accumulation in tumor tissues. These features account for the much lower toxicity shown by Caelyx in comparison to free doxorubicin, in terms of cardiotoxicity, vesicant effects, nausea, vomiting and alopecia. Pegylated liposomal doxorubicin also appeared to be less

  7. Multimodal targeted high relaxivity thermosensitive liposome for in vivo imaging

    NASA Astrophysics Data System (ADS)

    Kuijten, Maayke M. P.; Hannah Degeling, M.; Chen, John W.; Wojtkiewicz, Gregory; Waterman, Peter; Weissleder, Ralph; Azzi, Jamil; Nicolay, Klaas; Tannous, Bakhos A.

    2015-11-01

    Liposomes are spherical, self-closed structures formed by lipid bilayers that can encapsulate drugs and/or imaging agents in their hydrophilic core or within their membrane moiety, making them suitable delivery vehicles. We have synthesized a new liposome containing gadolinium-DOTA lipid bilayer, as a targeting multimodal molecular imaging agent for magnetic resonance and optical imaging. We showed that this liposome has a much higher molar relaxivities r1 and r2 compared to a more conventional liposome containing gadolinium-DTPA-BSA lipid. By incorporating both gadolinium and rhodamine in the lipid bilayer as well as biotin on its surface, we used this agent for multimodal imaging and targeting of tumors through the strong biotin-streptavidin interaction. Since this new liposome is thermosensitive, it can be used for ultrasound-mediated drug delivery at specific sites, such as tumors, and can be guided by magnetic resonance imaging.

  8. Liposomes as Advanced Delivery Systems for Nutraceuticals

    PubMed Central

    Shade, Christopher W.

    2016-01-01

    Liposomes are delivery vehicles for transporting substances into the body effectively via facilitating absorption directly in the mouth or by preventing breakdown by stomach acid. Since the 1970s, liposomes have been investigated as potential drug delivery systems because of their biocompatibility and ability to incorporate both hydrophilic and hydrophobic therapeutic agents. Despite early promise, it was decades later, in the late 1990s to the present, that liposome technologies could create successful commercial products. Oral deliveries are recently emerging as availability of quality phospholipids and reliable homogenization and sizing equipment have become routinely available. Nutritional industry use of liposomes will grow rapidly in the next 5–10 y. High-quality products with more complex mixtures of pure compounds and complex botanical mixtures will offer clinicians less-invasive options for dosing and delivery of these actives. PMID:27053934

  9. Liposomes as nanomedical devices.

    PubMed

    Bozzuto, Giuseppina; Molinari, Agnese

    2015-01-01

    Since their discovery in the 1960s, liposomes have been studied in depth, and they continue to constitute a field of intense research. Liposomes are valued for their biological and technological advantages, and are considered to be the most successful drug-carrier system known to date. Notable progress has been made, and several biomedical applications of liposomes are either in clinical trials, are about to be put on the market, or have already been approved for public use. In this review, we briefly analyze how the efficacy of liposomes depends on the nature of their components and their size, surface charge, and lipidic organization. Moreover, we discuss the influence of the physicochemical properties of liposomes on their interaction with cells, half-life, ability to enter tissues, and final fate in vivo. Finally, we describe some strategies developed to overcome limitations of the "first-generation" liposomes, and liposome-based drugs on the market and in clinical trials.

  10. Liposomes as nanomedical devices

    PubMed Central

    Bozzuto, Giuseppina; Molinari, Agnese

    2015-01-01

    Since their discovery in the 1960s, liposomes have been studied in depth, and they continue to constitute a field of intense research. Liposomes are valued for their biological and technological advantages, and are considered to be the most successful drug-carrier system known to date. Notable progress has been made, and several biomedical applications of liposomes are either in clinical trials, are about to be put on the market, or have already been approved for public use. In this review, we briefly analyze how the efficacy of liposomes depends on the nature of their components and their size, surface charge, and lipidic organization. Moreover, we discuss the influence of the physicochemical properties of liposomes on their interaction with cells, half-life, ability to enter tissues, and final fate in vivo. Finally, we describe some strategies developed to overcome limitations of the “first-generation” liposomes, and liposome-based drugs on the market and in clinical trials. PMID:25678787

  11. Targeting Therapy Resistant Tumor Vessels

    DTIC Science & Technology

    2008-08-01

    and nanoparticles (Fig. 5). In each case, the homing to axitinib-treated 4T1 tumors was confirmed. Fig. 3. iRGD, LyP-1, KAAKNK (KAA), and...control nanoworms (Park et al., 2008). The mice were pre-injected with nickel liposomes that prevent uptake of the nanoparticles by the liver (Simberg et...Ruoslahti, E. Biomimetic amplification of nanoparticle homing to tumors. Proc. Natl. Acad. Sci. U. S. A. 104:932-936 (2007). Yao, V.J., Ozawa, M.G

  12. Dodecaborate lipid liposomes as new vehicles for boron delivery system of neutron capture therapy.

    PubMed

    Ueno, Manabu; Ban, Hyun Seung; Nakai, Kei; Inomata, Ryu; Kaneda, Yasufumi; Matsumura, Akira; Nakamura, Hiroyuki

    2010-05-01

    Closo-dodecaborate lipid liposomes were developed as new vehicles for boron delivery system (BDS) of neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in combination with neutron irradiation. The liposomes composed of closo-dodecaborate lipids DSBL and DPBL displayed high cytotoxicity with thermal neutron irradiation. The closo-dodecaborate lipid liposomes were taken up into the cytoplasm by endocytosis without degradation of the liposomes. Boron concentration of 22.7 ppm in tumor was achieved by injection with DSBL-25% PEG liposomes at 20mg B/kg. Promising BNCT effects were observed in the mice injected with DSBL-25% PEG liposomes: the tumor growth was significantly suppressed after thermal neutron irradiation (1.8 x 10(12)neutrons/cm(2)).

  13. Liposomal carfilzomib nanoparticles effectively target multiple myeloma cells and demonstrate enhanced efficacy in vivo.

    PubMed

    Ashley, Jonathan D; Stefanick, Jared F; Schroeder, Valerie A; Suckow, Mark A; Alves, Nathan J; Suzuki, Rikio; Kikuchi, Shohei; Hideshima, Teru; Anderson, Kenneth C; Kiziltepe, Tanyel; Bilgicer, Basar

    2014-12-28

    Carfilzomib, a recently FDA-approved proteasome inhibitor, has remarkable anti-myeloma (MM) activity. However, its effectiveness is limited by associated severe side-effects, short circulation half-life, and limited solubility. Here, we report the engineering of liposomal carfilzomib nanoparticles to overcome these problems and enhance the therapeutic efficacy of carfilzomib by increasing tumoral drug accumulation while decreasing systemic toxicity. In our design, carfilzomib was loaded into the bilayer of liposomes to yield stable and reproducible liposomal nanoparticles. Liposomal carfilzomib nanoparticles were efficiently taken up by MM cells, demonstrated proteasome inhibition, induced apoptosis, and exhibited enhanced cytotoxicity against MM cells. In vivo, liposomal carfilzomib demonstrated significant tumor growth inhibition and dramatically reduced overall systemic toxicity compared to free carfilzomib. Finally, liposomal carfilzomib demonstrated enhanced synergy in combination with doxorubicin. Taken together, this study establishes the successful synthesis of liposomal carfilzomib nanoparticles that demonstrates improved therapeutic index and the potential to improve patient outcome in MM.

  14. Effective Prevention and Management of Tumor Lysis Syndrome in Children With Cancer: The Important Contributions of Pediatric Oncology Nurses.

    PubMed

    Li, Ho Cheung William; Chung, Oi Kwan Joyce; Tam, Ching Janice; Chiu, Sau Ying

    2015-01-01

    The practice guidelines aimed to identify appropriate nursing management for the prevention and treatment of tumor lysis syndrome, in line with the current evidence-based medical guidelines. Using a systematic approach, 15 relevant articles were identified for the review. The evaluation of patient risk factors for tumor lysis syndrome and the appropriate medical and nursing assessment were identified. The treatment algorithms for the prevention of tumor lysis syndrome from both the medical and nursing perspectives have been established. In particular, the guidelines highlight the importance of pediatric oncology nurses in contributing to the prevention and management of tumor lysis syndrome.

  15. Sphingomyelin Liposomes Containing Porphyrin-phospholipid for Irinotecan Chemophototherapy

    PubMed Central

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

    2016-01-01

    Porphyrin-phospholipid (PoP) liposomes can entrap anti-cancer agents and release them in response to near infrared (NIR) light. Doxorubicin, when remotely loaded via an ammonium sulfate gradient at a high drug-to-lipid ratio, formed elongated crystals that altered liposome morphology and could not be loaded into liposomes with higher PoP content. On the other hand, irinotecan could also be remotely loaded but did not form large crystals and did not induce liposome elongation. The loading, stability, and NIR light-triggered release of irinotecan in PoP liposomes was altered by the types of lipids used and the presence of PEGylation. Sphingomyelin, which has been explored previously for liposomal irinotecan, was found to produce liposomes with relatively improved serum stability and rapid NIR light-triggered drug release. PoP liposomes composed from sphingomyelin, cholesterol and 2 molar percent PoP rapidly released irinotecan in vivo in response to NIR irradiation as monitored by intravital microscopy and also induced effective tumor eradication in mice bearing MIA Paca-2 subcutaneous tumor xenografts. PMID:27877238

  16. Liposomal boron delivery for neutron capture therapy.

    PubMed

    Nakamura, Hiroyuki

    2009-01-01

    Tumor cell destruction in boron neutron capture therapy (BNCT) is due to the nuclear reaction between (10)B and thermal neutrons. The thermal neutrons have an energy of 0.025 eV, clearly below the threshold energy required to ionize tissue components. However, neutron capture by (10)B produces lithium ion and helium (alpha-particles), which are high linear energy transfer (LET) particles, and dissipate their kinetic energy before traveling one cell diameter (5-9 microm) in biological tissues, ensuring their potential for precise cell killing. BNCT has been applied clinically for the treatment of malignant brain tumors, malignant melanoma, head and neck cancer, and hepatoma using two boron compounds: sodium borocaptate (Na(2)(10)B(12)H(11)SH; Na(2)(10)BSH) and l-p-boronophenylalanine (l-(10)BPA). These low molecular weight compounds are cleared easily from the cancer cells and blood. Therefore, high accumulation and selective delivery of boron compounds into tumor tissues are most important to achieve effective BNCT and to avoid damage of adjacent healthy cells. Much attention has been focused on the liposomal drug delivery system (DDS) as an attractive, intelligent technology of targeting and controlled release of (10)B compounds. Two approaches have been investigated for incorporation of (10)B into liposomes: (1) encapsulation of (10)B compounds into liposomes and (2) incorporation of (10)B-conjugated lipids into the liposomal bilayer. Our laboratory has developed boron ion cluster lipids for application of the latter approach. In this chapter, our boron lipid liposome approaches as well as recent developments of the liposomal boron delivery system are summarized.

  17. Glioblastoma Treatment: Bypassing the Toxicity of Platinum Compounds by Using Liposomal Formulation and Increasing Treatment Efficiency With Concomitant Radiotherapy

    PubMed Central

    Charest, Gabriel; Sanche, Léon; Fortin, David; Mathieu, David; Paquette, Benoit

    2013-01-01

    PURPOSE Treatments of glioblastoma (GBM) with cisplatin or oxaliplatin only marginally improve the overall survival of patients and cause important side effects. To prevent adverse effects, improve delivery and optimize the tumor response to treatment in combination with radiotherapy, a potential approach consists in incorporating the platinum agent in a liposome. METHODS AND MATERIALS In this study, cisplatin, oxaliplatin, carboplatin, Lipoplatin™ and Lipoxal™, the liposomal formulations of cisplatin and oxaliplatin respectively, were tested on F98 glioma orthotopically implanted in Fischer rats. The platinum compounds were administered by intracarotid infusion and were assessed for the ability to reduce toxicity, improve cancer cell uptake and increase survival of animals when combined or not with radiotherapy. RESULTS The tumor uptake was 2.4-fold more important for Lipoxal™ than the liposome-free oxaliplatin. Lipoxal™ also improved the specificity of oxaliplatin as shown by a higher ratio of tumor/right hemisphere uptake. Surprisingly, Lipoplatin™ led to lower tumor uptake compare to cisplatin. However, Lipoplatin™ had the advantage of largely reducing the toxicity of cisplatin and allowed to capitalize on the anti-cancer activity of this agent. CONCLUSION Among the five platinum compounds tested, carboplatin showed the best increase in survival when combined with radiation for treatment of glioma implanted in Fischer rats. PMID:22284691

  18. Liposomal nanoparticles as a drug delivery vehicle against osteosarcoma

    NASA Astrophysics Data System (ADS)

    Dhule, Santosh Subhashrao

    The delivery of curcumin, a broad-spectrum anticancer drug, has been explored in the form of liposomal nanoparticles to treat osteosarcoma (OS). Curcumin is water insoluble and an effective delivery route is through encapsulation in cyclodextrins followed by a second encapsulation in liposomes. Liposomal curcumin's potential was evaluated against cancer models of mesenchymal (OS) and epithelial origin (breast cancer). The resulting 2-Hydroxypropyl-gamma-cyclodextrin/curcumin - liposome complex shows promising anticancer potential both in vitro and in vivo against KHOS OS cell line and MCF-7 breast cancer cell line. An interesting aspect is that liposomal curcumin initiates the caspase cascade that leads to apoptotic cell death in vitro in comparison with DMSO-curcumin induced autophagic cell death. In addition, the efficiency of the liposomal curcumin formulation was confirmed in vivo using a xenograft OS model. Curcumin-loaded gamma-cyclodextrin liposomes indicate significant potential as delivery vehicles for the treatment of cancers of different tissue origin. The second part of this study examines the anti-tumor potential of curcumin and C6 ceramide (C6) against osteosarcoma cell lines when both are encapsulated in the bilayer of liposomal nanoparticles. Curcumin in combination with C6 showed 1.5 times enhanced cytotoxic effect in the case of MG-63 and KHOS OS cell lines, in comparison with systems with curcumin alone. Interestingly, C6-curcumin liposomes were found to be less toxic on untransformed human cells in comparison to OS cell lines. In addition, cell cycle assays on a KHOS cell line after treatment revealed that curcumin only liposomes induced G 2/M arrest by upregulation of cyclin B1, while C6 only liposomes induced G1 arrest by downregulation of cyclin D1. C6-curcumin liposomes induced G2/M arrest and showed a combined effect in the expression levels of cyclin D1 and cyclin B1. Using pegylated liposomes to increase the plasma half-life and tagging

  19. [Development of high boron content liposomes and their promising antitumor effect for neutron capture therapy].

    PubMed

    Nakamura, Hiroyuki

    2013-01-01

      High accumulation and selective delivery of boron into tumor tissue are the most important requirements to achieve the efficient cell-killing effect of boron neutron capture therapy (BNCT) that relies on the nuclear reaction of two essentially nontoxic species, boron-10 ((10)B) and thermal neutrons in boron-loaded tissues. Recent development of boron cluster lipids and their liposomal boron delivery system (BDS) are summarized in this article. Boron compounds that have no affinity to tumor can potentially be delivered to tumor tissues by liposomes, therefore, liposomal BDS would be one of the most attractive approaches for efficient BNCT of various cancers. There are two approaches for BDS: encapsulation of boron compounds into liposomes and incorporation of boron-conjugated lipids into the liposomal bilayer. The combination of both approaches has a potential for reduction of the total dose of liposomes without reducing the efficacy of BNCT.

  20. Cancer prevention and therapy through the modulation of the tumor microenvironment

    PubMed Central

    Casey, Stephanie C.; Amedei, Amedeo; Aquilano, Katia; Benencia, Fabian; Bhakta, Dipita; Boosani, Chandra S.; Chen, Sophie; Ciriolo, Maria Rosa; Crawford, Sarah; Fujii, Hiromasa; Georgakilas, Alexandros G.; Guha, Gunjan; Halicka, Dorota; Helferich, William G.; Heneberg, Petr; Honoki, Kanya; Kerkar, Sid P.; Mohammed, Sulma I.; Niccolai, Elena; Nowsheen, Somaira; Rupasinghe, H. P. Vasantha; Samadi, Abbas; Singh, Neetu; Talib, Wamidh H.; Venkateswaran, Vasundara; Whelan, Richard; Yang, Xujuan; Felsher, Dean W.

    2015-01-01

    Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adapative immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2, 3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer. PMID:25865775

  1. Prevention and treatment of tumor lysis syndrome, and the efficacy and role of rasburicase

    PubMed Central

    Alakel, Nael; Middeke, Jan Moritz; Schetelig, Johannes; Bornhäuser, Martin

    2017-01-01

    Tumor lysis syndrome (TLS) is a potentially life-threatening condition that occurs in oncologic and hematologic patients with large tumor burden, either due to cytotoxic therapy or, less commonly, spontaneously because of massive tumor cell lysis. TLS is clinically characterized by acute renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. While limited options are available for treating TLS, identifying patients at high risk for developing TLS and prevention in high-risk patients remain an important aspect in the treatment of cancer patients. In general, treatment of TLS consists of intensive hydration, stimulation of diuresis, and, more specifically, in the use of allopurinol and rasburicase. Rasburicase, a recombinant urate oxidase, rapidly and effectively reduces hyperuricemia, which subsequently significantly decreases the risk of acute renal failure and other clinical manifestations of TLS. For this review, a comprehensive literature search using the term “tumor lysis syndrome” and/or “rasburicase” was performed considering articles listed in MEDLINE. Incidence, prevention, and therapy of TLS with a special focus on the role of rasburicase are discussed. We evaluated 120 relevant articles including 35 case reports, 32 clinical trials, and 14 meta-analyses. PMID:28203093

  2. A novel liposomal formulation of flavopiridol.

    PubMed

    Yang, Xiaojuan; Zhao, Xiaobin; Phelps, Mitch A; Piao, Longzhu; Rozewski, Darlene M; Liu, Qing; Lee, L James; Marcucci, Guido; Grever, Michael R; Byrd, John C; Dalton, James T; Lee, Robert J

    2009-01-05

    Flavopiridol has shown promising activities in hematologic and solid tumor models, as well as in clinical trials in chronic lymphocytic leukemia patients. Flavopiridol has relatively low solubility and high plasma protein-binding. To address these issues and to provide an alternative strategy to achieve clinical efficacy, we encapsulated flavopiridol into a liposomal carrier and characterized its physicochemical and pharmacokinetic properties. The liposomes, comprising hydrogenated soy phosphatidylcholine (HSPC), cholesterol and poly (ethylene glycol) 2000-distearoyl phosphatidylethanolamine (PEG-DSPE), were prepared by polycarbonate membrane extrusion and then loaded with flavopiridol by a pH-gradient driven remote loading procedure. The liposomes had a mean diameter of 120.7 nm and a flavopiridol entrapment efficiency of 70.4%. Pharmacokinetic study in mice after i.v. bolus injection showed that the liposomal flavopiridol had an increased elimination phase half-life (T((1/2)beta), 339.7 min vs. 57.0 min), decreased clearance (CL, 0.012 L/min vs. 0.036 L/min), and increased area under the plasma concentration-time curve (AUC, 10.8 min micromol/L vs. 3.4 min micromol/L) compared to the free drug. This indicates a significant and potentially beneficial change in flavopiridol pharmacokinetics for the liposomal formulation. Further preclinical studies are warranted to define the toxicity and therapeutic efficacy of this novel formulation.

  3. Enzymatic action of phospholipase A₂ on liposomal drug delivery systems.

    PubMed

    Hansen, Anders H; Mouritsen, Ole G; Arouri, Ahmad

    2015-08-01

    The overexpression of secretory phospholipase A2 (sPLA2) in tumors has opened new avenues for enzyme-triggered active unloading of liposomal antitumor drug carriers selectively at the target tumor. However, the effects of the liposome composition, drug encapsulation, and tumor microenvironment on the activity of sPLA2 are still not well understood. We carried out a physico-chemical study to characterize the sPLA2-assisted breakdown of liposomes using dye-release assays in the context of drug delivery and under physiologically relevant conditions. The influence of temperature, lipid concentration, enzyme concentration, and drug loading on the hydrolysis of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC, Tm=42°C) liposomes with snake venom sPLA2 was investigated. The sensitivity of human sPLA2 to the liposome composition was checked using binary lipid mixtures of phosphatidylcholine (PC) and phosphatidylglycerol (PG) phospholipids with C14 and C16 acyl chains. Increasing temperature (36-41°C) was found to mainly shorten the enzyme lag-time, whereas the effect on lipid hydrolysis rate was modest. The enzyme lag-time was also found to be inversely dependent on the lipid-to-enzyme ratio. Drug encapsulation can alter the hydrolysis profile of the carrier liposomes. The activity of human sPLA2 was highly sensitive to the phospholipid acyl-chain length and negative surface charge density of the liposomes. We believe our work will prove useful for the optimization of sPLA2-susceptible liposomal formulations as well as will provide a solid ground for predicting the hydrolysis profile of the liposomes in vivo at the target site.

  4. Fused liposome and acid induced method for liposome fusion

    SciTech Connect

    Huang, L.; Connor, J.

    1988-12-06

    This patent describes a method of fusing liposomes. It comprises: preparing a suspension of liposomes containing at least one lipid which has a tendency to form the inverted hexagonal phase and at least 20 mol percent of palmitoylhomocysteine; and in the absence of externally added divalent cations, proteins or other macromolecules, acidifying the liposome suspension to reduce the pH of the liposomes to below pH 7, such that at least about 20% of the liposomes fuse to one another.

  5. Liposome chaperon in cell-free membrane protein synthesis: one-step preparation of KcsA-integrated liposomes and electrophysiological analysis by the planar bilayer method.

    PubMed

    Ando, M; Akiyama, M; Okuno, D; Hirano, M; Ide, T; Sawada, S; Sasaki, Y; Akiyoshi, K

    2016-02-01

    Chaperoning functions of liposomes were investigated using cell-free membrane protein synthesis. KcsA potassium channel-reconstituted liposomes were prepared directly using cell-free protein synthesis. In the absence of liposomes, all synthesized KcsA protein aggregated. In the presence of liposomes, however, synthesized KcsA spontaneously integrated into the liposome membrane. The KscA-reconstituted liposomes were transferred to the planar bilayer across a small hole in a thin plastic sheet and the channel function of KcsA was examined. The original electrophysiological activities, such as voltage- and pH-dependence, were observed. These results suggested that in cell-free membrane protein synthesis, liposomes act as chaperones, preventing aggregation and assisting in folding and tetrameric formation, thereby allowing full channel activity.

  6. Liposome uptake into human colon adenocarcinoma cells in monlayer, spinner, and trypsinized cultures

    SciTech Connect

    Tom, B.H.; Macek, C.M.; Raphael, L.; Sengupta, J.; Cerny, E.A.; Jonah, M.M.; Rahman, Y.E.

    1983-01-01

    The nature of liposome interactions with colon tumor cells was investigated. Thus, experiments were performed to study the uptake and incorporation of multilamellar and of reverse-phase evaporation liposomes of neutral charge into monolayers, suspended spinner cultures, and trypsinized cells of a human colon adenocarcinoma cell line, LS174T. The results showed that the same tumor cells cultured under each condition exhibited a distinct pattern of vesicle uptake as determined at 0, 15, 30, 60, and 120 min. In monolayer cultures of LS174T cells, the uptake of liposomes bearing (/sup 3/H)actinomycin D in the lipid bilayers was linear throughout the incubation period. In contrast, in trypsinized and spinner suspension cultures, uptake of liposomes was biphasic. There was a proportional uptake of both liposome (labeled with (/sup 3/H)phosphantidylcholine or (/sup 14/C)cholesterol) and of actinomycin D (trace labeled with /sup 3/H) into the cells under all culture conditions, indicating quantitative delivery of the drug with the intact lipid vesicle. Although the amount of actinomycin D presented to tumor cells by the two liposomes was equivalent, reverse-phase evaporation liposomes were more effectve than multilamellar vesicles in inhibiting uridine uptake. In the presence of excess liposomes (10 times the uptake studies), saturation of the tumor cell surface occurred by 120 min. However, the liposomes remained accessible to enzymatic removal for 60 min. Liposome-saturated tumor cells remained refractory to further binding of liposomes for at least 2 hr. The results thus revealed that differences in cell uptake were due to the state of the target cells and not the liposome types, or their differential leakage of labels.

  7. pH-Sensitive Liposomes: Possible Clinical Implications

    NASA Astrophysics Data System (ADS)

    Yatvin, M. B.; Kreutz, W.; Horwitz, B. A.; Shinitzky, M.

    1980-12-01

    When pH-sensitive molecules are incorporated into liposomes, drugs can be specifically released from these vesicles by a change of pH in the ambient serum. Liposomes containing the pH-sensitive lipid palmitoyl homocysteine (PHC) were constructed so that the greatest pH differential (6.0 to 7.4) of drug release was obtained near physiological temperature. Such liposomes could be useful clinically if they enable drugs to be targeted to areas of the body in which pH is less than physiological, such as primary tumors and metastases or sites of inflammation and infection.

  8. Second generation liposomal cancer therapeutics: transition from laboratory to clinic.

    PubMed

    Sen, Kacoli; Mandal, Mahitosh

    2013-05-01

    Recent innovations and developments in nanotechnology have revolutionized cancer therapeutics. Engineered nanomaterials are the current workhorses in the emerging field of cancer nano-therapeutics. Lipid vesicles bearing anti-tumor drugs have turned out to be a clinically feasible and promising nano-therapeutic approach to treat cancer. Efficient entrapment of therapeutics, biocompatibility, biodegradability, low systemic toxicity, low immunogenicity and ability to bypass multidrug resistance mechanisms has made liposomes a versatile drug/gene delivery system in cancer chemotherapy. The present review attempts to explore the recent key advances in liposomal research and the vast arsenal of liposomal formulations currently being utilized in treatment and diagnosis of cancer.

  9. Ultrasound, liposomes, and drug delivery: principles for using ultrasound to control the release of drugs from liposomes.

    PubMed

    Schroeder, Avi; Kost, Joseph; Barenholz, Yechezkel

    2009-11-01

    Ultrasound is used in many medical applications, such as imaging, blood flow analysis, dentistry, liposuction, tumor and fibroid ablation, and kidney stone disruption. In the past, low frequency ultrasound (LFUS) was the main method to downsize multilamellar (micron range) vesicles into small (nano scale) unilamellar vesicles. Recently, the ability of ultrasound to induce localized and controlled drug release from liposomes, utilizing thermal and/or mechanical effects, has been shown. This review, deals with the interaction of ultrasound with liposomes, focusing mainly on the mechanical mechanism of drug release from liposomes using LFUS. The effects of liposome lipid composition and physicochemical properties, on one hand, and of LFUS parameters, on the other, on liposomal drug release, are addressed. Acoustic cavitation, in which gas bubbles oscillate and collapse in the medium, thereby introducing intense mechanical strains, increases release substantially. We suggest that the mechanism of release may involve formation and collapse of small gas nuclei in the hydrophobic region of the lipid bilayer during exposure to LFUS, thereby inducing the formation of transient pores through which drugs are released. Introducing PEG-lipopolymers to the liposome bilayer enhances responsivity to LFUS, most likely due to absorption of ultrasonic energy by the highly hydrated PEG headgroups. The presence of amphiphiles, such as phospholipids with unsaturated acyl chains, which destabilize the lipid bilayer, also increases liposome susceptibility to LFUS. Application of these principles to design highly LFUS-responsive liposomes is discussed.

  10. Current Trends in Development of Liposomes for Targeting Bacterial Biofilms

    PubMed Central

    Rukavina, Zora; Vanić, Željka

    2016-01-01

    Biofilm targeting represents a great challenge for effective antimicrobial therapy. Increased biofilm resistance, even with the elevated concentrations of very potent antimicrobial agents, often leads to failed therapeutic outcome. Application of biocompatible nanomicrobials, particularly liposomally-associated nanomicrobials, presents a promising approach for improved drug delivery to bacterial cells and biofilms. Versatile manipulations of liposomal physicochemical properties, such as the bilayer composition, membrane fluidity, size, surface charge and coating, enable development of liposomes with desired pharmacokinetic and pharmacodynamic profiles. This review attempts to provide an unbiased overview of investigations of liposomes destined to treat bacterial biofilms. Different strategies including the recent advancements in liposomal design aiming at eradication of existing biofilms and prevention of biofilm formation, as well as respective limitations, are discussed in more details. PMID:27231933

  11. Bioavailability of Polyphenol Liposomes: A Challenge Ahead

    PubMed Central

    Mignet, Nathalie; Seguin, Johanne; Chabot, Guy G.

    2013-01-01

    Dietary polyphenols, including flavonoids, have long been recognized as a source of important molecules involved in the prevention of several diseases, including cancer. However, because of their poor bioavailability, polyphenols remain difficult to be employed clinically. Over the past few years, a renewed interest has been devoted to the use of liposomes as carriers aimed at increasing the bioavailability and, hence, the therapeutic benefits of polyphenols. In this paper, we review the causes of the poor bioavailability of polyphenols and concentrate on their liposomal formulations, which offer a means of improving their pharmacokinetics and pharmacodynamics. The problems linked to their development and their potential therapeutic advantages are reviewed. Future directions for liposomal polyphenol development are suggested. PMID:24300518

  12. MAPK15 upregulation promotes cell proliferation and prevents DNA damage in male germ cell tumors

    PubMed Central

    Ilardi, Gennaro; Acunzo, Mario; Nigita, Giovanni; Sasdelli, Federica; Celetti, Angela; Strambi, Angela; Staibano, Stefania; Croce, Carlo Maria; Chiariello, Mario

    2016-01-01

    Germ cell tumors (GCT) are the most common malignancies in males between 15 and 35 years of age. Despite the high cure rate, achieved through chemotherapy and/or surgery, the molecular basis of GCT etiology is still largely obscure. Here, we show a positive correlation between MAPK15 (ERK8; ERK7) expression and specific GCT subtypes, with the highest levels found in the aggressive embryonal carcinomas (EC). Indeed, in corresponding cellular models for EC, MAPK15 enhanced tumorigenicity in vivo and promoted cell proliferation in vitro, supporting a role for this kinase in human GCT. At molecular level, we demonstrated that endogenous MAPK15 is necessary to sustain cell cycle progression of EC cells, by limiting p53 activation and preventing the triggering of p53-dependent mechanisms resulting in cell cycle arrest. To understand MAPK15-dependent mechanisms impinging on p53 activation, we demonstrate that this kinase efficiently protects cells from DNA damage. Moreover, we show that the ability of MAPK15 to control the autophagic process is necessary for basal management of DNA damage and for tumor formation controlled by the kinase. In conclusion, our findings suggest that MAPK15 overexpression may contribute to the malignant transformation of germ cells by controlling a “stress support” autophagic pathway, able to prevent DNA damage and the consequent activation of the p53 tumor suppressor. Moreover, in light of these results, MAPK15-specific inhibitors might represent new tools to enhance the therapeutic index of cytotoxic therapy in GCT treatment, and to increase the sensitivity to DNA-damaging drugs in other chemotherapy-resistant human tumors. PMID:26988910

  13. Epirubicin loaded with propylene glycol liposomes significantly overcomes multidrug resistance in breast cancer.

    PubMed

    Zhao, Ying-Zheng; Dai, Dan-Dan; Lu, Cui-Tao; Chen, Li-Juan; Lin, Min; Shen, Xiao-Tong; Li, Xiao-Kun; Zhang, Ming; Jiang, Xi; Jin, Rong-Rong; Li, Xing; Lv, Hai-Feng; Cai, Lu; Huang, Pin-Tong

    2013-03-01

    Multidrug resistance (MDR) is one of the major reasons for the failure of cancer chemotherapy. A newly reported liposome carrier, propylene glycol liposomes (EPI-PG-liposomes) were made to load epirubicin (EPI) which enhanced EPI absorption in MDR tumor cells to overcome the drug resistance. MDA-MB 435 and their mutant resistant (MDA-MB 435/ADR) cells were used to examine the cellular uptake and P-gp function in vitro for EPI-PG-liposomes by fluorescence microscopy and FCM, respectively. Mammary tumor model was also established to investigate the tumor growth inhibition and pharmacodynamics of EPI-PG-liposomes in vivo. Morphology evaluation showed that EPI-PG-liposomes had a homogeneous spherical shape with an average diameter of 182 nm. Based on cell viability assay, fluorescent microscopy examination, and EPI uptake assay, EPI-PG-liposomes exhibited an effective growth inhibition not only in MDA-MB-435 cells, but also in MDA-MB 435/ADR cells. EPI-PG-liposomes have high permeability not only on tumor cell membrane, but also on cell nucleus membrane. P-gp function assay showed that the anticancer action of EPI-PG-liposomes was not related to P-gp efflux pump, suggesting that PG-liposomes would not affect the normal physiological functions of membrane proteins. EPI-PG-liposomes also showed a better antitumor efficacy compared to EPI solution alone. With high entrapment efficiency, spherical morphology and effective inhibition on MDR cancer cells, EPI-PG-liposomes may represent a better chemotherapeutic vectors for cancer targeted therapy.

  14. Targeted drug delivery and enhanced intracellular release using functionalized liposomes

    NASA Astrophysics Data System (ADS)

    Garg, Ashish

    The ability to target cancer cells using an appropriate drug delivery system can significantly reduce the associated side effects from cancer therapies and can help in improving the overall quality of life, post cancer survival. Integrin alpha5beta1 is expressed on several types of cancer cells, including colon cancer and plays an important role in tumor growth and metastasis. Thus, the ability to target the integrin alpha 5beta1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth and reducing tumor metastasis. The work in this thesis focuses on designing and optimizing, functionalized stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that specifically target the integrin alpha5beta1. The PEG provides a steric barrier allowing the liposomes to circulate in the blood for longer duration and the functionalizing moiety, PR_b peptide specifically recognizes and binds to integrin alpha5beta1 expressing cells. The work demonstrates that by optimizing the amount of PEG and PR_b on the liposomal interface, nano-vectors can be engineered that bind to CT26.WT colon cancer cells in a specific manner and internalize through alpha 5beta1-mediated endocytosis. To further improve the efficacy of the system, PR_b functionalized pH-sensitive stealth liposomes that exhibit triggered release under mild acidic conditions present in endocytotic vesicles were designed. The study showed that PR_b functionalized pH-sensitive stealth liposomes, undergo destabilization under mildly acidic conditions and incorporation of the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b functionalized pH-sensitive stealth liposomes bind to CT26.WT colon carcinoma cells that express integrin alpha5beta 1, undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. PR_b-targeted pH-sensitive stealth liposomes encapsulating 5

  15. Gold conjugate-based liposomes with hybrid cluster bomb structure for liver cancer therapy.

    PubMed

    Zhang, Ning; Chen, Huan; Liu, Ai-Yun; Shen, Jia-Jia; Shah, Vishva; Zhang, Can; Hong, Jin; Ding, Ya

    2016-01-01

    Hybrid drug delivery system containing both organic and inorganic nanocarriers is expected to achieve its complementary advantages for the aim of improving the performance of antineoplastic drugs in tumor therapy. Here we report the use of liposomes and gold nanoparticles to construct a liposome with a hybrid Cluster Bomb structure and discuss its unique multi-order drug release property for liver tumor treatment. A very simple method is used for the hybrid liposome preparation and involves mixing two solutions containing liposomes loaded with either non-covalent or covalent Paclitaxel (PTX, namely free PTX or PTX-conjugated GNPs, respectively) by different ratio of volume (25:75, 50:50, 25:75, v/v). Various mixed liposomes were tested to determine the optimal conditions for maximum drug delivery. The optimized liposome was then tested using xenograft Heps tumor-bearing mice and showed the best efficacy for chemotherapeutic inhibition of tumor at PTX liposome: PTX-conjugated GNP liposome of 25:75 ratio (v/v). This system allows for simple and easy preparation while providing a more accurate site- and time-release mode for tumor treatment using antitumor drugs.

  16. Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials.

    PubMed

    Alberts, David S; Muggia, Franco M; Carmichael, James; Winer, Eric P; Jahanzeb, Mohammad; Venook, Alan P; Skubitz, Keith M; Rivera, Edgardo; Sparano, Joseph A; DiBella, Nicholas J; Stewart, Simon J; Kavanagh, John J; Gabizon, Alberto A

    2004-12-01

    Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients.

  17. In vitro and in vivo evaluation of sanguinarine liposomes prepared by a remote loading method with three different ammonium salts.

    PubMed

    Ke, X; Bei, J H; Zhang, Y; Li, J

    2011-04-01

    Sanguinarine liposomes were prepared by a remote loading method using three different ammonium salts. A series of studies, including in vitro release, in vitro and in vivo anti-tumor effects and pharmacokinetics in rats, were conducted. The three liposomes showed pH-sensitive release characteristics in vitro, but there were obvious variations in their release profiles. Among the three liposomes, the liposomes made using ammonium citrate and phosphate possessed better anti-tumor activity in vitro and in vivo, compared with the liposome using ammonium sulfate. Pharmacokinetics test results in rats indicated that sanguinarine liposomes have notably elevated AUC (P<0.05) and markedly lower CL (P<0.05) compared with the solution, but there were no obvious differences between the three liposomes. The present study may be useful for better understanding and better choice of a suitable ammonium salt for the remote loading method.

  18. External beam radiotherapy synergizes ¹⁸⁸Re-liposome against human esophageal cancer xenograft and modulates ¹⁸⁸Re-liposome pharmacokinetics.

    PubMed

    Chang, Chih-Hsien; Liu, Shin-Yi; Chi, Chih-Wen; Yu, Hsiang-Lin; Chang, Tsui-Jung; Tsai, Tung-Hu; Lee, Te-Wei; Chen, Yu-Jen

    2015-01-01

    External beam radiotherapy (EBRT) treats gross tumors and local microscopic diseases. Radionuclide therapy by radioisotopes can eradicate tumors systemically. Rhenium 188 ((188)Re)-liposome, a nanoparticle undergoing clinical trials, emits gamma rays for imaging validation and beta rays for therapy, with biodistribution profiles preferential to tumors. We designed a combinatory treatment and examined its effects on human esophageal cancer xenografts, a malignancy with potential treatment resistance and poor prognosis. Human esophageal cancer cell lines BE-3 (adenocarcinoma) and CE81T/VGH (squamous cell carcinoma) were implanted and compared. The radiochemical purity of (188)Re-liposome exceeded 95%. Molecular imaging by NanoSPECT/CT showed that BE-3, but not CE81T/VGH, xenografts could uptake the (188)Re-liposome. The combination of EBRT and (188)Re-liposome inhibited tumor regrowth greater than each treatment alone, as the tumor growth inhibition rate was 30% with EBRT, 25% with (188)Re-liposome, and 53% with the combination treatment at 21 days postinjection. Combinatory treatment had no additive adverse effects and significant biological toxicities on white blood cell counts, body weight, or liver and renal functions. EBRT significantly enhanced the excretion of (188)Re-liposome into feces and urine. In conclusion, the combination of EBRT with (188)Re-liposome might be a potential treatment modality for esophageal cancer.

  19. Cooperative antioxidative effects of zein hydrolysates with sage (Salvia officinalis) extract in a liposome system.

    PubMed

    Li, Yuanyuan; Liu, Haotian; Han, Qi; Kong, Baohua; Liu, Qian

    2017-05-01

    This study investigated the cooperative antioxidative effects of sage extract (SE) and zein hydrolysates (ZH). The combination of 3mg/ml ZH and 10μg/ml SE exhibited a significant synergism in inhibition of the formation of thiobarbituric acid-reactive substances and provided superior protection of liposomes against oxidation. Zeta-potential results revealed that the interactions between liposomes and ZH were electrostatic interactions. Particle size determination further proved that ZH and SE added to oxidized liposomes significantly decreased the mean particle size. Confocal laser scanning microscopy revealed that when ZH was present in the liposome oxidizing system, the droplet sizes were obviously decreased compared to oxidized samples. ZH dispersed more uniformly and the interfacial membrane was more compact in the ZH-SE liposome. Transmission electron microscopy conveyed that the ZH-SE complex around the liposome particles could form a denser network structure, preventing radicals and oxidants from the approach of the liposomes.

  20. Levofloxacin to Prevent Infection Following Chemotherapy in Treating Patients With Solid Tumors or Lymphoma

    ClinicalTrials.gov

    2013-08-01

    Brain and Central Nervous System Tumors; Breast Cancer; Extragonadal Germ Cell Tumor; Infection; Lung Cancer; Lymphoma; Ovarian Cancer; Small Intestine Cancer; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific

  1. Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1.

    PubMed

    Mazzieri, Roberta; Pietrogrande, Giovanni; Gerasi, Laura; Gandelli, Alessandro; Colombo, Piergiuseppe; Moi, Davide; Brombin, Chiara; Ambrosi, Alessandro; Danese, Silvio; Mignatti, Paolo; Blasi, Francesco; D'Alessio, Silvia

    2015-11-15

    The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development.

  2. Tumor prevention in HPV8 transgenic mice by HPV8-E6 DNA vaccination.

    PubMed

    Marcuzzi, Gian Paolo; Awerkiew, Sabine; Hufbauer, Martin; Schädlich, Lysann; Gissmann, Lutz; Eming, Sabine; Pfister, Herbert

    2014-06-01

    The genus beta human papillomavirus 8 (HPV8) is involved in the development of cutaneous squamous cell carcinomas (SCCs) in individuals with epidermodysplasia verruciformis. Immunosuppressed transplant recipients are prone to harbor particularly high betapapillomavirus DNA loads, which may contribute to their highly increased risk of SCC. Tumor induction in HPV8 transgenic mice correlates with increased expression of viral oncogenes E6 and E2. In an attempt to prevent skin tumor development, we evaluated an HPV8-E6-DNA vaccine, which was able to stimulate a detectable HPV8-E6-specific cell-mediated immune response in 8/15 immunized mice. When skin of HPV8 transgenic mice was grafted onto non-transgenic littermates, the grafted HPV8 transgenic tissue was not rejected and papillomas started to grow within 14 days all over the transplant of 9/9 non-vaccinated and 7/15 not successfully vaccinated mice. In contrast, no papillomas developed in 6/8 successfully vaccinated mice. In the other two of these eight mice, a large ulcerative lesion developed within the initial papilloma growth or papilloma development was highly delayed. As the vaccine completely or partially prevented papilloma development without rejecting the transplanted HPV8 positive skin, the immune system appears to attack only keratinocytes with increased levels of E6 protein, which would give rise to papillomas.

  3. Transient cerebral hypoperfusion assisted intraarterial cationic liposome delivery to brain tissue

    PubMed Central

    Joshi, Shailendra; Singh-Moon, Rajinder P.; Wang, Mei; Chaudhuri, Durba B.; Holcomb, Mark; Straubinger, Ninfa L.; Bruce, Jeffrey N.; Bigio, Irving J.; Straubinger, Robert M.

    2014-01-01

    Object Transient cerebral hypoperfusion (TCH) has empirically been used to assist intraarterial (IA) drug delivery to brain tumors. Transient (< 3 min) reduction of cerebral blood flow (CBF) occurs during many neuro- and cardiovascular interventions and has recently been used to better target IA drugs to brain tumors. In the present experiments, we assessed whether the effectiveness of IA delivery of cationic liposomes could be improved by TCH. Methods Cationic liposomes composed of 1:1 DOTAP:PC (dioleoyl-trimethylammonium-propane:phosphatidylcholine) were administered to three groups of Sprague Dawley rats. In the first group, we tested the effect of blood flow reduction on IA delivery of cationic liposomes. In the second group, we compared TCH-assisted IA liposomal delivery vs. intravenous (IV) administration of the same dose. In the third group, we assessed retention of cationic liposomes in brain four hours after TCH assisted delivery. The liposomes contained a near infrared dye, DilC18(7), whose concentration could be measured in vivo by diffuse reflectance spectroscopy. Results IA injections of cationic liposomes during TCH increased their delivery approximately four-fold compared to injections during normal blood flow. Optical pharmacokinetic measurements revealed that relative to IV injections, IA injection of cationic liposomes during TCH produced tissue concentrations that were 100-fold greater. The cationic liposomes were retained in the brain tissue four hours after a single IA injection. There was no gross impairment of neurological functions in surviving animals. Conclusions Transient reduction in CBF significantly increased IA delivery of cationic liposomes in the brain. High concentrations of liposomes could be delivered to brain tissue after IA injections with concurrent TCH while none could be detected after IV injection. IA-TCH injections were well tolerated and cationic liposomes were retained for at least 4 hours after IA administration. These

  4. COX-2 inhibitor prevents tumor induced down regulation of classical DC lineage specific transcription factor Zbtb46 resulting in immunocompetent DC and decreased tumor burden.

    PubMed

    Pandey, Vipul K; Amin, Prayag J; Shankar, Bhavani S

    2017-04-01

    The interaction between the immune and tumor cells in the microenvironment is an important factor deciding the progression of cancer. Though many of the soluble mediators in the microenvironment that mediate immunosuppression are known, the mechanism by which the tumor affects the distal progenitors is not known. We report that the tumor derived prostanoids down regulated classical dendritic cells DC (cDC) lineage specific transcription factor Zbtb46 in the progenitor cells which affects its differentiation. Prostanoids also induced ERK/CREB/IL-10 signaling pathway in DC that is more important for maturation of DC. This was observed under in vitro as well as in vivo conditions leading to phenotypic and functional impairment of DC. siRNA mediated knockdown of Zbtb46 and not exogenous IL-10 mimicked the effects of tumor conditioned medium (TCM) on suppression of maturation markers. Treatment of tumor cells with COX-2 inhibitor NS-398 averted TCM induced phenotypic impairment of DC in vitro. Treatment of tumor bearing mice with NS-398 prevented tumor induced down regulation of Zbtb46 resulting in immunocompetent DC which in turn led to a decrease in tumor burden. The effects of NS-398 was indeed through immunomodulation was corroborated by no such response in SCID mice. Our study provides novel insight into the distal regulation of progenitor cells by tumor and the importance of Zbtb46 expression in anti-tumor immunity. These results identify Zbtb46 expression as an indicator of immunocompetent DC in tumor and also highlights that COX-2 inhibitors could be useful in cancer immunotherapy.

  5. Spermidinium closo-dodecaborate-encapsulating liposomes as efficient boron delivery vehicles for neutron capture therapy.

    PubMed

    Tachikawa, Shoji; Miyoshi, Tatsuro; Koganei, Hayato; El-Zaria, Mohamed E; Viñas, Clara; Suzuki, Minoru; Ono, Koji; Nakamura, Hiroyuki

    2014-10-21

    closo-Dodecaborate-encapsulating liposomes were developed as boron delivery vehicles for neutron capture therapy. The use of spermidinium as a counter cation of closo-dodecaborates was essential not only for the preparation of high boron content liposome solutions but also for efficient boron delivery to tumors.

  6. Chloride channel-mediated brain glioma targeting of chlorotoxin-modified doxorubicine-loaded liposomes.

    PubMed

    Xiang, Yu; Liang, Liang; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Zhang, Qiang

    2011-06-30

    The chlorotoxin (ClTx), a scorpion-derived peptide, binding to gliomas with high specificity, was firstly applied to establish the ClTx-modified doxorubicin (DOX)-loaded liposome delivery system for targeting the brain glioma and improving the anticancer efficacy. In vitro physicochemical characterization of the novel liposome system presented satisfactory size of 100 nm with uniform distribution, high encapsulation efficiency and adequate loading capacity of both fluorescent probe and anticancer drug. It was demonstrated quantitatively by the spectrophotofluorometry and flow cytometry and qualitatively by the confocal microscopy that ClTx highly facilitated the uptake of liposomes by three glioma cell lines and one endothelial cell line. In vitro cytotoxicity studies proved that the presence of ClTx increased the cytotoxicity against glioma cells and endothelial cells with various levels for different cell lines. In BALB/c mice bearing U87 tumor xenografts, biodistribution of DiR-loaded liposomes by body imaging and anti-glioma pharmacodynamics of DOX-loaded liposomes were investigated. The ClTx-modified liposomes showed more accumulation in the subcutaneous and intracranial tumors, higher tumor growth inhibition and lower blood toxicity in the armpit tumor model. The in vitro and in vivo results exhibited good correlation of glioma targeting of the ClTx-modified liposomes. Significantly, with the ClTx as the targeting ligand, the liposomes might serve as an applicable delivery system for brain glioma therapy or imaging.

  7. Effect of Surface Properties on Liposomal siRNA Delivery

    PubMed Central

    Xia, Yuqiong; Tian, Jie; Chen, Xiaoyuan

    2015-01-01

    Liposomes are one of the most widely investigated carriers for siRNA delivery. The surface properties of liposomal carriers, including the surface charge, PEGylation, and ligand modification can significantly affect the gene silencing efficiency. Three barriers of systemic siRNA delivery (long blood circulation, efficient tumor penetration and efficient cellular uptake/endosomal escape) are analyzed on liposomal carriers with different surface charges, PEGylations and ligand modifications. Cationic formulations dominate siRNA delivery and neutral formulations also have good performance while anionic formulations are generally not proper for siRNA delivery. The PEG dilemma (prolonged blood circulation vs. reduced cellular uptake/endosomal escape) and the side effect of repeated PEGylated formulation (accelerated blood clearance) were discussed. Effects of ligand modification on cationic and neutral formulations were analyzed. Finally, we summarized the achievements in liposomal siRNA delivery, outlined existing problems and provided some future perspectives. PMID:26695117

  8. Remote loading of preencapsulated drugs into stealth liposomes.

    PubMed

    Sur, Surojit; Fries, Anja C; Kinzler, Kenneth W; Zhou, Shibin; Vogelstein, Bert

    2014-02-11

    Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.

  9. Liposomal squalenoyl-gemcitabine: formulation, characterization and anticancer activity evaluation

    NASA Astrophysics Data System (ADS)

    Pili, Barbara; ReddyCurrent Address: Sanofi-Aventis, 13 Quai Jules-Guesdes, 94403, Vitry-Sur-Seine, France., L. Harivardhan; Bourgaux, Claudie; Lepêtre-Mouelhi, Sinda; Desmaële, Didier; Couvreur, Patrick

    2010-08-01

    A new prodrug of gemcitabine, based on the covalent coupling of squalene to gemcitabine (GemSQ), has been designed to enhance the anticancer activity of gemcitabine, a nucleoside analogue active against a wide variety of tumors. In the present study, the feasibility of encapsulating GemSQ into liposomes either PEGylated or non-PEGylated has been investigated. The in vivo anticancer activity of these formulations has been tested on subcutaneous grafted L1210wt leukemia model and compared to that of free gemcitabine. The liposomal GemSQ appears to be a potential delivery system for the effective treatment of tumors.

  10. Liposomal squalenoyl-gemcitabine: formulation, characterization and anticancer activity evaluation.

    PubMed

    Pili, Barbara; Reddy, L Harivardhan; Bourgaux, Claudie; Lepêtre-Mouelhi, Sinda; Desmaële, Didier; Couvreur, Patrick

    2010-08-01

    A new prodrug of gemcitabine, based on the covalent coupling of squalene to gemcitabine (GemSQ), has been designed to enhance the anticancer activity of gemcitabine, a nucleoside analogue active against a wide variety of tumors. In the present study, the feasibility of encapsulating GemSQ into liposomes either PEGylated or non-PEGylated has been investigated. The in vivo anticancer activity of these formulations has been tested on subcutaneous grafted L1210wt leukemia model and compared to that of free gemcitabine. The liposomal GemSQ appears to be a potential delivery system for the effective treatment of tumors.

  11. Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells

    PubMed Central

    Ricciotti, Emanuela; Cufino, Valerio; Sacco, Angela; Grande, Rosalia; Alberti, Sara; Arena, Vincenzo; Cirillo, Mariangela; Patrono, Carlo; FitzGerald, Garret A.; Steinhilber, Dieter; Sgambato, Alessandro; Patrignani, Paola

    2016-01-01

    We investigated whether platelets prime colon cancer cells for metastasis and whether pharmacological inhibition of platelet function may prevent it. Coculturing HT29 human colon carcinoma cells with human platelets led to the induction of mesenchymal-like cancer cells characterized by downregulation of E-cadherin and upregulation of Twist1, enhanced cell mobility and a proaggregatory action on platelets. These changes were prevented by different antiplatelet agents, aspirin[an inhibitor of cyclooxygenase(COX)-1], DG-041[an antagonist of prostaglandin(PG)E2 EP3 receptor] and ticagrelor (a P2Y12 receptor antagonist). The injection of HT29 cells, exposed to platelets in vitro, into the tail vein of humanized immunodeficient mice led to higher incidence of lung metastasis compared to the injection of untreated HT29 cells. This effect was associated with enhanced systemic biosynthesis of thromboxane(TX)A2 and PGE2 in vivo. Platelet COX-1 inhibition by aspirin administration to mice prevented the increased rate of metastasis as well as the enhanced production of TXA2 and PGE2 induced by the in vitro priming of HT29 cells by platelets. In conclusion, targeting platelet COX-1 with low-dose aspirin exerts an antimetastatic action by averting the stem cell mimicry of cancer cells associated with enhanced proaggregatory effects induced by platelet-tumor cell interactions. These effects may be shared by other antiplatelet drugs. PMID:27074574

  12. Liposomal cytarabine for leukemic and lymphomatous meningitis: recent developments.

    PubMed

    Benesch, Martin; Urban, Christian

    2008-02-01

    Liposomal cytarabine (Depocyte) is a sustained-release formulation of cytarabine developed for intrathecal administration, ensuring prolonged cytotoxic drug concentrations of cytarabine in cerebrospinal fluid. Although liposomal cytarabine is increasingly used for the treatment (and prophylaxis) of CNS involvement in patients with leukemia/lymphoma, many of the recently presented clinical trials on liposomal cytarabine were retrospective in nature or used this drug on a compassionate basis. So far, one randomized Phase III study has shown significantly better response rates in patients with lymphomatous meningitis who received liposomal cytarabine compared with free cytarabine. Considerable concerns about the safety of this drug arose from recent observations that liposomal cytarabine might contribute to neurologic side effects when given too closely to high-dose systemic chemotherapy known to penetrate the brain-blood barrier. Superior efficacy of liposomal cytarabine compared with standard intrathecal therapy should be confirmed in prospective clinical trials. Careful adherence with preventive measures might help physicians to minimize side effects possibly related to the administration of liposomal cytarabine.

  13. Sorafenib and gadolinium co-loaded liposomes for drug delivery and MRI-guided HCC treatment.

    PubMed

    Xiao, Yanan; Liu, Yongjun; Yang, Shaomei; Zhang, Bo; Wang, Tianqi; Jiang, Dandan; Zhang, Jing; Yu, Dexin; Zhang, Na

    2016-05-01

    To improve the poor water solubility of sorafenib and to monitor its distribution and the early feedback effects on its in vivo treatment efficacy in a precise manner, sorafenib (SF) and gadolinium (Gd) co-loaded liposomes (SF/Gd-liposomes) were prepared. The simultaneous imaging and therapy efficacies of the SF/Gd-liposomes were tested. The solubility of SF in SF/Gd-liposomes was significantly increased from 0.21 μg/mL to 250 μg/mL. The imaging capability of SF/Gd-liposomes were tested by in-vitro and the in-vivo imaging ability tests and the results confirmed that SF/Gd-liposomes could be served as an effective contrast agent. The design of SF/Gd-liposomes allowed the MRI-guided in vivo visualization of the delivery and biodistribution of liposome. In the in vivo antitumor studies, SF/Gd-liposomes had better antitumor effects in H22 tumor-bearing mice than SF solution (oral or i.v. administration) (P<0.05). These findings indicated that the SF/Gd-liposomes could be used as the promising nano-carriers for the MRI-guided in vivo visualization of the delivery and HCC treatment.

  14. Cancer gene therapy utilized ultrasound (US)-sensitive liposome as non-viral vector

    NASA Astrophysics Data System (ADS)

    Suzuki, Ryo; Oda, Yusuke; Namai, Eisuke; Nishiie, Norihito; Hirata, Keiichi; Taira, Yuichiro; Utoguchi, Naoki; Negichi, Yoichi; Maruyama, Kazuo

    2010-03-01

    Sonoporation is an attractive technique to develop non-invasive and non-viral gene delivery system. However, simple sonoporation using only ultrasound (US) is not enough to establish effective cancer gene therapy because of low efficiency of gene delivery. Therefore, we improved this problem by the combination of US and novel US-sensitive liposome (Bubble liposome) which was a liposome containing US imaging gas (perfluoropropane). This was an effective gene delivery system with collapse (cavitation) that was induced by US exposure to Bubble liposome. In this study, we assessed the ability of this system in cancer gene therapy using IL-12 cording plasmid DNA. The combination of Bubble liposomes and ultrasound was dramatically suppressed tumor growth. Therefore, we concluded that the combination of Bubble liposomes and ultrasound would be a good non-viral vector system in IL-12 cancer gene therapy.

  15. Development of a bone targeted thermosensitive liposomal doxorubicin formulation based on a bisphosphonate modified non-ionic surfactant.

    PubMed

    Song, Heliang; Zhang, Jiabing; Liu, Xinrong; Deng, Tongming; Yao, Peng; Zhou, Shaobing; Yan, Weili

    2016-09-01

    Bone is among the most common sites of metastasis in cancer patients, so it is an urgent need to develop drug delivery systems targeting tumor bone metastasis with the feature of controlled release. This study aimed to delivery of thermosensitive liposomal doxorubicin to bone for tumor metastasis treatment. First, Brij78 (polyoxyethylene stearyl ether) was conjugated with Pamidronate (Pa). By incorporating Pa-Brij78 to DPPC/Chol liposomes, we developed Pa surface functionalized liposomes. The Pa-Brij78/DPPC/Chol liposomes (PB-liposomes) exhibited a stronger binding affinity to hydroxyapatite (HA), a major component of bone, than Brij78/DPPC/Chol liposomes (B-liposomes). Doxorubicin (Dox) was then encapsulated in PB-liposomes and the results demonstrated complete release of Dox from PB-liposomes or the complex of HA/PB-liposomes within 10 min at 42 °C. Next, human lung cancer A549 cells were treated with the thermosensitive complex of HA/PB-liposomes/Dox to mimic tumor bone metastasis treatment through bone targeted delivery of therapeutic agents. Pre-incubation of HA/PB-liposomes/Dox with mild heat at 42 °C induced subsequent higher cytotoxicity to A549 cells than incubation of the same complex at 37 °C, suggesting more active drug release triggered by heat. In conclusion, we synthesized a novel surfactant Pa-Brij78 and it has the potential to be used for development of a bone targeted thermosensitive liposome formulation for treatment of tumor bone metastasis.

  16. Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma.

    PubMed

    Huang, S K; Mayhew, E; Gilani, S; Lasic, D D; Martin, F J; Papahadjopoulos, D

    1992-12-15

    Three different liposome types were compared for blood clearance and tissue uptake in mice bearing C-26 colon carcinoma growing either s.c. or in liver. Therapeutic experiments were performed with the liposome preparation showing the highest tumor uptake. Liposomes were composed of solid-phase phosphatidylcholine, either distearoyl phosphatidylcholine or hydrogenated soy phosphatidylcholine, and cholesterol at a 2:1 molar ratio. These liposomes were compared with similar but sterically stabilized liposomes (SL) which, in addition, contained either GM1 ganglioside or phosphatidylethanolamine derivatized with poly(ethylene glycol). Pharmacokinetic analysis of drug disposition was based on the areas under the curve for liposome-entrapped 67Ga uptake per gram of tissue up to 96 h following i.v. injection. The highest tissue area under the curve values with both liposome types were obtained in spleen, liver, and tumor. However, the sterically stabilized liposomes gave an area under the curve value 2-3-fold higher in the s.c. tumor and about 2-fold lower in liver and spleen. The therapeutic efficacy of doxorubicin (DOX) and epirubicin (EPI) encapsulated in poly(ethylene glycol)-derivatized phosphatidylethanolamine-containing liposomes was compared with that of free drug at two doses, 6 and 9 (or 10) mg/kg animal weight. Liposomes containing drug were injected either as a single dose, at different times following tumor implantation, or as three weekly doses starting 10 days after implantation. When injected as a single dose, liposome-encapsulated DOX had the maximal effect on tumor growth when injected 6 to 9 days after tumor implantation. When injected as three weekly doses, with treatment starting with a delay of 10 days, tumors which had grown to a size of approximately 0.05-0.1 cm3 regressed in groups of animals treated with either liposome-encapsulated drug (SL-DOX or SL-EPI) but continued to grow unabated in untreated mice and in mice receiving either of the free

  17. Is primary prevention with antiepileptic drugs effective in brain tumors or brain metastases?

    PubMed

    Lobos-Urbina, Diego; Kittsteiner-Manubens, Lucas; Peña, José

    2017-03-21

    Patients with brain tumors –primary or metastatic- have an increased risk of presenting seizures during the course of their disease. So, prophylactic antiepileptic drugs have been proposed. However, the effects of this intervention are not yet clear. To answer this question, we searched in Epistemonikos database, which is maintained by screening multiple databases. We identified 12 systematic reviews including 80 studies overall. Twelve corresponded to randomized trials, but only two answered the question of interest. We extracted data, conducted a meta-analysis and generated a summary of findings table using the GRADE method. We concluded primary prevention with antiepileptic drugs might not reduce the risk of seizures, and it is associated to frequent adverse effects.

  18. Allometric scaling of pegylated liposomal anticancer drugs.

    PubMed

    Caron, Whitney P; Clewell, Harvey; Dedrick, Robert; Ramanathan, Ramesh K; Davis, Whitney L; Yu, Ning; Tonda, Margaret; Schellens, Jan H; Beijnen, Jos H; Zamboni, William C

    2011-10-01

    Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the disposition of nonliposomal drugs across species. The objectives of this study were to use allometric scaling to: (1) compare the disposition of pegylated liposomal drugs across speciesand determine the best scaling model and (2) predict PK parameters of pegylated liposomal drugs in humans. The PK of pegylated liposomal CKD-602 (S-CKD602), doxorubicin (Doxil®), and cisplatin (SPI-077) were compared. PK studies ofS-CKD602, Doxil®, and SPI-077 were performed at the maximum tolerated dose (MTD) in male and female mice, rats, dogs and patients with refractory solid tumors. The allometric equation used to evaluate the relationship between W and CL in each species was CL = a(W)(m) (a = empirical coefficient; m = allometric exponent). Substitution of physiological variables other than body weight, such as factors representative of the mononuclear phagocyte system (MPS) were evaluated. Dedrick Plots and Maximum Life-Span Potential (MLP) were used to determine scaling feasibility. Standard allometry demonstrated a relationship between clearance of S-CKD602, Doxil®, and SPI-077 and body, spleen, liver, and kidney weights, total monocyte count, and spleen and liver blood flow. However, using scaling to predict CL of these agents in humans often resulted in differences >30%. Despite a strong correlation between body weight and MPS-associated variables with CL among preclinical species, the use of the equations did not predict CL. Thus, new methods of allometric scaling and measures of MPS function need to be developed.

  19. Heating stents with radio frequency energy to prevent tumor ingrowth: modeling and experimental results

    NASA Astrophysics Data System (ADS)

    Ryan, Thomas P.; Lawes, Kate; Goldberg, S. Nahum

    1998-04-01

    Stents are often inserted into internal orifices to treat blockage due to tumor ingrowth. Stents are favored due to their minimally invasive nature, possible avoidance of a surgical procedure, and their ability to palliate surgically non-resectable disease. Because of rapid tumor growth however, a treatment means to prevent overgrowth through the stent and resultant blockage is required. To further this goal, experiments were performed in which a stent was placed in tissue and heated with radiofrequency (RF) energy to coagulate a cylinder of tissue, thereby eradicating viable tissue in the proximity of the stent. Temperatures were measured at the central stent surface and edges over time during a 5 - 10 minute heating in phantom and in fresh tissue. In addition, a finite element model was used to simulate the electric field and temperature distribution. Blood flow was also introduced in the model by evaluating RF application to stents to determine effectiveness of the energy applications. Changing perfusion and tissue electrical conductivity as a function of temperature was applied as the tissue was heated to 100 degree(s)C. Results from the electric field model will be shown as well as the thermal distribution over time from the simulations. Lastly, results from the damage integral will be discussed.

  20. Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy.

    PubMed

    Seguin, Johanne; Brullé, Laura; Boyer, Renaud; Lu, Yen Mei; Ramos Romano, Miriam; Touil, Yasmine S; Scherman, Daniel; Bessodes, Michel; Mignet, Nathalie; Chabot, Guy G

    2013-02-28

    The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) has shown antiangiogenic and anticancer properties. Because of fisetin limited water solubility, we designed a liposomal formulation and evaluated its biological properties in vitro and in Lewis lung carcinoma (LLC) bearing mice. A liposomal formulation was developed with DOPC and DODA-PEG2000, possessing a diameter in the nanometer range (173.5±2.4nm), a high homogeneity (polydispersity index 0.181±0.016) and high fisetin encapsulation (58%). Liposomal fisetin incubated with LLC cells were internalized, induced a typical fisetin morphological effect and increased the sub-G1 cell distribution. In vivo, liposomal fisetin allowed a 47-fold increase in relative bioavailability compared to free fisetin. The effect of liposomal fisetin on LLC tumor growth in mice at low dose (21mg/kg) allowed a higher tumor growth delay (3.3 days) compared to free fisetin at the same dose (1.6 day). Optimization of liposomal fisetin therapy was attempted by co-treatment with cyclophosphamide which led to a significant improvement in tumor growth delay (7.2 days) compared to cyclophosphamide with control liposomes (4.2 days). In conclusion, fisetin liposomes markedly improved fisetin bioavailability and anticancer efficacy in mice and this formulation could facilitate the administration of this flavonoid in the clinical setting.

  1. Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes.

    PubMed

    Gao, Jian-Qing; Lv, Qing; Li, Li-Ming; Tang, Xin-Jiang; Li, Fan-Zhu; Hu, Yu-Lan; Han, Min

    2013-07-01

    Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the glioma cells. Dual-targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy.

  2. Involvement of let-7 microRNA for the therapeutic effects of Rhenium-188-embedded liposomal nanoparticles on orthotopic human head and neck cancer model

    PubMed Central

    Lin, Liang-Ting; Chang, Chun-Yuan; Chang, Chih-Hsien; Wang, Hsin-Ell; Chiou, Shih-Hwa; Liu, Ren-Shyan; Lee, Te-Wei; Lee, Yi-Jang

    2016-01-01

    Human head and neck squamous cell carcinoma (HNSCC) is usually treated by surgical resection with adjuvant radio-chemotherapy. In this study, we examined whether the radiopharmaceutical 188Re-liposome could suppress the growth of HNSCC followed by an investigation of molecular mechanisms. The orthotopic HNSCC tumor model was established by human hypopharyngeal FaDu carcinoma cells harboring multiple reporter genes. The drug targeting and therapeutic efficacy of 188Re-liposome were examined using in vivo imaging, bio-distribution, pharmacokinetics, and dosimetry. The results showed that 188Re-liposome significantly accumulated in the tumor lesion compared to free 188Re. The circulation time and tumor targeting of 188Re-liposome were also longer than that of free 188Re in tumor-bearing mice. The tumor growth was suppressed by 188Re-liposome up to three weeks using a single dose treatment. Subsequently, microarray analysis followed by Ingenuity Pathway Analysis (IPA) showed that tumor suppressor let-7 microRNA could be an upstream regulator induced by 188Re-liposome to regulate downstream genes. Additionally, inhibition of let-7i could reduce the effects of 188Re-liposome on suppression of tumor growth, suggesting that let-7 family was involved in 188Re-liposome mediated suppression of tumor growth in vivo. Our data suggest that 188Re-liposome could be a novel strategy for targeting HNSCC partially via induction of let-7 microRNA. PMID:27588466

  3. Involvement of let-7 microRNA for the therapeutic effects of Rhenium-188-embedded liposomal nanoparticles on orthotopic human head and neck cancer model.

    PubMed

    Lin, Liang-Ting; Chang, Chun-Yuan; Chang, Chih-Hsien; Wang, Hsin-Ell; Chiou, Shih-Hwa; Liu, Ren-Shyan; Lee, Te-Wei; Lee, Yi-Jang

    2016-10-04

    Human head and neck squamous cell carcinoma (HNSCC) is usually treated by surgical resection with adjuvant radio-chemotherapy. In this study, we examined whether the radiopharmaceutical 188Re-liposome could suppress the growth of HNSCC followed by an investigation of molecular mechanisms. The orthotopic HNSCC tumor model was established by human hypopharyngeal FaDu carcinoma cells harboring multiple reporter genes. The drug targeting and therapeutic efficacy of 188Re-liposome were examined using in vivo imaging, bio-distribution, pharmacokinetics, and dosimetry. The results showed that 188Re-liposome significantly accumulated in the tumor lesion compared to free 188Re. The circulation time and tumor targeting of 188Re-liposome were also longer than that of free 188Re in tumor-bearing mice. The tumor growth was suppressed by 188Re-liposome up to three weeks using a single dose treatment. Subsequently, microarray analysis followed by Ingenuity Pathway Analysis (IPA) showed that tumor suppressor let-7 microRNA could be an upstream regulator induced by 188Re-liposome to regulate downstream genes. Additionally, inhibition of let-7i could reduce the effects of 188Re-liposome on suppression of tumor growth, suggesting that let-7 family was involved in 188Re-liposome mediated suppression of tumor growth in vivo. Our data suggest that 188Re-liposome could be a novel strategy for targeting HNSCC partially via induction of let-7 microRNA.

  4. Psoralen loaded liposomal nanocarriers for improved skin penetration and efficacy of topical PUVA in psoriasis.

    PubMed

    Doppalapudi, Sindhu; Jain, Anjali; Chopra, Dhiraj Kumar; Khan, Wahid

    2017-01-01

    Psoralen in combination with ultraviolet A radiation (PUVA) is an FDA recommended therapy for clinical application in the management of severe recalcitrant psoriasis. Psoralen acts by intercalation of DNA and upon exposure to UV-A, it forms monoadducts which in turn induce apoptosis. Poor skin deposition, weak percutaneous permeability of psoralen and adverse effects of severe burning, blisters, pigmentation associated with conventional topical psoralen vehicles hinders the therapeutic efficacy and safety of topical PUVA. The aim of the present study is to formulate psoralen loaded liposomal nanocarriers for enhanced skin penetration, safety and efficacy of topical PUVA in psoriasis. Two different liposomal compositions i.e., cationic liposomes composed of DC-Chol, cholesterol and anionic liposomes composed of egg lecithin, cholesterol, tetramyristoyl cardiolipin were prepared for the topical delivery of psoralen. Liposomal carriers were characterized with respect to size, zeta potential, entrapment efficiency, stability, in vitro drug release and in vivo studies. Both liposomes were prepared with particle size of nearly 100nm. Zeta potential and entrapment efficiency of cationic liposomes were +25.8mV, 75.12% and anionic liposomes were -28.5mV, 60.08% respectively. Liposomal dermal distribution demonstrated higher penetration of both liposomal carriers over solution. Similarly, skin permeation study indicated 5 fold increase in permeation of psoralen with liposomal carriers. Topical application of psoralen liposomal gels on imiquimod induced psoriatic plaque model reduced the symptoms of psoriasis and levels of key psoriatic cytokines such as tumor necrosis factor-α, IL-17 and IL-22. In conclusion, the developed liposomal carriers of psoralen were found to be promising and can find application for optimal safety and efficacy of topical PUVA in psoriasis.

  5. Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed.

    PubMed

    Ando, Hidenori; Kobayashi, Sakiko; Abu Lila, Amr S; Eldin, Noha Essam; Kato, Chihiro; Shimizu, Taro; Ukawa, Masami; Kawazoe, Kazuyoshi; Ishida, Tatsuhiro

    2015-12-28

    Malignant pleural mesothelioma (MPM) is an aggressive cancer that proliferates in the pleural cavity. Pemetrexed (PMX) in combination with cisplatin is currently the approved standard care for MPM, but a dismal response rate persists. Recently, we prepared various liposomal PMX formulations using different lipid compositions and evaluated their in vitro cytotoxicity against human mesothelioma cells (MSTO-211H). In the present study, we investigated the in vivo therapeutic effect of our liposomal PMX formulations using an orthotopic MPM tumor mouse model. PMX encapsulated within either cholesterol-containing (PMX/Chol CL) or cholesterol-free (PMX/Non-Chol CL) cationic liposome was intrapleurally injected into tumor-bearing mice. PMX encapsulated in cholesterol-free liposomes (PMX/Non-Chol CL) drastically inhibited the tumor growth in the pleural cavity, while free PMX and PMX encapsulated in cholesterol-containing liposomes (PMX/Chol CL) barely inhibited the tumor growth. The enhanced in vivo anti-tumor efficacy of PMX/Non-Chol CL was credited, on the one hand, for prolonging the retention of cationic liposomes in the pleural cavity via their electrostatic interaction with the negatively charged membranes of tumor cells, but on the other hand, it was charged with contributing to a higher drug release from the "fluid" liposomal membrane following intrapleural administration. This therapeutic strategy of direct intrapleural administration of liposomal PMX, along with the great advances in CL-guided therapeutics, might be a promising therapeutic approach to conquering the poor prognosis for MPM.

  6. Cancer Immunotherapy Utilized Bubble Liposomes and Ultrasound as Antigen Delivery System

    NASA Astrophysics Data System (ADS)

    Oda, Yusuke; Otake, Shota; Suzuki, Ryo; Otake, Shota; Nishiie, Norihito; Hirata, Keiichi; Taira, Yuichiro; Utoguchi, Naoki; Maruyama, Kazuo

    2010-03-01

    In dendritic cells (DCs)-based cancer immunotherapy, it is important to present the epitope peptide derived from tumor associated antigens (TAAs) on MHC class I in order to induce tumor specific cytotoxic T lymphocytes (CTLs). However, MHC class I molecules generally present the epitope peptides derived from endogenous antigens for DCs but not exogenous ones such as TAAs. Recently, we developed the novel liposomal bubbles (Bubble liposomes) encapsulating perfluoropropane nanobubbles. In this study, we attempted to establish the novel antigen delivery system to induce MHC class I presentation using the combination of ultrasound and Bubble liposomes. Using ovalbumin (OVA) as model antigen, the combination of Bubble liposomes and ultrasound exposure for the DC could induce MHC class I presentation. In addition, the viability of DCs was more than 80%. These results suggest that Bubble liposomes might be a novel ultrasound enhanced antigen delivery tool in DC-based cancer immunotherapy.

  7. Bioreactor droplets from liposome-stabilized all-aqueous emulsions

    NASA Astrophysics Data System (ADS)

    Dewey, Daniel C.; Strulson, Christopher A.; Cacace, David N.; Bevilacqua, Philip C.; Keating, Christine D.

    2014-08-01

    Artificial bioreactors are desirable for in vitro biochemical studies and as protocells. A key challenge is maintaining a favourable internal environment while allowing substrate entry and product departure. We show that semipermeable, size-controlled bioreactors with aqueous, macromolecularly crowded interiors can be assembled by liposome stabilization of an all-aqueous emulsion. Dextran-rich aqueous droplets are dispersed in a continuous polyethylene glycol (PEG)-rich aqueous phase, with coalescence inhibited by adsorbed ~130-nm diameter liposomes. Fluorescence recovery after photobleaching and dynamic light scattering data indicate that the liposomes, which are PEGylated and negatively charged, remain intact at the interface for extended time. Inter-droplet repulsion provides electrostatic stabilization of the emulsion, with droplet coalescence prevented even for submonolayer interfacial coatings. RNA and DNA can enter and exit aqueous droplets by diffusion, with final concentrations dictated by partitioning. The capacity to serve as microscale bioreactors is established by demonstrating a ribozyme cleavage reaction within the liposome-coated droplets.

  8. Gemcitabine-loaded liposomes: rationale, potentialities and future perspectives.

    PubMed

    Federico, Cinzia; Morittu, Valeria M; Britti, Domenico; Trapasso, Elena; Cosco, Donato

    2012-01-01

    This review describes the strategies used in recent years to improve the biopharmaceutical properties of gemcitabine, a nucleoside analog deoxycytidine antimetabolite characterized by activity against many kinds of tumors, by means of liposomal devices. The main limitation of using this active compound is the rapid inactivation of deoxycytidine deaminase following administration in vivo. Consequently, different strategies based on its encapsulation/complexation in innovative vesicular colloidal carriers have been investigated, with interesting results in terms of increased pharmacological activity, plasma half-life, and tumor localization, in addition to decreased side effects. This review focuses on the specific approaches used, based on the encapsulation of gemcitabine in liposomes, with particular attention to the results obtained during the last 5 years. These approaches represent a valid starting point in the attempt to obtain a novel, commercializable drug formulation as already achieved for liposomal doxorubicin (Doxil(®), Caelyx(®)).

  9. Learning about the Importance of Mutation Prevention from Curable Cancers and Benign Tumors

    PubMed Central

    Wang, Gangshi; Chen, Lichan; Yu, Baofa; Zellmer, Lucas; Xu, Ningzhi; Liao, D. Joshua

    2016-01-01

    Some cancers can be cured by chemotherapy or radiotherapy, presumably because they are derived from those cell types that not only can die easily but also have already been equipped with mobility and adaptability, which would later allow the cancers to metastasize without the acquisition of additional mutations. From a viewpoint of biological dispersal, invasive and metastatic cells may, among other possibilities, have been initial losers in the competition for resources with other cancer cells in the same primary tumor and thus have had to look for new habitats in order to survive. If this is really the case, manipulation of their ecosystems, such as by slightly ameliorating their hardship, may prevent metastasis. Since new mutations may occur, especially during and after therapy, to drive progression of cancer cells to metastasis and therapy-resistance, preventing new mutations from occurring should be a key principle for the development of new anticancer drugs. Such new drugs should be able to kill cancer cells very quickly without leaving the surviving cells enough time to develop new mutations and select resistant or metastatic clones. This principle questions the traditional use and the future development of genotoxic drugs for cancer therapy. PMID:26918057

  10. Incorporation of a selective sigma-2 receptor ligand enhances uptake of liposomes by multiple cancer cells

    PubMed Central

    Zhang, Yifei; Huang, Yixian; Zhang, Peng; Gao, Xiang; Gibbs, Robert B; Li, Song

    2012-01-01

    Background: The sigma-2 receptor is an attractive target for tumor imaging and targeted therapy because it is overexpressed in multiple types of solid tumors, including prostate cancer, breast cancer, and lung cancer. SV119 is a synthetic small molecule that binds to sigma-2 receptors with high affinity and specificity. This study investigates the utility of SV119 in mediating the selective targeting of liposomal vectors in various types of cancer cells. Methods: SV119 was covalently linked with polyethylene glycol-dioleyl amido aspartic acid conjugate (PEG-DOA) to generate a novel functional lipid, SV119-PEG-DOA. This lipid was utilized for the preparation of targeted liposomes to enhance their uptake by cancer cells. Liposomes with various SV119 densities (0, 1, 3, and 5 mole%) were prepared and their cellular uptake was investigated in several tumor cell lines. In addition, doxorubicin (DOX) was loaded into the targeted and unmodified liposomes, and the cytotoxic effect on the DU-145 cells was evaluated by MTT assay. Results: Liposomes with or without SV119-PEG-DOA both have a mean diameter of approximately 90 nm and a neutral charge. The incorporation of SV119-PEG-DOA significantly increased the cellular uptake of liposomes by the DU-145, PC-3, A549, 201T, and MCF-7 tumor cells, which was shown by fluorescence microscopy and the quantitative measurement of fluorescence intensity. In contrast, the incorporation of SV119 did not increase the uptake of liposomes by the normal BEAS-2B cells. In a time course study, the uptake of SV119 liposomes by DU-145 cells was also significantly higher at each time point compared to the unmodified liposomes. Furthermore, the DOX-loaded SV119 liposomes showed significantly higher cytotoxicity to DU-145 cells compared to the DOX-loaded unmodified liposomes. Conclusion: SV119 liposomes were developed for targeted drug delivery to cancer cells. The targeting efficiency and specificity of SV119 liposomes to cancer cells was

  11. Dual-targeting nanocarrier system based on thermosensitive liposomes and gold nanorods for cancer thermo-chemotherapy.

    PubMed

    Yu, Meng; Guo, Fang; Tan, Fengping; Li, Nan

    2015-10-10

    The primary challenge of cancer therapy was the failure of most chemotherapeutics to accumulate in the tumors, additionally causing serious systemic side effects. We designed a tumor-targeting accumulated and locally triggered-release nanocarrier system to increase the intratumoral drug concentration and thus the efficacy of chemotherapy, based on gold nanorods (GNRs) and thermosensitive liposomes (TSLs). PEGylated GNRs could not only make nanocarriers to co-accumulate in tumors depending on enhanced permeability and retention (EPR) effect, but also generated heat locally under near-infrared (NIR) stimulation. CO2 bubbles were generated by the encapsulated ammonium bicarbonate (ABC) under hyperthermia, thus the co-encapsulated drug was released and local drug concentration was increased along with the disintegration of liposomal membrane. On the other hand, this dual-targeting system prevented the drug leakage in blood circulation or other organs while facilitated most of the active agents delivered to tumors. In vitro and in vivo experiments revealed high cytotoxicity and good affinity of HTSL to MDA-MB-435 cells when used synergistically with GNRs, but low toxicity to normal cells at the same condition. When combined with thermotherapy, the smart nanocarrier system held significant promise for future cancer treatment for their markedly improved therapeutic efficacy and decreased systemic toxicity.

  12. Lead Ions Encapsulated in Liposomes and Their Effect on Staphylococcus aureus

    PubMed Central

    Kensova, Renata; Blazkova, Iva; Konecna, Marie; Kopel, Pavel; Chudobova, Dagmar; Zitka, Ondrej; Vaculovicova, Marketa; Hynek, David; Adam, Vojtech; Beklova, Miroslava; Kizek, Rene

    2013-01-01

    The aim of the study was the preparation of a liposome complex with encapsulated lead ions, which were electrochemically detected. In particular, experiments were focused on the potential of using an electrochemical method for the determination of free and liposome-encapsulated lead and determination of the encapsulation efficiency preventing the lead toxicity. Primarily, encapsulation of lead ions in liposomes and confirmation of successful encapsulation by electrochemical methods was done. Further, the reduction effect of the liposome matrix on the detected electrochemical signal was monitored. Besides encapsulation itself, comparison of toxicity of free lead ions and lead ions encapsulated in liposome was tested. The calculated IC50 values for evaluating the lead cytotoxicity showed significant differences between the lead enclosed in liposomes (28 µM) and free lead ions (237 µM). From the cytotoxicity studies on the bacterial strain of S. aureus it was observed that the free lead ions are less toxic in comparison with lead encapsulated in liposomes. Liposomes appear to be a suitable carrier of various substances through the inner cavity. Due to the liposome structure the lead enclosed in the liposome is more easily accepted into the cell structure and the toxicity of the enclosed lead is higher in comparison to free lead ions. PMID:24317385

  13. Length of hydrocarbon chain influences location of curcumin in liposomes: Curcumin as a molecular probe to study ethanol induced interdigitation of liposomes.

    PubMed

    El Khoury, Elsy; Patra, Digambara

    2016-05-01

    Using fluorescence quenching of curcumin in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes by brominated derivatives of fatty acids, the location of curcumin has been studied, which indicates length of hydrocarbon chain has an effect on the location of curcumin in liposomes. Change of fluorescence intensity of curcumin with temperature in the presence of liposomes helps to estimate the phase transition temperature of these liposomes, thus, influence of cholesterol on liposome properties has been studied using curcumin as a molecule probe. The cooperativity due to the interactions between the hydrocarbon chains during melting accelerates the phase transition of DPPC liposomes in the presence of high percentage of cholesterol whereas high percentage of cholesterol generates a rather rigid DMPC liposome over a wide range of temperatures. We used ethanol to induce interdigitation between the hydrophobic chains of the lipids and studied this effect using curcumin as fluorescence probe. As a result of interdigitation, curcumin fluorescence is quenched in liposomes. The compact arrangement of the acyl chains prevents curcumin from penetrating deep near the midplane. In the liquid crystalline phase ethanol introduces a kind of order to the more fluid liposome, and does not leave space for curcumin to be inserted away from water.

  14. In vivo and in vitro evaluation of octyl methoxycinnamate liposomes

    PubMed Central

    Varjão Mota, Aline de Carvalho; Faria de Freitas, Zaida Maria; Júnior, Eduardo Ricci; Dellamora-Ortiz, Gisela Maria; Santos-Oliveira, Ralph; Ozzetti, Rafael Antonio; Vergnanini, André Luiz; Ribeiro, Vanessa Lira; Silva, Ronald Santos; dos Santos, Elisabete Pereira

    2013-01-01

    Solar radiation causes damage to human skin, and photoprotection is the main way to prevent these harmful effects. The development of sunscreen formulations containing nanosystems is of great interest in the pharmaceutical and cosmetic industries because of the many potential benefits. This study aimed to develop and evaluate an octyl methoxycinnamate (OMC) liposomal nanosystem (liposome/OMC) to obtain a sunscreen formulation with improved safety and efficacy by retaining OMC for longer on the stratum corneum. Methods The liposome/OMC nanostructure obtained was tested for enzymatic hydrolysis with lipase from Rhizomucor miehei and biodistribution with liposomes labeled with technetium-99m. The liposome/OMC formulation was then incorporated in a gel formulation and tested for ocular irritation using the hen’s egg test-chorio-allantoic membrane (HET-CAM) assay, in vitro and in vivo sun protection factor, in vitro release profile, skin biometrics, and in vivo tape stripping. Results The liposome/OMC nanosystem was not hydrolyzed from R. miehei by lipase. In the biodistribution assay, the liposome/OMC formulation labeled with technetium-99m had mainly deposited in the skin, while for OMC the main organ was the liver, showing that the liposome had higher affinity for the skin than OMC. The liposome/OMC formulation was classified as nonirritating in the HET-CAM test, indicating good histocompatibility. The formulation containing liposome/OMC had a higher in vivo solar photoprotection factor, but did not show increased water resistance. Inclusion in liposomes was able to slow down the release of OMC from the formulation, with a lower steady-state flux (3.9 ± 0.33 μg/cm2/hour) compared with the conventional formulation (6.3 ± 1.21 μg/cm2/hour). The stripping method showed increased uptake of OMC in the stratum corneum, giving an amount of 22.64 ± 7.55 μg/cm2 of OMC, which was higher than the amount found for the conventional formulation (14.57 ± 2.30 μg/cm2

  15. Hyaluronic acid-coated liposomes for active targeting of gemcitabine.

    PubMed

    Arpicco, Silvia; Lerda, Carlotta; Dalla Pozza, Elisa; Costanzo, Chiara; Tsapis, Nicolas; Stella, Barbara; Donadelli, Massimo; Dando, Ilaria; Fattal, Elias; Cattel, Luigi; Palmieri, Marta

    2013-11-01

    The aim of this work was the preparation, characterization, and preliminary evaluation of the targeting ability toward pancreatic adenocarcinoma cells of liposomes containing the gemcitabine lipophilic prodrug [4-(N)-lauroyl-gemcitabine, C12GEM]. Hyaluronic acid (HA) was selected as targeting agent since it is biodegradable, biocompatible, and can be chemically modified and its cell surface receptor CD44 is overexpressed on various tumors. For this purpose, conjugates between a phospholipid, the 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and HA of two different low molecular weights 4800 Da (12 disaccharidic units) and 12,000 Da (32 disaccharidic units), were prepared, characterized, and introduced in the liposomes during the preparation. Different liposomal formulations were prepared and their characteristics were analyzed: size, Z potential, and TEM analyses underline a difference in the HA-liposomes from the non-HA ones. In order to better understand the HA-liposome cellular localization and to evaluate their interaction with CD44 receptor, confocal microscopy studies were performed. The results demonstrate that HA facilitates the recognition of liposomes by MiaPaCa2 cells (CD44(+)) and that the uptake increases with increase in the polymer molecular weight. Finally, the cytotoxicity of the different preparations was evaluated and data show that incorporation of C12GEM increases their cytotoxic activity and that HA-liposomes inhibit cell growth more than plain liposomes. Altogether, the results demonstrate the specificity of C12GEM targeting toward CD44-overexpressing pancreatic adenocarcinoma cell line using HA as a ligand.

  16. Peritoneal retention of liposomes: Effects of lipid composition, PEG coating and liposome charge.

    PubMed

    Dadashzadeh, S; Mirahmadi, N; Babaei, M H; Vali, A M

    2010-12-01

    for negatively charged liposomes. The positively charged PEGylated vesicles (DOTAP/PEG 100) had the second-greatest peritoneal level after DOTAP 1000; however, their peritoneal-to-blood AUC ratio was low (3.05). Overall, among the different liposomal formulations, the positively charged conventional liposomes (100 and 1000nm) provided greater peritoneal levels and retention. DOTAP/PEG100 may also be a more efficient formulation because this formulation can provide a high level of anticancer drug into the peritoneal cavity and also can passively target the primary tumor.

  17. Development of high boron content liposomes and their promising antitumor effect for neutron capture therapy of cancers.

    PubMed

    Koganei, Hayato; Ueno, Manabu; Tachikawa, Shoji; Tasaki, Lisa; Ban, Hyun Seung; Suzuki, Minoru; Shiraishi, Kouichi; Kawano, Kumi; Yokoyama, Masayuki; Maitani, Yoshie; Ono, Koji; Nakamura, Hiroyuki

    2013-01-16

    Mercaptoundecahydrododecaborate (BSH)-encapsulating 10% distearoyl boron lipid (DSBL) liposomes were developed as a boron delivery vehicle for neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in addition to its encapsulated agents. BSH-encapsulating 10% DSBL liposomes have high boron content (B/P ratio: 2.6) that enables us to prepare liposome solution with 5000 ppm boron concentration. BSH-encapsulating 10% DSBL liposomes displayed excellent boron delivery efficacy to tumor: boron concentrations reached 174, 93, and 32 ppm at doses of 50, 30, and 15 mg B/kg, respectively. Magnescope was also encapsulated in the 10% DSBL liposomes and the real-time biodistribution of the Magnescope-encapsulating DSBL liposomes was measured in a living body using MRI. Significant antitumor effect was observed in mice injected with BSH-encapsulating 10% DSBL liposomes even at the dose of 15 mg B/kg; the tumor completely disappeared three weeks after thermal neutron irradiation ((1.5-1.8) × 10(12) neutrons/cm(2)). The current results enabled us to reduce the total dose of liposomes to less than one-fifth compared with that of the BSH-encapsulating liposomes without reducing the efficacy of boron neutron capture therapy (BNCT).

  18. Evaluation of the protective effects of curcuminoid (curcumin and bisdemethoxycurcumin)-loaded liposomes against bone turnover in a cell-based model of osteoarthritis.

    PubMed

    Yeh, Chih-Chang; Su, Yu-Han; Lin, Yu-Jhe; Chen, Pin-Jyun; Shi, Chung-Sheng; Chen, Cheng-Nan; Chang, Hsin-I

    2015-01-01

    Curcumin (Cur) and bisdemethoxycurcumin (BDMC), extracted from Curcuma longa, are poorly water-soluble polyphenol compounds that have shown anti-inflammatory potential for the treatment of osteoarthritis. To increase cellular uptake of Cur and BDMC in bone tissue, soybean phosphatidylcholines were used for liposome formulation. In this study, curcuminoid (Cur and BDMC)-loaded liposomes were characterized in terms of particle size, encapsulation efficiency, liposome stability, and cellular uptake. The results show that there is about 70% entrapment efficiency of Cur and BDMC in liposomes and that particle sizes are stable after liposome formation. Both types of liposome can inhibit macrophage inflammation and osteoclast differential activities. In comparison with free drugs (Cur and BDMC), curcuminoid-loaded liposomes were less cytotoxic and expressed high cellular uptake of the drugs. Of note is that Cur-loaded liposomes can prevent liposome-dependent inhibition of osteoblast differentiation and mineralization, but BDMC-loaded liposomes could not. With interleukin (IL)-1β stimulation, curcuminoid-loaded liposomes can successfully downregulate the expression of inflammatory markers on osteoblasts, and show a high osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) ratio to prevent osteoclastogenesis. In the present study, we demonstrated that Cur and BDMC can be successfully encapsulated in liposomes and can reduce osteoclast activity and maintain osteoblast functions. Therefore, curcuminoid-loaded liposomes may slow osteoarthritis progression.

  19. Thermosensitive liposomal drug delivery systems: state of the art review

    PubMed Central

    Kneidl, Barbara; Peller, Michael; Winter, Gerhard; Lindner, Lars H; Hossann, Martin

    2014-01-01

    Thermosensitive liposomes are a promising tool for external targeting of drugs to solid tumors when used in combination with local hyperthermia or high intensity focused ultrasound. In vivo results have demonstrated strong evidence that external targeting is superior over passive targeting achieved by highly stable long-circulating drug formulations like PEGylated liposomal doxorubicin. Up to March 2014, the Web of Science listed 371 original papers in this field, with 45 in 2013 alone. Several formulations have been developed since 1978, with lysolipid-containing, low temperature-sensitive liposomes currently under clinical investigation. This review summarizes the historical development and effects of particular phospholipids and surfactants on the biophysical properties and in vivo efficacy of thermosensitive liposome formulations. Further, treatment strategies for solid tumors are discussed. Here we focus on temperature-triggered intravascular and interstitial drug release. Drug delivery guided by magnetic resonance imaging further adds the possibility of performing online monitoring of a heating focus to calculate locally released drug concentrations and to externally control drug release by steering the heating volume and power. The combination of external targeting with thermosensitive liposomes and magnetic resonance-guided drug delivery will be the unique characteristic of this nanotechnology approach in medicine. PMID:25258529

  20. Intracellular hyperthermia for cancer using magnetite cationic liposomes

    NASA Astrophysics Data System (ADS)

    Shinkai, Masashige; Yanase, Mitsugu; Suzuki, Masataka; Honda, Hiroyuki; Wakabayashi, Toshihiko; Yoshida, Jun; Kobayashi, Takeshi

    1999-04-01

    We have developed `magnetite cationic liposomes' (MCLs) as a new heating mediator for hyperthermia. The hyperthermic effect on solid glioma tissue grown subcutaneously in F344 rats was investigated. Complete tumor regression was observed in about 90% of the rats by three times of repeated heating. Furthermore, induction of antitumor immunity for T-9 rat glioma using MCLs was investigated.

  1. Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid.

    PubMed

    Jiang, Wen; Deng, Wentao; Bailey, Sarah K; Nail, Clint D; Frost, Andra R; Brouillette, Wayne J; Muccio, Donald D; Grubbs, Clinton J; Ruppert, J Michael; Lobo-Ruppert, Susan M

    2009-02-01

    The transcription factor KLF4 acts in post-mitotic epithelial cells to promote differentiation and functions in a context-dependent fashion as an oncogene. In the skin KLF4 is co-expressed with the nuclear receptors RARgamma and RXRalpha, and formation of the skin permeability barrier is a shared function of these three proteins. We utilized a KLF4-transgenic mouse model of skin cancer in combination with cultured epithelial cells to examine functional interactions between KLF4 and retinoic acid receptors. In cultured cells, activation of a conditional, KLF4-estrogen receptor fusion protein by 4-hydroxytamoxifen resulted in rapid upregulation of transcripts for nuclear receptors including RARgamma and RXRalpha. We tested retinoids in epithelial cell transformation assays, including an RAR-selective agonist (all-trans RA), an RXR-selective agonist (9-cis UAB30, rexinoid), and a pan agonist (9-cis RA). Unlike for several other genes, transformation by KLF4 was inhibited by each retinoid, implicating distinct nuclear receptor heterodimers as modulators of KLF4 transforming activity. When RXRalpha expression was suppressed by RNAi in cultured cells, transformation was promoted and the inhibitory effect of 9-cis UAB30 was attenuated. Similarly as shown for other mouse models of skin cancer, rexinoid prevented skin tumor initiation resulting from induction of KLF4 in basal keratinocytes. Rexinoid permitted KLF4 expression and KLF4-induced cell cycling, but attenuated the KLF4-induced misexpression of cytokeratin 1 in basal cells. Neoplastic lesions including hyperplasia, dysplasia and squamous cell carcinoma-like lesions were prevented for up to 30 days. Taken together, the results identify retinoid receptors including RXRalpha as ligand-dependent inhibitors of KLF4-mediated transformation or tumorigenesis.

  2. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by or linked with viruses are: Cervical cancer (human papillomavirus) Most anal cancers (human papillomavirus) Some throat ...

  3. Liposomes: Technologies and Analytical Applications

    NASA Astrophysics Data System (ADS)

    Jesorka, Aldo; Orwar, Owe

    2008-07-01

    Liposomes are structurally and functionally some of the most versatile supramolecular assemblies in existence. Since the beginning of active research on lipid vesicles in 1965, the field has progressed enormously and applications are well established in several areas, such as drug and gene delivery. In the analytical sciences, liposomes serve a dual purpose: Either they are analytes, typically in quality-assessment procedures of liposome preparations, or they are functional components in a variety of new analytical systems. Liposome immunoassays, for example, benefit greatly from the amplification provided by encapsulated markers, and nanotube-interconnected liposome networks have emerged as ultrasmall-scale analytical devices. This review provides information about new developments in some of the most actively researched liposome-related topics.

  4. Cationic liposomes as vaccine adjuvants.

    PubMed

    Christensen, Dennis; Korsholm, Karen Smith; Andersen, Peter; Agger, Else Marie

    2011-04-01

    The application of cationic liposomes as vaccine delivery systems and adjuvants has been investigated extensively over the last few decades. However, cationic liposomes are, in general, not sufficiently immunostimulatory, which is why the combination of liposomes with immunostimulating ligands has arisen as a strategy in the development of novel adjuvant systems. Within the last 5 years, two novel adjuvant systems based on cationic liposomes incorporating Toll-like receptor or non-Toll-like receptor immunostimulating ligands have progressed from preclinical testing in smaller animal species to clinical testing in humans. The immune responses that these clinical candidates induce are primarily of the Th1 type for which there is a profound unmet need. Furthermore, a number of new cationic liposome-forming surfactants with notable immunostimulatory properties have been discovered. In this article we review the recent progress on the application of cationic liposomes as vaccine delivery systems/adjuvants.

  5. Even With Very Small Breast Tumors, Studies Find HER2 Status Matters | Division of Cancer Prevention

    Cancer.gov

    Two retrospective studies have found that women with HER2-positive breast tumors (that is, tumors that produce too much of the HER2 protein) that are 1 centimeter or smaller had a higher risk of their disease returning within 5 years than women with similarly small HER2-negative tumors. |

  6. 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.

  7. Potential antitumor activity of novel DODAC/PHO-S liposomes

    PubMed Central

    Luna, Arthur Cássio de Lima; Saraiva, Greice Kelle Viegas; Filho, Otaviano Mendonça Ribeiro; Chierice, Gilberto Orivaldo; Neto, Salvador Claro; Cuccovia, Iolanda Midea; Maria, Durvanei Augusto

    2016-01-01

    In recent studies, we showed that synthetic phosphoethanolamine (PHO-S) has a great potential for inducing cell death in several tumor cell lines without damage to normal cells. However, its cytotoxic effect and selectivity against tumor cells could increase with encapsulation in cationic liposomes, such as dioctadecyldimethylammonium chloride (DODAC), due to electrostatic interactions between these liposomes and tumor cell membranes. Our aim was to use cationic liposomes to deliver PHO-S and to furthermore maximize the therapeutic effect of this compound. DODAC liposomes containing PHO-S (DODAC/PHO-S), at concentrations of 0.3–2.0 mM, prepared by ultrasonication, were analyzed by scanning electron microscopy (SEM) and dynamic light scattering. The cytotoxic effect of DODAC/PHO-S on B16F10 cells, Hepa1c1c7 cells, and human umbilical vein endothelial cells (HUVECs) was assessed by MTT assay. Cell cycle phases of B16F10 cells were analyzed by flow cytometry and the morphological changes by SEM, after treatment. The liposomes were spherical and polydisperse in solution. The liposomes were stable, presenting an average of ∼50% of PHO-S encapsulation, with a small reduction after 40 days. DODAC demonstrated efficient PHO-S delivery, with the lowest values of IC50% (concentration that inhibits 50% of the growth of cells) for tumor cells, compared with PHO-S alone, with an IC50% value of 0.8 mM for B16F10 cells and 0.2 mM for Hepa1c1c7 cells, and without significant effects on endothelial cells. The Hepa1c1c7 cells showed greater sensitivity to the DODAC/PHO-S formulation when compared to B16F10 cells and HUVECs. The use of DODAC/PHO-S on B16F10 cells induced G2/M-phase cell cycle arrest, with the proportion significantly greater than that treated with PHO-S alone. The morphological analysis of B16F10 cells by SEM showed changes such as “bleb” formation, cell detachment, cytoplasmic retraction, and apoptotic bodies after DODAC/PHO-S treatment. Cationic liposomal

  8. Tumor-Targeted Nanomedicines

    PubMed Central

    ElBayoumi, Tamer A.; Torchilin, Vladimir P.

    2009-01-01

    Purpose The efficacy of drug delivery systems can be enhanced by making them target-specific via the attachment of various ligands. We attempted to enhance tumor accumulation and therapeutic effect of doxorubicin-loaded long-circulating PEGylated liposomes (Doxil®, ALZA Corp.) by coupling to their surface the anti-cancer monoclonal antibody 2C5 (mAb 2C5) with nuclesome (NS)-restricted activity, that can recognize the surface of various tumor but not normal cells and specifically targets pharmaceutical carriers to tumor cells in vitro and in vivo. Following earlier in vitro results with various cancer cell lines, the mAb 2C5-liposomes were studied in vivo vs. plain and non-specific IgG-liposomes. Experimental design Antibody coupling to Doxil® was performed via the “post-insertion” technique. Using 111In-labeled liposomes, the tissue biodistribution and pharmacokinetic profile were studied, as well as their accumulation in tumors in mice was followed by the whole-body γ-scintigraphic imaging. Therapeutic efficacy of mAb 2C5-targeted Doxil® vs. non-specific IgG-modified and original Doxil® controls was followed by registering live tumor growth and determining tumor weights upon mice sacrifice. Results mAb2C5 antibody-targeted liposomes demonstrate enhanced accumulation in tumors, and the in vivo therapeutic activity of the mAb 2C5-Doxil® treatment was found to be significantly superior, resulting in final tumor weights of only 25-40% compared to all Doxil® control treatments, when tested against the subcutaneous primary murine tumors of 4T1 and C26 and human PC3 tumor in nude mice. Conclusions Our results demonstrate the remarkable capability of 2C5-targeted Doxil® to specifically deliver its cargo into various tumors significantly increasing the efficacy of therapy. PMID:19276264

  9. A new adjuvant delivery system 'cyclic di-GMP/YSK05 liposome' for cancer immunotherapy.

    PubMed

    Miyabe, Hiroko; Hyodo, Mamoru; Nakamura, Takashi; Sato, Yusuke; Hayakawa, Yoshihiro; Harashima, Hideyoshi

    2014-06-28

    Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. It is thought that c-di-GMP is recognized by ATP dependent RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers a signal via the tank binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as an adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm. Our group has been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic, pH sensitive lipid that has a high fusogenicity. We utilized this lipid as a carrier to transport c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/cholesterol=40/25/35 was found to induce IFN-β in Raw264.7 cells. The induction of IFN-β from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-β caused the activation of the STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo.

  10. Altered in vivo activity of liposome-incorporated lipopolysaccharide and lipid A.

    PubMed Central

    Dijkstra, J; Mellors, J W; Ryan, J L

    1989-01-01

    We compared the abilities of free and liposome-incorporated Salmonella minnesota wild-type lipopolysaccharide (LPS) and lipid A to activate peritoneal macrophages and induce lethal toxicity in mice. Incorporation of lipid A into multilamellar vesicles resulted in a 100-fold-decreased potency to prime macrophages for phorbol myristate acetate-triggered release of H2O2. In addition, liposome incorporation reduced the lethality of LPS and lipid A at least 10-fold in dactinomycin-sensitized mice. Similar results were obtained with multilamellar liposomes delivered intravenously and when small unilamellar vesicles were employed. The observed difference in toxicity was not dependent on dactinomycin treatment, since a similar decrease was obtained with large doses of liposomal LPS in unsensitized mice. Control liposomes, prepared without LPS and lipid A, did not reduce the activities of the free compounds. The administration of a sublethal amount of liposomal LPS induced within 20 days, but not during the first week, tolerance to a subsequently injected lethal dose of free endotoxin. The latter observation suggests that early-phase tolerance is not the mechanism responsible for the reduced toxicity of liposomal LPS. These data show that liposomal LPS and lipid A have reduced endotoxic activity in vivo and are consistent with our hypothesis that a direct interaction of lipid A with appropriate plasma membrane components is necessary to efficiently trigger biologic responses. This interaction, however, is prevented by the stable insertion of LPS into the liposomal membrane. PMID:2807528

  11. Roles of dextrans on improving lymphatic drainage for liposomal drug delivery system.

    PubMed

    Feng, Linglin; Zhang, Lei; Liu, Min; Yan, Zhiqiang; Wang, Chenyu; Gu, Bing; Liu, Yu; Wei, Gang; Zhong, Gaoren; Lu, Weiyue

    2010-04-01

    Our aim was to develop a novel liposomal drug delivery system containing dextrans to reduce undesirable retention of antineoplastic agents and thus alleviate local tissue damage. At the cell level, diethylaminoethyl-dextran (DEAE-Dx) showed the strongest inhibiting effect on liposome uptake by macrophages among tested dextrans. The distribution of radiolabeled liposomes mixed with dextrans in injection site and draining lymph node was investigated in rats after subcutaneous injection. DEAE-Dx substantially reduced the undesired local retention and promoted the draining of liposome into lymphatics, which was further confirmed by confocal microscopy images revealing the substantial prevention of rhodamine B-labelled liposome sequestration by macrophages in normal lymph node in rats. Pharmacokinetic data indicated the accelerated drainage of liposome through lymphatics back to systemic circulation by mixing with DEAE-Dx. In the toxicological study in rabbits, DEAE-Dx alleviated the local tissue damage caused by liposomal doxorubicin. In conclusion, dextrans, particularly DEAE-Dx, could efficiently enhanced liposomes drainage into lymphatics, which proves themselves as promising adjuvants for lymphatic-targeted liposomal drug delivery system.

  12. Interferon-gamma reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages.

    PubMed

    Duluc, Dorothée; Corvaisier, Murielle; Blanchard, Simon; Catala, Laurent; Descamps, Philippe; Gamelin, Erick; Ponsoda, Stéphane; Delneste, Yves; Hebbar, Mohamed; Jeannin, Pascale

    2009-07-15

    Tumor-associated macrophages (TAM) are M2d-polarized cells (IL-10(high), IL-12(low), ILT3(high), CD86(low)) that accumulate in tumor microenvironment. TAM inhibit antitumor T lymphocyte generation and function, contribute to tumor tolerance and are trophic for tumors. In this study, we investigated whether some immunological factors may reverse TAM immunosuppressive properties. Among 32 cytokines, we have identified IFNgamma on its ability to switch immunosuppressive TAM into immunostimulatory cells. Upon IFNgamma exposure, TAM purified from ovarian cancer ascites recover a M1 phenotype (IL-10(low), IL-12(high)), express high levels of CD86 and low levels of ILT3, enhance the proliferation of CD4(+) T lymphocytes and potentiate the cytotoxic properties of a MelanA-specific CD8(+) T cell clone. IFNgamma-treated TAM also secreted reduced levels of mediators promoting suppressive T cell accumulation (CCL18) and trophic for tumors (VEGF and MMP9). As TAM derive from the local differentiation of peripheral blood monocytes, we investigated whether IFNgamma may also affect TAM generation. In the presence of ovarian ascites, IFNgamma skewed monocyte differentiation from TAM-like cells to M1-polarized immunostimulatory macrophages. Together, these data show that IFNgamma overcomes TAM-induced immunosuppression by preventing TAM generation and functions. These data highlight that IFNgamma used locally at the tumor site could potentiate the efficacy of antitumor immunotherapies based on the generation of effector T cells.

  13. Reinforcing endothelial junctions prevents microvessel permeability increase and tumor cell adhesion in microvessels in vivo

    NASA Astrophysics Data System (ADS)

    Fu, Bingmei M.; Yang, Jinlin; Cai, Bin; Fan, Jie; Zhang, Lin; Zeng, Min

    2015-10-01

    Tumor cell adhesion to the microvessel wall is a critical step during tumor metastasis. Vascular endothelial growth factor (VEGF), a secretion of tumor cells, can increase microvessel permeability and tumor cell adhesion in the microvessel. To test the hypothesis that inhibiting permeability increase can reduce tumor cell adhesion, we used in vivo fluorescence microscopy to measure both microvessel permeability and adhesion rates of human mammary carcinoma MDA-MB-231 cells in post-capillary venules of rat mesentery under the treatment of VEGF and a cAMP analog, 8-bromo-cAMP, which can decrease microvessel permeability. By immunostaining adherens junction proteins between endothelial cells forming the microvessel wall, we further investigated the structural mechanism by which cAMP abolishes VEGF-induced increase in microvessel permeability and tumor cell adhesion. Our results demonstrate that 1) Pretreatment of microvessels with cAMP can abolish VEGF-enhanced microvessel permeability and tumor cell adhesion; 2) Tumor cells prefer to adhere to the endothelial cell junctions instead of cell bodies; 3) VEGF increases microvessel permeability and tumor cell adhesion by compromising endothelial junctions while cAMP abolishes these effects of VEGF by reinforcing the junctions. These results suggest that strengthening the microvessel wall integrity can be a potential approach to inhibiting hematogenous tumor metastasis.

  14. Reinforcing endothelial junctions prevents microvessel permeability increase and tumor cell adhesion in microvessels in vivo

    PubMed Central

    Fu, Bingmei M.; Yang, Jinlin; Cai, Bin; Fan, Jie; Zhang, Lin; Zeng, Min

    2015-01-01

    Tumor cell adhesion to the microvessel wall is a critical step during tumor metastasis. Vascular endothelial growth factor (VEGF), a secretion of tumor cells, can increase microvessel permeability and tumor cell adhesion in the microvessel. To test the hypothesis that inhibiting permeability increase can reduce tumor cell adhesion, we used in vivo fluorescence microscopy to measure both microvessel permeability and adhesion rates of human mammary carcinoma MDA-MB-231 cells in post-capillary venules of rat mesentery under the treatment of VEGF and a cAMP analog, 8-bromo-cAMP, which can decrease microvessel permeability. By immunostaining adherens junction proteins between endothelial cells forming the microvessel wall, we further investigated the structural mechanism by which cAMP abolishes VEGF-induced increase in microvessel permeability and tumor cell adhesion. Our results demonstrate that 1) Pretreatment of microvessels with cAMP can abolish VEGF-enhanced microvessel permeability and tumor cell adhesion; 2) Tumor cells prefer to adhere to the endothelial cell junctions instead of cell bodies; 3) VEGF increases microvessel permeability and tumor cell adhesion by compromising endothelial junctions while cAMP abolishes these effects of VEGF by reinforcing the junctions. These results suggest that strengthening the microvessel wall integrity can be a potential approach to inhibiting hematogenous tumor metastasis. PMID:26507779

  15. In vitro spectroscopic study of piperine-encapsulated nanosize liposomes.

    PubMed

    Pentak, Danuta

    2016-03-01

    Black pepper is a source of effective antioxidants. It contains several powerful antioxidants and is thus one of the most important spices for preventing and curtailing oxidative stress. There is considerable interest in the development of a drug-delivery systems that would result in the selective delivery of antioxidants to tissues in sufficient concentrations to ameliorate oxidant-induced tissue injuries. Liposomes are biocompatible, biodegradable and nontoxic artificial phospholipid vesicles that offer the possibility of carrying hydrophilic, hydrophobic and amphiphilic molecules. This article focuses on the use of liposomes for the delivery of antioxidants in the prevention or treatment of pathological conditions related to oxidative stress. Liposome formulations of piperine were analyzed with various spectroscopic methods. The formulation with the highest entrapment efficiency (90.5%) was formulated with an L-α-phosphatidylcholine dipalmitoyl (DPPC):piperine, 30:1 molar ratio, and total lipid count of 19.47 mg/ml in the final liposomal preparation. The liposome formulation was found to be stable after storage at 4 °C, protected from light, for a minimum of 3 weeks. The incremental process of piperine penetration through the phospholipid membrane was analyzed using the FT-IR, UV-Vis and NMR methods. Temperature stability studies carried out at 37 °C showed the highest percentage of piperine release in the first 3 h of incubation.

  16. Doxorubicin-loaded nanocarriers: A comparative study of liposome and nanostructured lipid carrier as alternatives for cancer therapy.

    PubMed

    Fernandes, Renata S; Silva, Juliana O; Monteiro, Liziane O F; Leite, Elaine A; Cassali, Geovanni D; Rubello, Domenico; Cardoso, Valbert N; Ferreira, Lucas A M; Oliveira, Mônica C; de Barros, André L B

    2016-12-01

    Nowadays cancer is one of the most common causes of deaths worldwide. Conventional antitumor agents still present various problems related to specificity for tumor cells often leading to therapeutic failure. Nanoscale particles are considered potential alternative to direct access of drugs into tumor cells, therefore increasing the drug accumulation and performance. The aim of this study was to evaluate the antitumor activity of doxorubicin (DOX)-loaded nanostructured lipid carriers (NLC) versus liposomes against a breast cancer animal experimental model. NLC-DOX and liposomes-DOX were successfully prepared and characterized. Tumor-bearing mice were divided into five groups (blank-NLC, blank-liposome, DOX, NLC-DOX, liposome-DOX). Each animal received by the tail vein four doses of antitumoral drugs (total dose, 16mg/kg), every 3 days. Antitumor efficacy was assessed by measuring 1) tumor volume, calculating the inhibitory ratio (TV-IR, see after) and 2) acquiring scintigraphic images of the tumor using doxorubicin radiolabeled with technetium-99m as an imaging tumor probe. Liposome-DOX and free DOX did not showed differences in the tumor mean volume, whereas NLC-DOX proved to be the best treatments in controlling the tumor growth. NLC-DOX showed an inhibition ration (TV-IR) of 73.5% while free DOX and liposome-DOX decreased TV-RI of 48.8% and 68.0%, respectively. Tumor was clearly visualized in controls, DOX, and liposome-DOX groups. Yet, regarding the NLC-DOX group, tumor was barely identified by the image, indicating antitumor efficacy. Moreover, both NLC and liposomes proved to be able to delay the occurrence of lung metastasis. In conclusion, results of this study indicated that NLC-DOX might be an alternative strategy to achieve an efficient antitumor activity.

  17. Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for H22 hepatocellular carcinoma both in vitro and in vivo.

    PubMed

    Liu, Min-Chen; Liu, Lin; Wang, Xia-Rong; Shuai, Wu-Ping; Hu, Ying; Han, Min; Gao, Jian-Qing

    2016-01-01

    The diacid metabolite of norcantharidin (DM-NCTD) is clinically effective against hepatocellular carcinoma (HCC), but is limited by its short half-life and high incidence of adverse effects at high doses. We developed a DM-NCTD-loaded, folic acid (FA)-modified, polyethylene glycolated (DM-NCTD/FA-PEG) liposome system to enhance the targeting effect and antitumor potency for HCC at a moderate dose based on our previous study. The DM-NCTD/FA-PEG liposome system produced liposomes with regular spherical morphology, with mean particle size approximately 200 nm, and an encapsulation efficiency >80%. MTT cytotoxicity assays demonstrated that the DM-NCTD/FA-PEG liposomes showed significantly stronger cytotoxicity effects on the H22 hepatoma cell line than did PEG liposomes without the FA modification (P<0.01). We used liquid chromatography-mass spectrometry for determination of DM-NCTD in tissues and tumors, and found it to be sensitive, rapid, and reliable. In addition, the biodistribution study showed that DM-NCTD liposomes improved tumor-targeting efficiency, and DM-NCTD/FA-PEG liposomes exhibited the highest efficiency of the treatments (P<0.01). Meanwhile, the results indicated that although the active liposome group had an apparently increased tumor-targeting efficiency of DM-NCTD, the risk to the kidney was higher than in the normal liposome group. With regard to in vivo antitumor activity, DM-NCTD/FA-PEG liposomes inhibited tumors in H22 tumor-bearing mice better than either free DM-NCTD or DM-NCTD/PEG liposomes (P<0.01), and induced considerably more significant cellular apoptosis in the tumors, with no obvious toxicity to the tissues of model mice or the liver tissue of normal mice, as shown by histopathological examination. All these results demonstrate that DM-NCTD-loaded FA-modified liposomes might have potential application for HCC-targeting therapy.

  18. Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

    DTIC Science & Technology

    2015-11-01

    tran- siently increased MB-231 tumor growth , but only when social iso- lation was initiated when tumor growth was near exponential phase. No...receptors (AR). In animal models using b-AR–expressing cancer cell lines, stressor exposure or b-AR stimulation increased tumor growth and/or metastasis by...Uses bone marrow transfer after irradiation. Source animals are one of 7 knockouts, for 7 candidate genes. ~50x7= 350 mice. Produces identity of

  19. Preparation of small amounts of sterile siRNA-liposomes with high entrapping efficiency by dual asymmetric centrifugation (DAC).

    PubMed

    Hirsch, Markus; Ziroli, Vittorio; Helm, Mark; Massing, Ulrich

    2009-04-02

    Liposomal formulation of siRNA is an attractive approach for improving its delivery in vivo, shielding the RNA from nucleases and promoting tumor targeting. Here, the production of very small batch sizes of siRNA-liposomes by using the "dual asymmetric centrifugation (DAC)" technique was investigated. This new technique combines rapid and sterile liposome preparation with very high entrapping efficiencies. DAC is here presented in conjunction with a non-destructive microscale analysis based on double fluorescence labeling, which enables monitoring of siRNA integrity during the liposomal preparation. Integrity is reflected in spatial proximity of the dyes, which results in measurable fluorescence resonance energy transfer (FRET). The combination of DAC and the sensitive FRET analysis allows the handling of batch sizes down to 20 mg of conventional liposomes (CL) and sterically stabilized liposomes (SL). These were prepared in common 2 ml reaction tubes and loaded with calcein or labeled siRNA. Liposome sizes were 79+/-16 nm for CL and 109+/-9 nm for SL loaded with siRNA. Trapping efficiencies ranged from 43 to 81%, depending on batch size, enclosed compound, and liposome composition. FRET monitoring showed that the siRNA remained intact throughout DAC and that liposomal formulations protected the siRNA from nucleases. siRNA-liposomes remained stable for at least 3 months.

  20. Monodisperse Uni- and Multicompartment Liposomes.

    PubMed

    Deng, Nan-Nan; Yelleswarapu, Maaruthy; Huck, Wilhelm T S

    2016-06-22

    Liposomes are self-assembled phospholipid vesicles with great potential in fields ranging from targeted drug delivery to artificial cells. The formation of liposomes using microfluidic techniques has seen considerable progress, but the liposomes formation process itself has not been studied in great detail. As a result, high throughput, high-yielding routes to monodisperse liposomes with multiple compartments have not been demonstrated. Here, we report on a surfactant-assisted microfluidic route to uniform, single bilayer liposomes, ranging from 25 to 190 μm, and with or without multiple inner compartments. The key of our method is the precise control over the developing interfacial energies of complex W/O/W emulsion systems during liposome formation, which is achieved via an additional surfactant in the outer water phase. The liposomes consist of single bilayers, as demonstrated by nanopore formation experiments and confocal fluorescence microscopy, and they can act as compartments for cell-free gene expression. The microfluidic technique can be expanded to create liposomes with a multitude of coupled compartments, opening routes to networks of multistep microreactors.

  1. Liposomal nanotechnology for cancer theranostics.

    PubMed

    Dai, Zhifei; Yue, Xiuli

    2017-03-05

    Liposomes are a type of biomimetic nanoparticles generated from self-assembling concentric lipid bilayer enclosing an aqueous core domain. They have been attractive nanocarriers for the delivery of many drugs (e.g. radiopharmaceuticals, chemotherapeutic agents, porphyrin) and diagnostic agents (e.g. fluorescent dyes, quantum dots, Gadolinium complex and Fe3O4) by encapsulating (or adsorbing) hydrophilic one inside the liposomal aqueous core domain (or on the bilayer membrane surface), and by entrapping hydrophobic one within the liposomal bilayer. Additionally, the liposome surface can be easily conjugated with targeting molecules. Liposomes may accumulate in cancerous tissues not only passively via enhanced permeability and retention (EPR) effect, but also actively by targeting cancer cell or angiogenic marker specifically. The multimodality imaging functionalization of liposomal therapeutic agents makes them highly attracting for individualized monitoring of the in vivo cancer targeting and pharmacokinetics of liposomes loading therapeutic drugs, and predicting therapeutic efficacy in combination with the helpful information from each imaging technique. The present review article will highlight some main advances of cancer theranostic liposomes with a view to activating further research in the nanomedicine community.

  2. Liposome: classification, preparation, and applications

    NASA Astrophysics Data System (ADS)

    Akbarzadeh, Abolfazl; Rezaei-Sadabady, Rogaie; Davaran, Soodabeh; Joo, Sang Woo; Zarghami, Nosratollah; Hanifehpour, Younes; Samiei, Mohammad; Kouhi, Mohammad; Nejati-Koshki, Kazem

    2013-02-01

    Liposomes, sphere-shaped vesicles consisting of one or more phospholipid bilayers, were first described in the mid-60s. Today, they are a very useful reproduction, reagent, and tool in various scientific disciplines, including mathematics and theoretical physics, biophysics, chemistry, colloid science, biochemistry, and biology. Since then, liposomes have made their way to the market. Among several talented new drug delivery systems, liposomes characterize an advanced technology to deliver active molecules to the site of action, and at present, several formulations are in clinical use. Research on liposome technology has progressed from conventional vesicles to `second-generation liposomes', in which long-circulating liposomes are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several molecules, such as glycolipids or sialic acid. This paper summarizes exclusively scalable techniques and focuses on strengths, respectively, limitations in respect to industrial applicability and regulatory requirements concerning liposomal drug formulations based on FDA and EMEA documents.

  3. Negatively charged liposomes show potent adjuvant activity when simply admixed with protein antigens

    PubMed Central

    Yanasarn, Nijaporn; Sloat, Brian R.; Cui, Zhengrong

    2011-01-01

    Liposomes have been investigated extensively as a vaccine delivery system. Herein the adjuvant activities of liposomes with different net surface charges (neutral, positive, or negative) were evaluated when admixed with protein antigens, ovalbumin (OVA, pI = 4.7), Bacillus anthracis protective antigen protein (PA, pI = 5.6), or cationized OVA (cOVA). Mice immunized subcutaneously with OVA admixed with different liposomes generated different antibody responses. Interestingly, OVA admixed with net negatively charged liposomes prepared with DOPA was as immunogenic as OVA admixed with positively charged liposomes prepared with DOTAP. Immunization of mice with the anthrax PA protein admixed with the net negatively charged DOPA liposomes also induced a strong and functional anti-PA antibody response. When the cationized OVA was used as a model antigen, liposomes with net neutral, negative, or positive charges showed comparable adjuvant activities. Immunization of mice with the OVA admixed with DOPA liposomes also induced OVA-specific CD8+ cytotoxic T lymphocyte responses and significantly delayed the growth of OVA-expressing B16-OVA tumors in mice. However, not all net negatively charged liposomes showed a strong adjuvant activity. The adjuvant activity of the negatively charged liposomes may be related to the liposome’s ability (i) to up-regulate the expression of molecules related to the activation and maturation of antigen-presenting cells and (ii) to slightly facilitate the uptake of the antigens by antigen-presenting cells. Simply admixing certain negatively charged liposomes with certain protein antigens of interest may represent a novel platform for vaccine development. PMID:21615153

  4. Modification of radiation-induced oxidative damage in liposomal and microsomal membrane by eugenol

    NASA Astrophysics Data System (ADS)

    Pandey, B. N.; Lathika, K. M.; Mishra, K. P.

    2006-03-01

    Radiation-induced membrane oxidative damage, and their modification by eugenol, a natural antioxidant, was investigated in liposomes and microsomes. Liposomes prepared with DPH showed decrease in fluorescence after γ-irradiation, which was prevented significantly by eugenol and correlated with magnitude of oxidation of phospholipids. Presence of eugenol resulted in substantial inhibition in MDA formation in irradiated liposomes/microsomes, which was less effective when added after irradiation. Similarly, the increase in phospholipase C activity observed after irradiation in microsomes was inhibited in samples pre-treated with eugenol. Results suggest association of radio- oxidative membrane damage with alterations in signaling molecules, and eugenol significantly prevented these membrane damaging events.

  5. Simple and efficient liposomal encapsulation of topotecan by ammonium sulfate gradient: stability, pharmacokinetic and therapeutic evaluation.

    PubMed

    Liu, Jun-Jen; Hong, Ruey-Long; Cheng, Wen-Fang; Hong, Keelung; Chang, Fu-Hsiung; Tseng, Yun-Long

    2002-08-01

    Topotecan (TPT), a topoisomerase I inhibitor, is presently undergoing clinical evaluation worldwide. Previous studies have shown that entrapping TPT within multi-lamellar vesicle liposome can stabilize the lactone moiety, which is structurally important for biological activity. However, low drug:lipid ratios due to the amphipathic character and small entrapment volume in the unilamellar vesicle limits the development of pharmaceutically acceptable liposomal formulation. With an aim to improve on this drawback, we herein describe a method that utilizes the ammonium sulfate gradient to entrap TPT into liposomes. By this method, the encapsulation efficiency was over 90% and a drug:lipid molar ratio as high as 1:5.4 was reached. In comparison with free drug, liposome-encapsulated TPT is more stable in physiological conditions and shows higher in vitro cytotoxicity. Because of increased blood circulation time, the initial plasma concentration and area under the plasma concentration of liposomal drugs were 14 and 40 times, respectively, of those of free drug. Furthermore, liposome encapsulation enhanced the antitumor activity of TPT in syngeneic murine C-26 and human HTB-9 xenograft models in vivo. At a dose of 5 mg/kg, the tumor growth delay of liposomal formulation was significantly than that of free TPT. Based on these results, we believe that this liposomal TPT formulation is worthy of further clinical study.

  6. Diamagnetic chemical exchange saturation transfer (diaCEST) liposomes: physicochemical properties and imaging applications.

    PubMed

    Chan, Kannie W Y; Bulte, Jeff W M; McMahon, Michael T

    2014-01-01

    Chemical exchange saturation transfer (CEST) is a new type of magnetic resonance imaging (MRI) contrast based on labile spins which rapidly exchange with solvent, resulting in an amplification of signal which allows detection of solute protons at millimolar to micromolar concentrations. An additional feature of these agents is that natural organic and biodegradable compounds can provide strong CEST contrast, allowing the development of diamagnetic CEST (diaCEST) MRI contrast agents. The sensitivity of the CEST approach per unit of agent increases further when diaCEST contrast agents are loaded into liposomes to become diaCEST liposomes. In this review, we will discuss the unique and favorable features of diaCEST liposomes which are well suited for in vivo imaging. diaCEST liposomes are nanocarriers which feature high concentrations of encapsulated contrast material, controlled release of payload, and an adjustable coating for passive or active tumor targeting. These liposomes have water permeable bilayers and both the interior and exterior can be fine-tuned for many biomedical applications. Furthermore, a number of liposome formulations are used in the clinic including Doxil™, which is an approved product for treating patients with cancer for decades, rapid translation of these materials can be envisaged. diaCEST liposomes have shown promise in imaging of cancer, and monitoring of chemotherapy and cell transplants. The unique features of diaCEST liposomes are discussed to provide an overview of the applications currently envisioned for this new technology and to provide an overall insight of their potential.

  7. Use of a passive equilibration methodology to encapsulate cisplatin into preformed thermosensitive liposomes.

    PubMed

    Woo, Janet; Chiu, Gigi N C; Karlsson, Göran; Wasan, Ellen; Ickenstein, Ludger; Edwards, Katarina; Bally, Marcel B

    2008-02-12

    A conventional, cholesterol-containing liposome formulation of cisplatin has demonstrated insignificant activity in clinical trials, due in part, to insufficient release of encapsulated content following localization within solid tumors. For this reason, the development of a triggered release liposome formulation is desirable. In this report, cisplatin was encapsulated into lysolipid-containing thermosensitive liposomes (LTSL) using a novel technique, which relies on the equilibration of cisplatin across the liposomal membrane at temperatures above the gel-to-liquid crystalline phase transition temperature (TC) of the bulk phospholipid. Mild heating and drug loading into LTSL did not induce morphological changes of the liposomes. In vitro data demonstrated that >95% of encapsulated cisplatin was released from LTSL within 5 min following mild heating at 42 degrees C, while <5% was released at 37 degrees C. Under similar conditions, lysolipid-free thermosensitive liposomes exhibited 70% release of cisplatin at 42 degrees C, and cholesterol-containing liposomes exhibited negligible drug release at 42 degrees C. The pharmacokinetic profiles of LTSL- and TSL-cisplatin indicated that these formulations were rapidly eliminated from circulation (terminal t(1/2) of 1.09 and 2.83 h, respectively). The therapeutic utility of LTSL-cisplatin formulation will be based on strategies where hyperthermia is applied prior to the administration of the liposomal drug-a strategy similar to that used in the clinical assessment of LTSL-doxorubicin formulation.

  8. The tumor-educated-macrophage increase of malignancy of human pancreatic cancer is prevented by zoledronic acid.

    PubMed

    Hiroshima, Yukihiko; Maawy, Ali; Hassanein, Mohamed K; Menen, Rhiana; Momiyama, Masashi; Murakami, Takashi; Miwa, Shinji; Yamamoto, Mako; Uehara, Fuminari; Yano, Shuya; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2014-01-01

    We previously defined macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors as "tumor-educated-macrophages" (Edu) and macrophages harvested from mice without tumors as "naïve-macrophages" (Naïve), and demonstrated that Edu-macrophages promoted tumor growth and metastasis. In this study, Edu- and Naïve-macrophages were compared for their ability to enhance pancreatic cancer malignancy at the cellular level in vitro and in vivo. The inhibitory efficacy of Zoledronic acid (ZA) on Edu-macrophage-enhanced metastasis was also determined. XPA1 human pancreatic cancer cells in Gelfoam co-cultured with Edu-macrophages proliferated to a greater extent compared to XPA1 cells cultured with Naïve-macrophages (P = 0.014). XPA1 cells exposed to conditioned medium harvested from Edu culture significantly increased proliferation (P = 0.016) and had more migration stimulation capability (P<0.001) compared to cultured cancer cells treated with the conditioned medium from Naïve. The mitotic index of the XPA1 cells, expressing GFP in the nucleus and RFP in the cytoplasm, significantly increased in vivo in the presence of Edu- compared to Naïve-macrophages (P = 0.001). Zoledronic acid (ZA) killed both Edu and Naïve in vitro. Edu promoted tumor growth and metastasis in an orthotopic mouse model of the XPA1 human pancreatic cancer cell line. ZA reduced primary tumor growth (P = 0.006) and prevented metastasis (P = 0.025) promoted by Edu-macrophages. These results indicate that ZA inhibits enhanced primary tumor growth and metastasis of human pancreatic cancer induced by Edu-macrophages.

  9. Liposomal encapsulated anti-cancer drugs.

    PubMed

    Hofheinz, Ralf-Dieter; Gnad-Vogt, Senta Ulrike; Beyer, Ulrich; Hochhaus, Andreas

    2005-08-01

    Among several drug delivery systems, liposomal encapsulated anti-cancer agents represent an advanced and versatile technology. Several formulations of liposomal anthracyclines are approved, e.g. for the treatment of metastatic breast cancer (pegylated and non-pegylated liposomal doxorubicin) or AIDS-related Kaposi's sarcoma (pegylated liposomal doxorubicin and liposomal daunorubicin). Meanwhile, virtually all anti-cancer drugs have been encapsulated in liposomes using different technologies. This review will summarize preclinical and clinical data of approved and exemplary emerging liposomal anti-cancer agents.

  10. Architectonics of phage-liposome nanowebs as optimized photosensitizer vehicles for photodynamic cancer therapy

    PubMed Central

    Sreeram, Kalarical Janardhanan; Narayan, Shoba; Gopal, Abbineni; Hayhurst, Andrew; Mao, Chuanbin

    2010-01-01

    Filamentous M13 phage can be engineered to display cancer cell-targeting or tumor-homing peptides through phage display. It would be highly desirable if the tumor targeting phage can also carry anti-cancer drugs to deliver them to the cancer cells. We studied the evolution of structures of the complexes between anionic filamentous M13 phage and cationic serum-stable liposomes which encapsulate the monomeric photosensitizer, zinc naphthalocyanine. At specific phage-liposome ratios, multiple phage nanofibers and liposomes are interwoven into a “nanoweb”. The chemical and biological properties of the phage-liposome nanoweb were evaluated for possible application in drug delivery. This study highlights the ability of phageliposome nanowebs to serve as efficient carriers to transport photosensitizers to cancer cells. PMID:20807781

  11. Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides.

    PubMed

    Henriksen, Gjermund; Schoultz, B W; Michaelsen, T E; Bruland, Ø S; Larsen, R H

    2004-05-01

    The alpha-particle emitting radionuclides (223)Ra (t(1/2) = 11.4 d), (224)Ra (t(1/2) = 3.6 d), and (225)Ac(t(1/2) = 10.0 d) may have a broad application in targeted radiotherapy provided that they could be linked to vehicles with tumor affinity. The potential usefulness of liposomes as carriers was studied in the present work. Radium and actinium radionuclides could be loaded in good yields into sterically stabilized liposomes. Subsequent coating of the liposomes with a folate-F(ab')(2) construct yielded a product with affinity towards tumor cells expressing folate receptors. Radionuclide loaded liposomes showed excellent stability in serum in vitro.

  12. Novel approaches to treatment of hepatocellular carcinoma and hepatic metastases using thermal ablation and thermosensitive liposomes.

    PubMed

    Dewhirst, Mark W; Landon, Chelsea D; Hofmann, Christina L; Stauffer, Paul R

    2013-07-01

    Because of the limitations of surgical resection, thermal ablation is commonly used for the treatment of hepatocellular carcinoma and liver metastases. Current methods of ablation can result in marginal recurrences of larger lesions and in tumors located near large vessels. This review presents a novel approach for extending treatment out to the margins where temperatures do not provide complete treatment with ablation alone, by combining thermal ablation with drug-loaded thermosensitive liposomes. A history of the development of thermosensitive liposomes is presented. Clinical trials have shown that the combination of radiofrequency ablation and doxorubicin-loaded thermosensitive liposomes is a promising treatment.

  13. Radiation therapy for favorable histology Wilms tumor: Prevention of flank recurrence did not improve survival on National Wilms Tumor Studies 3 and 4

    SciTech Connect

    Breslow, Norman E. . E-mail: norm@u.washington.edu; Beckwith, J. Bruce; Haase, Gerald M.; Kalapurakal, John A.; Ritchey, Michael L.; Shamberger, Robert C.; Thomas, Patrick; D'Angio, Giulio J.; Green, Daniel M.

    2006-05-01

    Purpose: To determine whether radiation therapy (RT) of patients with Wilms tumor of favorable histology prevented flank recurrence and thereby improved the survival outcomes. Methods and Materials: Recurrence and mortality risks were compared among groups of patients with Stage I-IV/favorable histology Wilms tumor enrolled in the third (n = 1,640) and fourth (n = 2,066) National Wilms Tumor Study Group studies. Results: Proportions of patients with flank recurrence were 0 of 513 = 0.0% for 20 Gy, 12 of 805 = 1.5% for 10 Gy, and 44 of 2,388 = 1.8% for no flank RT (p trend 0.001 adjusted for stage and doxorubicin); for intra-abdominal (including flank) recurrence they were 5 of 513 = 1.0%, 30 of 805 = 3.7%, and 58 of 2,388 = 2.4%, respectively (p trend = 0.02 adjusted). Survival percentages at 8 years after intra-abdominal recurrence were 0 of 5 = 0% for 20 Gy, 10 of 30 = 33% for 10 Gy, and 34 of 58 = 56% for no RT (p trend = 0.0001). NWTS-4 discontinued use of 20 Gy RT, and the 8-year flank recurrence risk increased to 2.1% from 1.0% on NWTS-3 (p = 0.013). However, event-free survival was unaltered (88% vs. 86%, p = 0.39), and overall survival was better (93.8% vs. 90.8%, p = 0.036) on NWTS-4. Conclusions: Partly because of lower postrecurrence mortality among nonirradiated patients, prevention of flank recurrence by RT did not improve survival. It is important to evaluate entire treatment policies with regard to long-term outcomes.

  14. Tumor cells prevent mouse dendritic cell maturation induced by TLR ligands.

    PubMed

    Idoyaga, Juliana; Moreno, José; Bonifaz, Laura

    2007-08-01

    Tumor cells can evade the immune system through several mechanisms, one of which is to block DC maturation. It has been suggested that signaling via Toll-like receptors (TLR) may be involved in the induction of prophylactic anti-cancer immunity and in the treatment of established tumors. In the present study we found that high numbers of tumor cells interfere with BMDC activation induced by the TLR ligands LPS and poly IC. Tumor cells blocked TLR3- and TLR4-mediated induction of MHCII and the co-stimulatory molecules CD40 and CD86, as well as the cytokines IL-12, TNF-alpha and IL-6. Importantly, tumor cells induced inhibitory molecules (B7-DC, B7-H1 and CD80) on spleen DC in vivo and on BMDC, even in the presence of TLR ligands. Moreover, after a long exposure with tumor cells, purified BMDC were unable to respond to a second challenge with TLR ligands. The failure of tumor exposed-BMDC to express co-stimulatory molecules and cytokines in the presence of TLR ligands has implications for the future development of DC-based cancer immune therapies using TLR ligands as adjuvants for the activation of DC.

  15. Surface functionalization of liposomes with proteins and carbohydrates for use in anti-cancer applications

    NASA Astrophysics Data System (ADS)

    Platt, Virginia M.

    Liposomes can be used to exploit the altered biology of cancer thereby increasing delivery of liposome-associated anti-cancer drugs. In this dissertation, I explore methods that utilize the unique cancer expression of the polymeric glycosaminoglycan hyaluronan (HA) and the HA receptor CD44 to target liposomes to tumors, using liposomes functionalized with proteins or oligosaccharides on their surface. To make it easier to prepare protein-functionalized liposomes, a non-covalent protein/liposome association method based upon metal chelation/his 6 interaction was devised and characterized. I evaluated non-covalent attachment of the prodrug converting enzyme yeast cytosine deaminase, the far-red fluorescent protein mKate, two antigens ovalbumin and the membrane proximal region of an HIV GAG and hyaluronidase, a HA-degrading enzyme. In Chapter 2, I describe the synthesis of hyaluronan-oligosaccharide (HA-O) lipid conjugates and their incorporation into liposomes to target CD44-overexpressing cancer cells. HA-O ligands of defined-length, up to 10 monosaccharides, were attached to lipids via various linkers by reductive amination. The HA-lipids were easily incorporated into liposomes but did not mediate binding of liposomes to CD44 overexpressing cells. In Chapter 3, I evaluate the capacity of tris-NTA-Ni-lipids incorporated within a liposome bilayer to associate with his6-tagged proteins. Tris-NTA-lipids of differing structures and avidities were used to associate yeast cytosine deaminase and mKate to the surface of liposomes. Two tris-NTA-lipids and a mono-NTA lipid associated his-tagged proteins to a 1:1 molar ratio in solution. The proteins remained active while associated with the liposome surface. When challenged in vitro with fetal calf serum, tris-NTA-containing liposomes retained his-tagged proteins longer than mono-NTA. However, the tris-NTA/his6 interaction was found to be in a dynamic state; free yeast cytosine deaminase rapidly competed with pre-bound m

  16. Comparative study of liposomes, transfersomes and ethosomes as carriers for improving topical delivery of celecoxib.

    PubMed

    Bragagni, Marco; Mennini, Natascia; Maestrelli, Francesca; Cirri, Marzia; Mura, Paola

    2012-01-01

    Topical administration of celecoxib proved to be an effective mean of preventing skin cancer development and improving anticancer drugs effectiveness in skin tumors treatment. The aim of this study was the development of an effective topical formulation of celecoxib, able to promote drug skin delivery, providing its in depth penetration through the skin layers. Three kinds of vesicular formulations have been investigated as drug carriers: liposomes containing a surfactant, or transfersomes and ethosomes, containing suitable edge activators. Firstly, the effect of membrane composition variations on the system performance has been evaluated for each vesicle type. Selected formulations were characterized for particle size, polydispersity index and encapsulation efficiency. The best formulations were subjected to ex vivo permeation studies through excised human skin. All vesicular formulations markedly (p < 0.001) improved the drug amount penetrated into the skin with respect to an aqueous suspension, from 2.0 to 6.5, up to 9.0 folds for liposomes, transfersomes and ethosomes, respectively. In particular, ethosomes containing Tween 20 as edge activator not only showed the best vesicle dimensions and homogeneity, and the highest encapsulation efficacy (54.4%), but also enabled the highest increase in drug penetration through the skin, probably due to the simultaneous presence in their composition of ethanol and Tween 20, both acting as permeation enhancers. Therefore, among the various vesicular formulations examined in the study, Tween 20-ethosomes can be considered the most promising one as carrier for topical celecoxib applications aimed to prevent skin cancer development and increase the anticancer drugs effectiveness against skin tumors.

  17. Biological activity of liposomal vanillin.

    PubMed

    Castan, Leniher; Del Toro, Grisel; Fernández, Adolfo A; González, Manuel; Ortíz, Emilia; Lobo, Daliana

    2013-06-01

    This article presents a study of vanillin encapsulation inside multilamellar liposomes, with emphasis on the evaluation of antioxidant activity, the hemolytic effect, and the antisickling properties of these products. Egg phosphatidylcholine-cholesterol and egg phosphatidylcholine-cholesterol-1-O-decylglycerol liposomes were prepared by mechanical dispersion, all with vanillin included. Vesicles were characterized by determination of encapsulation efficiency and vanillin retention capacity. Antioxidant activity was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. The hemolytic effect of liposomes was also evaluated by spectrophotometry, as well as the antisickling activity by the Huck test using optical microscopy. Results showed that the lipid composition of liposomes did not significantly affect the encapsulation efficiency. Stable vesicles were obtained with a high retention percentage of vanillin. Liposomes exhibited a high capture of the DPPH radical compared to free vanillin and 1-O-decylglycerol (C10) in solution. Vesicles caused no significant hemolisys in normal erythrocytes, nor in those coming from patients with sickle cell anemia. Vanillin encapsulated in liposomes retained its antisickling activity, with a greater effect for C10-containing vesicles. Our results show that vanillin encapsulation in liposomes is a way to enhance the pharmacologic properties of this molecule using a suitable vehicle.

  18. Liposome: classification, preparation, and applications

    PubMed Central

    2013-01-01

    Liposomes, sphere-shaped vesicles consisting of one or more phospholipid bilayers, were first described in the mid-60s. Today, they are a very useful reproduction, reagent, and tool in various scientific disciplines, including mathematics and theoretical physics, biophysics, chemistry, colloid science, biochemistry, and biology. Since then, liposomes have made their way to the market. Among several talented new drug delivery systems, liposomes characterize an advanced technology to deliver active molecules to the site of action, and at present, several formulations are in clinical use. Research on liposome technology has progressed from conventional vesicles to ‘second-generation liposomes’, in which long-circulating liposomes are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several molecules, such as glycolipids or sialic acid. This paper summarizes exclusively scalable techniques and focuses on strengths, respectively, limitations in respect to industrial applicability and regulatory requirements concerning liposomal drug formulations based on FDA and EMEA documents. PMID:23432972

  19. Hyaluronic acid-coated liposomes for targeted delivery of paclitaxel, in-vitro characterization and in-vivo evaluation.

    PubMed

    Ravar, Fatemeh; Saadat, Ebrahim; Gholami, Mehdi; Dehghankelishadi, Pouya; Mahdavi, Mehdi; Azami, Samira; Dorkoosh, Farid A

    2016-05-10

    Breast cancer is the leading cause of cancer death in women. Chemotherapy is regarded as the most essential strategy in inhibiting the proliferation of tumor cells. Paclitaxel is a widely used taxane; however, the side effects of available Cremophor-based formulations and also the limitations of passive targeting uncovered an essential need to develop tumor-specific targeted nanocarriers. A hyaluronic acid targeted liposomal formulation of paclitaxel was prepared in which, hyaluronic acid was electrostatistically attracted to the surface of liposomes. Liposomes, had a particle size of 106.4±3.2nm, a weakly negative zeta potential of -9.7±0.8mV and an acceptable encapsulation efficiency of 92.1±1.7%. The release profile of liposomes in buffer showed that 95% of PTX was released during 40h. Confocal laser scanning microscopy and flow cytometry analysis showed the greater cellular internalization of coumarin-loaded liposomes compared to free coumarin. MTT assay on 4T1 and T47D cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. Cell cycle analysis showed that cells were mainly blocked at G2/M phases after 48h treatment with liposomes. In vivo real time imaging on 4T1 tumor-bearing mice revealed that the liposomal formulation mainly accumulated in the tumor area. Liposomes also had better antitumor efficacy against Cremophor-based formulation. In conclusion, hyaluronic acid targeted paclitaxel liposome can serve as a promising targeted formulation of paclitaxel for future cancer chemotherapy.

  20. Ganglioside inserted into PEGylated liposome attenuates anti-PEG immunity.

    PubMed

    Mima, Yu; Abu Lila, Amr S; Shimizu, Taro; Ukawa, Masami; Ando, Hidenori; Kurata, Yasuko; Ishida, Tatsuhiro

    2017-03-28

    Despite the clinical introduction of a vast number of polyethylene glycol (PEG)-conjugated therapeutics, conjugated PEG is also known for an unfortunate inclination toward immunogenicity. Immunogenicity of PEG, manifested by the robust production of anti-PEG IgM, is known to compromise the therapeutic efficacy and/or reduce the tolerance of PEGylated therapeutics. In the present study, we inserted ganglioside into the membrane of PEGylated liposome (PL) to prepare ganglioside-modified PEGylated liposomes (G-PL), and investigated its efficacy in attenuating the anti-PEG IgM response against PL. A single intravenous injection of G-PL significantly attenuated the anti-PEG IgM production, compared with that of naïve PL. In addition, pretreatment with G-PL substantially alleviated the anti-PEG IgM response elicited by a subsequent dose of PL, presumably via inducing B cell tolerance, and as a consequence, this modification abrogated/attenuated the incidence of the rapid clearance of subsequently administrated PL. These results indicate that incorporating gangliosides in PEGylated liposome membrane not only prevents the immunogenicity of PEG but also induces the tolerance of B cells to subsequent doses of the immunogenic PL. Consequently, liposomal membrane modification with ganglioside might represent a promising approach to attenuating the immunogenicity of PEGylated liposomes while preserving their therapeutic efficacy, particularly upon repeated administration.

  1. Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

    SciTech Connect

    Hrycushko, Brian A.; Li Shihong; Goins, Beth; Otto, Randal A.; Bao, Ande

    2011-03-15

    Purpose: Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle (liposome)-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. Methods: {sup 99m}Tc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts in nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, {sup 186}Re/{sup 188}Re liposomes. Effective uniform dose (EUD) and tumor control probability (TCP) were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. Results: Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy/MBq (318.2 Gy/mCi) and 5.7 Gy/MBq (209.1 Gy/mCi) could be delivered with this protocol of radiation delivery for {sup 186}Re/{sup 188}Re liposomes, respectively, and 37-92 MBq (1-2.5 mCi)/g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating

  2. Pitfalls, prevention, and treatment of hyperuricemia during tumor lysis syndrome in the era of rasburicase (recombinant urate oxidase)

    PubMed Central

    Pession, Andrea; Melchionda, Fraia; Castellini, Claudia

    2008-01-01

    Along with hydration and urinary alkalinization, allopurinol has been the standard agent for the management of hyperuricemia in patients with a high tumor burden at risk of tumor lysis syndrome; however, this agent often fails to prevent and treat this complication effectively. Rasburicase (recombinant urate oxidase) has been shown to be effective in reducing uric acid and preventing uric acid accumulation in patients with hematologic malignancies with hyperuricemia or at high risk of developing it. Rasburicase acts at the end of the purine catabolic pathway and, unlike allopurinol, does not induce accumulation of xanthine or hypoxanthine. Its rapid onset of action and the ability to lower pre-existing elevated uric acid levels are the advantages of rasburicase over allopurinol. Rasburicase represents an effective alternative to allopurinol to promptly reduce uric acid levels, improve patient’s electrolyte status, and reverse renal insufficiency. The drug, initially studied in pediatric patients with acute lymphoblastic leukemia and aggressive non-Hodgkin lymphoma, seems to show comparable benefit in adults with similar lymphoid malignancies or at high risk of tumor lysis syndrome. Current and future trials will evaluate alternative doses and different schedules of rasburicase to maintain its efficacy while reducing its cost. The review provides a comprehensive and detailed review of pathogenesis, laboratory, and clinical presentation of TLS together with clinical studies already performed both in pediatric and adult patients. PMID:19707436

  3. Liposome Technology for Industrial Purposes

    PubMed Central

    Wagner, Andreas; Vorauer-Uhl, Karola

    2011-01-01

    Liposomes, spherical vesicles consisting of one or more phospholipid bilayers, were first described in the mid 60s by Bangham and coworkers. Since then, liposomes have made their way to the market. Today, numerous lab scale but only a few large-scale techniques are available. However, a lot of these methods have serious limitations in terms of entrapment of sensitive molecules due to their exposure to mechanical and/or chemical stress. This paper summarizes exclusively scalable techniques and focuses on strengths, respectively, limitations in respect to industrial applicability. An additional point of view was taken to regulatory requirements concerning liposomal drug formulations based on FDA and EMEA documents. PMID:21490754

  4. Hyaluronic acid ion-pairing nanoparticles for targeted tumor therapy.

    PubMed

    Li, Wenhao; Yi, Xiaoli; Liu, Xing; Zhang, Zhirong; Fu, Yao; Gong, Tao

    2016-03-10

    Hyaluronic acid (HA)-based doxorubicin (DOX) nanoparticles (HA-NPs) were fabricated via ion-pairing between positively charged DOX and negatively charged HA, which displayed near-spherical shapes with an average size distribution of 180.2nm (PDI=0.184). Next, HA-NPs were encapsulated in liposomal carriers to afford HA-based DOX liposomes (HA-LPs), which also showed near-spherical morphology with an average size of 130.5nm (PDI=0.201). HA-NPs and HA-LPs displayed desirable sustained-release profiles compared to free DOX, and moreover, HA-LPs were proven to prevent premature release of DOX from HA-NPs. Cell based studies demonstrated HA-NPs and HA-LPs were selectively taken up by CD44(+) tumor cells, and DOX was released intracellularly to target the cell nuclei. Both HA-NPs and HA-LPs showed comparable levels of penetration efficiency in tumor spheroids. In vivo studies revealed that HA-NPs and HA-LPs significantly prolonged the blood circulation time of DOX, decreased accumulation in the normal tissues and enriched drugs into the tumors. Furthermore, HA-NPs and HA-LPs greatly enhanced therapeutic efficacy of DOX in tumor-bearing mice and minimized systemic toxicity against vital organs. In sum, HA-NPs and HA-LPs represent promising nanocarriers for CD44(+) tumor-targeted delivery.

  5. Synthesis and characterization of PEGylated bolaamphiphiles with enhanced retention in liposomes.

    PubMed

    Zhang, Yingyue; Mintzer, Evan; Uhrich, Kathryn E

    2016-11-15

    Long-circulating liposomes are typically prepared with poly(ethylene glycol)- (PEG-) modified lipids, where the lipid portion is inserted in the lipid bilayers as an anchor and the hydrophilic PEG coats the surface to prevent liposome aggregation and rapid clearance in vivo. However, these steric protection effects are compromised upon systemic administration due to low retention of PEGylated lipids within liposome membranes upon dilution. Hence, a series of PEGylated bolaamphiphiles (PEG-bolas) were for the first time developed to increase retention in the lipid bilayer, presumably leading to enhanced integrity of the PEG protective layer upon dilution. We hypothesized that PEG-bolas with a sufficiently long hydrophobic domain and rigid central group could predominantly adopt a membrane-spanning configuration, taking full advantage of steric protection offered by PEG and enhanced retention in liposomes enabled by the bola geometry. In this paper, liposomes stabilized by PEG-bolas comprised of a biphenyl core and twelve-carbon alkyl chain not only exhibited similar storage and biological stability compared to conventional PEGylated lipid stabilized liposomes, but also significantly improved retention upon dilution. Our findings facilitate new designs of liposome-stabilizing agents and can be applied to improve the delivery efficiency of liposomal delivery vehicles in vivo.

  6. Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats

    PubMed Central

    Matsuzaki, Takashi; Araki, Ryo; Tsuchida, Shota; Thanikachalam, Punniyakoti V.; Fukuta, Tatsuya; Asai, Tomohiro; Yamato, Masaki; Sanada, Shoji; Asanuma, Hiroshi; Asano, Yoshihiro; Asakura, Masanori; Hanawa, Haruo; Hao, Hiroyuki; Oku, Naoto; Takashima, Seiji; Kitakaze, Masafumi; Sakata, Yasushi; Minamino, Tetsuo

    2016-01-01

    Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug’s effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents. PMID:27501378

  7. How Are Wilms Tumors Diagnosed?

    MedlinePlus

    ... Tumor Early Detection, Diagnosis, and Staging How Are Wilms Tumors Diagnosed? Wilms tumors are usually found when a ... Your Child’s Doctor About Wilms Tumor? More In Wilms Tumor About Wilms Tumor Causes, Risk Factors, and Prevention ...

  8. ePTFE/FEP-Covered Metallic Stents for Palliation of MalignantBiliary Disease: Can Tumor Ingrowth Be Prevented?

    SciTech Connect

    Hatzidakis, Adam Krokidis, Miltiadis; Kalbakis, Kostantinos; Romanos, Jiannis; Petrakis, Ioannis; Gourtsoyiannis, Nicholas

    2007-09-15

    Purpose. To determine the application and clinical effectiveness of ePTFE/FEP-covered metallic stents for palliation of malignant biliary disease, and to evaluate the efficiency of stent coverage in preventing tumor ingrowth. Methods. During a 3-year period, 36 patients with malignant obstructive jaundice were treated with ePTFE/FEP-covered stents, with or without proximal side holes. The stricture was located in the lower common bile duct (CBD) in 18 cases, the upper CBD in 9, the lower common hepatic duct (CHD) in 6, and the upper CHD in 3 patients. Results.Thirty-seven covered stents were percutaneously implanted. The technical success rate was 97%. Reintervention was required in 6 cases. The 30-day mortality rate was 40%, not procedure-related. Mean survival was 128 days. Primary patency rates were 100%,55.5%, and 25% at 3, 6, and 12 months, respectively, while the assisted patency rate was 100% at 12 months. Stents without side holes had higher primary patency rates compared with those with side holes, where occlusion was always due to tumor ingrowth. Tumor ingrowth did not occur in the completely covered stents. No stent dysfunction due to sludge incrustation was found.Complications were 1 case of arterial laceration that occurred during percutaneous transhepatic cholangiography, and a subcapsular hematoma and 1 case of bile peritonitis, that both occurred during primary stenting. No complications followed the secondary stenting technique. Conclusion. ePTFE/FEP-covered metallic stents are safe and effective for palliation of malignant biliary disease. The presence of the ePTFE/FEP coating is likely to prevent from tumor ingrowth.

  9. Milatuzumab-Conjugated Liposomes as Targeted Dexamethasone Carriers for Therapeutic Delivery in CD74+ B-cell Malignancies

    PubMed Central

    Mao, Yicheng; Triantafillou, Georgia; Hertlein, Erin; Towns, William; Stefanovski, Matthew; Mo, Xiaokui; Jarjoura, David; Phelps, Mitch; Marcucci, Guido; Lee, Ly James; Goldenberg, David M.; Lee, Robert J.; Byrd, John C.; Muthusamy, Natarajan

    2013-01-01

    Purpose: Corticosteroids are widely used for the treatment of B-cell malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia; however, this class of drug is associated with undesirable off-target effects. Herein, we developed novel milatuzumab-conjugated liposomes as a targeted dexamethasone carrier for therapeutic delivery in CD74+ B-cell malignancies and explored its effect against the disease. Experimental Design: The targeting efficiency of milatuzumab-targeted liposomes to CD74+ cells was evaluated in vitro. The effect of CD74-targeted liposomal dexamethasone was compared with free dexa-methasone in primary CLL cells and cell lines in vitro. The therapeutic efficacy of CD74-targeted liposomal dexamethasone was evaluated in a Raji-severe combined immunodeficient (SCID) xenograft model in vivo. Results: Milatuzumab-targeted liposomes promoted selective incorporation of carrier molecules into transformed CD74-positive B cells as compared with CD74-negative T-cells. The CD74-dexamethasone-targeted liposomes (CD74-IL-DEX) promoted and increased killing in CD74-positive tumor cells and primary CLL cells. Furthermore, the targeted drug liposomes showed enhanced therapeutic efficacy against a CD74-positive B-cell model as compared with free, or non-targeted, liposomal dexamethasone in SCID mice engrafted with Raji cells in vivo. Conclusions: These studies provide evidence and support for a potential use of CD74-targeted liposomal dexamethasone as a new therapy for B-cell malignancies. PMID:23209030

  10. Targeting gemcitabine containing liposomes to CD44 expressing pancreatic adenocarcinoma cells causes an increase in the antitumoral activity.

    PubMed

    Dalla Pozza, Elisa; Lerda, Carlotta; Costanzo, Chiara; Donadelli, Massimo; Dando, Ilaria; Zoratti, Elisa; Scupoli, Maria Teresa; Beghelli, Stefania; Scarpa, Aldo; Fattal, Elias; Arpicco, Silvia; Palmieri, Marta

    2013-05-01

    Pancreatic adenocarcinoma is often diagnosed when metastatic events have occurred. The early spread of circulating cancer cells expressing the CD44 receptor may play a crucial role in this process. In this study, we have investigated the cellular delivery ability and both in vitro and in vivo anti-tumoral activity of liposomes conjugated with two different low molecular weight hyaluronic acids (HA 4.8kDa and HA 12kDa), the primary ligand of CD44, and containing a lipophilic gemcitabine (GEM) pro-drug. By confocal microscopy and flow cytometry analyses, we demonstrate that the cellular uptake into a highly CD44-expressing pancreatic adenocarcinoma cell line is higher with HA-conjugated (12kDa>4.8kDa) than non-conjugated liposomes. Consistently, in vitro cytotoxic assays display an increased sensitivity towards GEM containing HA-liposomes, compared to non-conjugated liposomes. Conversely, CD44 non-expressing normal cells show a similar uptake and in vitro cytotoxicity with both HA-conjugated and non-conjugated liposomes. Furthermore, we demonstrate that the HA-liposomes are taken up into the cells via lipid raft-mediated endocytosis. All the liposome formulations containing GEM show a higher antitumoral activity than free GEM in a mouse xenograft tumor model of human pancreatic adenocarcinoma. The 12kDa HA-liposomes have the strongest efficiency, while non-conjugated liposomes and the 4.8kDa HA-liposomes are similarly active. Taken together, our results provide a strong rationale for further development of HA-conjugated liposomes to treat pancreatic adenocarcinoma.

  11. Liposome encapsulation of chelating agents

    DOEpatents

    Rahman, Yueh Erh

    1976-01-13

    A method for transferring a chelating agent across a cellular membrane by encapsulating the charged chelating agent within liposomes and carrying the liposome-encapsulated chelating agent to the cellular membrane where the liposomes containing the chelating agent will be taken up by the cells, thereby transferring the chelating agent across the cellular membrane. A chelating agent can be introduced into the interior of a cell of a living organism wherein the liposomes will be decomposed, releasing the chelating agent to the interior of the cell. The released chelating agent will complex intracellularly deposited toxic heavy metals, permitting the more soluble metal complex to transfer across the cellular membrane from the cell and subsequently be removed from the living organism.

  12. Extravasation and transcytosis of liposomes in Kaposi's sarcoma-like dermal lesions of transgenic mice bearing the HIV tat gene.

    PubMed

    Huang, S K; Martin, F J; Jay, G; Vogel, J; Papahadjopoulos, D; Friend, D S

    1993-07-01

    Transgenic mice bearing the HIV tat gene develop dermal lesions resembling a common malignant tumor in AIDS, Kaposi's sarcoma (KS). To evaluate the permeability characteristics of these lesions and the therapeutic potential of drug-carrying liposomes, we have studied the localization of sterically stabilized liposomes, which show long circulation time in blood and increased accumulation in tumors. Liposomes encapsulating colloidal gold were injected intravenously into transgenic mice bearing KS lesions, and tissues were processed 24 hours later for both electron microscopy and for light microscopy with silver enhancement. Liposomes and silver marker were detected predominantly in the dermis surrounding the early and mature KS lesions, which were characterized by a proliferation of fibroblast-like spindle cells and abnormal blood vessels close to the epidermis. The silver-enhanced gold marker often surrounded vascular channels and scattered erythrocytes. As determined by electron microscopy, some spindle cells and macrophages had ingested intact liposomes. Transendothelial transport of liposomes was observed both through open channels between endothelial cells and also through endothelial cells lining intact vessels. Both extravasation and transcytosis of liposomes through irregular endothelium were much higher in KS lesions than in the adjacent normal skin. The high accumulation of sterically stabilized liposomes in KS lesions and their intracellular uptake by some spindle cells enhances their potential as carriers of chemotherapeutic agents against this neoplasm.

  13. RGD-modified liposomes enhance efficiency of aclacinomycin A delivery: evaluation of their effect in lung cancer.

    PubMed

    Feng, Chan; Li, Xiaoyan; Dong, Chunyan; Zhang, Xuemei; Zhang, Xie; Gao, Yong

    2015-01-01

    In this study, long-circulating Arg-Gly-Asp (RGD)-modified aclacinomycin A (ACM) liposomes were prepared by thin film hydration method. Their morphology, particle size, encapsulation efficiency, and in vitro release were investigated. The RGD-ACM liposomes was about 160 nm in size and had the visual appearance of a yellowish suspension. The zeta potential was -22.2 mV and the encapsulation efficiency was more than 93%. The drug-release behavior of the RGD-ACM liposomes showed a biphasic pattern, with an initial burst release and followed by sustained release at a constant rate. After being dissolved in phosphate-buffered saline (pH 7.4) and kept at 4°C for one month, the liposomes did not aggregate and still had the appearance of a milky white colloidal solution. In a pharmacokinetic study, rats treated with RGD-ACM liposomes showed slightly higher plasma concentrations than those treated with ACM liposomes. Maximum plasma concentrations of RGD-ACM liposomes and ACM liposomes were 4,532 and 3,425 ng/mL, respectively. RGD-ACM liposomes had a higher AUC0-∞ (1.54-fold), mean residence time (2.09-fold), and elimination half-life (1.2-fold) when compared with ACM liposomes. In an in vivo study in mice, both types of liposomes inhibited growth of human lung adenocarcinoma (A549) cells and markedly decreased tumor size when compared with the control group. There were no obvious pathological tissue changes in any of the treatment groups. Our results indicate that RGD-modified ACM liposomes have a better antitumor effect in vivo than their unmodified counterparts.

  14. Phospholipid liposomes functionalized by protein

    NASA Astrophysics Data System (ADS)

    Glukhova, O. E.; Savostyanov, G. V.; Grishina, O. A.

    2015-03-01

    Finding new ways to deliver neurotrophic drugs to the brain in newborns is one of the contemporary problems of medicine and pharmaceutical industry. Modern researches in this field indicate the promising prospects of supramolecular transport systems for targeted drug delivery to the brain which can overcome the blood-brain barrier (BBB). Thus, the solution of this problem is actual not only for medicine, but also for society as a whole because it determines the health of future generations. Phospholipid liposomes due to combination of lipo- and hydrophilic properties are considered as the main future objects in medicine for drug delivery through the BBB as well as increasing their bioavailability and toxicity. Liposomes functionalized by various proteins were used as transport systems for ease of liposomes use. Designing of modification oligosaccharide of liposomes surface is promising in the last decade because it enables the delivery of liposomes to specific receptor of human cells by selecting ligand and it is widely used in pharmacology for the treatment of several diseases. The purpose of this work is creation of a coarse-grained model of bilayer of phospholipid liposomes, functionalized by specific to the structural elements of the BBB proteins, as well as prediction of the most favorable orientation and position of the molecules in the generated complex by methods of molecular docking for the formation of the structure. Investigation of activity of the ligand molecule to protein receptor of human cells by the methods of molecular dynamics was carried out.

  15. Prevention of pulmonary metastasis from subcutaneous tumors by binary system-based sustained delivery of catalase.

    PubMed

    Hyoudou, Kenji; Nishikawa, Makiya; Ikemura, Mai; Kobayashi, Yuki; Mendelsohn, Adam; Miyazaki, Nobuhiko; Tabata, Yasuhiko; Yamashita, Fumiyoshi; Hashida, Mitsuru

    2009-07-20

    Catalase delivery can be effective in inhibiting reactive oxygen species (ROS)-mediated acceleration of tumor metastasis. Our previous studies have demonstrated that increasing the plasma half-life of catalase by pegylation (PEG-catalase) significantly increases its potency of inhibiting experimental pulmonary metastasis in mice. In the present study, a biodegradable gelatin hydrogel formulation was used to further increase the circulation time of PEG-catalase. Implantation of (111)In-PEG-catalase/hydrogel into subcutaneous tissues maintained the radioactivity in plasma for more than 14 days. Then, the effect of the PEG-catalase/hydrogel on spontaneous pulmonary metastasis of tumor cells was evaluated in mice with subcutaneous tumor of B16-BL6/Luc cells, a murine melanoma cell line stably expressing luciferase. Measuring luciferase activity in the lung revealed that the PEG-catalase/hydrogel significantly (P<0.05) inhibited the pulmonary metastasis compared with PEG-catalase solution. These findings indicate that sustaining catalase activity in the blood circulation achieved by the use of pegylation and gelatin hydrogel can reduce the incidence of tumor cell metastasis.

  16. A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation.

    PubMed

    Ho, Victor W; Leung, Kelvin; Hsu, Anderson; Luk, Beryl; Lai, June; Shen, Sung Yuan; Minchinton, Andrew I; Waterhouse, Dawn; Bally, Marcel B; Lin, Wendy; Nelson, Brad H; Sly, Laura M; Krystal, Gerald

    2011-07-01

    Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression.

  17. Determination of Liposomal Cisplatin by High-Performance Liquid Chromatography and Its Application in Pharmacokinetic Studies

    PubMed Central

    Toro-Córdova, Alfonso; Ledezma-Gallegos, Fabricio; Mondragon-Fuentes, Laura; Jurado, Rafael; Medina, Luis A.; Pérez-Rojas, Jazmin M.; Garcia-Lopez, Patricia

    2016-01-01

    Liposomes have been employed as carriers for antineoplastic drugs to improve delivery. We describe an HPLC–UV method for determining cisplatin levels in liposomal and biological samples, which represents an attractive alternative to the widely used flame atomic absorption spectroscopy. Liposomal cisplatin was extracted from liposomes, plasma and tissue samples by using acetonitrile and separated on a Symmetry C18 column. The mobile phase was a mixture of water, methanol and acetonitrile, and detection was performed at 254 nm. The method was linear in the range of 0.5–10 µg/mL. Using this method, cisplatin concentration was measured in plasma, kidney, liver and tumor at different times post-administration of liposomal cisplatin. This method is proved suitable for measuring the levels of cisplatin encapsulated in a liposomal system, in plasma or tissue samples of experimental animals, after intravenous administration of liposomal cisplatin. Owing to the small plasma volume employed, a complete pharmacokinetic study can be done with a single animal. PMID:27013666

  18. Meta-analysis of clinical and preclinical studies comparing the anticancer efficacy of liposomal versus conventional non-liposomal doxorubicin.

    PubMed

    Petersen, Grant H; Alzghari, Saeed K; Chee, Wayne; Sankari, Sana S; La-Beck, Ninh M

    2016-06-28

    While liposome-mediated delivery of cytotoxic chemotherapy has been shown to significantly enhance drug tolerability in patients as compared to the conventional formulation, the fundamental question remains whether they also improve anticancer efficacy. Thus, we performed a systematic literature search for randomized clinical trials directly comparing efficacy of liposomal cytotoxic chemotherapy versus their equivalent conventional formulation. The search yielded 14 clinical trials (8 anthracycline, 4 cisplatin, 1 paclitaxel, 1 irinotecan) that meet inclusion criteria, with a total of 2589 patients. We found that efficacy in patients was not different between liposomal and conventional chemotherapy as assessed by objective response (odds ratio 1.03; 95% confidence interval [CI] 0.82-1.30), overall survival (hazard ratio [HR] 1.05; 95% CI 0.95-1.17), and progression free survival rates (HR 1.01; 95% CI, 0.92-1.11). Subgroup analyses of only the anthracycline trials also did not show any efficacy advantage for the liposomal formulation. Since pegylated liposomal doxorubicin (PLD) was the most prevalent formulation in these clinical trials, we also performed a meta-analysis of 11 preclinical studies comparing efficacy of PLD and conventional doxorubicin in tumor-bearing mice. In contrast with clinical results, animal studies showed significantly increased survival in mice treated with PLD compared to conventional doxorubicin (HR 0.39; 95% CI 0.27-0.56). We discuss the possible reasons why the pharmacological advantages of carrier-mediated chemotherapy did not translate into enhanced clinical efficacy including the role of the enhanced permeability and retention (EPR) effect and the tumor microenvironment, the optimal dosing regimen for carrier-mediated agents, and the lack of standardization in the conduct and reporting of preclinical studies evaluating anticancer efficacy of these agents. Our study shows that the full clinical potential of carrier-mediated drugs

  19. Insulin, not glutamine dipeptide, reduces lipases expression and prevents fat wasting and weight loss in Walker 256 tumor-bearing rats.

    PubMed

    de Morais, Hely; Silva, Flaviane de Fatima; da Silva, Francemilson Goulart; Silva, Milene Ortiz; Graciano, Maria Fernanda Rodrigues; Martins, Maria Isabel Lovo; Rafael Carpinelli, Ângelo; Mazucco, Tânia Longo; Bazotte, Roberto Barbosa; de Souza, Helenir Medri

    2017-04-05

    Cachexia is the main cause of mortality in advanced cancer patients. We investigated the effects of insulin (INS) and glutamine dipeptide (GDP), isolated or associated, on cachexia and metabolic changes induced by Walker 256 tumor in rats. INS (NPH, 40 UI/kg, sc) or GDP (1.5g/kg, oral gavage) was once-daily administered during 11 days after tumor cell inoculation. GDP, INS or INS+GDP treatments did not influence the tumor growth. However, INS and INS+GDP prevented retroperitoneal fat wasting and body weight loss of tumor-bearing rats. In consistency, INS and INS+GDP prevented the increased expression of triacylglycerol lipase (ATGL) and hormone sensitive lipase (HSL), without changing the expression of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in the retroperitoneal adipose tissue of tumor-bearing rats. INS and INS+GDP also prevented anorexia and hyperlactatemia of tumor-bearing rats. However, INS and INS+GDP accentuated the loss of muscle mass (gastrocnemius, soleus and long digital extensor) without affecting the myostatin expression in the gastrocnemius muscle and blood corticosterone. GDP treatment did not promote beneficial effects. It can be concluded that treatment with INS (INS or INS + GDP), not with GDP, prevented fat wasting and weight loss in tumor-bearing rats without reducing tumor growth. These effects might be attributed to the reduction of lipases expression (ATGL and LHS) and increased food intake. The results show the physiological function of INS in the suppression of lipolysis, induced by cachexia mediators in tumor-bearing rats.

  20. Preparation and properties evaluation of a novel pH-sensitive liposomes based on imidazole-modified cholesterol derivatives.

    PubMed

    Ju, Liang; Cailin, Fang; Wenlan, Wu; Pinghua, Yu; Jiayu, Gao; Junbo, Li

    2017-02-25

    As a new kind of drug carries, pH-sensitive liposomes have been widely studied in tumor therapy for their advantages of target ability and sustained-release. Here, we synthesized a pH-sensitive material, N-(3-Aminopropyl)imidazole-cholesterol (IM-Chol) and prepared a novel pH-sensitive liposomes using IM-Chol and phosphatidylcholine. IM-Chol was synthesized through amidation reaction between the amino group of N-(3-Aminopropyl)imidazole and acyl chloride group of cholesteryl chloroformate in a weak base solution. Optimal conditions to prepare liposomes were obtained by the orthogonal experiment with the higher encapsulation efficiency as the evaluation indicator. The properties of liposomes, such as particle size, zeta potential, morphology, encapsulation efficiency, drug release behavior and in vitro cell toxicity were evaluated by transmission electron microscopy (TEM), dynamic light scattering (DLS) and MTT assay respectively. The results showed that the average particle size of IM-Chol liposomes was 141nm (PDI 0.323). Liposomes can assemble into uniform spheres at pH 7.4, but under the condition of pH 5.0, the spherical structure of IM-Chol liposomes was broken, exhibiting pH-sensitive property. In vitro drug releasing studies demonstrated the controlled-release behavior of the curcumin (CUR) in the IM-Chol liposomes. The cumulative release of CUR reached to 72.5% in the first 24h at pH 5.0, faster than that at pH 7.4, which confirmed that the drug carrier displayed pH-sensitive release behaviors. In addition, the MTT assay was employed to test the cytotoxicity of IM-Chol liposomes and CUR IM-Chol liposomes. All cell viabilities were greater than 80% after incubating for 24h, even up to the highest dose of 500mg/L, indicating that IM-Chol liposomes had good biocompatibility. The tumor inhibitory results towards EC109 cells of free CUR and CUR-loaded IM-Chol liposomes indicated that IM-Chol liposomes indeed enhanced the cell killing effect of CUR. These results

  1. In vivo antitumor effect of cromolyn in PEGylated liposomes for pancreatic cancer.

    PubMed

    Kim, Cha-Eun; Lim, Sun-Kyung; Kim, Jin-Seok

    2012-01-30

    A PEGylated liposomal formulation of cromolyn, composed of dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), distearoylphosphatidylcholine (DSPC) and 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000), has been developed with the purpose of improving the antitumor activity of cromolyn for human pancreatic adenocarcinoma. In stability study, the amount of proteins adsorbed onto the PEGylated liposomes encapsulating cromolyn was 4.5-fold lower than the non-PEGylated liposome. In vitro study showed that the cromolyn in PEGylated liposome exhibited better anti-proliferative effect in BxPC-3 cells than in Panc-1 cells, which indicates higher level of endogenous S100P protein in BxPC-3 cells than in Panc-1 cells as a target protein for this drug. Moreover, the combination of cromolyn with gemcitabine in PEGylated liposomes demonstrated the strongest cytotoxicity to BxPC-3 pancreatic cancer cells in vitro and the highest anti-tumor activity against the BxPC-3 tumor bearing nude mice in vivo. Thus, this PEGylated liposomal formulation of cromolyn is expected to provide a novel approach to the treatment of pancreatic cancer in the future.

  2. pH-sensitive polymer-liposome-based antigen delivery systems potentiated with interferon-γ gene lipoplex for efficient cancer immunotherapy.

    PubMed

    Yuba, Eiji; Kanda, Yuhei; Yoshizaki, Yuta; Teranishi, Ryoma; Harada, Atsushi; Sugiura, Kikuya; Izawa, Takeshi; Yamate, Jyoji; Sakaguchi, Naoki; Koiwai, Kazunori; Kono, Kenji

    2015-10-01

    Potentiation of pH-sensitive liposome-based antigen carriers with IFN-γ gene lipoplexes was attempted to achieve efficient induction of tumor-specific immunity. 3-Methylglutarylated poly(glycidol) (MGluPG)-modified liposomes and cationic liposomes were used, respectively, for the delivery of antigenic protein ovalbumin (OVA) and IFN-γ-encoding plasmid DNA (pDNA). The MGluPG-modified liposomes and the cationic liposome-pDNA complexes (lipoplexes) formed hybrid complexes via electrostatic interactions after their mixing in aqueous solutions. The hybrid complexes co-delivered OVA and IFN-γ-encoding pDNA into DC2.4 cells, a murine dendritic cell line, as was the case of MGluPG-modified liposomes for OVA or the lipoplexes for pDNA. Both the lipoplexes and the hybrid complexes transfected DC2.4 cells and induced IFN-γ protein production, but transfection activities of the hybrid complexes were lower than those of the parent lipoplexes. Subcutaneous administration of hybrid complexes to mice bearing E.G7-OVA tumor reduced tumor volumes, which might result from the induction of OVA-specific cytotoxic T lymphocytes (CTLs). However, the hybrid complex-induced antitumor effect was the same level of the MGluPG-modified liposome-mediated antitumor immunity. In contrast, an extremely strong antitumor immune response was derived when these liposomes and lipoplexes without complexation were injected subcutaneously at the same site of tumor-bearing mice. Immunohistochemical analysis of tumor sections revealed that immunization through the liposome-lipoplex combination promoted the infiltration of CTLs to tumors at an early stage of treatment compared with liposomes, resulting in strong therapeutic effects.

  3. The future of cancer research: prevention, screening, vaccines, and tumor-specific drug combos.

    PubMed

    Blanck, George

    2014-01-01

    New cancer research strategies have developed very rapidly over the past five years, including extensive DNA sequencing of tumor and normal cells; use of highly sensitive cancer cell detection methods; vaccine development and tumor-specific (designer) drugs. These developments have raised questions about where to concentrate efforts in the near future when establishing clinical trials, particularly important in an age of diminishing resources and during a period when competing strategies for cancer control are likely to overwhelm the opportunities for establishing large, effective clinical trials. In particular, it behooves the research community to be mindful of the inevitable, challenging obligation to responsibly choose between clinical trials that offer the credible hope of incremental advances vs. trials that are less traditional but may have revolutionary outcomes.

  4. TGF-β: Duality of Function Between Tumor Prevention and Carcinogenesis

    PubMed Central

    2014-01-01

    Several mechanisms underlying tumor progression have remained elusive, particularly in relation to transforming growth factor beta (TGF-β). Although TGF-β initially inhibits epithelial growth, it appears to promote the progression of advanced tumors. Defects in normal TGF-β pathways partially explain this paradox, which can lead to a cascade of downstream events that drive multiple oncogenic pathways, manifesting as several key features of tumorigenesis (uncontrolled proliferation, loss of apoptosis, epithelial-to-mesenchymal transition, sustained angiogenesis, evasion of immune surveillance, and metastasis). Understanding the mechanisms of TGF-β dysregulation will likely reveal novel points of convergence between TGF-β and other pathways that can be specifically targeted for therapy. PMID:24511106

  5. Anticancer activity of liposomal bergamot essential oil (BEO) on human neuroblastoma cells.

    PubMed

    Celia, Christian; Trapasso, Elena; Locatelli, Marcello; Navarra, Michele; Ventura, Cinzia Anna; Wolfram, Joy; Carafa, Maria; Morittu, Valeria Maria; Britti, Domenico; Di Marzio, Luisa; Paolino, Donatella

    2013-12-01

    Citrus extracts, particularly bergamot essential oil (BEO) and its fractions, have been found to exhibit anticancer efficacy. However, the poor water solubility, low stability and limited bioavailability have prevented the use of BEO in cancer therapy. To overcome such drawbacks, we formulated BEO liposomes that improved the water solubility of the phytocomponents and increased their anticancer activity in vitro against human SH-SY5Y neuroblastoma cells. The results warrant further investigation of BEO liposomes for in vivo applications.

  6. Naked DNA Immunization for Prevention of Prostate Cancer in a Dunning Rat Prostate Tumor Model

    DTIC Science & Technology

    2005-06-01

    Medical Center, Washington DC 2- Central Laboratory for Immunology , St. Ivan Rilski Hospital, Sofia, Bulgaria 3- Department of Urology, St. Ann...Head, Tumor Immunology Laboratory Department of Medicine The George Washington Medical Center 2300 Eye Street, N.W., Ross Hall 705 Washington, DC 20037...containing plasmid was kindly provided by Jan Geliebter, New York Medical College, Department of Microbiology and Immunology , Valhalla, NY, USA. The clone

  7. Naked DNA Immunization of Prevention of Prostate Cancer in a Dunning Rat Prostate Tumor Model

    DTIC Science & Technology

    2006-06-01

    George Washington University Medical Center, Washington DC Central Laboratory for Immunology , St. Ivan Rilski Hospital, Sofia, Bulgaria Department of...author: Milcho Mincheff Head, Tumor Immunology Laboratory Department of Medicine The George Washington Medical Center 2300 Eye Street, N.W., Ross...regulatory role of CTLA-4. Immunity. 1995;3(5):541-547. 42. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse

  8. Prevention and Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

    DTIC Science & Technology

    2015-04-01

    MPNST clinical trials if our pre-clinical testing yields positive results. 15. SUBJECT TERMS Apoptosis; autophagy; lysosomotropic agents; Bcl2 family ...ability of tumor cells to evade normal cell death inducing stimuli. Numerous studies have shown that overexpression of anti-apoptotic Bcl-2 family ...Lysosomotropic agents Bcl2 family members 3. Accomplishments What were the major goals of the project? 1. To determine therapeutic effects of BH3 mimetics

  9. Priming the Tumor Immune Microenvironment Improves Immune Surveillance of Cancer Stem Cells and Prevents Cancer Recurrence

    DTIC Science & Technology

    2013-10-01

    specifically inhibited with Caþþ-channel blockers [18]. The dye-effluxing population was given the designation side population (SP) based on their low dye...antibody (Santa Cruz Biotechnology, Santa Cruz, CA, http://www.scbt.com). We also used polyclonal rabbit anti-mouse N-cadherin and beta catenin...increased release of proangiogenic factors, including matrix metallopeptidase 9 (MMP-9), VEGF and transforming growth factor beta (TGF-b), from tumor

  10. CD8+ T-cell responses against hemoglobin-beta prevent solid tumor growth.

    PubMed

    Komita, Hideo; Zhao, Xi; Taylor, Jennifer L; Sparvero, Louis J; Amoscato, Andrew A; Alber, Sean; Watkins, Simon C; Pardee, Angela D; Wesa, Amy K; Storkus, Walter J

    2008-10-01

    Bone marrow-derived dendritic cells engineered using recombinant adenovirus to secrete high levels of IL-12p70 dramatically inhibited the growth of established CMS4 sarcomas in BALB/c mice after intratumoral administration. An analysis of splenic CD8(+) T cells in regressor mice revealed a strong, complex reactivity pattern against high-performance liquid chromatography (HPLC)-resolved peptides isolated by acid elution from single-cell suspensions of surgically resected CMS4 lesions. Mass spectrometry analyses defined two major overlapping peptide species that derive from the murine hemoglobin-beta (HBB) protein within the most stimulatory HPLC fractions. Although cultured CMS4 tumor cells failed to express HBB mRNA based on reverse transcription-PCR analyses, prophylactic vaccination of BALB/c mice with vaccines containing HBB peptides promoted specific CD8(+) T-cell responses that protected mice against a subsequent challenge with CMS4 or unrelated syngeneic (HBB(neg)) tumors of divergent histology (sarcoma, carcinomas of the breast or colon). In situ imaging suggested that vaccines limit or destabilize tumor-associated vascular structures, potentially by promoting immunity against HBB+ vascular pericytes. Importantly, there were no untoward effects of vaccination with the HBB peptide on peripheral RBC numbers, RBC hemoglobin content, or vascular structures in the brain or eye.

  11. CD8+ T Cell Responses Against Hemoglobin-β Prevent Solid Tumor Growth

    PubMed Central

    Komita, Hideo; Zhao, Xi; Taylor, Jennifer L.; Sparvero, Louis J.; Amoscato, Andrew A.; Alber, Sean; Watkins, Simon C.; Pardee, Angela D.; Wesa, Amy K.; Storkus, Walter J.

    2008-01-01

    Bone marrow-derived dendritic cells (DCs) engineered using recombinant adenovirus to secrete high levels of IL-12p70 dramatically inhibited the growth of established CMS4 sarcomas in BALB/c mice after intratumoral administration. An analysis of splenic CD8+ T cells in regressor mice revealed a strong, complex reactivity pattern against HPLC-resolved peptides isolated by acid elution from single-cell suspensions of surgically-resected CMS4 lesions. Mass spectrometry analyses defined 2 major overlapping peptide species that derive from the murine hemoglobin-β (HBB) protein within the most stimulatory HPLC fractions. Although cultured CMS4 tumor cells failed to express HBB mRNA based on RT-PCR analyses, prophylactic vaccination of BALB/c mice with vaccines containing HBB peptides promoted specific CD8+ T cell responses that protected mice against a subsequent challenge with CMS4, or unrelated syngenic (HBBneg) tumors of divergent histology (sarcoma, carcinomas of the breast or colon). In situ imaging suggested that vaccines limit or destabilize tumor-associated vascular structures, potentially by promoting immunity against HBB+ vascular pericytes. Importantly, there were no untoward effects of vaccination with the HBB peptide on peripheral red blood cell (RBC) numbers, RBC hemoglobin content or vascular structures in the brain or eye. PMID:18829566

  12. Quercetin liposome sensitizes colon carcinoma to thermotherapy and thermochemotherapy in mice models.

    PubMed

    He, Bing; Wang, Xin; Shi, Hua-shan; Xiao, Wen-jing; Zhang, Jing; Mu, Bo; Mao, Yong-qiu; Wang, Wei; Wang, Yong-sheng

    2013-05-01

    Thermotherapy and thermochemotherapy have been used in clinics to treat patients with malignant diseases, including colon cancer, and their efficacy has been well proved. Heat shock proteins (HSPs), especially Hsp70, play important roles in neutralizing their efficacy. It has been reported that quercetin can suppress cancer by inhibiting the intratumoral expression of Hsp70. This study was designed to investigate whether quercetin could enhance sensitivity to thermotherapy and thermochemotherapy. Soluble quercetin liposome was used in this study. The effects of quercetin were investigated in vitro and in mouse colon cancer models of subcutaneous tumor and peritoneal carcinomatosis. The results showed that quercetin liposome inhibited the upregulation of Hsp70 and enhanced apoptosis induced by hyperthermia and thermochemotherapy. Systemic administration of quercetin liposome can sensitize CT26 cells to thermotherapy and chemothermotherapy. This study suggests that quercetin liposome might be potentially applied for clinical cancer therapy.

  13. [Preparation and quality evaluation of Iohexol liposomes].

    PubMed

    Zhou, Rongli; Zhu, Xiali; Hung, Guihua; Zhang, Na; Zhang, Bingjie

    2007-08-01

    The liposomes were prepared by reverse-phase evaporation technique. The morphology of the liposomes, the entrapment efficiency and the particle size distribution were evaluated. The CT signals of Iohexol liposomes in rabbits were compared with those of Iohexol injection in rabbits. The entrapment efficiency of Iohexol liposomes was 82.35% +/- 1.82%. The liposmes were spherical or ellipsoidal shape in shape. The mean diameter of the Iohexol liposomes was 207 7 nm. The polydispersity index was 0.355. The Zeta potential was--1.83 mV. The drug was highly entrapped into the liposomes with good reproduction and stability. The in vitro release of Iohexol liposomes was significantly slower than that of Iohexol,and was 98.57% at 24 h. Iohexol liposomes may reduce the dosage, prolong the effective time of the developing agent, and could reduce the side effects of Iohexol on the blood vessels and cerebral nerves.

  14. Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis

    PubMed Central

    Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

    2016-01-01

    Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis. PMID:27729789

  15. Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis.

    PubMed

    Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

    Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis.

  16. Prevention

    MedlinePlus

    ... our e-newsletter! Aging & Health A to Z Prevention Basic Facts & Information Some factors that affect your ... control of the things that you can change. Preventive Recommendations for Adults Aged 65 and Older The ...

  17. Prevention

    MedlinePlus

    ... Is Strong Error processing SSI file About Heart Disease & Stroke Prevention Heart disease and stroke are an epidemic in ... to avoid secondhand smoke. Barriers to Effective Heart Disease & Stroke Prevention Many people with key risk factors for heart ...

  18. [Liposomal amphotericin B].

    PubMed

    Fukasawa, Masatomo

    2005-01-01

    Liposomal amphotericin B (AmBisome) is a DDS (drug delivery system) formulation of amphotericin B (AMPH-B), and has been developed in an attempt to reduce the toxicity of AMPH-B while retaining its therapeutic efficacy. AMPH-B has been the "gold standard" of antifungal therapy over the past four decades. It has a broad spectrum of fungicidal activity against a number of clinically important pathogens including Aspergillus and Candida. The mechanism of action of AMPH-B involves binding to ergosterol, the principal sterol in fungal cell membranes. Binding to ergosterol causes an increase in fungal membrane permeability, electrolyte leakage, and cell death. AMPH-B has affinity for cholesterol in mammalian membranes, which leads to severe side-effects including kidney damage. AmBisome is a unilamellar vesicle composed of AMPH-B and phospholipid. Upon administration, AmBisome remains intact in the blood and distributes to the tissues where fungal infection may occur, and is disrupted after attachment to the outside of fungal cells, resulting in fungal cell death. AmBisome and AMPH-B show similar in vitro and in vivo antifungal activity and clinical efficacy. However, AmBisome has less infusion-related toxicity and nephrotoxicity than AMPH-B.

  19. Modeling protective anti-tumor immunity via preventative cancer vaccines using a hybrid agent-based and delay differential equation approach.

    PubMed

    Kim, Peter S; Lee, Peter P

    2012-01-01

    A next generation approach to cancer envisions developing preventative vaccinations to stimulate a person's immune cells, particularly cytotoxic T lymphocytes (CTLs), to eliminate incipient tumors before clinical detection. The purpose of our study is to quantitatively assess whether such an approach would be feasible, and if so, how many anti-cancer CTLs would have to be primed against tumor antigen to provide significant protection. To understand the relevant dynamics, we develop a two-compartment model of tumor-immune interactions at the tumor site and the draining lymph node. We model interactions at the tumor site using an agent-based model (ABM) and dynamics in the lymph node using a system of delay differential equations (DDEs). We combine the models into a hybrid ABM-DDE system and investigate dynamics over a wide range of parameters, including cell proliferation rates, tumor antigenicity, CTL recruitment times, and initial memory CTL populations. Our results indicate that an anti-cancer memory CTL pool of 3% or less can successfully eradicate a tumor population over a wide range of model parameters, implying that a vaccination approach is feasible. In addition, sensitivity analysis of our model reveals conditions that will result in rapid tumor destruction, oscillation, and polynomial rather than exponential decline in the tumor population due to tumor geometry.

  20. Topical liposome targeting of dyes, melanins, genes, and proteins selectively to hair follicles.

    PubMed

    Hoffman, R M

    1998-01-01

    For therapeutic and cosmetic modification of hair, we have developed a hair-follicle-selective macromolecule and small molecule targeting system with topical application of phosphatidylcholine-based liposomes. Liposome-entrapped melanins, proteins, genes, and small-molecules have been selectively targeted to the hair follicle and hair shafts of mice. Liposomal delivery of these molecules is time dependent. Negligible amounts of delivered molecules enter the dermis, epidermis, or bloodstream thereby demonstrating selective follicle delivery. Naked molecules are trapped in the stratum corneum and are unable to enter the follicle. The potential of the hair-follicle liposome delivery system for therapeutic use for hair disease as well as for cosmesis has been demonstrated in 3-dimensional histoculture of hair-growing skin and mouse in vivo models. Topical liposome selective delivery to hair follicles has demonstrated the ability to color hair with melanin, the delivery of the active lac-Z gene to hair matrix cells and delivery of proteins as well. Liposome-targeting of molecules to hair follicles has also been achieved in human scalp in histoculture. Liposomes thus have high potential in selective hair follicle targeting of large and small molecules, including genes, opening the field of gene therapy and other molecular therapy of the hair process to restore hair growth, physiologically restore or alter hair pigment, and to prevent or accelerate hair loss.

  1. Chest discomfort associated with liposomal amphotericin B: report of three cases and review of the literature.

    PubMed

    Johnson, M D; Drew, R H; Perfect, J R

    1998-01-01

    Liposomal formulations of amphotericin B are designed to maintain therapeutic efficacy of amphotericin B deoxycholate while reducing its associated toxicities. In three patients chest discomfort occurred during planned 1-hour infusions of liposomal amphotericin B (AmBisome) 3 mg/kg/day during an open-label trial. The first patient experienced chest tightness and difficulty breathing and the second had dyspnea and acute hypoxia, both within 10 minutes of the start of the infusion. The third patient complained of chest pain 5 minutes after the start of two infusions. All symptoms resolved on terminating therapy. Two patients were later rechallenged with slower infusions and tolerated the drug well. A review of the English-language literature revealed only two other case reports of infusion-related chest or pulmonary reactions with the drug, although similar reactions were noted in several reports of clinical trials. Further review of the literature revealed reports of chest and pulmonary adverse events with other liposomal formulations of amphotericin B, liposomal daunorubicin, liposomal doxorubicin, and liposomes. The pathophysiology of such reactions remains unclear, and premedication with diphenhydramine did not completely prevent this reaction in one of our patients. We recommend infusing liposomal amphotericin B over at least 2 hours with careful monitoring for adverse reactions.

  2. The use of liposomal anthracycline analogues for childhood malignancies: A systematic review.

    PubMed

    Sieswerda, E; Kremer, L C M; Caron, H N; van Dalen, E C

    2011-09-01

    In an effort to prevent or reduce anthracycline-induced cardiotoxicity, liposomal anthracyclines have been developed. The objective of this systematic review was to summarise all available evidence on the benefits and risks of liposomal anthracyclines in children with cancer. We searched databases (MEDLINE (1966-September 2009), EMBASE (1980-September 2009) and CENTRAL (The Cochrane Library, issue 3 2009)), reference lists of relevant articles and ongoing trial databases for relevant studies. Two reviewers independently performed study selection, data extraction and quality assessment of included studies. No randomised controlled trials (RCTs) or controlled clinical trials (CCTs) were found. Fifteen observational studies described the use of liposomal anthracyclines in children with cancer. Most patients had been treated extensively in the past. Some patients developed cardiotoxicity, serious allergic reactions, mucositis, infections, hematotoxicities and/or hepatotoxicity after single agent treatment. However, due to the low quality of the currently available research, it is unclear what the exact risks are. In conclusion, there is no evidence available from RCTs or CCTs about the benefits and risks of liposomal anthracyclines in children with cancer. Limited data from observational studies suggest that children treated with liposomal anthracyclines are at risk for developing cardiotoxicity and other serious toxicities. There is an urgent need for results of well-designed studies which accurately evaluate the benefits and risks of liposomal anthracyclines in children with cancer. Until high quality evidence is available, we recommend monitoring of cardiac function in childhood cancer patients treated with a liposomal anthracycline and awareness of other serious toxicities.

  3. Phytoestrogens regulate vitamin D metabolism in the mouse colon: relevance for colon tumor prevention and therapy.

    PubMed

    Kállay, Enikö; Adlercreutz, Herman; Farhan, Hesso; Lechner, Daniel; Bajna, Erika; Gerdenitsch, Waltraud; Campbell, Moray; Cross, Heide S

    2002-11-01

    Soybean products are highly represented in the traditional Asian diet. Major components of soy proteins are phytoestrogens, such as isoflavones. They may be responsible for the extremely low incidence of prostate and mammary tumors and possibly also of colon cancer in countries such as China and Japan. Serum 1,25-dihydroxyvitamin D3 level is inversely related to incidence of some cancers. Levels are determined by skin exposure to ultraviolet light or, to a minor extent, nutritional uptake and by subsequent conversion of the precursor vitamin D to the active hormone by the cytochrome P450 hydroxylases CYP27A1, CYP27B1 (responsible for synthesis) and CYP24 (responsible for catabolism) in liver and kidney. However, vitamin D synthesis is also found in colonocytes and is enhanced during incipient malignancy. This may indicate an autocrine/paracrine role for this differentiation-inducing hormone in defense against progression. We were able to demonstrate that either a single large oral dose of genistein or feeding soy protein for 4 mo elevated CYP27B1 and decreased CYP24 expression in the mouse colon. Our data therefore suggest that an inverse correlation of soy product consumption with colon tumor incidence may be consequent to enhanced colonic synthesis of the antimitotic hormone 1,25-dihydroxyvitamin D3.

  4. Topical delivery of DNA oligonucleotide to induce p53 generation in the skin via thymidine dinucleotide (pTT)-encapsulated liposomal carrier

    PubMed Central

    Fang, Yi-Ping

    2011-01-01

    Introduction Transcription factor p53 has a powerful tumor suppressing function that is associated with many cancers. Since the molecular weight of p53 is 53 kDa, it is difficult to transport across cell membranes. Thymidine dinucleotide (pTT) is an oligonucleotide that can activate the p53 transcription factor and trigger the signal transduction cascade. However, the negative charge and high water solubility of pTT limit its transport through cellular membranes, thereby preventing it from reaching its target in the nucleus. A suitable delivery carrier for pTT is currently not available. Objective The purpose of this study was to employ a nanoscale liposomal carrier to resolve the delivery problem, and increase the bioavailability and efficiency of pTT. Methodology The approach was to employ liposomes to deliver pTT and then evaluate the particle size and zeta potential by laser light scattering (LLS), and permeation properties of pTT in vitro in a Franz diffusion assembly, and in vivo in a murine model using confocal laser scanning microscopy (CLSM). Results We found that dioleoylphosphatidylethanolamine (DOPE) combined with cholesterol 3 sulfate (C3S) were the best ingredients to achieve an average desired vehicle size of 133.6 ± 2.8 nm, a polydispersity index (PDI, representing the distribution of particle sizes) of 0.437, and a zeta potential of −93.3 ± 1.88. An in vitro penetration study showed that the liposomal carrier was superior to the free form of pTT at 2–24 hours. CLSM study observed that the penetration depth of pTT reached the upper epidermis and potential of penetration maintained up to 24 hours. Conclusion These preliminary data demonstrate that nanosized DOPE/C3S liposomes can be exploited as a potential carrier of drugs for topical use in treating skin diseases. PMID:22267922

  5. Prevention and Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

    DTIC Science & Technology

    2016-04-01

    almost no effect on patient mortality. NF1 patients have an approximate 10% lifetime risk of developing an MPNST and this risk increases to...approximately 30% in patients with plexiform neurofibromas. Thus, development of safe and effective MPNST preventative therapies could have an important...examining the mechanisms of action and in vivo utility of two classes of drugs , BH3 mimetics and lysosomotropic agents, on MPNSTs. The drugs that we

  6. Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide.

    PubMed Central

    Fidler, I J; Sone, S; Fogler, W E; Barnes, Z L

    1981-01-01

    The multiple systemic administration of multilamellar liposomes composed of phosphatidylserine and phosphatidylcholine (molar ratio 3:7) that contained water-soluble muramyl dipeptide (MDP) activated alveolar macrophages to become tumoricidal and eradicated established spontaneous pulmonary and lymph node metastases. Spontaneously metastasizing melanoma cells were injected into the footpads of mice. After 4-5 weeks, the tumors were resected by a midfemoral amputation; 3 days later, twice-weekly injections of liposomes were initiated and continued for 4 weeks. In some experiments the mice were killed 2 weeks after the final treatment. Seventy-four percent of animals injected with liposomes containing MDP were free of visible metastases. In a separate life-span experiment, 60% of mice treated with liposome-encapsulated MDP were tumor-free 120 days after the last liposome treatment or 110 days after all control mice treated with free MDP or control liposome preparations had died of disseminated cancer. These data suggest that the systemic administration of liposomes containing MDP, or similar compounds that produce macrophage activation, may provide an additional useful approach to the therapeutic regimens currently used to eradicate cancer metastases. Images PMID:6940181

  7. Liposomes as delivery systems for antibiotics.

    PubMed

    Drulis-Kawa, Zuzanna; Dorotkiewicz-Jach, Agata

    2010-03-15

    Liposomes are currently in common use as universal drug carriers in the cosmetic and pharmaceutical industries. The manipulation of different physicochemical properties of liposomes enables the design of particular carriers with the desired pharmacokinetic and pharmacodynamic properties. Most studies regarding liposomal antibiotics deal with aminoglycosides, quinolones, polypeptides, and betalactames. Some of the studies focused on improving pharmacokinetics and reducing toxicity, while others involved enhancing antibacterial activity. In an era of an avalanche of increasing bacterial resistance and severe problems in treating bacterial infections, the application of liposomal antibiotic carriers could be useful, but the high cost of liposome preparation and treatment should also be considered.

  8. Targeting vincristine plus tetrandrine liposomes modified with DSPE-PEG2000-transferrin in treatment of brain glioma.

    PubMed

    Song, Xiao-Li; Liu, Shuang; Jiang, Ying; Gu, Li-Yan; Xiao, Yao; Wang, Xin; Cheng, Lan; Li, Xue-Tao

    2017-01-01

    Glioma is the most frequent primary tumor, and the treatment efficiency is unsatisfactory for the obstacle of the blood brain barrier (BBB), the multidrug resistance (MDR) and the properties of cancer cell invasion and vasculogenic mimicry (VM) formation. In this study, a kind of TF modified vincristine plus tetrandrine liposomes was developed to overcome those limitations. In vitro results showed that TF modified vincristine plus tetrandrine liposomes with suitable physicochemical property could enhance the transport across the BBB, increase the cellular uptake, inhibit the MDR, and block the cancer cell invasion and VM channels. In vivo results demonstrated that TF modified vincristine plus tetrandrine liposomes could significantly prolong the circulation time, obviously accumulate in brain tumor location, thus leading to a robust anticancer efficacy in glioma-bearing mice. These data suggest that TF modified vincristine plus tetrandrine liposomes offer a promising strategy for treating brain glioma.

  9. Inhibition of peritoneal dissemination of colon cancer by hyperthermic CO2 insufflation: A novel approach to prevent intraperitoneal tumor spread

    PubMed Central

    Zhou, Houming; Zheng, Minhua

    2017-01-01

    Background The increasing use of laparoscopic surgery for advanced gastrointestinal cancer raises concerns about intra-peritoneal tumor spread. Prevention of peritoneal dissemination is extremely important but a preventive modality is lacking. The aim of this study was to examine a novel approach (hyperthermic CO2 insufflation, HT-CO2) for preventing peritoneal dissemination during laparoscopic surgery. Methods A peritoneal dissemination model was established in Balb/c nu/nu mice by intraperitoneal injection of human colon cancer cells (SW1116, 1×106). The mice (n = 48) were subsequently randomized into two groups and subjected to hyperthermic CO2 (43°C, >95% humidity, HT-CO2 group) or standard normothermic CO2 (21°C, <1% relative humidity, NT-CO2 group) insufflation for 3 hours. The mice were sacrificed 28 days later. The peritoneal dissemination was quantitatively analyzed by counting and weighing the peritoneal nodules. The port sites and ascites volume were measured. The peritoneal damage of HT-CO2 was histologically examined with light microscopy and scanning electron microscopy. Intra-abdominal adhesions were evaluated 4 weeks later. Results The number of peritoneal nodules in the HT-CO2 group was significantly less than that in the NT-CO2 group (10.21±3.72 vs. 67.12±5.49, P<0.01). The mean weight of metastatic tumors in the HT-CO2 group was significantly lower than that in the NT-CO2 group (0.31±0.10g vs. 2.16±0.31g, P<0.01). Massive ascites were found in the NT-CO2 group while significantly less ascites developed in HT-CO2- treated mice (8.26±0.31ml vs. 1.27±0.28ml, P<0.01). No port-site metastases were detected in the HT-CO2 group while the incidence of the NT-CO2 group was 12.5% (3/24). HT-CO2 subjection resulted in slight peritoneal damage; the peritoneum returned to normal within five days. No adhesions formed after HT-CO2 treatment. Conclusions HT-CO2 can suppress peritoneal dissemination of colon cancer cells and only causes slight and

  10. Engineering Remotely Triggered Liposomes to Target Triple Negative Breast Cancer

    PubMed Central

    Sneider, Alexandra; Jadia, Rahul; Piel, Brandon; VanDyke, Derek; Tsiros, Christopher; Rai, Prakash

    2017-01-01

    Triple Negative Breast Cancer (TNBC) continues to present a challenge in the clinic, as there is still no approved targeted therapy. TNBC is the worst sub-type of breast cancer in terms of prognosis and exhibits a deficiency in estrogen, progesterone, and human epidermal growth factor 2 (HER2) receptors. One possible option for the treatment of TNBC is chemotherapy. The issue with many chemotherapy drugs is that their effectiveness is diminished due to poor water solubility, and the method of administration directly or with a co-solvent intravenously can lead to an increase in toxicity. The issues of drug solubility can be avoided by using liposomes as a drug delivery carrier. Liposomes are engineered, biological nanoconstructs that possess the ability to encapsulate both hydrophobic and hydrophilic drugs and have been clinically approved to treat cancer. Specific targeting of cancer cell receptors through the use of ligands conjugated to the surface of drug-loaded liposomes could lessen damage to normal, healthy tissue. This study focuses on polyethylene glycol (PEG)-coated, folate conjugated, benzoporphyrin derivative (BPD)-loaded liposomes for treatment via photodynamic therapy (PDT). The folate receptor is over expressed on TNBC cells so these liposomes are targeted for greater uptake into cancer cells. PDT involves remotely irradiating light at 690 nm to trigger BPD, a hydrophobic photosensitive drug, to form reactive oxygen species that cause tumor cell death. BPD also displays a fluorescence signal when excited by light making it possible to image the fluorescence prior to PDT and for theranostics. In this study, free BPD, non-targeted and folate-targeted PEGylated BPD-loaded liposomes were introduced to a metastatic breast cancer cell line (MDA-MB-231) in vitro. The liposomes were reproducibly synthesized and characterized for size, polydispersity index (PDI), zeta potential, stability, and BPD release kinetics. Folate competition tests, fluorescence

  11. Targeting of pegylated liposomal mitomycin-C prodrug to the folate receptor of cancer cells: Intracellular activation and enhanced cytotoxicity.

    PubMed

    Patil, Yogita; Amitay, Yasmine; Ohana, Patricia; Shmeeda, Hilary; Gabizon, Alberto

    2016-03-10

    Mitomycin C (MMC) is a powerful anti-bacterial, anti-fungal and anti-tumor antibiotic, often active against multidrug resistant cells. Despite a broad spectrum of antitumor activity, MMC clinical use is relatively limited due to its fast clearance and dose-limiting toxicity. To exploit the potential antitumor activity of MMC and reduce its toxicity we have previously developed a formulation of pegylated liposomes with a lipophilic prodrug of MMC (PL-MLP), activated by endogenous reducing agents which are abundant in the tumor cell environment in the form of different thiols. PL-MLP has minimal in vitro cytotoxicity unless reducing agents are added to the cell culture to activate the prodrug. In the present study, we hypothesized that targeting PL-MLP via folate receptors will facilitate intracellular activation of prodrug and enhance cytotoxic activity without added reducing agents. We grafted a lipophilic folate conjugate (folate-PEG(5000)-DSPE) to formulate folate targeted liposomes (FT-PL-MLP) and examined in vitro cell uptake and cytotoxic activity in cancer cell lines with high folate receptors (HiFR). 3H-cholesterol-hexadecyl ether (3H-Chol)-radiolabeled liposomes were prepared to study liposome-cell binding in parallel to cellular uptake of prodrug MLP. 3H-Chol and MLP cell uptake levels were 4-fold and 9-fold greater in KB HiFR cells when FT-PL-MLP is compared to non-targeted PL-MLP liposomes. The cytotoxic activity of FT-PL-MLP liposomes was significantly increased up to ~5-fold compared with PL-MLP liposomes in all tested HiFR expressing cell lines. The enhanced uptake and intracytoplasmic liposome delivery was confirmed by confocal fluorescence studies with Rhodamine-labeled liposomes. In vivo, no significant differences in pharmacokinetics and biodistribution were observed when PL-MLP was compared to FT-PL-MLP by the intravenous route. However, when liposomes were directly injected into the peritoneal cavity of mice with malignant ascites of J6456 Hi

  12. Liposomes for entrapping local anesthetics: a liposome electrokinetic chromatographic study.

    PubMed

    Lokajová, Jana; Laine, Jaana; Puukilainen, Esa; Ritala, Mikko; Holopainen, Juha M; Wiedmer, Susanne K

    2010-05-01

    Bupivacaine is a lipophilic, long-acting, amide class local anesthetic commonly used in clinical practice to provide local anesthesia during surgical procedures. Several cases of accidental overdose with cardiac arrest and death have been reported since bupivacaine was introduced to human use. Recent case reports have suggested that Intralipid (Fresenius Kabi) is an effective therapy for cardiac toxicity from high systemic concentrations of, e.g. bupivacaine, even though the mechanism behind the interaction is not fully clear yet. Our long-term aim is to develop a sensitive, efficient, and non-harmful lipid-based formulation to specifically trap harmful substances in vivo. In this study, the in vitro interaction of local anesthetics (bupivacaine, prilocaine, and lidocaine) with Intralipid or lipid vesicles containing phosphatidylglycerol, phosphatidylcholine, cardiolipin, cholesterol, and N-palmitoyl-D-erythro-sphingosine (ceramide) was determined by liposome electrokinetic chromatography. The interactions were evaluated by calculating the retention factors and distribution constants. Atomic force microscopy measurements were carried out to confirm that the interaction mechanism was solely due to interactions between the analytes and the moving pseudostationary phase and not by interactions with a stationary lipid phase adsorbed to the fused-silica wall. The heterogeneity of the liposomes was also studied by atomic force microscopy. The liposome electrokinetic chromatography results demonstrate that there is higher interaction between the drugs and negatively charged liposome dispersion than with the commercial Intralipid dispersion.

  13. Chitosan/lecithin liposomal nanovesicles as an oral insulin delivery system.

    PubMed

    Al-Remawi, Mayyas; Elsayed, Amani; Maghrabi, Ibrahim; Hamaidi, Mohammad; Jaber, Nisrein

    2017-05-01

    In the present work, insulin-chitosan polyelectrolyte complexes associated to lecithin liposomes were investigated as a new carrier for oral delivery of insulin. The preparation was characterized in terms of particle size, zeta potential and encapsulation efficiency. Surface tension measurements revealed that insulin-chitosan polyelectrolyte complexes have some degree of hydrophobicity and should be added to lecithin liposomal dispersion and not the vice versa to prevent their adsorption on the surface. Stability of insulin was enhanced when it was associated to liposomes. Significant reduction of blood glucose levels was noticed after oral administration of liposomal preparation to streptozotocin diabetic rats compared to control. The hypoglycemic activity was more prolonged compared to subcutaneously administered insulin.

  14. Carbon nanotubes-liposomes conjugate as a platform for drug delivery into cells.

    PubMed

    Karchemski, Faina; Zucker, Daniel; Barenholz, Yechezkel; Regev, Oren

    2012-06-10

    Carbon nanotubes (CNT) are widely explored as carriers for drug delivery due to their facile transport through cellular membranes. However, the amount of loaded drug on a CNT is rather small. Liposomes, on the other hand, are employed as a carrier of a large amount of drug. The aim of this research is to develop a new drug delivery system, in which drug-loaded liposomes are covalently attached to CNT to form a CNT-liposomes conjugate (CLC). The advantage of this novel approach is the large amount of drug that can be delivered into cells by the CLC system, thus preventing potential adverse systemic effects of CNT when administered at high doses. This system is expected to provide versatile and controlled means for enhanced delivery of one or more agents stably associated with the liposomes.

  15. Liposome-like Nanostructures for Drug Delivery

    PubMed Central

    Gao, Weiwei; Hu, Che-Ming J.; Fang, Ronnie H.; Zhang, Liangfang

    2013-01-01

    Liposomes are a class of well-established drug carriers that have found numerous therapeutic applications. The success of liposomes, together with recent advancements in nanotechnology, has motivated the development of various novel liposome-like nanostructures with improved drug delivery performance. These nanostructures can be categorized into five major varieties, namely: (1) polymer-stabilized liposomes, (2) nanoparticle-stabilized liposomes, (3) core-shell lipid-polymer hybrid nanoparticles, (4) natural membrane-derived vesicles, and (5) natural membrane coated nanoparticles. They have received significant attention and have become popular drug delivery platforms. Herein, we discuss the unique strengths of these liposome-like platforms in drug delivery, with a particular emphasis on how liposome-inspired novel designs have led to improved therapeutic efficacy, and review recent progress made by each platform in advancing healthcare. PMID:24392221

  16. Polymerization of actin by positively charged liposomes

    PubMed Central

    1988-01-01

    By cosedimentation, spectrofluorimetry, and electron microscopy, we have established that actin is induced to polymerize at low salt concentrations by positively charged liposomes. This polymerization occurs only at the surface of the liposomes, and thus monomers not in direct contact with the liposome remain monomeric. The integrity of the liposome membrane is necessary to maintain actin in its polymerized state since disruption of the liposome depolymerizes actin. Actin polymerized at the surface of the liposome is organized into two filamentous structures: sheets of parallel filaments in register and a netlike organization. Spectrofluorimetric analysis with the probe N- pyrenyl-iodoacetamide shows that actin is in the F conformation, at least in the environment of the probe. However, actin assembly induced by the liposome is not accompanied by full ATP hydrolysis as observed in vitro upon addition of salts. PMID:3360852

  17. Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan

    PubMed Central

    Kohli, Aditya G.; Kivimäe, Saul; Tiffany, Matthew R.; Szoka, Francis C.

    2014-01-01

    Liposomes improve the pharmacokinetics and safety of rapidly cleared drugs, but have not yet improved the clinical efficacy compared to the non-encapsulated drug. This inability to improve efficacy may be partially due to the non-uniform distribution of liposomes in solid tumors. The tumor extra-cellular matrix is a barrier to distribution and includes the high molecular weight glycosaminoglycan, hyaluronan (HA). Strategies to remove HA or block its synthesis may improve drug delivery into solid tumors. Orally administered methylumbelliferone (MU) is an inhibitor of HA synthesis, but it is limited by low potency and limited solubility. In this study, we encapsulate a water-soluble phosphorylated prodrug of MU (MU-P) in a liposome (L-MU-P). We demonstrate that L-MU-P is a more potent inhibitor of HA synthesis than oral MU in the 4T1 murine mammary carcinoma model using both a quantitative ELISA and histochemistry. We show that HA depletion improves the tumor distribution of liposomes computed using Mander’s colocalization analysis of liposomes with the tumor vasculature. Hyaluronan depletion also increases the fraction of the tumor area positive for liposomes. This improved distribution extends the overall survival of mice treated with Doxil®. PMID:24852095

  18. Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan.

    PubMed

    Kohli, Aditya G; Kivimäe, Saul; Tiffany, Matthew R; Szoka, Francis C

    2014-10-10

    Liposomes improve the pharmacokinetics and safety of rapidly cleared drugs, but have not yet improved the clinical efficacy compared to the non-encapsulated drug. This inability to improve efficacy may be partially due to the non-uniform distribution of liposomes in solid tumors. The tumor extra-cellular matrix is a barrier to distribution and includes the high molecular weight glycosaminoglycan, hyaluronan (HA). Strategies to remove HA or block its synthesis may improve drug delivery into solid tumors. Orally administered methylumbelliferone (MU) is an inhibitor of HA synthesis, but it is limited by low potency and limited solubility. In this study, we encapsulate a water-soluble phosphorylated prodrug of MU (MU-P) in a liposome (L-MU-P). We demonstrate that L-MU-P is a more potent inhibitor of HA synthesis than oral MU in the 4T1 murine mammary carcinoma model using both a quantitative ELISA and histochemistry. We show that HA depletion improves the tumor distribution of liposomes computed using Mander's colocalization analysis of liposomes with the tumor vasculature. Hyaluronan depletion also increases the fraction of the tumor area positive for liposomes. This improved distribution extends the overall survival of mice treated with Doxil®.

  19. Efficacy and Toxicity of Intrathecal Liposomal Cytarabine in First-line Therapy of Childhood Acute Lymphoblastic Leukemia.

    PubMed

    Levinsen, Mette; Harila-Saari, Arja; Grell, Kathrine; Jonsson, Olafur Gisli; Taskinen, Mervi; Abrahamsson, Jonas; Vettenranta, Kim; Åsberg, Ann; Risteli, Juha; Heldrup, Jesper; Schmiegelow, Kjeld

    2016-11-01

    We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy (TIT) with liposomal cytarabine during maintenance therapy among 40 acute lymphoblastic leukemia patients. Twenty-eight of 29 patients in the TIT arm received TIT and 9/11 in the liposomal cytarabine arm received liposomal cytarabine. Arachnoiditis occurred in all initial 5 patients given liposomal cytarabine and intrathecal prednisolone succinate. Subsequently liposomal cytarabine was given with systemic dexamethasone. Neurotoxicity occurred at 6/27 liposomal cytarabine administrations with concomitant dexamethasone (22%). More liposomal cytarabine-treated patients experienced neurotoxicity in relation to intrathecal therapy during at least 1 cycle compared with TIT-treated patients (6/9 [67%] vs. 3/28 [11%], P=0.002). Apart from intermittent lower extremity sensory pain in 1 liposomal cytarabine-treated patient, no permanent adverse neurological sequelae were observed. In intention-to-treat analysis, projected 5-year event-free survival (pEFS-5y) was borderline higher for patients in the liposomal cytarabine arm compared with the TIT arm (1.0 vs. 0.69, P=0.046). However, pEFS-5y and projected 5-year relapse-free survival did not differ signficantly between patients treated with liposomal cytarabine or TIT (1.0 vs. 0.73, P=0.10; 1.0 vs. 0.76, P=0.12). Larger prospective trials are needed to explore whether liposomal cytarabine should be used as first-line prevention of relapse.

  20. ED-110, a novel indolocarbazole, prevents the growth of experimental tumors in mice.

    PubMed

    Arakawa, H; Iguchi, T; Yoshinari, T; Kojiri, K; Suda, H; Okura, A

    1993-05-01

    A new indolocarbazole compound, ED-110, which was obtained by glucosylating a microbial product (BE-13793C) and is a potent topoisomerase I inhibitor, showed characteristic inhibitory effects on the growth of 12 human tumor cell lines tested. The IC50 values of ED-110 against 9 of the 12 lines ranged from 11.5 micrograms/ml to 0.07 microgram/ml, while the remaining 3 lines were quite resistant (IC50, > 100 micrograms/ml). In in vivo experiments, i.p. treatment with ED-110 increased the survival period by more than two-fold in mice implanted i.p. with P388, L1210, L5178Y or EL4 murine leukemic cells. The minimum effective dose increasing the life-span of mice bearing P388 leukemia by 25% was < 2.5 mg/kg/day x 10 and the maximum tolerated dose was > 160 mg/kg/day x 10. ED-110 was also effective against the spontaneous metastasis of mouse Meth A fibrosarcoma cells and the growth of xenografted MKN-45 human stomach cancer cells as well as s.c. implanted mouse colon 26 and IMC carcinoma cells. These results indicated that ED-110 may have potential as a new antineoplastic agent with a large chemotherapeutic index and a wide range of effective doses.

  1. Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma.

    PubMed

    Jung, Sara; Nagy, Zoltan; Fassnacht, Martin; Zambetti, Gerard; Weiss, Max; Reincke, Martin; Igaz, Peter; Beuschlein, Felix; Hantel, Constanze

    2016-10-01

    Systemic therapy of adrenocortical carcinoma (ACC) is limited by heterogeneous tumor response and adverse effects. Recently, we demonstrated anti-tumor activity of LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane), a liposomal variant of EDP-M (etoposide, doxorubicin, cisplatin, mitotane). To improve the therapeutic efficacy and off-target profiles of the clinical gold standard EDP-M, we investigated liposomal EDP-M regimens in different preclinical settings and in a small number of ACC patients with very advanced disease. Short- and long-term experiments were performed on two ACC models (SW-13 and SJ-ACC3) in vivo We evaluated the anti-tumoral effects and off-target profiles of EDP-M, LEDP-M and a novel regimen L(l)EDP-M including liposomal etoposide. Furthermore, the role of plasma microRNA-210 as a therapeutic biomarker and first clinical data were assessed. Classical and liposomal protocols revealed anti-proliferative efficacy against SW-13 (EDP-M P < 0.01; LEDP-M: P < 0.001; L(l)EDP-M: P < 0.001 vs controls), whereas in SJ-ACC3, only EDP-M (P < 0.05 vs controls) was slightly effective. Long-term experiments in SW-13 demonstrated anti-tumor efficacy for all treatment schemes (EDP-M: P < 0.01, LEDP-M: P < 0.05, L(l)EDP-M P < 0.001 vs controls). The analysis of pre-defined criteria leading to study termination revealed significant differences for control (P < 0.0001) and EDP-M (P = 0.003) compared to L(l)EDP-M treatment. Raising its potential for therapy monitoring, we detected elevated levels of circulating microRNA-210 in SW-13 after LEDP-M treatment (P < 0.05). In contrast, no comparable effects were detectable for SJ-ACC3. However, overall histological evaluation demonstrated improved off-target profiles following liposomal regimens. The first clinical data indicate improved tolerability of liposomal EDP-M, thus confirming our results. In summary, liposomal EDP-M regimens represent promising

  2. Effects of the protein corona on liposome–liposome and liposome–cell interactions

    PubMed Central

    Corbo, Claudia; Molinaro, Roberto; Taraballi, Francesca; Toledano Furman, Naama E; Sherman, Michael B; Parodi, Alessandro; Salvatore, Francesco; Tasciotti, Ennio

    2016-01-01

    A thorough understanding of interactions occurring at the interface between nanocarriers and biological systems is crucial to predict and interpret their biodistribution, targeting, and efficacy, and thus design more effective drug delivery systems. Upon intravenous injection, nanoparticles are coated by a protein corona (PC). This confers a new biological identity on the particles that largely determines their biological fate. Liposomes have great pharmaceutical versatility, so, as proof of concept, their PC has recently been implicated in the mechanism and efficiency of their internalization into the cell. In an attempt to better understand the interactions between nanocarriers and biological systems, we analyzed the plasma proteins adsorbed on the surface of multicomponent liposomes. Specifically, we analyzed the physical properties and ultrastructure of liposome/PC complexes and the aggregation process that occurs when liposomes are dispersed in plasma. The results of combined confocal microscopy and flow cytometry experiments demonstrated that the PC favors liposome internalization by both macrophages and tumor cells. This work provides insights into the effects of the PC on liposomes’ physical properties and, consequently, liposome–liposome and liposome–cell interactions. PMID:27445473

  3. Liposomal bupivacaine and clinical outcomes.

    PubMed

    Tong, Yi Cai Isaac; Kaye, Alan David; Urman, Richard D

    2014-03-01

    In the multimodal approach to the management of postoperative pain, local infiltration and regional blocks have been increasingly utilized for pain control. One of the limitations of local anesthetics in the postoperative setting is its relatively short duration of action. Multivesicular liposomes containing bupivacaine have been increasingly utilized for their increased duration of action. Compared with bupivacaine HCl, local infiltration of liposomal bupivacaine has shown to have an increase in duration of action and causes delay in peak plasma concentration. In this article, we attempt to review the clinical literature surrounding liposomal bupivacaine and its evolving role in perioperative analgesia. This new bupivacaine formation may have promising implications in postoperative pain control, resulting in increased patient satisfaction and a decrease in both hospital stay and opioid-induced adverse events (AEs). Although more studies are needed, the preliminary clinical trials suggest that liposomal bupivacaine has predictable pharmacokinetics, a similar side effect profile compared with bupivacaine HCl, and is effective in providing increased postoperative pain control.

  4. Blockade of the tumor necrosis factor-related apoptosis inducing ligand death receptor DR5 prevents beta-amyloid neurotoxicity.

    PubMed

    Uberti, Daniela; Ferrari-Toninelli, Giulia; Bonini, Sara Anna; Sarnico, Ilenia; Benarese, Marina; Pizzi, Marina; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Spano, PierFranco; Facchetti, Fabio; Memo, Maurizio

    2007-04-01

    We originally suggested that inhibition of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) death pathway could be taken into consideration as a potential therapeutic strategy for Alzheimer's disease (AD). However, because the critical role of TRAIL in immune surveillance, the neutralization of TRAIL protein by an antibody to prevent its binding to death receptors is definitely a risky approach. Here, we demonstrated that the blockade of the TRAIL death receptor DR5 with a specific antibody completely prevented amyloid beta peptide (A beta) neurotoxicity in both neuronal cell line and primary cortical neurons. DR5 was demonstrated to be a key factor in TRAIL death pathway. In fact, whereas TRAIL expression was enhanced dose-dependently by concentrations of beta amyloid ranging from 10 nM to 1 microM, only the highest toxic dose of A beta (25 microM) induced the increased expression of DR5 and neuronal cell death. In addition, the increased expression of DR5 receptor after beta amyloid treatment was sustained by p53 transcriptional activity, as demonstrated by the data showing that the p53 inhibitor Pifithrin alpha prevented both beta amyloid-induced DR5 induction and cell death. These data suggest a sequential activation of p53 and DR5 upon beta amyloid exposure. Further insight into the key role of DR5 in AD was suggested by data showing a significant increase of DR5 receptor in cortical slices of AD brain. Thus, these findings may give intracellular TRAIL pathway a role in AD pathophysiology, making DR5 receptor a possible candidate as a pharmacological target.

  5. Reversal of the multidrug resistance by drug combination using multifunctional liposomes

    NASA Astrophysics Data System (ADS)

    Patel, Niravkumar R.

    One of the major obstacles to the success of cancer chemotherapy is the multi-drug resistance (MDR) that results due mainly to the over-expression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results against MDR. However, P-gp is also expressed in normal tissues like the blood-brain barrier, gastrointestinal tract, liver and kidney. It is therefore important to limit the exposure of P-gp inhibitors to normal tissues and increase their co-localization with anticancer agents in tumor tissues to maximize the efficacy of a P-gp inhibitor. To minimize non-specific binding and increase its delivery to tumor tissues, liposomes, self-assembling phospholipid vesicles, were chosen as a drug delivery vehicle. The liposome has been identified as a system capable of carrying molecules with diverse physicochemical properties. It can also alter the pharmacokinetic profile of loaded molecules which is a concern with both tariquidar and paclitaxel. Liposomes can easily be surface-modified rendering them cell-specific as well as organelle-specific. The main objective of present study was to develop an efficient liposomal delivery system which would deliver therapeutic molecules of interest to tumor tissues and avoid interaction with normal tissues. In this study, the co-delivery of tariquidar and paclitaxel into tumor cells to reverse the MDR using long-circulating cationic liposomes was investigated. SKOV-3TR, the resistant variant of SKOV-3 and MCF-7/ADR, the resistant variant of MCF-7 were used as model cell lines. Uniform liposomal formulations were generated with high incorporation efficiency and no apparent decrease in tariquidar potency towards P-gp. Tariquidar- and paclitaxel- co-loaded long-circulating liposomes showed significant re-sensitization of SKOV-3TR and MCF-7/ADR for paclitaxel in vitro. Further modification of these liposomes with antitumor 2C5 resulted

  6. Positron Emission Tomography Based Elucidation of the Enhanced Permeability and Retention Effect in Dogs with Cancer Using Copper-64 Liposomes.

    PubMed

    Hansen, Anders E; Petersen, Anncatrine L; Henriksen, Jonas R; Boerresen, Betina; Rasmussen, Palle; Elema, Dennis R; af Rosenschöld, Per Munck; Kristensen, Annemarie T; Kjær, Andreas; Andresen, Thomas L

    2015-07-28

    Since the first report of the enhanced permeability and retention (EPR) effect, the research in nanocarrier based antitumor drugs has been intense. The field has been devoted to treatment of cancer by exploiting EPR-based accumulation of nanocarriers in solid tumors, which for many years was considered to be a ubiquitous phenomenon. However, the understanding of differences in the EPR-effect between tumor types, heterogeneities within each patient group, and dependency on tumor development stage in humans is sparse. It is therefore important to enhance our understanding of the EPR-effect in large animals and humans with spontaneously developed cancer. In the present paper, we describe a novel loading method of copper-64 into PEGylated liposomes and use these liposomes to evaluate the EPR-effect in 11 canine cancer patients with spontaneous solid tumors by PET/CT imaging. We thereby provide the first high-resolution analysis of EPR-based tumor accumulation in large animals. We find that the EPR-effect is strong in some tumor types but cannot be considered a general feature of solid malignant tumors since we observed a high degree of accumulation heterogeneity between tumors. Six of seven included carcinomas displayed high uptake levels of liposomes, whereas one of four sarcomas displayed signs of liposome retention. We conclude that nanocarrier-radiotracers could be important in identifying cancer patients that will benefit from nanocarrier-based therapeutics in clinical practice.

  7. A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging.

    PubMed

    Bornmann, C; Graeser, R; Esser, N; Ziroli, V; Jantscheff, P; Keck, T; Unger, C; Hopt, U T; Adam, U; Schaechtele, C; Massing, U; von Dobschuetz, E

    2008-03-01

    Despite its rapid enzymatic inactivation and therefore limited activity in vivo, Gemcitabine is the standard drug for pancreatic cancer treatment. To protect the drug, and achieve passive tumor targeting, we developed a liposomal formulation of Gemcitabine, GemLip (Ø: 36 nm: 47% entrapment). Its anti-tumoral activity was tested on MIA PaCa-2 cells growing orthotopically in nude mice. Bioluminescence measurement mediated by the stable integration of the luciferase gene was employed to randomize the mice, and monitor tumor growth. GemLip (4 and 8 mg/kg), Gemcitabine (240 mg/kg), and empty liposomes (equivalent to 8 mg/kg GemLip) were injected intravenously once weekly for 5 weeks. GemLip (8 mg/kg) stopped tumor growth, as measured via in vivo bioluminescence, reducing the primary tumor size by 68% (SD +/- 8%; p < 0.02), whereas Gemcitabine hardly affected tumor size (-7%; +/- 1.5%). In 80% of animals, luciferase activity in the liver indicated the presence of metastases. All treatments, including the empty liposomes, reduced the metastatic burden. Thus, GemLip shows promising antitumoral activity in this model. Surprisingly, empty liposomes attenuate the spread of metastases similar to Gemcitabine and GemLip. Further, luciferase marked tumor cells are a powerful tool to observe tumor growth in vivo, and to detect and quantify metastases.

  8. Anti-inflammatory activity of liposomes of Asparagus racemosus root extracts prepared by various methods

    PubMed Central

    Plangsombat, Nathsiree; Rungsardthong, Kanin; Kongkaneramit, Lalana; Waranuch, Neti; Sarisuta, Narong

    2016-01-01

    Asparagus racemosus root extracts (AR) have been reported to possess a variety of pharmacological properties. The aim of the present study was to develop liposomes of AR and to assess their physicochemical characteristics and anti-inflammatory activity in the monocytic leukemia cell line THP-1. Liposomes containing various ratios of AR to lipid and a phosphatidylcholine to cholesterol molar ratio of 7:3 were prepared by thin-film hydration (TF), reverse-phase evaporation (REV) and polyol dilution (PD). The results showed that AR liposomes prepared by TF had a multilamellar structure and a large size, whereas those prepared by REV and PD were oligolamellar in structure, and of a smaller size. The particle sizes and zeta potentials of the liposomes ranged from 196.5 to 456.6 nm and from −4.34 to −18.94 mV, respectively. The AR to lipid ratio was shown to have no significant influence on particle size, while the zeta potential generally increased with increasing AR to lipid ratio. The highest entrapment efficiency values were detected in liposomes with an AR to lipid ratio of 1:5, and for liposomes prepared by TF, REV and PD methods, the entrapment efficiencies were 55.71±2.04, 56.21±3.59 and 67.68±1.37%, respectively. AR was found to exert no toxicity on THP-1 cells. The maximum anti-inflammatory activities of AR and AR liposomes, evaluated in terms of the percentage inhibition of tumor necrosis factor-α in THP-1 cells, were ~52% at a concentration of 1 µg/ml. It can be concluded from the present study that AR liposomes have the potential to be used a formulation for topical and/or transdermal drug delivery to provide anti-inflammatory activity. PMID:27698785

  9. 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

  10. Prevention

    MedlinePlus

    ... Ban For Clinicians Clinical Recognition Specimen Collection Treatment Smallpox Vaccine Guidance Infection Control: Hospital Infection Control: Home ... Mouth Infection) Poxvirus and Rabies Branch Travelers’ Health: Smallpox & Other Orthopoxvirus-Associated Infections Poxvirus Prevention Recommend on ...

  11. CXCR4-antagonist Peptide R-liposomes for combined therapy against lung metastasis.

    PubMed

    Ieranò, Caterina; Portella, Luigi; Lusa, Sara; Salzano, Giuseppina; D'Alterio, Crescenzo; Napolitano, Maria; Buoncervello, Maria; Macchia, Daniele; Spada, Massimo; Barbieri, Antonio; Luciano, Antonio; Barone, Maria Vittoria; Gabriele, Lucia; Caraglia, Michele; Arra, Claudio; De Rosa, Giuseppe; Scala, Stefania

    2016-04-14

    The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination. While there has been great enthusiasm for exploiting the CXCR4-CXCL12 axis as a target in cancer therapy, to date the promise has yet to be fulfilled. A new class of CXCR4-antagonist cyclic peptides was recently developed and the compound named Peptide R was identified as the most active. With the intent to improve the efficacy and biodistribution of Peptide R, stealth liposomes decorated with Peptide R were developed (PL-Peptide R). In vitro PL-Peptide R efficiently inhibited CXCR4-dependent migration and in vivo it significantly reduced lung metastases and increased overall survival in B16-CXCR4 injected C57BL/6 mice. To evaluate if PL-Peptide R could also be a drug delivery system for CXCR4 expressing tumors, the PL-Peptide R was loaded with doxorubicin (DOX) (PL-Peptide R-DOX). PL-Peptide R-DOX efficiently delivered DOX to CXCR4 expressing cell lines with a consequent decrease in the DOX IC50 efficient dose. In vivo, B16-CXCR4 injected C57BL/6 mice treated with PL-Peptide R-DOX developed fewer lung metastases compared to PL-DOX treated mice. This work provides the proof-of-concept to prevent metastasis by using combined nanomedicine.

  12. Peptide-Mediated Liposomal Doxorubicin Enhances Drug Delivery Efficiency and Therapeutic Efficacy in Animal Models

    PubMed Central

    Chang, De-Kuan; Li, Pi-Chun; Lu, Ruei-Min; Jane, Wann-Neng; Wu, Han-Chung

    2013-01-01

    Lung cancer ranks among the most common malignancies, and is the leading cause of cancer-related mortality worldwide. Chemotherapy for lung cancer can be made more specific to tumor cells, and less toxic to normal tissues, through the use of ligand-mediated drug delivery systems. In this study, we investigated the targeting mechanism of the ligand-mediated drug delivery system using a peptide, SP5-2, which specifically binds to non-small cell lung cancer (NSCLC) cells. Conjugation of SP5-2 to liposomes enhanced the amount of drug delivered directly into NSCLC cells, through receptor-mediated endocytosis. Functional SP5-2 improved the therapeutic index of Lipo-Dox by enhancing therapeutic efficacy, reducing side effects, and increasing the survival rate of tumor-bearing mice in syngenic, metastatic and orthotopic animal models. Accumulation of SP5-2-conjugated liposomal doxorubicin (SP5-2-LD) in tumor tissues was 11.2-fold higher than that of free doxorubicin, and the area under the concentration-time curve (AUC0–72 hours) was increased 159.2-fold. Furthermore, the experiment of bioavailability was assessed to confirm that SP5-2 elevates the uptake of the liposomal drugs by the tumor cells in vivo. In conclusion, the use of SP5-2-conjugated liposomes enhances pharmacokinetic properties, improves efficacy and safety profiles, and allows for controlled biodistribution and drug release. PMID:24386166

  13. Chemotherapy of glioblastoma by targeted liposomal platinum compounds with focused ultrasound.

    PubMed

    Yang, Feng-Yi; Horng, Shih-Cheng

    2013-01-01

    Giloblastoma multiforme (GBM) is the most aggressive brain neoplasm, and patients have a poor prognosis after radiation and chemotherapy. The chemotherapy protocols still marginally improve the anti-tumor effect of patients with glioblastoma because the therapeutic dosage of many drugs is impeded by the blood-brain barrier (BBB). The use of liposomal drugs to GBM treatment might benefit from a more crossing of the BBB due to the lipid nature achieving higher doses of drug at the tumor sites. Human GBM-bearing mice were injected intravenously with cisplatin encapsulated in atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes or unconjugated liposome. Moreover, the administration of AP-1 liposomal cisplatin (lipoplatin) followed by focused ultrasound (FUS)-induced BBB disruption. Tumor progression was monitored by biophotonic imaging. The preliminary data demonstrated that the GBM chemotherapy with AP-1 lipoplatin followed by pulsed FUS showed a modest improvement of tumor growth in the brain compared to the group treated with lipoplatin alone. Further investigations are needed to use this new targeted lipoplatin in treatment of malignancies.

  14. Multiple organ damage caused by tumor necrosis factor and prevented by prior neutrophil depletion.

    PubMed

    Mallick, A A; Ishizaka, A; Stephens, K E; Hatherill, J R; Tazelaar, H D; Raffin, T A

    1989-05-01

    The effect of TNF on nonpulmonary multiple organ damage (MOD) was studied. Since polymorphonuclear leukocytes (PMN) are thought to play an important role in septic or TNF-induced MOD, we investigated both neutrophil sufficient (PMN+) and neutropenic (PMN-) guinea pigs. Sepsis was induced by Escherichia coli administration (2 x 10(9)/kg) or recombinant human TNF (1.4 x 10(6) U/kg) was infused into PMN+ and PMN- guinea pigs. During necropsy, the PMN+/TNF and PMN+/E coli animals exhibited marked damage in the adrenal glands, kidneys and liver as evidenced by hemorrhage, congestion, and PMN sequestration on histopathologic examination. There was also increased tissue albumin accumulation in the adrenal glands, kidneys, spleen, heart, and liver as demonstrated by 125I-labeled albumin determinations. In contrast, the PMN-/TNF group did not reveal histopathologic damage in any organ system and there was no abnormal organ accumulation of 125I-albumin. However, in PMN-/E coli animals, marked histopathologic damage in the adrenal glands and liver was evident. Furthermore, there were marked accumulations of 125I-albumin in the adrenals, heart, kidneys, liver, and spleen. Moreover, the PMN-/E coli guinea pigs had a much greater accumulation (p less than 0.01) of 125I-albumin in the kidneys than any other group including the PMN+/E coli group. Thus, nonpulmonary MOD in guinea pigs is caused by TNF administration and can be prevented by PMN depletion. However, while E coli administration also caused marked nonpulmonary MOD in neutrophil sufficient guinea pigs, equivalent or greater damage was produced in neutropenic animals. This suggests that while TNF-induced MOD may be primarily mediated by PMN, E coli-induced MOD seems to be mediated by more than PMN.

  15. Multiple organ damage caused by tumor necrosis factor and prevented by prior neutrophil depletion

    SciTech Connect

    Mallick, A.A.; Ishizaka, A.; Stephens, K.E.; Hatherill, J.R.; Tazelaar, H.D.; Raffin, T.A. )

    1989-05-01

    The effect of TNF on nonpulmonary multiple organ damage (MOD) was studied. Since polymorphonuclear leukocytes (PMN) are thought to play an important role in septic or TNF-induced MOD, we investigated both neutrophil sufficient (PMN+) and neutropenic (PMN-) guinea pigs. Sepsis was induced by Escherichia coli administration (2 x 10(9)/kg) or recombinant human TNF (1.4 x 10(6) U/kg) was infused into PMN+ and PMN- guinea pigs. During necropsy, the PMN+/TNF and PMN+/E coli animals exhibited marked damage in the adrenal glands, kidneys and liver as evidenced by hemorrhage, congestion, and PMN sequestration on histopathologic examination. There was also increased tissue albumin accumulation in the adrenal glands, kidneys, spleen, heart, and liver as demonstrated by {sup 125}I-labeled albumin determinations. In contrast, the PMN-/TNF group did not reveal histopathologic damage in any organ system and there was no abnormal organ accumulation of {sup 125}I-albumin. However, in PMN-/E coli animals, marked histopathologic damage in the adrenal glands and liver was evident. Furthermore, there were marked accumulations of {sup 125}I-albumin in the adrenals, heart, kidneys, liver, and spleen. Moreover, the PMN-/E coli guinea pigs had a much greater accumulation (p less than 0.01) of {sup 125}I-albumin in the kidneys than any other group including the PMN+/E coli group. Thus, nonpulmonary MOD in guinea pigs is caused by TNF administration and can be prevented by PMN depletion. However, while E coli administration also caused marked nonpulmonary MOD in neutrophil sufficient guinea pigs, equivalent or greater damage was produced in neutropenic animals. This suggests that while TNF-induced MOD may be primarily mediated by PMN, E coli-induced MOD seems to be mediated by more than PMN.

  16. Can Wilms Tumor Be Found Early?

    MedlinePlus

    ... Wilms Tumor Early Detection, Diagnosis, and Staging Can Wilms Tumor Be Found Early? Wilms tumors are usually found ... Your Child’s Doctor About Wilms Tumor? More In Wilms Tumor About Wilms Tumor Causes, Risk Factors, and Prevention ...

  17. What Happens After Treatment for Wilms Tumor?

    MedlinePlus

    ... Tumor After Treatment What Happens After Treatment for Wilms Tumor? During and after treatment for Wilms tumors, the ... Wilms Tumor Survivors and Their Families More In Wilms Tumor About Wilms Tumor Causes, Risk Factors, and Prevention ...

  18. Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy.

    PubMed

    Kipps, Emma; Young, Kate; Starling, Naureen

    2017-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan.

  19. Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy

    PubMed Central

    Kipps, Emma; Young, Kate; Starling, Naureen

    2017-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan. PMID:28344661

  20. Liposomes containing recombinant E protein vaccine against duck Tembusu virus in ducks.

    PubMed

    Ma, Tengfei; Liu, Yongxia; Cheng, Jia; Liu, Yanhan; Fan, Wentao; Cheng, Ziqiang; Niu, Xudong; Liu, Jianzhu

    2016-04-27

    To obtain an effective vaccine candidate against duck Tembusu viral (DTMUV) disease which causes egg-drop and great economical loss in the Chinese duck industry, liposome vaccines containing recombinant E protein were prepared and assessed in this study. The recombinant plasmid (PET28a-E) was constructed and transformed into BL21 (DE3) cells to produce E proteins. The recombinant E proteins were purified and entrapped by liposomes through reverse-phase evaporation. Eighty-four cherry valley ducks were randomly divided into seven groups and inoculated intramuscularly at one- or seven-day-old with liposomes-E protein or Freund's adjuvant-E protein vaccine. Blood samples were collected from the first week to the tenth week for serum antibody, plasma for viremia, as well as oropharyngeal and cloacal swabs for virus shedding analyses after being challenged with a 10(2.4) 50% tissue culture infective dose (TCID50) of duck Tembusu virus. Results showed that serum antibody level of the liposomes vaccine was higher than the Freund's adjuvant vaccine, and inoculating twice was superior to once; furthermore, the viremia and virus shedding tests also proved that the liposomes vaccine can provide complete protection against DTMUV challenge. These results demonstrated that the liposomes-E protein vaccine could be used as a potential candidate vaccine to prevent DTMUV infection in ducks.

  1. siRNA liposome-gold nanorod vectors for multispectral optoacoustic tomography theranostics

    NASA Astrophysics Data System (ADS)

    Taruttis, Adrian; Lozano, Neus; Nunes, Antonio; Jasim, Dhifaf A.; Beziere, Nicolas; Herzog, Eva; Kostarelos, Kostas; Ntziachristos, Vasilis

    2014-10-01

    Therapeutic applications of gene silencing using siRNA have seen increasing interest over the past decade. The optimization of the delivery and biodistribution of siRNA using liposome-gold nanorod (AuNRs) nanoscale carriers can greatly benefit from adept imaging methods that can visualize the time-resolved delivery performance of such vectors. In this work, we describe the effect of AuNR length incorporated with liposomes and show their complexation with siRNA as a novel gene delivery vehicle. We demonstrate the application of multispectral optoacoustic tomography (MSOT) to longitudinally visualize the localisation of siRNA carrying liposome-AuNR hybrids within tumors. Combination of in vivo MSOT with ex vivo fluorescence cryo-slice imaging offers further insight into the siRNA transport and activity obtained.Therapeutic applications of gene silencing using siRNA have seen increasing interest over the past decade. The optimization of the delivery and biodistribution of siRNA using liposome-gold nanorod (AuNRs) nanoscale carriers can greatly benefit from adept imaging methods that can visualize the time-resolved delivery performance of such vectors. In this work, we describe the effect of AuNR length incorporated with liposomes and show their complexation with siRNA as a novel gene delivery vehicle. We demonstrate the application of multispectral optoacoustic tomography (MSOT) to longitudinally visualize the localisation of siRNA carrying liposome-AuNR hybrids within tumors. Combination of in vivo MSOT with ex vivo fluorescence cryo-slice imaging offers further insight into the siRNA transport and activity obtained. Electronic supplementary information (ESI) available: Experimental section and dark-field microscopy in both tumors 24 h after injection of the complex have been included. See DOI: 10.1039/c4nr04164j

  2. Supplementation with L-glutamine prevents tumor growth and cancer-induced cachexia as well as restores cell proliferation of intestinal mucosa of Walker-256 tumor-bearing rats.

    PubMed

    Martins, Heber Amilcar; Sehaber, Camila Caviquioli; Hermes-Uliana, Catchia; Mariani, Fernando Augusto; Guarnier, Flavia Alessandra; Vicentini, Geraldo Emílio; Bossolani, Gleison Daion Piovezana; Jussani, Laraine Almeida; Lima, Mariana Machado; Bazotte, Roberto Barbosa; Zanoni, Jacqueline Nelisis

    2016-12-01

    This study aimed to evaluate the intestinal mucosa of the duodenum and jejunum of Walker-256 tumor-bearing rats supplemented with L-glutamine. Thirty-two male 50-day-old Wistar rats (Rattus norvegicus) were randomly divided into four groups: control (C), control supplemented with 2 % L-glutamine (GC), Walker-256 tumor (WT), and Walker-256 tumor supplemented with 2 % L-glutamine (TWG). Walker-256 tumor was induced by inoculation viable tumor cells in the right rear flank. After 10 days, celiotomy was performed and duodenal and jejunal tissues were removed and processed. We evaluated the cachexia index, proliferation index, villus height, crypt depth, total height of the intestinal wall, and number of goblet cells by the technique of periodic acid-Schiff (PAS). Induction of Walker-256 tumor promoted a reduction of metaphase index in the TW group animals, which was accompanied by a reduction in the villous height and crypt depths, resulting in atrophy of the intestinal wall as well as increased PAS-positive goblet cells. Supplementation with L-glutamine reduced the tumor growth and inhibited the development of the cachectic syndrome in animals of the TWG group. Furthermore, amino acid supplementation promoted beneficial effects on the intestinal mucosa in the TWG animals through restoration of the number of PAS-positive goblet cells. Therefore, supplementation with 2 % L-glutamine exhibited a promising role in the prevention of tumor growth and cancer-associated cachexia as well as restoring the intestinal mucosa in the duodenum and jejunum of Walker-256 tumor-bearing rats.

  3. Entrapment of ovalbumin into liposomes--factors affecting entrapment efficiency, liposome size, and zeta potential.

    PubMed

    Brgles, Marija; Jurasin, Darija; Sikirić, Maja Dutour; Frkanec, Ruza; Tomasić, Jelka

    2008-01-01

    Various amounts of Ovalbumin (OVA) were encapsulated into positively and negatively charged multilamellar liposomes, with the aim to investigate the entrapment efficiency in different buffers and to study their effects on the liposome size and zeta potential. Results showed that the entrapment efficiency of OVA in anionic liposomes was the same in 10 mM Phosphate Buffer (PB) as in Phosphate-Buffered Saline (PBS; PB + 0.15 M NaCl). Also, liposome size was approximately 1200 nm for all anionic liposomes incorporating OVA. The entrapment efficiency of OVA in cationic liposomes was highly dependent on ionic strength. The size of cationic liposomes was approximately 1200 nm in PBS, regardless of protein content, but increased with the amount of the incorporated protein in PB. Aggregation of cationic liposomes in PB was observed when the mass of the protein was 2.5 mg or greater. The zeta potential of anionic liposomes was negative and of cationic liposomes positive in the whole range of protein mass tested. These results show how different compositions of lipid and aqueous phases can be used to vary the entrapment efficiency, liposome size, and zeta potential--the factors that are of great importance for the use of liposomes as drug carriers.

  4. Analysis of interaction between liposome membranes induced by stress condition: utilization of liposomes immobilized on indium tin oxide electrode.

    PubMed

    Ishii, Haruyuki; Shimanouchi, Toshinori; Umakoshi, Hiroshi; Kuboi, Ryoichi

    2009-11-01

    NBD-cholesterol (NBD-Ch)-modified liposome was immobilized on indium tin oxide (ITO) electrode via the covalent binding method. The transfer of NBD-Ch between the immobilized liposomes and the target liposomes was observed by using a fluorescent microscope. The addition of liposome suspension co-incubated with alpha-chymotrypsin or stimuli-responsive polymer to the surface of the above ITO electrode, enhanced the liposome-liposome interaction, resulting in the promotion of NBD-Ch transfer. The apparent transfer rate constant of NBD-Ch was found to be correlated with the index for the liposome-liposome interaction evaluated by an immobilized liposome chromatography. This suggests that the present method using the liposome-immobilized ITO electrode was effective to evaluate the liposome-liposome interaction induced by the protein or the stimuli-responsive polymer under stress conditions.

  5. Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis

    PubMed Central

    Gril, Brunilde; Palmieri, Diane; Qian, Yong; Smart, DeeDee; Ileva, Lilia; Liewehr, David J.; Steinberg, Seth M.; Steeg, Patricia S.

    2010-01-01

    Purpose Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested pazopanib, a recently approved anti-angiogenic drug that targets VEGFR1-3, PDGFRβ, PDGFRα and c-kit, for prevention of experimental brain metastases and mechanism of action. Experimental Design In vitro assays included B-Raf enzymatic assays, western blots and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or pazopanib beginning on day 3 post-injection. Brain metastases were counted histologically, imaged and immunostained. Results Treatment with 100 mg/kg pazopanib resulted in a 73% decline in large 231-BR-HER2 metastases (p<0.0001) and 39% decline in micrometastases (p=0.004). In vitro, pazopanib was directly anti-proliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that pazopanib directly inhibited the wild type and exon 11 oncogenic mutant, but not the V600E mutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in pazopanib treated brain metastases while blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental brain metastasis model, pazopanib reduced overall brain metastasis volume upon MRI imaging by 55% (p=0.067), without affecting brain metastasis vascular density. Conclusions The data identify a new activity for pazopanib directly on tumor cells as a pan-Raf inhibitor, and suggest its potential for prevention of brain metastatic colonization of HER2+ breast cancer. PMID:21081656

  6. Evaluation of Extrusion Technique for Nanosizing Liposomes.

    PubMed

    Ong, Sandy Gim Ming; Chitneni, Mallikarjun; Lee, Kah Seng; Ming, Long Chiau; Yuen, Kah Hay

    2016-12-21

    The aim of the present study was to study the efficiency of different techniques used for nanosizing liposomes. Further, the aim was also to evaluate the effect of process parameters of extrusion techniques used for nanosizing liposomes on the size and size distribution of the resultant liposomes. To compare the efficiency of different nanosizing techniques, the following techniques were used to nanosize the liposomes: extrusion, ultrasonication, freeze-thaw sonication (FTS), sonication and homogenization. The extrusion technique was found to be the most efficient, followed by FTS, ultrasonication, sonication and homogenization. The extruder used in the present study was fabricated using readily available and relatively inexpensive apparatus. Process parameters were varied in extrusion technique to study their effect on the size and size distribution of extruded liposomes. The results obtained indicated that increase in the flow rate of the extrusion process decreased the size of extruded liposomes however the size homogeneity was negatively impacted. Furthermore, the liposome size and distribution was found to decline with decreasing membrane pore size. It was found that by extruding through a filter with a pore size of 0.2 µm and above, the liposomes produced were smaller than the pore size, whereas, when they were extruded through a filter with a pore size of less than 0.2 µm the resultant liposomes were slightly bigger than the nominal pore size. Besides that, increment of extrusion temperature above transition temperature of the pro-liposome had no effect on the size and size distribution of the extruded liposomes. In conclusion, the extrusion technique was reproducible and effective among all the methods evaluated. Furthermore, processing parameters used in extrusion technique would affect the size and size distribution of liposomes. Therefore, the process parameters need to be optimized to obtain a desirable size range and homogeneity, reproducible for

  7. Evaluation of Extrusion Technique for Nanosizing Liposomes

    PubMed Central

    Ong, Sandy Gim Ming; Chitneni, Mallikarjun; Lee, Kah Seng; Ming, Long Chiau; Yuen, Kah Hay

    2016-01-01

    The aim of the present study was to study the efficiency of different techniques used for nanosizing liposomes. Further, the aim was also to evaluate the effect of process parameters of extrusion techniques used for nanosizing liposomes on the size and size distribution of the resultant liposomes. To compare the efficiency of different nanosizing techniques, the following techniques were used to nanosize the liposomes: extrusion, ultrasonication, freeze-thaw sonication (FTS), sonication and homogenization. The extrusion technique was found to be the most efficient, followed by FTS, ultrasonication, sonication and homogenization. The extruder used in the present study was fabricated using readily available and relatively inexpensive apparatus. Process parameters were varied in extrusion technique to study their effect on the size and size distribution of extruded liposomes. The results obtained indicated that increase in the flow rate of the extrusion process decreased the size of extruded liposomes however the size homogeneity was negatively impacted. Furthermore, the liposome size and distribution was found to decline with decreasing membrane pore size. It was found that by extruding through a filter with a pore size of 0.2 µm and above, the liposomes produced were smaller than the pore size, whereas, when they were extruded through a filter with a pore size of less than 0.2 µm the resultant liposomes were slightly bigger than the nominal pore size. Besides that, increment of extrusion temperature above transition temperature of the pro-liposome had no effect on the size and size distribution of the extruded liposomes. In conclusion, the extrusion technique was reproducible and effective among all the methods evaluated. Furthermore, processing parameters used in extrusion technique would affect the size and size distribution of liposomes. Therefore, the process parameters need to be optimized to obtain a desirable size range and homogeneity, reproducible for

  8. Use of Autoantigen-Loaded Phosphatidylserine-Liposomes to Arrest Autoimmunity in Type 1 Diabetes

    PubMed Central

    Pujol-Autonell, Irma; Serracant-Prat, Arnau; Cano-Sarabia, Mary; Ampudia, Rosa M.; Rodriguez-Fernandez, Silvia; Sanchez, Alex; Izquierdo, Cristina; Stratmann, Thomas; Puig-Domingo, Manuel; Maspoch, Daniel; Verdaguer, Joan; Vives-Pi, Marta

    2015-01-01

    Introduction The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes. Objective To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes. Methods A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides. Results We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion. Conclusions We conclude that this innovative immunotherapy based on the use of liposomes

  9. Sialylneolacto-N-tetraose c (LSTc)-bearing liposomal decoys capture influenza A virus.

    PubMed

    Hendricks, Gabriel L; Weirich, Kim L; Viswanathan, Karthik; Li, Jing; Shriver, Zachary H; Ashour, Joseph; Ploegh, Hidde L; Kurt-Jones, Evelyn A; Fygenson, Deborah K; Finberg, Robert W; Comolli, James C; Wang, Jennifer P

    2013-03-22

    Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand binding interactions for a high avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co-localize with fluorescently tagged influenza virus, whereas control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains.

  10. Sialylneolacto-N-tetraose c (LSTc)-bearing Liposomal Decoys Capture Influenza A Virus*

    PubMed Central

    Hendricks, Gabriel L.; Weirich, Kim L.; Viswanathan, Karthik; Li, Jing; Shriver, Zachary H.; Ashour, Joseph; Ploegh, Hidde L.; Kurt-Jones, Evelyn A.; Fygenson, Deborah K.; Finberg, Robert W.; Comolli, James C.; Wang, Jennifer P.

    2013-01-01

    Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand binding interactions for a high avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co-localize with fluorescently tagged influenza virus, whereas control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains. PMID:23362274

  11. Photothermally activated drug release from liposomes coupled to hollow gold nanoshells

    NASA Astrophysics Data System (ADS)

    Forbes, Natalie; Zasadzinski, Joseph A.

    2011-03-01

    Liposomes show great promise as intravenous drug delivery vehicles, but it is difficult to combine stability in the circulation, extended drug retention and rapid, targeted release at the site of interest. Accessorizing conventional and multicompartment liposomes with photo-activated hollow gold nanoshells (HGN) provides a convenient method to initiate drug release with spatial and temporal control. HGN efficiently absorb near infrared (NIR) light and rapidly convert the absorbed optical energy into heat. Femto- to nano-second NIR light pulses cause the HGNs to rapidly heat, creating large temperature gradients between the HGNs and surrounding fluid. The formation and collapse of unstable vapor bubbles transiently rupture liposome and other bilayer membranes to trigger contents release. Near-complete contents release occurs when the nanoshells are encapsulated within the liposome or tethered to the outer surface of the liposome, with no chemical damage to the contents. Release is achieved by focusing the laser beam at the target, eliminating the need for highly specific targeting ligands or antibodies. Although HGN heating can be intense, the overall energy input is small causing minimal heating of the surroundings. To ensure that drugs are retained within the liposomes until delivery in a physiological environment, we have made novel multicompartment carriers called vesosomes, which consist of an outer lipid bilayer shell that encloses and protects the drug-carrying liposomes. The second bilayer increases the serum half-life of ciprofloxacin from <10 minutes in liposomes to 6 hours in vesosomes and alters the release kinetics. The enhanced drug retention is due to the outer membrane preventing enzymes and proteins in the blood from breaking down the drug-carrying interior compartments.

  12. Interleukin-10: an anti-inflammatory marker to target atherosclerotic lesions via PEGylated liposomes.

    PubMed

    Almer, Gunter; Frascione, Daniela; Pali-Schöll, Isabella; Vonach, Caroline; Lukschal, Anna; Stremnitzer, Caroline; Diesner, Susanne C; Jensen-Jarolim, Erika; Prassl, Ruth; Mangge, Harald

    2013-01-07

    Atherosclerosis (AS) causes cardiovascular disease, which leads to fatal clinical end points like myocardial infarction or stroke, the most prevalent causes of death in developed countries. An early, noninvasive method of detection and diagnosis of atherosclerotic lesions is necessary to prevent and treat these clinical end points. Working toward this goal, we examined recombinant interleukin-10 (IL-10), stealth liposomes with nanocargo potency for NMRI relevant contrast agents, and IL-10 coupled to stealth liposomes in an ApoE-deficient mouse model using confocal laser-scanning microscopy (CLSM). Through ex vivo incubation and imaging with CLSM, we showed that fluorescently labeled IL-10 is internalized by AS plaques, and a low signal is detected in both the less injured aortic surfaces and the arteries of wild-type mice. In vivo experiments included intravenous injections of (i) fluorescent IL-10, (ii) IL-10 targeted carboxyfluorescin (CF-) labeled stealth liposomes, and (iii) untargeted CF-labeled stealth liposomes. Twenty-four hours after injection the arteries were dissected and imaged ex vivo. Compared to free IL-10, we observed a markedly stronger fluorescence intensity with IL-10 targeted liposomes at AS plaque regions. Moreover, untargeted CF-labeled liposomes showed only weak, unspecific binding. Neither free IL-10 nor IL-10 targeted liposomes showed significant immune reaction when injected into wild-type mice. Thus, the combined use of specific anti-inflammatory proteins, high payloads of contrast agents, and liposome particles should enable current imaging techniques to better recognize and visualize AS plaques for research and prospective therapeutic strategies.

  13. Consensus on the Prevention, Screening, Early Diagnosis and Treatment of Colorectal Tumors in China: Chinese Society of Gastroenterology, October 14-15, 2011, Shanghai, China

    PubMed Central

    Fang, Jing-Yuan; Zheng, Shu; Jiang, Bo; Lai, Mao-De; Fang, Dian-Chun; Han, Ying; Sheng, Qian-Jiu; Li, Jing-Nan; Chen, Ying-Xuan; Gao, Qin-Yan

    2014-01-01

    Background Colorectal cancer (CRC) is steadily increasing in China. Colorectal adenoma (CRA) is the most important precancerous disease of CRC. Screening for colorectal tumors can aid early diagnosis. Advances in endoscopic mucosal resection and endoscopic submucosal dissection can aid the early treatment of colorectal tumors. Furthermore, because of high risk of recurrence after removal of adenomas under endoscopy, factors contributing to recurrence, the follow-up mode and the interval established, and the feasibility of application and the time of various chemical preventions should be concerned. However, a relevant consensus on the screening, early diagnosis and treatment, and prevention of colorectal tumors in China is lacking. Summary The consensus recommendations include epidemiology, pathology, screening, early diagnosis, endoscopic treatment, monitoring and follow-up, and chemoprevention of colorectal tumors in China. Key Message This is the first consensus on the prevention, screening, early diagnosis and treatment of CRA and CRC in China based on evidence in the literature and on local data. Practical Implications Through reviewing the literature, regional data and passing the consensus by an anonymous vote, gastroenterology experts from all over China launch the consensus recommendations in Shanghai. The incidence and mortality of CRC in China has increased, and the incidence or detection rate of CRA has increased rapidly. Screening for colorectal tumors should be performed at age 50-74 years. Preliminary screening should be undertaken to find persons at high risk, followed by colonoscopy. A screening cycle of 3 years is recommended for persistent interventions. Opportunistic screening is a mode suitable for the current healthcare system and national situation. Colonoscopy combined with pathological examination is the standard method for the diagnosis of colorectal tumors. CRA removal under endoscopy can prevent CRC to some extent, but CRA has an obvious

  14. Interactions of liposomes with dental restorative materials.

    PubMed

    Nguyen, Sanko; Adamczak, Malgorzata; Hiorth, Marianne; Smistad, Gro; Kopperud, Hilde Molvig

    2015-12-01

    The in vitro adsorption and retention of liposomes onto four common types of dental restorative materials (conventional and silorane-based resin composites as well as conventional and resin-modified glass ionomer cements (GIC)) have been investigated due to their potential use in the oral cavity. Uncoated liposomes (positively and negatively charged) and pectin (low- and high-methoxylated) coated liposomes were prepared and characterized in terms of particle size and zeta potential. The adsorption of liposomes was performed by immersion, quantified by fluorescence detection, and visualized by fluorescence imaging and atomic force microscopy. Positive liposomes demonstrated the highest adsorption on all four types of materials likely due to their attractive surface charge. They also retained well (minimum 40% after 60 min) on both conventional resin composite and GIC even when exposed to simulated salivary flow. Although an intermediate initial level of adsorption was found for the pectin coated liposomes, at least 70% high methoxylated-pectin coated liposomes still remained on the conventional resin composite after 60 min flow exposure. This indicates significant contribution of hydrophobic interactions in the prolonged binding of liposomes to resin composites. Based on these results, the present paper suggests two new possible applications of liposomes in the preservation of dental restorations.

  15. Liposomal drug delivery systems--clinical applications.

    PubMed

    Goyal, Parveen; Goyal, Kumud; Vijaya Kumar, Sengodan Gurusamy; Singh, Ajit; Katare, Om Prakash; Mishra, Dina Nath

    2005-03-01

    Liposomes have been widely investigated since 1970 as drug carriers for improving the delivery of therapeutic agents to specific sites in the body. As a result, numerous improvements have been made, thus making this technology potentially useful for the treatment of certain diseases in the clinics. The success of liposomes as drug carriers has been reflected in a number of liposome-based formulations, which are commercially available or are currently undergoing clinical trials. The current pharmaceutical preparations of liposome-based therapeutic systems mainly result from our understanding of lipid-drug interactions and liposome disposition mechanisms. The insight gained from clinical use of liposome drug delivery systems can now be integrated to design liposomes that can be targeted on tissues, cells or intracellular compartments with or without expression of target recognition molecules on liposome membranes. This review is mainly focused on the diseases that have attracted most attention with respect to liposomal drug delivery and have therefore yielded most progress, namely cancer, antibacterial and antifungal disorders. In addition, increased gene transfer efficiencies could be obtained by appropriate selection of the gene transfer vector and mode of delivery.

  16. Serious stomatitis and esophagitis: a peculiar mucous reaction induced by pegylated liposomal doxorubicin.

    PubMed

    Ma, Han; Chen, Meilan; Liu, Junru; Li, Ying; Li, Juan

    2015-01-01

    Pegylated liposomal doxorubicin is an important antineoplastic agent with activity in a variety of solid tumors. It has a totally different profile of pharmacokinetics and toxicity compared with doxorubicin. It rarely causes side-effects like cardiotoxicity or hair loss, but frequently results in many kinds of mucocutaneous reactions, including palmar-plantar erythrodysesthesia, diffuse follicular rash, intertrigo-like eruption, new formation of melanotic macules, stomatitis and radiation recall dermatitis. We present a rare case of multiple myeloma who immediately developed serious stomatitis and esophatitis associated with minor palmar-plantar erythrodysesthesia after a single course of pegylated liposomal doxorubicin.

  17. Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations.

    PubMed

    Zisman, Natalia; Dos Santos, Nancy; Johnstone, Sharon; Tsang, Alan; Bermudes, David; Mayer, Lawrence; Tardi, Paul

    2011-01-01

    The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (T(m)) ranged from 42-55°C. The high T(m) formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest T(m) formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.

  18. Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations

    PubMed Central

    Zisman, Natalia; Dos Santos, Nancy; Johnstone, Sharon; Tsang, Alan; Bermudes, David; Mayer, Lawrence; Tardi, Paul

    2011-01-01

    The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (Tm) ranged from 42–55°C. The high Tm formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest Tm formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle. PMID:22312548

  19. The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth.

    PubMed

    Cañibano, Carmen; Rodriguez, Noela L; Saez, Carmen; Tovar, Sulay; Garcia-Lavandeira, Montse; Borrello, Maria Grazia; Vidal, Anxo; Costantini, Frank; Japon, Miguel; Dieguez, Carlos; Alvarez, Clara V

    2007-04-18

    Somatotrophs are the only pituitary cells that express Ret, GFRalpha1 and GDNF. This study investigated the effects of Ret in a somatotroph cell line, in primary pituitary cultures and in Ret KO mice. Ret regulates somatotroph numbers by inducing Pit-1 overexpression, leading to increased p53 expression and apoptosis, both of which can be prevented with Ret or Pit-1 siRNA. The Pit-1 overexpression is mediated by sustained activation of PKCdelta, JNK, c/EBPalpha and CREB induced by a complex of Ret, caspase 3 and PKCdelta. In the presence of GDNF, Akt is activated, and the Pit-1 overexpression and resulting apoptosis are blocked. The adenopituitary of Ret KO mice is larger than normal, showing Pit-1 and somatotroph hyperplasia. In normal animals, activation of the Ret/Pit-1/p53 pathway by retroviral introduction of Ret blocked tumor growth in vivo. Thus, somatotrophs have an intrinsic mechanism for controlling Pit-1/GH production through an apoptotic/survival pathway. Ret might be of value for treatment of pituitary adenomas.

  20. The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth

    PubMed Central

    Cañibano, Carmen; Rodriguez, Noela L; Saez, Carmen; Tovar, Sulay; Garcia-Lavandeira, Montse; Borrello, Maria Grazia; Vidal, Anxo; Costantini, Frank; Japon, Miguel; Dieguez, Carlos; Alvarez, Clara V

    2007-01-01

    Somatotrophs are the only pituitary cells that express Ret, GFRα1 and GDNF. This study investigated the effects of Ret in a somatotroph cell line, in primary pituitary cultures and in Ret KO mice. Ret regulates somatotroph numbers by inducing Pit-1 overexpression, leading to increased p53 expression and apoptosis, both of which can be prevented with Ret or Pit-1 siRNA. The Pit-1 overexpression is mediated by sustained activation of PKCδ, JNK, c/EBPα and CREB induced by a complex of Ret, caspase 3 and PKCδ. In the presence of GDNF, Akt is activated, and the Pit-1 overexpression and resulting apoptosis are blocked. The adenopituitary of Ret KO mice is larger than normal, showing Pit-1 and somatotroph hyperplasia. In normal animals, activation of the Ret/Pit-1/p53 pathway by retroviral introduction of Ret blocked tumor growth in vivo. Thus, somatotrophs have an intrinsic mechanism for controlling Pit-1/GH production through an apoptotic/survival pathway. Ret might be of value for treatment of pituitary adenomas. PMID:17380130

  1. Liposomal formulations of cytotoxic drugs.

    PubMed

    Janknegt, R

    1996-07-01

    Liposomes are microscopic particles of lipid bilayer membrane that enclose aqueous internal compartments. These drug-delivery systems offer a very interesting opportunity for delivering cytotoxic drugs with equal or improved clinical efficacy and reduced toxicity. The most important clinical application of liposomes until now has been the inclusion of amphotericin B. At the same dose level, liposomal amphotericin B is as effective or slightly less effective than the conventional formulation, but much higher dosages, up to 5-7 mg kg-1day-1, can be given with acceptable toxicity. There are three preparations of cytotoxic drugs in an advanced stage of commercial development. Two of these (Doxil and TLD D99) contain doxorubicin and the other (DaunoXome) contains daunorubicin. The cardiac toxicity of the three preparations under clinical evaluation appears to be low in comparison with conventional doxorubicin or daunorubicin. No direct comparisons between the new formulations are available, so it is not yet possible to make any statements concerning their relative efficacy and toxicity. DaunoXome is the only drug that is approved in any country, and is also the best documented. It is too early to make recommendations concerning the place of these drugs in therapy. The marked increase in concentrations at the site of the tumour has yet to lead to increased therapeutic efficacy. These findings need further investigation. The efficacy of liposomal preparations in Kaposi's sarcoma appears to be similar to that of standard therapy and the clinical tolerance is good. Perhaps combination therapy with other cytotoxic agents could result in improved clinical efficacy. Their cost will probably be high in comparison with standard therapies.

  2. Inertial cavitation to non-invasively trigger and monitor intratumoral release of drug from intravenously delivered liposomes.

    PubMed

    Graham, Susan M; Carlisle, Robert; Choi, James J; Stevenson, Mark; Shah, Apurva R; Myers, Rachel S; Fisher, Kerry; Peregrino, Miriam-Bazan; Seymour, Len; Coussios, Constantin C

    2014-03-28

    The encapsulation of cytotoxic drugs within liposomes enhances pharmacokinetics and allows passive accumulation within tumors. However, liposomes designed to achieve good stability during the delivery phase often have compromised activity at the target site. This problem of inefficient and unpredictable drug release is compounded by the present lack of low-cost, non-invasive methods to measure such release. Here we show that focused ultrasound, used at pressures similar to those applied during diagnostic ultrasound scanning, can be utilised to both trigger and monitor release of payload from liposomes. Notably, drug release was influenced by liposome composition and the presence of SonoVue® microbubbles, which provided the nuclei for the initiation of an event known as inertial cavitation. In vitro studies demonstrated that liposomes formulated with a high proportion of 1,2 distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) released up to 30% of payload following ultrasound exposure in the presence of SonoVue®, provided that the exposure created sufficient inertial cavitation events, as characterised by violent bubble collapse and the generation of broadband acoustic emissions. In contrast a 'Doxil'-like liposome formulation gave no such triggered release. In pre-clinical studies, ultrasound was used as a non-invasive, targeted stimulus to trigger a 16-fold increase in the level of payload release within tumors following intravenous delivery. The inertial cavitation events driving this release could be measured remotely in real-time and were a reliable predictor of drug release.

  3. Use of liposomal doxorubicin for adjuvant chemotherapy of breast cancer in clinical practice*

    PubMed Central

    Zhao, Ming; Ding, Xian-feng; Shen, Jian-yu; Zhang, Xi-ping; Ding, Xiao-wen; Xu, Bin

    2017-01-01

    Breast cancer is one of the malignant tumors with the highest morbidity and mortality. It is helpful to reduce the rate of tumor recurrence and metastasis by treating breast cancer with adjuvant chemotherapy, so as to increase the cure rate or survival of patients. In recent years, liposomes have been regarded as a kind of new carrier for targeted drugs. Being effective for enhancing drug efficacy and reducing side effects, they have been widely used for developing anticancer drugs. As a kind of anthracycline with high anticancer activity, doxorubicin can treat or alleviate a variety of malignant tumors effectively when it is used on its own or in combination with other anticancer drugs. Although liposomal doxorubicin has been extensively used in the adjuvant chemotherapy of breast cancer, its exact therapeutic efficacy and side effects have not been definitely proven. Various clinical studies have adopted different combined regimes, dosages, and staging, so their findings differ to certain extent. This paper reviews the clinical application of liposomal doxorubicin in the adjuvant chemotherapy of breast cancer and illustrates therapeutic effects and side effects of pegylated liposomal doxorubicin (PLD) and non-PLD (NPLD) in clinical research, in order to discuss the strategies for applying these drugs in such adjuvant chemotherapy, looking forward to providing references for related research and clinical treatment in terms of dosage, staging, combined regimes, and analysis methods and so on. PMID:28070993

  4. Disposition of aerosolized liposomal amphotericin B.

    PubMed

    Lambros, M P; Bourne, D W; Abbas, S A; Johnson, D L

    1997-09-01

    Amphotericin B (AmB) is an important drug for the treatment of fungal infection, but toxicity limits the lung tissue doses which may be achieved through intravenous administration. Although incorporation of AmB in liposomes reduces these effects and increases the therapeutic index for intravenous administration, targeted delivery to lung tissues via inhaled liposomal AmB aerosol may be a more effective approach. Aerosolization of liposomal amphotericin B targets the lungs, the organs first infested by many fungi. Development of optimal aerosolized liposomal AmB therapies requires a better understanding of the effect that liposome surface charge has on lung clearance kinetics. In this work we evaluated the clearance kinetics and organ distribution of inhaled liposomal AmB in male Balb/C mice. Mice were exposed via nose only to AmB-containing liposomal aerosols having positive, negative, or neutral surface charge characteristics. The formulations were aerosolized using a Collison nebulizer. Groups of animals were euthanized at predetermined times and the lungs and other organs were analyzed for AmB. AmB was not detected in serum and other organs such as kidneys, liver, and brain. The disposition of neutral and positive liposomal amphotericin B in lungs followed biexponential kinetics. The alpha and beta phase half-lives for positive liposomes were 1.3 and 15.1 days, respectively, and 2.3 and 22 days for neutral liposomes. AmB delivered via negative liposomes exhibited monoexponential clearance with a half-life of 4.5 days. These results suggest that toxic side effects in nontarget tissues are minimal and may indicate a potential for long term protection against fungal infections.

  5. Nanoparticle Stabilized Liposomes for Acne Therapy

    NASA Astrophysics Data System (ADS)

    Fu, Victoria

    Acne vulgaris is a common skin disease that affects over 40 million people in the United States alone. The main cause of acne vulgaris is Propionibacterium acnes (P. acnes), resides deep in the pores and follicles of the skin in order to feed on oil produced by the sebaceous glands. The liposome is a lipid based nanoparticle with numerous advantages over free drug molecules as an acne treatment alternative. Bare liposomes loaded with lauric acid (LipoLA) were found to show strong antimicrobial activity against P. acnes while generating minimal toxicity. However, the platform is limited by the spontaneous tendency of liposomes to fuse with each other. Attaching nanoparticles to the surface of liposomes can overcome this challenge by providing steric repulsion and reduce surface tension. Thus, carboxyl-functionalized gold nanoparticles (AuC) were attached to the surface of liposomes (AuC-liposomes) loaded with doxycycline, a general tetracycline antibiotic. These particles were found to have a diameter of 120 nm and a zeta potential of 20.0 mV. Both fluorescent and antimicrobial studies demonstrated that based on electrostatic interaction, negatively charged AuC attached to the liposome's positively charged surface and stabilized liposomes in a neutral pH environment (pH = 7.4). Upon entering the skin's acidic environment (pH = 4), AuC detached from the liposome's surface and liposomes could fuse with P. acnes residing in the pores. Furthermore, toxicity studies showed that AuC-liposomes did not induce any significant toxicity, while two of the leading over-the-counter therapies, benzoyl peroxide and salicylic acid, generated substantial skin irritation.

  6. Insertion stability of poly(ethylene glycol)-cholesteryl-based lipid anchors in liposome membranes.

    PubMed

    Molnar, Daniel; Linders, Jürgen; Mayer, Christian; Schubert, Rolf

    2016-06-01

    Liposomes consist of a hydrophilic core surrounded by a phospholipid (PL) bilayer. In human blood, the half-life of such artificial vesicles is limited. To prolong their stability in the circulation, liposomal bilayers can be modified by inserting poly(ethylene glycol) (PEG) molecules using either PL or sterols as membrane anchors. This establishes a hydrophilic steric barrier, reducing the adsorption of serum proteins, recognition and elimination by cells of the immune system. In addition, targeting ligands (such as antibodies) are frequently coupled to the distal end of the PEG chains to direct the vesicles (then called 'immuno-liposomes') to specific cell types, such as tumor cells. To our knowledge, experiments on the stability of ligand anchoring have so far only been conducted with PL-based PEGs and not with sterol-based PEGs after insertion via the sterol-based post-insertion technique (SPIT). Therefore, our study examines the insertion stability of PEG-cholesteryl ester (Chol-PEG) molecules with PEG chains of 1000, 1500 and 2000Da molecular mass which have been inserted into the membranes of liposomes using SPIT. For this study we used different acceptor media and multiple analytical techniques, including pulsed-field-gradient nuclear magnetic resonance (PFG-NMR), free-flow electrophoresis, size exclusion chromatography and ultracentrifugation. The obtained data consistently showed that a higher molar mass of PEG chains positively correlates with higher release from the liposome membranes. Furthermore, we could detect and quantify the migration of Chol-PEG molecules from radioactively double-labeled surface-modified liposomes to negatively charged acceptor liposomes via free-flow electrophoresis. Insertion of Chol-PEG molecules into the membrane of preformed liposomes using SPIT is an essential step for the functionalization of liposomes with the aim of specific targeting. For the first time, we present a kinetic analysis of this insertion process using PFG

  7. Sirolimus encapsulated liposomes for cancer therapy: physicochemical and mechanical characterization of sirolimus distribution within liposome bilayers.

    PubMed

    Onyesom, Ichioma; Lamprou, Dimitrios A; Sygellou, Lamprini; Owusu-Ware, Samuel K; Antonijevic, Milan; Chowdhry, Babur Z; Douroumis, Dennis

    2013-11-04

    Sirolimus has recently been introduced as a therapeutic agent for breast and prostate cancer. In the current study, conventional and Stealth liposomes were used as carriers for the encapsulation of sirolimus. The physicochemical characteristics of the sirolimus liposome nanoparticles were investigated including the particle size, zeta potential, stability and membrane integrity. In addition atomic force microscopy was used to study the morphology, surface roughness and mechanical properties such as elastic modulus deformation and deformation. Sirolimus encapsulation in Stealth liposomes showed a high degree of deformation and lower packing density especially for dipalmitoyl-phosphatidylcholine (DPPC) Stealth liposomes compared to unloaded. Similar results were obtained by differential scanning calorimetry (DSC) studies; sirolimus loaded liposomes were found to result in a distorted state of the bilayer. X-ray photon electron (XPS) analysis revealed a uniform distribution of sirolimus in multilamellar DPPC Stealth liposomes compared to a nonuniform, greater outer layer lamellar distribution in distearoylphosphatidylcholine (DSPC) Stealth liposomes.

  8. Electrochemical analysis in a liposome suspension using lapachol as a hydrophobic electro active species.

    PubMed

    Okumura, Noriko; Wakamatsu, Shiori; Uno, Bunji

    2014-01-01

    This study demonstrated that the electro-chemical analysis of hydrophobic quinones can be performed in liposome suspension systems. We prepared and analyzed liposome suspensions containing lapachol, which is a quinone-based anti-tumor activity compound. In this suspension system, a simple one redox couple of lapachol is observed. These results are quite different from those obtained in organic solvents. In addition, the pH dependence of redox behaviors of lapachol could be observed in multilamellar vesicle (MLV) suspension system. This MLV suspension system method may approximate the electrochemical behavior of hydrophobic compounds in aqueous conditions. A benefit of this liposome suspension system for electrochemical analysis is that it enables to observe water-insoluble compounds without using organic solvents.

  9. Delivering minocycline into brain endothelial cells with liposome-based technology.

    PubMed

    Xing, Changhong; Levchenko, Tatyana; Guo, Shuzhen; Stins, Monique; Torchilin, Vladimir P; Lo, Eng H

    2012-06-01

    Minocycline has been proposed as a way to blunt neurovascular injury from matrix metalloproteinases (MMPs) during stroke. However, recent clinical trials suggest that high levels of minocycline may have deleterious side-effects. Here, we showed that very high minocycline concentrations damage endothelial cells via calpain/caspase pathways. To alleviate this potential cytotoxicity, we encapsulated minocycline in liposomes. Low concentrations of minocycline could not reduce tumor necrosis factor α (TNFα)-induced MMP-9 release from endothelial cells. But low concentrations of minocycline-loaded liposomes significantly reduced TNFα-induced MMP-9 release. This study provides proof-of-concept that liposomes may be used to deliver lower levels of minocycline for targeting MMPs in cerebral endothelium.

  10. Near-infrared-fluorescence imaging of lymph nodes by using liposomally formulated indocyanine green derivatives.

    PubMed

    Toyota, Taro; Fujito, Hiromichi; Suganami, Akiko; Ouchi, Tomoki; Ooishi, Aki; Aoki, Akira; Onoue, Kazutaka; Muraki, Yutaka; Madono, Tomoyuki; Fujinami, Masanori; Tamura, Yutaka; Hayashi, Hideki

    2014-01-15

    Liposomally formulated indocyanine green (LP-ICG) has drawn much attention as a highly sensitive near-infrared (NIR)-fluorescence probe for tumors or lymph nodes in vivo. We synthesized ICG derivatives tagged with alkyl chains (ICG-Cn), and we examined NIR-fluorescence imaging for lymph nodes in the lower extremities of mice by using liposomally formulated ICG-Cn (LP-ICG-Cn) as well as conventional liposomally formulated ICG (LP-ICG) and ICG. Analysis with a noninvasive preclinical NIR-fluorescence imaging system revealed that LP-ICG-Cn accumulates in only the popliteal lymph node 1h after injection into the footpad, whereas LP-ICG and ICG accumulate in the popliteal lymph node and other organs like the liver. This result indicates that LP-ICG-Cn is a useful NIR-fluorescence probe for noninvasive in vivo bioimaging, especially for the sentinel lymph node.

  11. Encapsulation of trans-dehydrocrotonin in liposomes: an enhancement of the antitumor activity.

    PubMed

    Lapenda, T L S; Morais, W A; Almeida, F J F; Ferraz, M S; Lira, M C B; Santos, N P S; Maciel, M A M; Santos-Magalhães, N S

    2013-03-01

    The aim of this study was the encapsulation of trans-dehydrocrotonin (t-DCTN) and its inclusion complexes with hydropropyl-beta-cyclodextrin (HP-beta-CD) in liposomes to improve t-DCTN antitumor activity. The in vitro kinetic profiles of t-DCTN-loaded liposomes (LD) and t-DCTN:HP-beta-CD-loaded liposomes (LC) were evaluated using the dialysis technique. The antitumor activity of LD and LC were investigated against Sarcoma 180 in Swiss mice. Histopathological and hematological analyses were carried out. The amounts of t-DCTN and t-DCTN:HP-beta-CD inclusion complex encapsulated in liposomes were equivalent to 1 mg of t-DCTN. The encapsulation efficiencies of LD and LC were 95.0 +/- 3.8% and 91.1 +/- 5.6%, respectively. In relation to kinetics, the drug release profiles of t-DCTN are in substantial agreement with the Fickian model. The treatment of animals with LD and LC produced tumor inhibitions of 79.4 +/- 9.6% and 63.5 +/- 5.5%, respectively. The liposomal encapsulation of t-DCTN by entrapment in the phospholipid bilayer increased at twice the antitumor activity. Moreover, the liposomal formulations reduced the hepatotoxicity effect of the drug and no significant hematological toxicity was observed in the treated animals. However, the counting of platelets was slightly decreased. Thus, the results show that the development of liposomal formulations containing t-DCTN or t-DCTN:HP-beta-CD is an important advance for enabling this drug to be use in therapy.

  12. Site-specific conjugation of single domain antibodies to liposomes enhances photosensitizer uptake and photodynamic therapy efficacy

    NASA Astrophysics Data System (ADS)

    Broekgaarden, M.; van Vught, R.; Oliveira, S.; Roovers, R. C.; van Bergen En Henegouwen, P. M. P.; Pieters, R. J.; van Gulik, T. M.; Breukink, E.; Heger, M.

    2016-03-01

    Photodynamic therapy for therapy-resistant cancers will greatly benefit from targeted delivery of tumor photosensitizing agents. In this study, a strategy for the site-specific conjugation of single domain antibodies onto liposomes containing the photosensitizer zinc phthalocyanine was developed and tested.Photodynamic therapy for therapy-resistant cancers will greatly benefit from targeted delivery of tumor photosensitizing agents. In this study, a strategy for the site-specific conjugation of single domain antibodies onto liposomes containing the photosensitizer zinc phthalocyanine was developed and tested. Electronic supplementary information (ESI) available: Materials and methods. See DOI: 10.1039/c6nr00014b

  13. Targeted delivery of chemically modified anti-miR-221 to hepatocellular carcinoma with negatively charged liposomes.

    PubMed

    Zhang, Wendian; Peng, Fangqi; Zhou, Taotao; Huang, Yifei; Zhang, Li; Ye, Peng; Lu, Miao; Yang, Guang; Gai, Yongkang; Yang, Tan; Ma, Xiang; Xiang, Guangya

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Gene therapy was established as a new strategy for treating HCC. To explore the potential delivery system to support the gene therapy of HCC, negatively charged liposomal delivery system was used to deliver miR-221 antisense oligonucleotide (anti-miR-221) to the transferrin (Tf) receptor over expressed HepG2 cells. The liposome exhibited a mean particle size of 122.5 nm, zeta potential of -15.74 mV, anti-miR-221 encapsulation efficiency of 70%, and excellent colloidal stability at 4°C. Anti-miR-221-encapsulated Tf-targeted liposome demonstrated a 15-fold higher delivery efficiency compared to nontargeted liposome in HepG2 cells in vitro. Anti-miR-221 Tf-targeted liposome effectively delivered anti-miR-221 to HepG2 cells, upregulated miR-221 target genes PTEN, P27(kip1), and TIMP3, and exhibited greater silencing efficiency over nontargeted anti-miR-221 liposome. After intravenous injection into HepG2 tumor-bearing xenografted mice with Cy3-labeled anti-miR-221 Tf-targeted liposome, Cy3-anti-miR-221 was successfully delivered to the tumor site and increased the expressions of PTEN, P27(kip1), and TIMP3. Our results demonstrate that the Tf-targeted negatively charged liposome could be a potential therapeutic modality in the gene therapy of human HCC.

  14. Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats.

    PubMed

    Huo, Tianyao; Barth, Rolf F; Yang, Weilian; Nakkula, Robin J; Koynova, Rumiana; Tenchov, Boris; Chaudhury, Abhik Ray; Agius, Lawrence; Boulikas, Teni; Elleaume, Helene; Lee, Robert J

    2012-01-01

    The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (NSCLC). The second, produced in our laboratory, was based on the ability of cisplatin to form coordination complexes with lipid cholesteryl hemisuccinate (CHEMS). The in vitro tumoricidal activity of the former previously has been described in detail by other investigators. The CHEMS liposomal formulation had a Pt loading efficiency of 25% and showed more potent in vitro cytotoxicity against F98 glioma cells than free cisplatin at 24 h. In vivo CHEMS liposomes showed high retention at 24 h after intracerebral (i.c.) convection enhanced delivery (CED) to F98 glioma bearing rats. Neurotoxicologic studies were carried out in non-tumor bearing Fischer rats following i.c. CED of Lipoplatin™ or CHEMS liposomes or their "hollow" counterparts. Unexpectedly, Lipoplatin™ was highly neurotoxic when given i.c. by CED and resulted in death immediately following or within a few days after administration. Similarly "hollow" Lipoplatin™ liposomes showed similar neurotoxicity indicating that this was due to the liposomes themselves rather than the cisplatin. This was particularly surprising since Lipoplatin™ has been well tolerated when administered intravenously. In contrast, CHEMS liposomes and their "hollow" counterparts were clinically well tolerated. However, a variety of dose dependent neuropathologic changes from none to severe were seen at either 10 or 14 d following their administration. These findings suggest that further refinements in the design and formulation of cisplatin containing liposomes will be required before they can be administered i.c. by CED for the treatment of brain tumors and that a formulation that may be safe when given systemically may be

  15. Preparation, Biodistribution and Neurotoxicity of Liposomal Cisplatin following Convection Enhanced Delivery in Normal and F98 Glioma Bearing Rats

    PubMed Central

    Huo, Tianyao; Barth, Rolf F.; Yang, Weilian; Nakkula, Robin J.; Koynova, Rumiana; Tenchov, Boris; Chaudhury, Abhik Ray; Agius, Lawrence; Boulikas, Teni; Elleaume, Helene; Lee, Robert J.

    2012-01-01

    The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (NSCLC). The second, produced in our laboratory, was based on the ability of cisplatin to form coordination complexes with lipid cholesteryl hemisuccinate (CHEMS). The in vitro tumoricidal activity of the former previously has been described in detail by other investigators. The CHEMS liposomal formulation had a Pt loading efficiency of 25% and showed more potent in vitro cytotoxicity against F98 glioma cells than free cisplatin at 24 h. In vivo CHEMS liposomes showed high retention at 24 h after intracerebral (i.c.) convection enhanced delivery (CED) to F98 glioma bearing rats. Neurotoxicologic studies were carried out in non-tumor bearing Fischer rats following i.c. CED of Lipoplatin™ or CHEMS liposomes or their “hollow” counterparts. Unexpectedly, Lipoplatin™ was highly neurotoxic when given i.c. by CED and resulted in death immediately following or within a few days after administration. Similarly “hollow” Lipoplatin™ liposomes showed similar neurotoxicity indicating that this was due to the liposomes themselves rather than the cisplatin. This was particularly surprising since Lipoplatin™ has been well tolerated when administered intravenously. In contrast, CHEMS liposomes and their “hollow” counterparts were clinically well tolerated. However, a variety of dose dependent neuropathologic changes from none to severe were seen at either 10 or 14 d following their administration. These findings suggest that further refinements in the design and formulation of cisplatin containing liposomes will be required before they can be administered i.c. by CED for the treatment of brain tumors and that a formulation that may be safe when given

  16. Peptide-22 and Cyclic RGD Functionalized Liposomes for Glioma Targeting Drug Delivery Overcoming BBB and BBTB.

    PubMed

    Chen, Cuitian; Duan, Ziqing; Yuan, Yan; Li, Ruixiang; Pang, Liang; Liang, Jianming; Xu, Xinchun; Wang, Jianxin

    2017-02-22

    Chemotherapy outcomes for the treatment of glioma remain unsatisfied due to the inefficient drug transport across BBB/BBTB and poor drug accumulation in the tumor site. Nanocarriers functionalized with different targeting ligands are considered as one of the most promising alternatives. However, few studies were reported to compare the targeting efficiency of the ligands and develop nanoparticles to realize BBB/BBTB crossing and brain tumor targeting simultaneously. In this study, six peptide-based ligands (Angiopep-2, T7, Peptide-22, c(RGDfK), D-SP5 and Pep-1), widely used for brain delivery, were selected to decorate liposomes, respectively, so as to compare their targeting ability to BBB or BBTB. Based on the in vitro cellular uptake results on BCECs and HUVECs, Peptide-22 and c(RGDfK) were picked to construct a BBB/BBTB dual-crossing, glioma-targeting liposomal drug delivery system c(RGDfK)/Pep-22-DOX-LP. In vitro cellular uptake demonstrated that the synergetic effect of c(RGDfK) and Peptide-22 could significantly increase the internalization of liposomes on U87 cells. In vivo imaging further verified that c(RGDfK)/Pep-22-LP exhibited higher brain tumor distribution than single ligand modified liposomes. The median survival time of glioma-bearing mice treated with c(RGDfK)/Pep-22-DOX-LP (39.5 days) was significantly prolonged than those treated with free doxorubicin or other controls. In conclusion, the c(RGDfK) and Peptide-22 dual-modified liposome was constructed based on the targeting ability screening of various ligands. The system could effectively overcome BBB/BBTB barriers, target to tumor cells and inhibit the growth of glioma, which proved its potential for improving the efficacy of chemotherapeutics for glioma therapy.

  17. Therapeutic efficacy evaluation of 111in-VNB-liposome on human colorectal adenocarcinoma HT-29/ luc mouse xenografts

    NASA Astrophysics Data System (ADS)

    Lee, Wan-Chi; Hwang, Jeng-Jong; Tseng, Yun-Long; Wang, Hsin-Ell; Chang, Ya-Fang; Lu, Yi-Ching; Ting, Gann; Whang-Peng, Jaqueline; Wang, Shyh-Jen

    2006-12-01

    The purpose of this study is to evaluate the therapeutic efficacy of the liposome encaged with vinorelbine (VNB) and 111In-oxine on human colorectal adenocarcinoma (HT-29) using HT-29/ luc mouse xenografts. HT-29 cells stably transfected with plasmid vectors containing luciferase gene ( luc) were transplanted subcutaneously into the male NOD/SCID mice. Biodistribution of the drug was performed when tumor size reached 500-600 mm 3. The uptakes of 111In-VNB-liposome in tumor and normal tissues/organs at various time points postinjection were assayed. Multimodalities, including gamma scintigraphy, bioluminescence imaging (BLI) and whole-body autoradiography (WBAR), were applied for evaluating the therapeutic efficacy when tumor size was about 100 mm 3. The tumor/blood ratios of 111In-VNB-liposome were 0.044, 0.058, 2.690, 20.628 and 24.327, respectively, at 1, 4, 24, 48 and 72 h postinjection. Gamma scinitigraphy showed that the tumor/muscle ratios were 2.04, 2.25 and 4.39, respectively, at 0, 5 and 10 mg/kg VNB. BLI showed that significant tumor control was achieved in the group of 10 mg/kg VNB ( 111In-VNB-liposome). WBAR also confirmed this result. In this study, we have demonstrated a non-invasive imaging technique with a luciferase reporter gene and BLI for evaluation of tumor treatment efficacy in vivo. The SCID mice bearing HT-29/ luc xenografts treated with 111In-VNB-liposome were shown with tumor reduction by this technique.

  18. Methods for using redox liposome biosensors

    DOEpatents

    Cheng, Quan; Stevens, Raymond C.

    2002-01-01

    The present invention provides methods and compositions for detecting the presence of biologically-important analytes by using redox liposome biosensors. In particular, the present invention provides liposome/sol-gel electrodes suitable for the detection of a wide variety of organic molecules, including but not limited to bacterial toxins.

  19. Structure of DNA-liposome complexes

    SciTech Connect

    Lasic, D.D.; Strey, H.; Podgornik, R.; Stuart, M.C.A.; Frederik, P.M.

    1997-01-29

    Despite numerous studies and commericially available liposome kits, however, the structure of DNA-cationic liposome complexes is still not yet well understood. We have investigated the structure of these complexes using high-resolution cryo electron microscopy (EM) and small angle X-ray scattering (SAXS). 14 refs., 3 figs.

  20. Liposome-Encapsulated Hemoglobin for Emergency Resuscitation.

    DTIC Science & Technology

    1984-10-01

    have infused liposome -encapsulated amphotericin B to treat patients with systemic fungal infections. Their formulation includes 30% dimyristoyl...procedure, including exploring new industrial-scale methodologies for liposome manufacture. In addition we have focused on basic problems of biophysics...circulation persistance of this new formulation , as produced by the Microfluidizer, is obviously necessary. The influence of negatively-charged lipids on

  1. The protein corona of circulating PEGylated liposomes.

    PubMed

    Palchetti, Sara; Colapicchioni, Valentina; Digiacomo, Luca; Caracciolo, Giulio; Pozzi, Daniela; Capriotti, Anna Laura; La Barbera, Giorgia; Laganà, Aldo

    2016-02-01

    Following systemic administration, liposomes are covered by a 'corona' of proteins, and preserving the surface functionality is challenging. Coating the liposome surface with polyethylene glycol (PEG) is the most widely used anti-opsonization strategy, but it cannot fully preclude protein adsorption. To date, protein binding has been studied following in vitro incubation to predict the fate of liposomes in vivo, while dynamic incubation mimicking in vivo conditions remains largely unexplored. The main aim of this investigation was to determine whether shear stress, produced by physiologically relevant dynamic flow, could influence the liposome-protein corona. The corona of circulating PEGylated liposome was thoroughly compared with that formed by incubation in vitro. Systematic comparison in terms of size, surface charge and quantitative composition was made by dynamic light scattering, microelectrophoresis and nano-liquid chromatography tandem mass spectrometry (nanoLC-MS/MS). Size of coronas formed under static vs. dynamic incubation did not appreciably differ from each other. On the other side, the corona of circulating liposomes was more negatively charged than its static counterpart. Of note, the variety of protein species in the corona formed in a dynamic flow was significantly wider. Collectively, these results demonstrated that the corona of circulating PEGylated liposomes can be considerably different from that formed in a static fluid. This seems to be a key factor to predict the biological activity of a liposomal formulation in a physiological environment.

  2. Intravesical liposome therapy for interstitial cystitis.

    PubMed

    Tyagi, Pradeep; Kashyap, Mahendra; Majima, Tsuyoshi; Kawamorita, Naoki; Yoshizawa, Tsuyoshi; Yoshimura, Naoki

    2017-03-04

    Over the past two decades, there has been lot of interest in the use of liposomes as lipid-based biocompatible carriers for drugs administered by the intravesical route. The lipidic bilayer structure of liposomes facilitates their adherence to the apical membrane surface of luminal cells in the bladder, and their vesicular shape allows them to co-opt the endocytosis machinery for bladder uptake after instillation. Liposomes have been shown to enhance the penetration of both water-soluble and insoluble drugs, toxins, and oligonucleotides across the bladder epithelium. Empty liposomes composed entirely of the endogenous phospholipid, sphingomyelin, could counter mucosal inflammation and promote wound healing in patients suffering from interstitial cystitis. Recent clinical studies have tested multilamellar liposomes composed entirely of sphingomyelin as a novel intravesical therapy for interstitial cystitis. In addition, liposomes have been used as a delivery platform for the instillation of botulinum toxin in overactive bladder patients. The present review discusses the properties of liposomes that are important for their intrinsic therapeutic effect, summarizes the recently completed clinical studies with intravesical liposomes and covers the latest developments in this field.

  3. The milk protein α-casein functions as a tumor suppressor via activation of STAT1 signaling, effectively preventing breast cancer tumor growth and metastasis.

    PubMed

    Bonuccelli, Gloria; Castello-Cros, Remedios; Capozza, Franco; Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Tsirigos, Aristotelis; Xuanmao, Jiao; Whitaker-Menezes, Diana; Howell, Anthony; Lisanti, Michael P; Sotgia, Federica

    2012-11-01

    Here, we identified the milk protein α-casein as a novel suppressor of tumor growth and metastasis. Briefly, Met-1 mammary tumor cells expressing α-casein showed a ~5-fold reduction in tumor growth and a near 10-fold decrease in experimental metastasis. To identify the molecular mechanism(s), we performed genome-wide transcriptional profiling. Interestingly, our results show that α-casein upregulates gene transcripts associated with interferon/STAT1 signaling and downregulates genes associated with "stemness." These findings were validated by immunoblot and FACS analysis, which showed the upregulation and hyperactivation of STAT1 and a decrease in the number of CD44(+) "cancer stem cells." These gene signatures were also able to predict clinical outcome in human breast cancer patients. Thus, we conclude that a lactation-based therapeutic strategy using recombinant α-casein would provide a more natural and non-toxic approach to the development of novel anticancer therapies.

  4. Docosahexaenoic acid liposomes for targeting chronic inflammatory diseases and cancer: an in vitro assessment

    PubMed Central

    Alaarg, Amr; Jordan, Nan Yeun; Verhoef, Johan JF; Metselaar, Josbert M; Storm, Gert; Kok, Robbert J

    2016-01-01

    Inflammation, oxidative stress, and uncontrolled cell proliferation are common key features of chronic inflammatory diseases, such as atherosclerosis and cancer. ω3 polyunsaturated fatty acids (PUFAs; also known as omega3 fatty acids or fish oil) have beneficial effects against inflammation upon dietary consumption. However, these effects cannot be fully exploited unless diets are enriched with high concentrations of fish oil supplements over long periods of time. Here, a nanomedicine-based approach is presented for delivering effective levels of PUFAs to inflammatory cells. Nanoparticles are internalized by immune cells, and hence can adequately deliver bioactive lipids into these target cells. The ω3 FA docosahexaenoic acid was formulated into liposomes (ω-liposomes), and evaluated for anti-inflammatory effects in different types of immune cells. ω-Liposomes strongly inhibited the release of reactive oxygen species and reactive nitrogen species from human neutrophils and murine macrophages, and also inhibited the production of the proinflammatory cytokines TNFα and MCP1. Moreover, ω-liposomes inhibited tumor-cell proliferation when evaluated in FaDu head and neck squamous carcinoma and 4T1 breast cancer cells in in vitro cultures. We propose that ω-liposomes are a promising nanonutraceutical formulation for intravenous delivery of fish oil FAs, which may be beneficial in the treatment of inflammatory disorders and cancer. PMID:27785012

  5. OSTEOPONTIN BINDING TO LIPOPOLYSACCHARIDE LOWERS TUMOR NECROSIS FACTOR-α AND PREVENTS EARLY ALCOHOL-INDUCED LIVER INJURY IN MICE

    PubMed Central

    Ge, Xiaodong; Leung, Tung-Ming; Arriazu, Elena; Lu, Yongke; Urtasun, Raquel; Christensen, Brian; Fiel, Maria Isabel; Mochida, Satoshi; Sørensen, Esben S.; Nieto, Natalia

    2013-01-01

    Rationale: Although osteopontin (OPN) is induced in alcoholic patients, its role in the pathophysiology of alcoholic liver disease (ALD) remains unclear. Increased translocation of lipopolysaccharide (LPS) from the gut is key for the onset of ALD since it promotes macrophage infiltration and activation, tumor necrosis factor-α (TNFα) production and liver injury. Since OPN is protective for the intestinal mucosa, we postulated that enhancing OPN expression in the liver and consequently in the blood and/or in the gut could protect from early alcohol-induced liver injury. Results: Wild-type (WT), OPN knockout (Opn−/−) and transgenic mice overexpressing OPN in hepatocytes (OpnHEP Tg) were chronically fed either the control or the ethanol Lieber-DeCarli diet. Ethanol increased hepatic, plasma, biliary and fecal OPN more in OpnHEP Tg than in WT mice. Steatosis was lesser in ethanol-treated OpnHEP Tg mice as shown by decreased liver-to-body weight ratio, hepatic triglycerides, the steatosis score, oil red-O staining and lipid peroxidation. There was also less inflammation and liver injury as demonstrated by lower ALT activity, hepatocyte ballooning degeneration, LPS levels, the inflammation score and the number of macrophages and TNFα+ cells. To establish if OPN could limit LPS availability and its noxious effects in the liver, binding studies were performed. OPN showed affinity for LPS and the binding prevented macrophage activation, reactive oxygen and nitrogen species generation and TNFα production. Treatment with milk OPN (m-OPN) blocked LPS translocation in vivo and protected from early alcohol-induced liver injury. Conclusion: Natural induction plus forced overexpression of OPN in the liver and treatment with m-OPN protect from early alcohol-induced liver injury by blocking the gut-derived LPS and TNFα effects in the liver. PMID:24214181

  6. Brucella suis prevents human dendritic cell maturation and antigen presentation through regulation of tumor necrosis factor alpha secretion.

    PubMed

    Billard, Elisabeth; Dornand, Jacques; Gross, Antoine

    2007-10-01

    Brucella is a facultative intracellular pathogen and the etiological agent of brucellosis. In some cases, human brucellosis results in a persistent infection that may reactivate years after the initial exposure. The mechanisms by which the parasite evades clearance by the immune response to chronically infect its host are unknown. We recently demonstrated that dendritic cells (DCs), which are critical components of adaptive immunity, are highly susceptible to Brucella infection and are a preferential niche for the development of the bacteria. Here, we report that in contrast to several intracellular bacteria, Brucella prevented the infected DCs from engaging in their maturation process and impaired their capacities to present antigen to naïve T cells and to secrete interleukin-12. Moreover, Brucella-infected DCs failed to release tumor necrosis factor alpha (TNF-alpha), a defect involving the bacterial protein Omp25. Exogenous TNF-alpha addition to Brucella-infected DCs restored cell maturation and allowed them to present antigens. Two avirulent mutants of B. suis, B. suis bvrR and B. suis omp25 mutants, which do not express the Omp25 protein, triggered TNF-alpha production upon DC invasion. Cells infected with these mutants subsequently matured and acquired the ability to present antigens, two properties which were dramatically impaired by addition of anti-TNF-alpha antibodies. In light of these data, we propose a model in which virulent Brucella alters the maturation and functions of DCs through Omp25-dependent control of TNF-alpha production. This model defines a specific evasion strategy of the bacteria by which they can escape the immune response to chronically infect their host.

  7. Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy?

    PubMed

    Cui, Jingxia; Li, Chunlei; Guo, Wenmin; Li, Yanhui; Wang, Caixia; Zhang, Li; Zhang, Lan; Hao, Yanli; Wang, Yongli

    2007-04-02

    Rationally designed liposomes could improve the therapeutic indexes of chemotherapeutic drugs, which is due to alterations in the pharmacokinetics and biodistribution of encapsulated drugs. For traditional drug delivery systems, the accumulation of drugs in healthy and malignant tissues could be correlated with toxicity and efficacy. Some previous studies also indicate that the higher tumor AUC, the better therapeutic efficacy, suggestive of the possible existence of positive correlation. Are AUC values of liposomal drugs really predictive? For the purpose to address this question, we designed two pegylated liposomal doxorubicin formulations (PLD-75 and PLD-100), which had the same lipid/drug ratio and bilayer composition, but different size and internal ammonium sulfate concentration. In vitro drug retention experiments revealed that drug was released at a faster rate from PLD-75, a small size formulation. The plasma pharmacokinetics of PLD-75 was similar to that of PLD-100, regardless of whether the mice were tumor-free or not. It should be noted, though, that in tumor-bearing mice the plasma doxorubicin level in PLD-75 group was only about 59% of that in PLD-100 group at 48 h post injection. Furthermore, their biodistribution behavior in S-180 tumor-bearing KM mice was significantly different. Compared with animals receiving PLD-100, those receiving PLD-75 showed a 19.2%, 27.8%, and 23.5% decrease in liver (p<0.01), spleen (p<0.001) and lung (p<0.05) AUC, respectively. In other healthy tissues except kidney, the drug deposition also reduced by 10-15%, but the difference was not significant. The tumor AUC after administration of PLD-100 and PLD-75 were 1285.3 ugh/g and 762.0 ugh/g, respectively (p<0.001). Maximum drug levels achieved in the tumors were 33.80 microg/g (for PLD-100) and 20.85 microg/g (for PLD-75), and peak tumor concentration was achieved faster in PLD-75 group. However, enhanced drug accumulation does not mean increased antineoplastic effect, and

  8. Synergistic locoregional chemoradiotherapy using a composite liposome-in-gel system as an injectable drug depot

    PubMed Central

    GuhaSarkar, Shruti; Pathak, Kamal; Sudhalkar, Niyati; More, Prachi; Goda, Jayant Sastri; Gota, Vikram; Banerjee, Rinti

    2016-01-01

    The use of radiosensitizers in clinical radiotherapy is limited by systemic toxicity. The biopolymeric, biodegradable, injectable liposome-in-gel-paclitaxel (LG-PTX) system was developed for regional delivery of the radiosensitizer paclitaxel (PTX), and its efficacy was evaluated with concurrent fractionated radiation. LG-PTX is composed of nano-sized drug-loaded fluidizing liposomes, which are incorporated into a porous biodegradable gellan hydrogel. This allows enhanced drug permeation while maintaining a localization of the drug depot. LG-PTX had an IC50 of 325±117 nM in B16F10 melanoma cells, and cytotoxicity with concurrent doses of fractionated radiation showed significant increase in apoptotic cells (75%) compared to radiation (39%) or LG-PTX (43%) alone. Peri-tumoral injection in tumor-bearing mice showed PTX localization in the tumor 2 hours after administration, with no drug detected in plasma or other organs. LG-PTX administration with doses of focal radiation (5×3 Gy) significantly reduced tumor volumes compared to control (6.4 times) and radiation alone (1.6 times) and improved animal survival. LG-PTX thus efficiently localizes the drug at the tumor site and synergistically enhances the effect of concurrent radiotherapy. This novel liposome-in-gel system can potentially be used as a platform technology for the delivery of radiosensitizing drugs to enhance the efficacy of chemoradiotherapy. PMID:27942215

  9. Synergistic locoregional chemoradiotherapy using a composite liposome-in-gel system as an injectable drug depot.

    PubMed

    GuhaSarkar, Shruti; Pathak, Kamal; Sudhalkar, Niyati; More, Prachi; Goda, Jayant Sastri; Gota, Vikram; Banerjee, Rinti

    The use of radiosensitizers in clinical radiotherapy is limited by systemic toxicity. The biopolymeric, biodegradable, injectable liposome-in-gel-paclitaxel (LG-PTX) system was developed for regional delivery of the radiosensitizer paclitaxel (PTX), and its efficacy was evaluated with concurrent fractionated radiation. LG-PTX is composed of nano-sized drug-loaded fluidizing liposomes, which are incorporated into a porous biodegradable gellan hydrogel. This allows enhanced drug permeation while maintaining a localization of the drug depot. LG-PTX had an IC50 of 325±117 nM in B16F10 melanoma cells, and cytotoxicity with concurrent doses of fractionated radiation showed significant increase in apoptotic cells (75%) compared to radiation (39%) or LG-PTX (43%) alone. Peri-tumoral injection in tumor-bearing mice showed PTX localization in the tumor 2 hours after administration, with no drug detected in plasma or other organs. LG-PTX administration with doses of focal radiation (5×3 Gy) significantly reduced tumor volumes compared to control (6.4 times) and radiation alone (1.6 times) and improved animal survival. LG-PTX thus efficiently localizes the drug at the tumor site and synergistically enhances the effect of concurrent radiotherapy. This novel liposome-in-gel system can potentially be used as a platform technology for the delivery of radiosensitizing drugs to enhance the efficacy of chemoradiotherapy.

  10. Denosumab for the treatment of cancer therapy-induced bone loss and prevention of skeletal-related events in patients with solid tumors.

    PubMed

    Lipton, Allan; Balakumaran, Arun

    2012-07-01

    Development of bone metastasis is common among patients with advanced cancer. Improvements in chemotherapeutic agents have allowed these patients to live longer with metastatic-stage disease. Thus, treatments to prevent skeletal complications of metastatic bone disease, such as skeletal-related events and pain, are increasingly important. As the skeletal damage with bone metastases is largely caused by increased osteoclast activity, antiresorptive agents (denosumab or bisphosphonates) are recommended for use in these patients. Denosumab, a fully human monoclonal antibody to RANKL, a key mediator of osteoclast activity, was shown to be superior to zoledronic acid for the prevention of skeletal-related events in patients with solid tumors and bone metastases. In addition, denosumab is the only agent currently approved for the treatment of bone loss in patients with breast or prostate cancer receiving hormone-ablation therapy. Denosumab is also being evaluated in several other indications, including adjuvant treatment of breast cancer and giant cell tumor of the bone.

  11. "Smart" liposomal nanocontainers in biology and medicine.

    PubMed

    Tarahovsky, Y S

    2010-07-01

    The perspectives of using liposomes for delivery of drugs to desired parts of the human body have been intensively investigated for more than 30 years. During this time many inventions have been suggested and different kinds of liposomal devices developed, and a number of them have reached the stages of preclinical or clinical trials. The latest techniques can be used to develop biocompatible nano-sized liposomal containers having some abilities of artificial intellect, such as the presence of sensory and responsive units. However, only a few have been clinically approved. Further improvements in this area depend on our knowledge of the interactions of drugs with the lipid bilayer of liposomes. Further studies on liposomal transport through the human body, their targeting of cells requiring therapeutic treatment, and finally, the development of techniques for controlled drug delivery to desired acceptors on cell surfaces or in cytoplasm are still required.

  12. Neuronal chemotaxis by optically manipulated liposomes

    NASA Astrophysics Data System (ADS)

    Pinato, G.; Lien, L. T.; D'Este, E.; Torre, V.; Cojoc, D.

    2011-08-01

    We probe chemotaxis of single neurons, induced by signalling molecules which were optically delivered from liposomes in the neighbourhood of the cells. We implemented an optical tweezers setup combined with a micro-dissection system on an inverted microscope platform. Molecules of Netrin-1 protein were encapsulated into micron-sized liposomes and manipulated to micrometric distances from a specific growth cone of a hippocampal neuron by the IR optical tweezers. The molecules were then released by breaking the liposomes with UV laser pulses. Chemotaxis induced by the delivered molecules was confirmed by the migration of the growth cone toward the liposome position. Since the delivery can be manipulated with high temporal and spatial resolution and the number of molecules released can be controlled quite precisely by tuning the liposome size and the solution concentration, this technique opens new opportunities to investigate the effect of physiological active compounds as Netrin-1 to neuronal signalling and guidance, which represents an important issue in neurobiology.

  13. Delayed photolysis of liposomes: a strategy for the precision timing of bolus drug release using ex-vivo photochemical sensitization

    NASA Astrophysics Data System (ADS)

    Kozikowski, Raymond T.; Sorg, Brian S.

    2012-03-01

    Chemotherapy is a standard treatment for metastatic cancer. However drug toxicity limits the dosage that can safely be used, thus reducing treatment efficacy. Drug carrier particles, like liposomes, can help reduce toxicity by shielding normal tissue from drug and selectively depositing drug in tumors. Over years of development, liposomes have been optimized to avoid uptake by the Reticuloendothelial System (RES) as well as effectively retain their drug content during circulation. As a result, liposomes release drug passively, by slow leakage, but this uncontrolled drug release can limit treatment efficacy as it can be difficult to achieve therapeutic concentrations of drug at tumor sites even with tumor-specific accumulation of the carriers. Lipid membranes can be photochemically lysed by both Type I (photosensitizer-substrate) and Type II (photosensitizer-oxygen) reactions. It has been demonstrated in red blood cells (RBCs) in vitro that these photolysis reactions can occur in two distinct steps: a light-initiated reaction followed by a thermally-initiated reaction. These separable activation steps allow for the delay of photohemolysis in a controlled manner using the irradiation energy, temperature and photosensitizer concentration. In this work we have translated this technique from RBCs to liposomal nanoparticles. To that end, we present in vitro data demonstrating this delayed bolus release from liposomes, as well as the ability to control the timing of this event. Further, we demonstrate for the first time the improved delivery of bioavailable cargo selectively to target sites in vivo.

  14. Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response.

    PubMed

    Jiang, Lei; Li, Li; He, Xiaodan; Yi, Qiangying; He, Bin; Cao, Jun; Pan, Weisan; Gu, Zhongwei

    2015-06-01

    Mitochondrion-orientated transportation of smart liposomes has been developed as a promising strategy to deliver anticancer drugs directly to tumor sites, and these have a tremendous potential for killing cancer cells, especially those with multidrug resistance (MDR). Herein we report a novel dual-functional liposome system possessing both extracellular pH response and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of drug-resistant cancer cells. Briefly, peptide D[KLAKLAK]2 (KLA) was modified with 2, 3-dimethylmaleic anhydride (DMA) and combined with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a DSPE-KLA-DMA (DKD) lipid. This dual-functional DKD was then mixed with other commercially available lipids to fabricate liposomes. In vitro anticancer efficacy of this liposome system was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/Taxol cells. At tumor extracellular pH (∼6.8), liposomes could reverse their surface charge (negative to positive), facilitating liposome internalization. After cellular uptake, KLA peptide directed delivery-enabled selective accumulation of these liposomes into mitochondria and favored release of their cargo paclitaxel (PTX) into desired sites. Specifically, enhanced apoptosis of MDR cancer cells through mitochondrial signaling pathways was evidenced by release of cytochrome c and increased activity of caspase-9 and -3. These dual-functional liposomes had the greatest efficacy for treating A549 cells and A549/Taxol cells in vitro, and in treating drug-resistant lung cancer A549/Taxol cells xenografted onto nude mice (tumor growth inhibition 86.7%). In conclusion, dual-functional liposomes provide a novel and versatile approach for overcoming MDR in cancer treatment.

  15. Clinical overview on Lipoplatin: a successful liposomal formulation of cisplatin.

    PubMed

    Boulikas, Teni

    2009-08-01

    Nanoparticle formulations for packaging existing drugs have been used to treat cancer. Lipoplatin is a liposomal cisplatin encapsulated into liposome nanoparticles of an average diameter of 110 nm. Lipoplatin has substantially reduced the renal toxicity, peripheral neuropathy, ototoxicity, myelotoxicity as well as nausea/vomiting and asthenia of cisplatin in Phase I, II and III clinical studies with enhanced or similar efficacy to cisplatin. During clinical development, 10- to 200-fold higher accumulation of Lipoplatin in solid tumors compared to adjacent normal tissue was found in patients. Targeting of tumor vasculature by Lipoplatin in animals suggested its antiangiogenesis potential and Lipoplatin was proposed to act like a double-sword: as chemotherapy and an antiangiogenesis drug. Lipoplatin has finished successfully one Phase III non-inferiority clinical study as first-line against NSCLC in its combination with paclitaxel showing statistically significant reduction in nephrotoxicity; two more Phase III studies are in progress, one in NSCLC with gemcitabine also showing noninferiority with reduced toxicity and another in squamous cell carcinoma of the head and neck with 5-fluorouracil. A registrational Phase II/III study against pancreatic cancer is in progress under the orphan drug status granted to Lipoplatin by the European Medicines Agency. Phase II studies are continuing in advanced breast cancer with vinorelbine and gastrointestinal cancers with radiotherapy and 5-fluorouracil. The highlights of the clinical development of Lipoplatin are reviewed.

  16. Safety and tolerability of intrathecal liposomal cytarabine as central nervous system prophylaxis in patients with acute lymphoblastic leukemia.

    PubMed

    Valentin, Angelika; Troppan, Katharina; Pfeilstöcker, Michael; Nösslinger, Thomas; Linkesch, Werner; Neumeister, Peter

    2014-08-01

    Central nervous system recurrence in acute lymphoblastic leukemia (ALL) occurs in up to 15% of patients and is frequently associated with poor outcome. The purpose of our study was to evaluate the efficacy and safety of a slow-release liposomal formulation of cytarabine for intrathecal (IT) meningeal prophylaxis in patients suffering from ALL. Forty patients aged 20-77 years (median 36) were preventively treated with a total of 96 (range 1-6) single doses containing 50 mg of liposomal cytarabine on a compassionate use basis. After a median observation period of 23 months (range 2-118) only two patients experienced a combined medullary-leptomeningeal disease recurrence after primary diagnosis. Except for headache grade 2 in two patients, no specific toxicity attributable to IT liposomal cytarabine application was noted. Long-term neurological side effects were not observed. IT liposomal cytarabine therapy with concomitant dexamethasone appears to be feasible and well tolerated.

  17. A Content Incontinent: Report of Liposomal Bupivacaine Induced Fecal Incontinence

    PubMed Central

    Rai, Vinay K.

    2016-01-01

    Proper surgical management of anal fistula demands sound clinical judgment and extraordinary care to prevent incontinence and adequate postoperative pain control and provide satisfactory resolution to optimize quality of life. Fecal incontinence can be a devastating complication of procedures performed for fistula in ano. We report a unique case in which temporary incontinence (for less than 4 days) followed injection of liposomal bupivacaine for postoperative pain control after draining seton placement for fistula in ano. Patients and physicians should be aware as it may be mistaken for a more serious anatomical and permanent cause of fecal incontinence. PMID:27747127

  18. Multifunctional targeting vinorelbine plus tetrandrine liposomes for treating brain glioma along with eliminating glioma stem cells

    PubMed Central

    Li, Xue-tao; Tang, Wei; Jiang, Ying; Wang, Xiao-min; Wang, Yan-hong; Cheng, Lan; Meng, Xian-sheng

    2016-01-01

    Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood–brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma. PMID:27029055

  19. A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo

    PubMed Central

    Huang, Yifei; Yang, Tan; Zhang, Wendian; Lu, Yao; Ye, Peng; Yang, Guang; Li, Bin; Qi, Shibo; Liu, Yong; He, Xingxing; Lee, Robert J; Xu, Chuanrui; Xiang, Guangya

    2014-01-01

    Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents. PMID:25302024

  20. Novel chitosan derivative for temperature and ultrasound dual-sensitive liposomal microbubble gel.

    PubMed

    Chen, Daquan; Yu, Hongyun; Mu, Hongjie; Wei, Junhua; Song, Zhenkun; Shi, Hong; Liang, Rongcai; Sun, Kaoxiang; Liu, Wanhui

    2013-04-15

    In this study, a novel liposome-loaded microbubble gel based on N-cholesteryl hemisuccinate-O-sulfate chitosan (NCHOSC) was designed. The structure of the NCHOSC was characterized by FTIR and (1)H NMR. The liposomal microbubble gel based on NCHOSC with a high encapsulation efficiency of curcumin was formed and improved the solubility of curcumin. The diameter of most liposomal microbubble was about 950 nm. The temperature-sensitive CS/GP gel could be formulated at room temperature and would form a gel at body temperature. Simultaneously, the ultrasound-sensitive induced release of curcumin was 85% applying ultrasound. The results of cytotoxicity assay indicated that encapsulated curcumin in Cur-LM or Cur-LM-G was less toxic. The anti-tumor efficacy in vivo suggested that Cur-LM-G by ultrasound suppressed tumor growth most efficiently. These findings have shed some light on the potential NCHOSC material used to liposome-loaded microbubble gel for temperature and ultrasound dual-sensitive drug delivery.

  1. Liposome-based delivery systems for ginsenoside Rh2: in vitro and in vivo comparisons

    NASA Astrophysics Data System (ADS)

    Xu, Linqiang; Yu, Hua; Yin, Shaoping; Zhang, Ruixia; Zhou, Yudan; Li, Juan

    2015-10-01

    The Ginsenoside Rh2 (Rh2) has been shown to possess anti-cancer properties both in vitro and in vivo. However, the poor bioavailability and fast plasma elimination limit the further clinical applications of Rh2 for cancer treatments. In the present study, three types of Rh2-loaded liposomes including Rh2-loaded normal liposome (Rh2-LP), Rh2-loaded cationic liposome (Rh2-CLP), and Rh2-loaded Methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) liposome (Rh2-PLP) have been optimized and prepared with mean particle size of 80-125 nm. Compared to Rh2-LP, surface modifications with mPEG or octadecylamine significantly improve the physicochemical and biological properties both in vitro and in vivo. Moreover, PLP presented better tumor accumulation of the fluorescent cyanine dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) in HepG2-xenografted nude mice than CLP (1.3-fold) or LP (1.6-fold) and prolong the resident time of DiR in tumor and organs (more than 24 h). The in vivo anti-cancer efficacy assessments indicate that Rh2-PLP presents the most activity on suppressing tumor growth in HepG2-xenografted mice than Rh2-LP and Rh2-CLP and without any significant toxicity. Our results indicate that mPEG-PLA modified liposome should be a potential and promising strategy to enhance the therapeutic index for anti-cancer agents.

  2. Oral peptide delivery by tetraether lipid liposomes.

    PubMed

    Parmentier, Johannes; Thewes, Bernhard; Gropp, Felix; Fricker, Gert

    2011-08-30

    The aim of this study is to improve of oral peptide delivery by a novel type of liposomes containing tetraether lipids (TELs) derived from archaea bacteria. Liposomes were used for the oral delivery of the somatostatin analogue octreotide. TELs were extracted from Sulfolobus acidocaldarius and subsequently purified to single compounds. Liposomes were prepared by the film method followed by extrusion. Vesicles in size between 130 and 207 nm were obtained as confirmed by photon correlation spectroscopy. The pharmacokinetics of radiolabeled TELs in liposomes was investigated after oral administration to rats. 1.6% of the applied radioactivity in fed and 1.5% in fasted rats was recovered in the blood and inner organs after 2h, while most of the radioactivity remained in the gastro-intestinal tract. After 24h the percentage of radioactivity in inner organs was reduced to 0.6% in fed rats, respectively 1.0% in fasted animals. Several liposomal formulations containing dipalmitoyl phosphatidylcholine (DPPC) and TELs in different ratios were loaded with octreotide and orally administered. Liposomes with 25% TEL could improve the oral bioavailability of octreotide 4.1-fold and one formulation with a cationic TEL derivative 4.6-fold. TEL-liposomes probably act by protecting the peptide in the gastro-intestinal tract.

  3. Signs and Symptoms of Wilms Tumor

    MedlinePlus

    ... Detection, Diagnosis, and Staging Signs and Symptoms of Wilms Tumor Wilms tumors can be hard to find early ... Your Child’s Doctor About Wilms Tumor? More In Wilms Tumor About Wilms Tumor Causes, Risk Factors, and Prevention ...

  4. Preparation of connexin43-integrated giant Liposomes by a baculovirus expression-liposome fusion method.

    PubMed

    Kamiya, Koki; Tsumoto, Kanta; Arakawa, Satoko; Shimizu, Shigeomi; Morita, Ikuo; Yoshimura, Tetsuro; Akiyoshi, Kazunari

    2010-12-01

    Connexin-43 (Cx43) containing giant liposomes (GL) were prepared by a baculovirus expression-liposome fusion method. Recombinant budded viruses expressing Cx43 were prepared and then fused with GLs containing DOPG/DOPC at pH 4.5. Connexon formation on the GL membrane was observed by transmission electron microscope. Hydrophilic fluorescent dye transfers were observed through a Cx43-mediated pathway not only between Sf9 (Spodoptera frugiperda) cells with Cx43 but also from giant Cx43 liposomes to Cx43-expressing U2OS cells (human osteosarcoma cell). The functional connexin-containing liposome is expected to be useful for cellular cytosolic delivery systems. The original orientation and function of Cx43 was maintained after integration into the liposomes. The liposome fusion method will create new opportunities as a tool for analysis of channel membrane proteins.

  5. Helicobacter pylori TlyA agglutinates liposomes and induces fusion and permeabilization of the liposome membranes.

    PubMed

    Lata, Kusum; Chattopadhyay, Kausik

    2014-06-10

    Helicobacter pylori TlyA is a pore-forming hemolysin with potent cytotoxic activity. To explore the potential membrane-damaging activity of H. pylori TlyA, we have studied its interaction with the synthetic liposome vesicles. In our study, H. pylori TlyA shows a prominent ability to associate with the liposome vesicles without displaying an obligatory requirement for any protein receptor on the liposome membranes. Interaction of TlyA triggers agglutination of the liposome vesicles. Such agglutinating activity of TlyA could also be observed with erythrocytes before the induction of its pore-forming hemolytic activity. In addition to its agglutinating activity against liposomes, TlyA also induces fusion and disruption of the liposome membranes. Altogether, our study highlights novel membrane-damaging properties of H. pylori TlyA that have not been documented previously with any other TlyA family protein.

  6. Validated RP-HPLC method for the simultaneous analysis of gemcitabine and LY-364947 in liposomal formulations.

    PubMed

    Bansal, Shyam S; Celia, Christian; Ferrati, Silvia; Zabre, Erika; Ferrari, Mauro; Palapattu, Ganesh; Grattoni, Alessandro

    2013-08-01

    Combined use of gemcitabine (Gem) and LY-364947 (LY), a TGF-β1 receptor inhibitor, has shown promise for the treatment of fibrotic pancreatic cancer, by reducing collagen production and improving tumor drug penetration. The preparation and optimization of novel Gem and LY formulations, including co-encapsulation in liposomes, require a validated method for the simultaneous quantification of both drugs, a method that had yet to be developed. Here we demonstrate an RP-HPLC protocol for the simultaneous detection of Gem and LY at 266 and 228 nm with retention times of 3.37 and 11.34 mins, respectively. The method, which uses a C18 column and a KH2PO4 (10 mM)-methanol mobile phase, was validated for linearity, precision, accuracy, limits of detection, and robustness. Co-loaded liposomes with both Gem and LY (Gem/LY liposomes) were developed to investigate the protocol applicability to pharmacokinetic analysis and formulation characterization. The method specificity was evaluated in presence of liposomal components in fetal bovine serum (FBS). Finally, the method was demonstrated by quantifying Gem/LY liposomal encapsulation efficiency and concentration liposomes-spiked FBS.

  7. Development and evaluation of emulsion-liposome blends for resveratrol delivery.

    PubMed

    Hung, Chi-Feng; Chen, Jan-Kan; Liao, Mei-Hui; Lo, Huey-Ming; Fang, Jia-You

    2006-01-01

    Nano- and submicron-sized vesicles are beneficial for the controlled delivery of drugs. Resveratrol, the main active polyphenol in red wine, was incorporated into various combinations of emulsions and liposomes to examine its physicochemical characteristics and cardiovascular protection. The blends of emulsion-liposome were composed of coconut oil, soybean lecithin, glycerol formal, and non-ionic surfactants. Multiple systems were assessed by evaluating the droplet size, surface charge, drug encapsulation, release rate, and stability. The vesicle diameter of the systems ranged from 114 to 195 nm. The liposomal vesicles in the systems had smaller diameters (of 43 approximately 56 nm) (F6 and F7). Drug encapsulation of approximately 70% were achieved by the vesicles. The inclusion of resveratrol in these systems retarded the drug release in both the presence and absence of plasma in vitro. The emulsion-liposome blends which incorporated Brij 98 (F5) exhibited the slowest release at zero-order for resveratrol delivery. Treatment using resveratrol in the blended formulations dramatically inhibited vascular intimal thickening, which was tested in an experimental model in which endothelial injury was produced in normal rat carotid arteries. Intraperitoneal injection of the multiple systems was associated with no or negligible liver and kidney toxicity. We concluded that encapsulation by the emulsion-liposome blends is a potent way to enhance the preventative and therapeutic benefits of resveratrol.

  8. Preparation and investigation of Ulex europaeus agglutinin I-conjugated liposomes as potential oral vaccine carriers.

    PubMed

    Li, KeXin; Chen, DaWei; Zhao, XiuLi; Hu, HaiYang; Yang, ChunRong; Pang, DaHai

    2011-11-01

    We prepared and optimized Ulex europaeus agglutinin I (UEAI)-modified Bovine serum albumin (BSA)-encapsulating liposomes (UEAI-LIP) as oral vaccine carriers and examined the feasibility of inducing systemic and mucosal immune responses by oral administration of UEAILIP. The prepared systems were characterized in vitro for their average size, zeta potential, encapsulation efficiency (EE%) and conjugation efficiency (CE%). In vitro release studies indicated that the presence of UEAI around the optimized liposomes was able to prevent a burst release of loaded BSA and provide sustained release of the encapsulated protein. In vivo immune-stimulating results in KM mice showed that BSA given intramuscularly generated systemic response only but both systemic and mucosal immune responses could be induced simultaneously in the groups in which BSA-loaded liposomes (LIP) and UEAI-LIP were administered intragastrically. Furthermore, the modification of UEAI on the surface of liposomes could further enhance the IgA and IgG levels obviously. In conclusion, this study demonstrated the high potential of lectin-modified liposomes containing the antigen as carriers for oral vaccine.

  9. Polymer-associated liposomes for the oral delivery of grape pomace extract.

    PubMed

    Manconi, Maria; Marongiu, Francesca; Castangia, Ines; Manca, Maria Letizia; Caddeo, Carla; Tuberoso, Carlo Ignazio Giovanni; D'hallewin, Guy; Bacchetta, Gianluigi; Fadda, Anna Maria

    2016-10-01

    The pomaces from red grapes were used as a source of phenolic antioxidants, which are known to have health-promoting effects. Environmentally-friendly extraction strategies were investigated to improve the rate and recovery of an extract with high phenolic content and antioxidant activity, which were evaluated by the Folin-Ciocalteu, DPPH, ABTS(+), CUPRAC and FRAP assays. The extract was incorporated in liposomes, which were stabilized by the addition of a natural polysaccharide, sodium alginate or arabic gum, widely used in pharmaceutical and food industries as thickeners and stabilizers. Results showed that the polymer-associated liposomes were approximately 300nm in size, spherical in shape, and with high entrapment efficiency. The polymers prevented vesicle degradation in the gastric environment, and played a key role in improving liposomes' performances, especially arabic gum. The polymer-associated liposomes were biocompatible and protected Caco-2 cells against oxidative stress. The achieved results suggest a potential application of the polymer-associated liposomes loaded with the grape pomace extract in the nutraceutical field.

  10. The Role of Cavitation in Liposome Formation

    PubMed Central

    Richardson, Eric S.; Pitt, William G.; Woodbury, Dixon J.

    2007-01-01

    Liposome size is a vital parameter of many quantitative biophysical studies. Sonication, or exposure to ultrasound, is used widely to manufacture artificial liposomes, yet little is known about the mechanism by which liposomes are affected by ultrasound. Cavitation, or the oscillation of small gas bubbles in a pressure-varying field, has been shown to be responsible for many biophysical effects of ultrasound on cells. In this study, we correlate the presence and type of cavitation with a decrease in liposome size. Aqueous lipid suspensions surrounding a hydrophone were exposed to various intensities of ultrasound and hydrostatic pressures before measuring their size distribution with dynamic light scattering. As expected, increasing ultrasound intensity at atmospheric pressure decreased the average liposome diameter. The presence of collapse cavitation was manifested in the acoustic spectrum at high ultrasonic intensities. Increasing hydrostatic pressure was shown to inhibit the presence of collapse cavitation. Collapse cavitation, however, did not correlate with decreases in liposome size, as changes in size still occurred when collapse cavitation was inhibited either by lowering ultrasound intensity or by increasing static pressure. We propose a mechanism whereby stable cavitation, another type of cavitation present in sound fields, causes fluid shearing of liposomes and reduction of liposome size. A mathematical model was developed based on the Rayleigh-Plesset equation of bubble dynamics and principles of acoustic microstreaming to estimate the shear field magnitude around an oscillating bubble. This model predicts the ultrasound intensities and pressures needed to create shear fields sufficient to cause liposome size change, and correlates well with our experimental data. PMID:17766335

  11. Liposomes for targeting of antigens and drugs: immunoadjuvant activity and liposome-mediated depletion of macrophages.

    PubMed

    van Rooijen, Nico

    2008-08-01

    Liposomes have proven their use as a tool in various immunological studies. In our own studies, both their application as antigen carriers and as drug carriers appeared to be useful. Immune responses were elicited against free soluble protein antigens and against the same antigens in a liposome-associated (particulate) form, in order to compare both types of response. Since we were especially interested in the role of splenic macrophages in both types of response, we developed a liposome-mediated macrophage suicide approach, based on the liposome-mediated internalization of the small hydrophilic molecule clodronate in macrophages. This molecule has a very short half life when released in the circulation, but does not easily cross phospholipid bilayers of liposomes or cell membranes. As a consequence, once ingested by a macrophage in a liposome-encapsulated form, it will be accumulated within the cell as soon as the liposomes are digested with the help of its lysosomal phospholipases. At a certain intracellular clodronate concentration, the macrophage is eliminated by apoptosis. Given the fact that neither the liposomal phospholipids chosen nor clodronate are toxic to other (non-phagocytic) cells, this method has proven its efficacy for depletion of macrophage subsets in various organs. In several cases, organ-specific depletion can be obtained by choosing the right administration route for the clodronate liposomes.

  12. Omega-3 Polyunsaturated Fatty Acids Inhibited Tumor Growth via Preventing the Decrease of Genomic DNA Methylation in Colorectal Cancer Rats.

    PubMed

    Huang, Qionglin; Wen, Juan; Chen, Guangzhao; Ge, Miaomiao; Gao, Yihua; Ye, Xiaoxia; Liu, Chunan; Cai, Chun

    2016-01-01

    Omge-3 polyunsaturated fatty acids (PUFAs) exhibited significant effect in inhibiting various tumors. However, the mechanisms of its anticancer role have not been fully demonstrated. The declination of 5-methylcytosine (5 mC) was closely associated with poor prognosis of tumors. To explore whether omega-3 PUFAs influences on DNA methylation level in tumors, colorectal cancer (CRC) rat model were constructed using N-methyl phosphite nitrourea and omega-3 PUFAs were fed to part of the rats during tumor induction. The PUFAs contents in the rats of 3 experimental groups were measured using gas chromatography and 5 mC level were detected by liquid chromatography tandem mass spectrometry. The results showed that tumor incidence in omega-3 treated rats was much lower than in CRC model rats, which confirmed significant antitumor role of omega-3 PUFAs. Six PUFA members categorized to omega-3 and omega-6 families were quantified and the ratio of omega-6/omega-3 PUFAs was remarkably lower in omega-3 PUFAs treatment group than in CRC model group. 5 mC content in omega-3 PUFAs treated rats was higher than in CRC model rats, suggesting omega-3 PUFAs promoted 5 mC synthesis. Therefore, omega-3 PUFAs probably inhibited tumor growth via regulating DNA methylation process, which provided a novel anticancer mechanism of omega-3 PUFAs from epigenetic view.

  13. Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes.

    PubMed

    Rezaei-Sadabady, Rogaie; Eidi, Akram; Zarghami, Nosratollah; Barzegar, Abolfazl

    2016-01-01

    Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a natural bio-flavonoid originating from fruits, vegetables, seeds, berries, and tea. The antioxidant activity of quercetin and its protective effects against cardiovascular disorders, anti-cancer, anti-inflammatory, and anti-viral activities have been extensively documented; however, the clinical request of quercetin in cancer treatment is significantly limited due to its very poor delivery features. In order to increase the hydrophilicity and drug delivery capability, we encapsulated quercetin into liposomes. Our data indicated that liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be used as an effective antioxidant for ROS protection within the polar cytoplasm, and the nano-sized quercetin encapsulated by liposomes enhanced the cellular uptake (cancer cell human MCF_7). Quercetin has many pharmaceutical applications, many of which arise from its potent antioxidant properties. The present research examined the antioxidant activities of quercetin in polar solvents by a comparative study using reduction of ferric iron in aqueous medium, intracellular ROS/toxicity assays, and reducing DPPH assays. Cell viability and ROS assays demonstrated that quercetin was able to penetrate into the polar medium inside the cells and to protect them against the highly toxic and deadly belongings of cumene hydroperoxide. The purpose of this study was to determine whether a liposomal formulation of quercetin can suggestively improve its solubility and bioavailability and can be a possible request in the treatment of tumor. The authors encapsulated quercetin in a liposomal delivery system. They studied the in vitro effects of this compound on proliferation using human MCF-7 carcinoma cells. The activity of liposomal quercetin was equal to or better than that of free quercetin at equimolar concentrations. Our data indicated that liposomal quercetin can significantly improve the

  14. Site-specific conjugation of single domain antibodies to liposomes enhances photosensitizer uptake and photodynamic therapy efficacy.

    PubMed

    Broekgaarden, M; van Vught, R; Oliveira, S; Roovers, R C; van Bergen en Henegouwen, P M P; Pieters, R J; Van Gulik, T M; Breukink, E; Heger, M

    2016-03-28

    Photodynamic therapy for therapy-resistant cancers will greatly benefit from targeted delivery of tumor photosensitizing agents. In this study, a strategy for the site-specific conjugation of single domain antibodies onto liposomes containing the photosensitizer zinc phthalocyanine was developed and tested.

  15. The effect of thermosensitive liposomal formulations on loading and release of high molecular weight biomolecules.

    PubMed

    Huang, Xiaoyi; Li, Min; Bruni, Riccardo; Messa, Piergiorgio; Cellesi, Francesco

    2017-04-02

    Thermosensitive liposomes are clinically-relevant nanocarriers which have been used to deliver chemotherapeutic agents to tumors in combination with local hyperthermia. However, the encapsulation and release of macromolecular therapeutic agents (proteins, nucleic acids, bioactive polymers) is often hindered by their instability during the liposome formation as well as by the low encapsulation efficiency. The objective of this study was to investigate the influence of the thermosensitive liposomal formulation on the encapsulation and release of low and high molecular weight hydrophilic drugs, in order to identify the key parameters to control during nanocarrier design, depending on the specific drug delivery application. Thermosensitive liposomes with different formulations were prepared through the combinations of different lipids, including dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cholesterol (Chol), 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (P-Lyso-PC), and the PEGylated lipid distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(PEG)-2000 (DSPE-PEG2000). The thin film hydration method was used for liposome preparation and loading of different water soluble molecules. The encapsulation efficiency and release profiles were investigated for a low molecular weight compound such as carboxyfluorescein (CF), proteins (albumin), and hydrophilic polymers which do not interact with the lipid bilayer, such as a linear dextran and a poly(ethylene glycol)-based star polymer. An optimised liposomal formulation [DPPC/P-lyso-PC/DSPE-PEG2000 90/10/4 (mol/mol) (LTSL)] was chosen for further application in encapsulating therapeutic proteins, such as lysozyme and the brain-derived neurotrophic factor (BDNF), which are recognized as drug carriers and potential therapeutic agents for kidney diseases and neurological disorders.

  16. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells.

    PubMed

    Pasquier, Benoit

    2015-04-03

    Autophagy plays an important role in cancer and it has been suggested that it functions not only as a tumor suppressor pathway to prevent tumor initiation, but also as a prosurvival pathway that helps tumor cells endure metabolic stress and resist death triggered by chemotherapeutic agents. We recently described the discovery of inhibitors of PIK3C3/Vps34 (phosphatidylinositol 3-kinase, catalytic subunit type 3), the lipid kinase component of the class III phosphatidylinositol 3-kinase (PtdIns3K). This PtdIns3K isoform has attracted significant attention in recent years because of its role in autophagy. Following chemical optimization we identified SAR405, a low molecular mass kinase inhibitor of PIK3C3, highly potent and selective with regard to other lipid and protein kinases. We demonstrated that inhibiting the catalytic activity of PIK3C3 disrupts vesicle trafficking from late endosomes to lysosomes. SAR405 treatment also inhibits autophagy induced either by starvation or by MTOR (mechanistic target of rapamycin) inhibition. Finally our results show that combining SAR405 with everolimus, the FDA-approved MTOR inhibitor, results in a significant synergy on the reduction of cell proliferation using renal tumor cells. This result indicates a potential therapeutic application for PIK3C3 inhibitors in cancer.

  17. CXCR4-antagonist Peptide R-liposomes for combined therapy against lung metastasis

    NASA Astrophysics Data System (ADS)

    Ieranò, Caterina; Portella, Luigi; Lusa, Sara; Salzano, Giuseppina; D'Alterio, Crescenzo; Napolitano, Maria; Buoncervello, Maria; Macchia, Daniele; Spada, Massimo; Barbieri, Antonio; Luciano, Antonio; Barone, Maria Vittoria; Gabriele, Lucia; Caraglia, Michele; Arra, Claudio; De Rosa, Giuseppe; Scala, Stefania

    2016-03-01

    The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination. While there has been great enthusiasm for exploiting the CXCR4-CXCL12 axis as a target in cancer therapy, to date the promise has yet to be fulfilled. A new class of CXCR4-antagonist cyclic peptides was recently developed and the compound named Peptide R was identified as the most active. With the intent to improve the efficacy and biodistribution of Peptide R, stealth liposomes decorated with Peptide R were developed (PL-Peptide R). In vitro PL-Peptide R efficiently inhibited CXCR4-dependent migration and in vivo it significantly reduced lung metastases and increased overall survival in B16-CXCR4 injected C57BL/6 mice. To evaluate if PL-Peptide R could also be a drug delivery system for CXCR4 expressing tumors, the PL-Peptide R was loaded with doxorubicin (DOX) (PL-Peptide R-DOX). PL-Peptide R-DOX efficiently delivered DOX to CXCR4 expressing cell lines with a consequent decrease in the DOX IC50 efficient dose. In vivo, B16-CXCR4 injected C57BL/6 mice treated with PL-Peptide R-DOX developed fewer lung metastases compared to PL-DOX treated mice. This work provides the proof-of-concept to prevent metastasis by using combined nanomedicine.The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination. While there has been great enthusiasm for exploiting the CXCR4-CXCL12 axis as a target in cancer therapy, to date the promise has yet to be fulfilled. A new class of CXCR4-antagonist cyclic peptides was recently developed and the compound named Peptide R was identified as the most active. With the intent to improve the efficacy and biodistribution of Peptide R, stealth liposomes decorated with Peptide

  18. Liposomes as delivery systems for antineoplastic drugs

    NASA Astrophysics Data System (ADS)

    Medina, Luis Alberto

    2014-11-01

    Liposome drug formulations are defined as pharmaceutical products containing active drug substances encapsulated within the lipid bilayer or in the interior aqueous space of the liposomes. The main importance of this drug delivery system is based on its drastic reduction in systemic dose and concomitant systemic toxicity that in comparison with the free drug, results in an improvement of patient compliance and in a more effective treatment. There are several therapeutic drugs that are potential candidates to be encapsulated into liposomes; particular interest has been focused in therapeutic and antineoplastic drugs, which are characterized for its low therapeutic index and high systemic toxicity. The use of liposomes as drug carriers has been extensively justified and the importance of the development of different formulations or techniques to encapsulate therapeutic drugs has an enormous value in benefit of patients affected by neoplastic diseases.

  19. [The entrapped efficiency of BSA liposome].

    PubMed

    Hou, Dong-Zhi; Liu, Chang-Ke; Ping, Qi-Neng; Liang, Xiao-Hui

    2007-05-01

    BSA liposomes were prepared with approximately 100 nm mean particle size under rather gentle experiment conditions, and two-colorimetric coomassie brilliant blue protein was employed to measure the free drug in the entrapped efficiency (EE%) determination of BSA liposomes. Gel filtration was used to measure the EE%, and several Sephadex gels were examined by the separation of liposomes and free drug. To determine the free drug, three methods were compared on two-colorimetric UV spectrophotography, Bradford and two-colorimetric coomassie brilliant blue, separately. Two-colorimetric coomassie brilliant blue process increased the accuracy and improved the sensitivity of the assay about 20-fold comparing with the Bradford method. Two-colorimetric coomassie brilliant blue assay appeared to be more sensitive and showed broader dynamic range to measure the free BSA in the EE% determination of BSA liposome.

  20. Liposomal anticancer therapy: pharmacokinetic and clinical aspects.

    PubMed

    Di Paolo, A

    2004-11-01

    Liposomes, which are vesicles composed of a phospholipid bilayer surrounding an aqueous milieu, represent a new strategy for anticancer drug delivery. Extravasation and accumulation of liposomal drugs within neoplastic tissues are possible because of the leaky vasculature and scarce lymphatic vessels of tumours (the enhanced permeability and retention effect). Furthermore, liposomal chemotherapeutic agents display distinctive pharmacokinetic characteristics, because they possess longer elimination half-lives, reduced clearance and smaller volume of distribution with respect to corresponding free drugs. Taken together, these features lead to highest levels of cytotoxic agents in tumours, as demonstrated in preclinical models and clinical trials, whereas healthy tissues are spared from toxicity. In fact, liposomal drugs (i.e., doxorubicin), alone or in combination with other cytotoxic agents, lead to improved clinical effectiveness and ameliorated toxicity profile with respect to corresponding free drugs when they are used for the treatment of metastatic breast and ovarian cancers, and Kaposi's sarcoma.

  1. Use of Liposomes as Drug Delivery Vehicles for Treatment of Melanoma

    PubMed Central

    Tran, Melissa A.; Watts, Rebecca J.; Robertson, Gavin P.

    2009-01-01

    Melanoma is a progressive disease that claims many lives each year due to lack of therapeutics effective for the long-term treatment of patients. Currently, the best treatment option is early detection followed by surgical removal. Better melanoma therapies that are effectively delivered to tumors with minimal toxicity for patients are urgently needed. Nanotechnologies provide one approach to encapsulate therapeutic agents leading to improvements in circulation time, enhanced tumor uptake, avoidance of the reticulo-endothelial system, and minimization of toxicity. Liposomes in particular are a promising nanotechnology that can be used for more effective delivery of therapeutic agents to treat melanoma. Liposomes delivering chemotherapies, siRNA, asODNs, DNA, and radioactive particles are just some of the promising new nanotechnology based therapies under development for the treatment of melanoma that are discussed in this review. PMID:19493316

  2. The Effectiveness of Raloxifene-Loaded Liposomes and Cochleates in Breast Cancer Therapy.

    PubMed

    Ağardan, N Başaran Mutlu; Değim, Zelihagül; Yılmaz, Şükran; Altıntaş, Levent; Topal, Turgut

    2016-08-01

    Liposome (spherical vesicles) and cochleate (multilayer crystalline, spiral structure) formulations containing raloxifene have been developed having dimethyl-β-cyclodextrin (DM-β-CD) or sodium taurocholate (NaTC). Raloxifene was approved initially for the treatment of osteoporosis but it is also effective on breast tissue and endometrial cells. Raloxifene inhibits matrix metalloproteinase-2 (MMP-2) enzyme, which is known to be responsible for tumor invasion and the initiation of angiogenesis during the tumor growth. Therefore, raloxifene was selected as a model drug. A series of raloxifene-loaded liposome and cochleate formulations were prepared. In vitro release studies and in vivo tests were performed. Breast cancer cell lines (MCF-7) were also used to find the most effective formulation. Highest antitumor activity was observed, and MMP-2 enzyme was also found to be inhibited with raloxifene-loaded cochleates containing DM-β-CD. These developed formulations can be helpful for further treatment alternatives and new strategies for cancer therapy.

  3. Surface fractals in liposome aggregation.

    PubMed

    Roldán-Vargas, Sándalo; Barnadas-Rodríguez, Ramon; Quesada-Pérez, Manuel; Estelrich, Joan; Callejas-Fernández, José

    2009-01-01

    In this work, the aggregation of charged liposomes induced by magnesium is investigated. Static and dynamic light scattering, Fourier-transform infrared spectroscopy, and cryotransmission electron microscopy are used as experimental techniques. In particular, multiple intracluster scattering is reduced to a negligible amount using a cross-correlation light scattering scheme. The analysis of the cluster structure, probed by means of static light scattering, reveals an evolution from surface fractals to mass fractals with increasing magnesium concentration. Cryotransmission electron microscopy micrographs of the aggregates are consistent with this interpretation. In addition, a comparative analysis of these results with those previously reported in the presence of calcium suggests that the different hydration energy between lipid vesicles when these divalent cations are present plays a fundamental role in the cluster morphology. This suggestion is also supported by infrared spectroscopy data. The kinetics of the aggregation processes is also analyzed through the time evolution of the mean diffusion coefficient of the aggregates.

  4. Status of liposomes as MR contrast agents.

    PubMed

    Unger, E C; Shen, D K; Fritz, T A

    1993-01-01

    Recent work on the development of liposomal magnetic resonance (MR) contrast agents has yielded structures with higher overall relaxivity than that of other nanoparticles of similar diameter. Liposomes incorporating membrane-bound complexes of manganase ("memsomes") produce greater hepatic enhancement per micromole of metal ion than either ferrite particles or paramagnetic chelates. Memsomes also hold promise for targeting of sites outside the liver. Work is in progress to take these agents into clinical trials.

  5. Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance.

    PubMed

    Dou, Yannan N; Weersink, Robert A; Foltz, Warren D; Zheng, Jinzi; Chaudary, Naz; Jaffray, David A; Allen, Christine

    2015-12-13

    Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e., gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.

  6. Development of Liposomal Formulation for Delivering Anticancer Drug to Breast Cancer Stem-Cell-Like Cells and its Pharmacokinetics in an Animal Model.

    PubMed

    Ahmad, Ajaz; Mondal, Sujan Kumar; Mukhopadhyay, Debabrata; Banerjee, Rajkumar; Alkharfy, Khalid M

    2016-03-07

    The objective of the present study is to develop a liposomal formulation for delivering anticancer drug to breast cancer stem-cell-like cells, ANV-1, and evaluate its pharmacokinetics in an animal model. The anticancer drug ESC8 was used in dexamethasone (Dex)-associated liposome (DX) to form ESC8-entrapped liposome named DXE. ANV-1 cells showed high-level expression of NRP-1. To enhance tumor regression, we additionally adapted to codeliver the NRP-1 shRNA-encoded plasmid using the established DXE liposome. In vivo efficacy of DXE-NRP-1 was carried out in mice bearing ANV-1 cells as xenograft tumors and the extent of tumor growth inhibition was evaluated by tumor-size measurement. A significant difference in tumor volume started to reveal between DXE-NRP-1 group and DXE-Control group. DXE-NRP-1 group showed ∼4 folds and ∼2.5 folds smaller tumor volume than exhibited by untreated and DXE-Control-treated groups, respectively. DXE disposition was evaluated in Sprague-Dawley rats following an intraperitoneal dose (3.67 mg/kg of ESC8 in DXE). The plasma concentrations of ESC8 in the DXE formulation were measured by liquid chromatography mass spectrometry and pharmacokinetic parameters were determined using a noncompartmental analysis. ESC8 had a half-life of 11.01 ± 0.29 h, clearance of 2.10 ± 3.63 L/kg/h, and volume of distribution of 33.42 ± 0.83 L/kg. This suggests that the DXE liposome formulation could be administered once or twice daily for therapeutic efficacy. In overall, we developed a potent liposomal formulation with favorable pharmacokinetic and tumor regressing profile that could sensitize and kill highly aggressive and drug-resistive cancer stem-cell-like cells.

  7. Prevention and reversal of tumor cell-induced monocyte deactivation by cytokines, purified protein derivative (PPD), and anti-IL-10 antibody.

    PubMed

    Baj-Krzyworzeka, Monika; Baran, Jaroslaw; Szatanek, Rafal; Stankiewicz, Danuta; Siedlar, Maciej; Zembala, Marek

    2004-08-25

    Upon contact with tumor cells when cocultured in vitro, human monocytes become unresponsive (deactivated) to restimulation and demonstrate decreased production of TNF-alpha and IL-12, and enhanced IL-10 secretion. The present study was undertaken to determine whether immunomodulatory agents (proinflammatory cytokines and PPD of tuberculin) could either prevent or reverse the deactivation of monocytes. Monocytes were treated with the agents either before or after being cocultured with tumor cells. Pretreatment of monocytes with IFN-gamma, either alone or in combination with TNF-alpha, GM-CSF, or PPD, significantly enhanced TNF-alpha and IL-12 production by deactivated monocytes. TNF-alpha, GM-CSF, and PPD alone were inactive. Treatment of monocytes following coculture with IFN-gamma, TNF-alpha, GM-CSF, PPD or IFN-gamma in combination with these agents reversed the depressed TNF-alpha release, whereas IL-12 production was enhanced by IFN-gamma alone. All the agents had no or only a limited effect on the enhanced IL-10 secretion by deactivated monocytes. However, treatment of cocultured monocytes with anti-IL-10 mAb significantly increased the production of TNF-alpha and IL-12 by deactivated monocytes. Moreover, coengraftment of deactivated monocytes with human pancreatic carcinoma cells into SCID mice caused an enhancement of the tumor growth that was alleviated by the treatment of monocytes in vitro with IFN-gamma alone or in combination with GM-CSF or PPD. These results suggest that activation of monocytes with certain proinflammatory cytokines and/or selective inhibition of IL-10 by a mAb may prevent or reverse monocyte deactivation caused by tumor cells.

  8. Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma

    PubMed Central

    Oberyszyn, Tatiana M.

    2013-01-01

    Ultraviolet B (UVB) light is the major environmental carcinogen contributing to non-melanoma skin cancer (NMSC) development. There are over 3.5 million NMSC diagnoses in two million patients annually, with men having a 3-fold greater incidence of squamous cell carcinoma (SCC) compared with women. Chronic inflammation has been linked to tumorigenesis, with a key role for the cyclooxygenase-2 (COX-2) enzyme. Diclofenac, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, currently is prescribed to patients as a short-term therapeutic agent to induce SCC precursor lesion regression. However, its efficacy as a preventative agent in patients without evidence of precursor lesions but with significant UVB-induced cutaneous damage has not been explored. We previously demonstrated in a murine model of UVB-induced skin carcinogenesis that when exposed to equivalent UVB doses, male mice had lower levels of inflammation but developed increased tumor multiplicity, burden and grade compared with female mice. Because of the discrepancy in the degree of inflammation between male and female skin, we sought to determine if topical treatment of previously damaged skin with an anti-inflammatory COX-2 inhibitor would decrease tumor burden and if it would be equally effective in the sexes. Our results demonstrated that despite observed sex differences in the inflammatory response, prolonged topical diclofenac treatment of chronically UVB-damaged skin effectively reduced tumor multiplicity in both sexes. Unexpectedly, tumor burden was significantly decreased only in male mice. Our data suggest a new therapeutic use for currently available topical diclofenac as a preventative intervention for patients predisposed to cutaneous SCC development before lesions appear. PMID:23125227

  9. Liposomal Formulation of Amphiphilic Fullerene Antioxidants

    PubMed Central

    Zhou, Zhiguo; Lenk, Robert P.; Dellinger, Anthony; Wilson, Stephen R.; Sadler, Robert; Kepley, Christopher L.

    2010-01-01

    Novel amphiphilic fullerene[70] derivatives that are rationally designed to intercalate in lipid bilayers are reported, as well as its vesicular formulation with surprisingly high loading capacity up to 65% by weight. The amphiphilic C70 bisadduct forms uniform and dimensionally stable liposomes with auxiliary natural phospholipids as demonstrated by buoyant density test, particle size distribution and 31P NMR. The antioxidant property of fullerenes is retained in the bipolarly functionalized C70 derivative, Amphiphilic Liposomal Malonylfullerene[70] (ALM) as well as in its liposomal formulations, as shown by both electron paramagnetic resonance (EPR) studies and in vitro reactive oxygen species (ROS) inhibition experiments. The liposomally formulated ALM efficiently quenched hydroxyl radicals and superoxide radicals. In addition, the fullerene liposome inhibited radical-induced lipid peroxidation and maintained the integrity of the lipid bilayer structure. This new class of liposomally formulated, amphipathic fullerene compounds represents a novel drug delivery system for fullerenes and provides a promising pathway to treat oxidative stress-related diseases. PMID:20839887

  10. Liposomal amphotericin B: clinical experience and perspectives.

    PubMed

    Gibbs, Winter J; Drew, Richard H; Perfect, John R

    2005-04-01

    While amphotericin B deoxycholate (Fungizone, Apothecon Pharmaceuticals) has been considered by many to be the gold standard for the treatment for numerous invasive fungal infections for over 45 years, toxicities associated with its use often necessitate treatment modification or discontinuation. Lipid-based formulations, including liposomal amphotericin B (AmBisome, Fujisawa Healthcare, Inc.), were developed to decrease many of these toxicities while retaining broad antifungal spectrum and potency of amphotericin B. In clinical trials, liposomal amphotericin B has demonstrated efficacy comparable to that of amphotericin B deoxycholate while reducing the incidence of treatment-related nephrotoxicity, electrolyte-wasting, and infusion-related reactions. In addition, recent clinical trials have also compared liposomal amphotericin B with other antifungal classes. Acquisition costs of liposomal amphotericin B are substantially higher than those of amphotericin B deoxycholate and other antifungals. While pharmacoeconomic analyses consider outcomes and other treatment-related costs, they have yet to clearly demonstrate the cost-effectiveness of liposomal amphotericin B when compared with amphotericin B deoxycholate or other antifungal agents. This review will focus primarily on recent liposomal amphotericin B experience and attempt to put its use into perspective considering other available antifungal agents.

  11. Plasmon resonant liposomes for controlled drug delivery

    NASA Astrophysics Data System (ADS)

    Knights-Mitchell, Shellie S.; Romanowski, Marek

    2015-03-01

    Nanotechnology use in drug delivery promotes a reduction in systemic toxicity, improved pharmacokinetics, and better drug bioavailability. Liposomes continue to be extensively researched as drug delivery systems (DDS) with formulations such as Doxil® and Ambisome® approved by FDA and successfully marketed in the United States. However, the limited ability to precisely control release of active ingredients from these vesicles continues to challenge the broad implementation of this technology. Moreover, the full potential of the carrier to sequester drugs until it can reach its intended target has yet to be realized. Here, we describe a liposomal DDS that releases therapeutic doses of an anticancer drug in response to external stimulus. Earlier, we introduced degradable plasmon resonant liposomes. These constructs, obtained by reducing gold on the liposome surface, facilitate spatial and temporal release of drugs upon laser light illumination that ultimately induces an increase in temperature. In this work, plasmon resonant liposomes have been developed to stably encapsulate and retain doxorubicin at physiological conditions represented by isotonic saline at 37o C and pH 7.4. Subsequently, they are stimulated to release contents either by a 5o C increase in temperature or by laser illumination (760 nm and 88 mW/cm2 power density). Successful development of degradable plasmon resonant liposomes responsive to near-infrared light or moderate hyperthermia can provide a new delivery method for multiple lipophilic and hydrophilic drugs with pharmacokinetic profiles that limit clinical utility.

  12. Octanol-assisted liposome assembly on chip

    NASA Astrophysics Data System (ADS)

    Deshpande, Siddharth; Caspi, Yaron; Meijering, Anna E. C.; Dekker, Cees

    2016-01-01

    Liposomes are versatile supramolecular assemblies widely used in basic and applied sciences. Here we present a novel microfluidics-based method, octanol-assisted liposome assembly (OLA), to form monodisperse, cell-sized (5-20 μm), unilamellar liposomes with excellent encapsulation efficiency. Akin to bubble blowing, an inner aqueous phase and a surrounding lipid-carrying 1-octanol phase is pinched off by outer fluid streams. Such hydrodynamic flow focusing results in double-emulsion droplets that spontaneously develop a side-connected 1-octanol pocket. Owing to interfacial energy minimization, the pocket splits off to yield fully assembled solvent-free liposomes within minutes. This solves the long-standing fundamental problem of prolonged presence of residual oil in the liposome bilayer. We demonstrate the unilamellarity of liposomes with functional α-haemolysin protein pores in the membrane and validate the biocompatibility by inner leaflet localization of bacterial divisome proteins (FtsZ and ZipA). OLA offers a versatile platform for future analytical tools, delivery systems, nanoreactors and synthetic cells.

  13. Octanol-assisted liposome assembly on chip.

    PubMed

    Deshpande, Siddharth; Caspi, Yaron; Meijering, Anna E C; Dekker, Cees

    2016-01-22

    Liposomes are versatile supramolecular assemblies widely used in basic and applied sciences. Here we present a novel microfluidics-based method, octanol-assisted liposome assembly (OLA), to form monodisperse, cell-sized (5-20 μm), unilamellar liposomes with excellent encapsulation efficiency. Akin to bubble blowing, an inner aqueous phase and a surrounding lipid-carrying 1-octanol phase is pinched off by outer fluid streams. Such hydrodynamic flow focusing results in double-emulsion droplets that spontaneously develop a side-connected 1-octanol pocket. Owing to interfacial energy minimization, the pocket splits off to yield fully assembled solvent-free liposomes within minutes. This solves the long-standing fundamental problem of prolonged presence of residual oil in the liposome bilayer. We demonstrate the unilamellarity of liposomes with functional α-haemolysin protein pores in the membrane and validate the biocompatibility by inner leaflet localization of bacterial divisome proteins (FtsZ and ZipA). OLA offers a versatile platform for future analytical tools, delivery systems, nanoreactors and synthetic cells.

  14. Resistive-pulse detection of multilamellar liposomes.

    PubMed

    Holden, Deric A; Watkins, John J; White, Henry S

    2012-05-15

    The resistive-pulse method was used to monitor the pressure-driven translocation of multilamellar liposomes with radii between 190 and 450 nm through a single conical nanopore embedded in a glass membrane. Liposomes (0% and 5% 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (sodium salt) in 1,2-dilauroyl-sn-glycero-3-phosphocholine or 0%, 5%, and 9% 1,2-dipalmitoyl-sn-glycero-3-phospho(1'-rac-glycerol) (sodium salt) in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine) were prepared by extrusion through a polycarbonate membrane. Liposome translocation through a glass nanopore was studied as a function of nanopore size and the temperature relative to the lipid bilayer transition temperature, T(c). All translocation events through pores larger than the liposome, regardless of temperature, show translocation times between 30 and 300 μs and current pulse heights between 0.2% and 15% from the open pore baseline. However, liposomes at temperatures below the T(c) were captured at the pore orifice when translocation was attempted through pores of smaller dimensions, but squeezed through the same pores when the temperature was raised above T(c). The results provide insights into the deformation and translocation of individual liposomes through a porous material.

  15. Octanol-assisted liposome assembly on chip

    PubMed Central

    Deshpande, Siddharth; Caspi, Yaron; Meijering, Anna E. C.; Dekker, Cees

    2016-01-01

    Liposomes are versatile supramolecular assemblies widely used in basic and applied sciences. Here we present a novel microfluidics-based method, octanol-assisted liposome assembly (OLA), to form monodisperse, cell-sized (5–20 μm), unilamellar liposomes with excellent encapsulation efficiency. Akin to bubble blowing, an inner aqueous phase and a surrounding lipid-carrying 1-octanol phase is pinched off by outer fluid streams. Such hydrodynamic flow focusing results in double-emulsion droplets that spontaneously develop a side-connected 1-octanol pocket. Owing to interfacial energy minimization, the pocket splits off to yield fully assembled solvent-free liposomes within minutes. This solves the long-standing fundamental problem of prolonged presence of residual oil in the liposome bilayer. We demonstrate the unilamellarity of liposomes with functional α-haemolysin protein pores in the membrane and validate the biocompatibility by inner leaflet localization of bacterial divisome proteins (FtsZ and ZipA). OLA offers a versatile platform for future analytical tools, delivery systems, nanoreactors and synthetic cells. PMID:26794442

  16. Vaccination with ErbB-2 peptides prevents cancer stem cell expansion and suppresses the development of spontaneous tumors in MMTV-PyMT transgenic mice.

    PubMed

    Gil, Eun-Young; Jo, Uk-Hyun; Lee, Hye Jin; Kang, Jinho; Seo, Jae Hong; Lee, Eun Sook; Kim, Yeul Hong; Kim, InSun; Phan-Lai, Vy; Disis, Mary L; Park, Kyong Hwa

    2014-08-01

    ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

  17. Development and characterization of oral liposomes of vegetal ceramide based amphotericin B having enhanced dry solubility and solubility.

    PubMed

    Skiba-Lahiani, Malika; Hallouard, François; Mehenni, Lyes; Fessi, Hatem; Skiba, Mohamed

    2015-03-01

    Despite the development of new antifungal, amphotericin B remains one of the most effective agents in the treatment of systemic fungal infections. Many patients exhibit nevertheless intolerance to amphotericin B at higher dosages and parenteral formulations present unlike per os ones, associated risks and high care cost. Free amphotericin B per os showed however an apparently poor absorption. In this study, we evaluate the potential of amphotericin B liposomes formulated with vegetal ceramides for oral administration. Ceramides, one of the constituents of cellular cytoplasmic membranes, constitute an important element in the construction and stability of their lipid bilayer. To fulfill this objective, vegetal ceramides, composed essentially of glucosylceramides, were firstly incorporated in various liposome preparations, entrapping or not amphotericin B, in comparison with phosphatidylcholine liposomes. Then, these preparations were introduced in an "Artificial-Stomach-Duodenum" model to improve their stability for oral administration. The formulation of amphotericin B liposomes containing ceramides presented a mean hydrodynamic size of about 200nm. We showed also that cholesterol and phospholipids are required to prevent drug leakage and to obtain lamellar structure respectively. In "Artificial-Stomach-Duodenum" model, ceramides conferred to liposomes better membrane stability. In addition, ceramides did not alter their drug encapsulation yield being by 75%. This could be explained by the fact that ceramides as we proved, limited the detergent effect of bile salts on liposome membranes.

  18. Comprehensive study of liposome-assisted synthesis of membrane proteins using a reconstituted cell-free translation system

    PubMed Central

    Niwa, Tatsuya; Sasaki, Yoshihiro; Uemura, Eri; Nakamura, Shugo; Akiyama, Minato; Ando, Mitsuru; Sawada, Shinichi; Mukai, Sada-atu; Ueda, Takuya; Taguchi, Hideki; Akiyoshi, Kazunari

    2015-01-01

    Membrane proteins play pivo