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Sample records for chemotherapeutic drug delivery

  1. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment.

    PubMed

    Kang, Lin; Gao, Zhonggao; Huang, Wei; Jin, Mingji; Wang, Qiming

    2015-05-01

    The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems. PMID:26579443

  2. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

    PubMed Central

    Kang, Lin; Gao, Zhonggao; Huang, Wei; Jin, Mingji; Wang, Qiming

    2015-01-01

    The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems. PMID:26579443

  3. Ultrasound-targeted microbubble destruction for chemotherapeutic drug delivery to solid tumors

    PubMed Central

    2013-01-01

    Ultrasound-targeted microbubble destruction (UTMD) is a promising technique for non-invasive, targeted drug delivery, and its applications in chemotherapeutic drug delivery to solid tumors have attracted growing interest. Ultrasound, which has been conventionally used for diagnostic imaging, has evolved as a promising tool for therapeutic applications mainly because of its ability to be focused deep inside the human body, providing a modality for targeted delivery. Although originally being introduced into clinics as ultrasound contrast agents, microbubbles (MBs) have been developed as a diagnostic and therapeutic agent that can both be tracked through non-invasive imaging and deliver therapeutic agents selectively at ultrasound-targeted locations. Whereas free drugs often possess harmful side effects, their encapsulation in MBs and subsequent local release at the targeted tissue by ultrasound triggering may help improve the margin of safety. In the past 10 years, the feasibility and safety of UTMD have been extensively tested using normal animal models. Most recently, a growing number of preclinical studies have been reported on the therapeutic benefits of UTMD in the delivery of chemotherapeutic drugs to various malignant tumors, such as brain, liver, eyelid, pancreas, and breast tumors. Increased drug concentration in tumors and reduced tumor sizes were achieved in those tumors treated with UTMD in combination with chemotherapeutic drugs, when compared to tumors treated with chemotherapy drugs alone. This review presents an overview of current preclinical applications of UTMD in chemotherapeutic drug delivery for the treatment of cancers along with a discussion of its future developments. PMID:25512858

  4. Integrin Targeted Delivery of Chemotherapeutics

    PubMed Central

    Chen, Kai; Chen, Xiaoyuan

    2011-01-01

    Targeted delivery of chemotherapeutics is defined in the sense, that is, to maximize the therapeutic index of a chemotherapeutic agent by strictly localizing its pharmacological activity to the site or tissue of action. Integrins are a family of heterodimeric transmembrane glycoproteins involved in a wide range of cell-to-extracellular matrix (ECM) and cell-to-cell interactions. As cell surface receptors, integrins readily interact with extracellular ligands and play a vital role in angiogenesis, leukocytes function and tumor development, which sets up integrins as an excellent target for chemotherapy treatment. The peptide ligands containing the arginine-glycine-aspartic acid (RGD), which displays a strong binding affinity and selectivity to integrins, particularly to integrin αvβ3, have been developed to conjugate with various conventional chemotherapeutic agents, such as small molecules, peptides and proteins, and nanoparticle-carried drugs for integtrin targeted therapeutic studies. This review highlights the recent advances in integrin targeted delivery of chemotherapeutic agents with emphasis on target of integrin αvβ3, and describes the considerations for the design of the diverse RGD peptide-chemotherapeutics conjugates and their major applications. PMID:21547159

  5. A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs

    PubMed Central

    Gidwani, Bina; Vyas, Amber

    2015-01-01

    Most of the cytotoxic chemotherapeutic agents have poor aqueous solubility. These molecules are associated with poor physicochemical and biopharmaceutical properties, which makes the formulation difficult. An important approach in this regard is the use of combination of cyclodextrin and nanotechnology in delivery system. This paper provides an overview of limitations associated with anticancer drugs, their complexation with cyclodextrins, loading/encapsulating the complexed drugs into carriers, and various approaches used for the delivery. The present review article aims to assess the utility of cyclodextrin-based carriers like liposomes, niosomes, nanoparticles, micelles, millirods, and siRNA for delivery of antineoplastic agents. These systems based on cyclodextrin complexation and nanotechnology will camouflage the undesirable properties of drug and lead to synergistic or additive effect. Cyclodextrin-based nanotechnology seems to provide better therapeutic effect and sustain long life of healthy and recovered cells. Still, considerable study on delivery system and administration routes of cyclodextrin-based carriers is necessary with respect to their pharmacokinetics and toxicology to substantiate their safety and efficiency. In future, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents. PMID:26582104

  6. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    PubMed Central

    Li, Xiaoyu; Wu, Meiying; Pan, Limin; Shi, Jianlin

    2016-01-01

    To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. PMID:26766908

  7. Synthesis and Applications of Multimodal Hybrid Albumin Nanoparticles for Chemotherapeutic Drug Delivery and Photothermal Therapy Platforms

    NASA Astrophysics Data System (ADS)

    Peralta, Donna V.

    cellular uptake of AuNR-HSAPs via fluorescence microscopy. Finally, camptothecin (CPT) an antineoplastic agent and BACPT (7-butyl-10-aminocamptothecin) were loaded into HSAPs to combat their aqueous insolubility. BACPT-HSAPs loaded up to 5.25 micrograms BACPT/ mg of HSA. CPT encapsulation could not be determined. BACPT-HSAPs and CPT-HSAPs showed cytotoxicity to human sarcoma cells in vitro. Key words: Hybrid Nanoparticles, Photothermal Therapy, Gold Nanomaterials, Drug Delivery, Combinational Cancer Therapies, Materials, Human Serum Albumin, Colloidal Carriers.

  8. Focused ultrasound induced blood-brain barrier disruption to enhance chemotherapeutic drugs (BCNU) delivery for glioblastoma treatment

    NASA Astrophysics Data System (ADS)

    Liu, Hao-Li; Hua, Mu-Yi; Chen, Pin-Yuan; Huang, Chiung-Yin; Wang, Jiun-Jie; Wei, Kuo-Chen

    2010-03-01

    Focused ultrasound has been recently found to capable of temporally and reversibly disrupt local blood-brain barrier (BBB) and opens new frontier in delivering varies type of drugs into brain for central nerve system (CNS) disorder treatment. In this study, we aim to investigate the feasibility of delivering 1, 3-bits (2-chloroethyl) -1-nitrosourea (BCNU) to treat glioblastoma in animal models and evaluate whether this approach would gain treatment efficacy. Under the presence of microbubbles administration, a 400-kHz focused ultrasound was employed to deliver burst-tone ultrasonic energy stimulation to disrupt BBB in animal brains transcranially, and in-vivo monitored by magnetic-resonance imaging (MRI). C6-glioma cells were cultured and implanted into Sprague-Dawley rats as the brain-tumor model. BCNU deposited in brain was quantified by using high-performance liquid chromatography (HPLC), and brain tissues were examined histologically. MRI was employed to longitudinal evaluate the brain tumor treatment including the analysis of tumor progression and animal survival. We confirmed that the focused ultrasound, under the secure ultrasonic energy level, can significantly enhance the BCNU penetration through BBB over 300% than control without cause hemorrhage. Apparent improvement of treatment efficacy achieved by combining focused ultrasound with BCNU delivery, including significant suppression of tumor growth and a prolonged animal survival. This study highly support that this treatment strategy could be clinically-relevant and may help to provide another potential strategy in increasing local chemotherapeutic drugs for brain-tumor treatment.

  9. (Radiopharmaceutical and chemotherapeutic drug technology)

    SciTech Connect

    Srivastava, P.C.

    1988-01-14

    The purpose was to undertake a TOKTEN Distinguished Scientist Award assignment sponsored by the United Nations Development Programme (UNDP) in cooperation with the Council of Scientific and Industrial Research (CSIR) of India to conduct research in the areas of nucleosides and protein labeling agents at the Central Drug Research Institute (CDRI), Lucknow, and to help research scientists develop chemotherapeutic drugs in India. His work at CDRI consisted of syntheses of imidazole nucleosides, iodination reactions of nucleosides, synthesis of a bifunctional bismaleimide protein labeling agent, coordination of protein labeling studies with the Membrane Biology Group of CDRI, and initiation of several new collaborative research projects at CDRI. In addition, as a part of the CSIR-UNDP, the traveler visited several academic and industrial research institutions in India, delivered five seminars describing various aspects of radiopharmaceutical development at ORNL, and interacted extensively with scientists in India on current drug and radiopharmaceutical develop technologies in India and abroad.

  10. Lapatinib as a chemotherapeutic drug.

    PubMed

    Obajimi, Oluwakemi

    2009-11-01

    Human epidermal growth factor receptor (HER) signaling is frequently associated with the development and progression of several types of cancers. Both the MAPK and the PI3K/Akt pathways have been implicated as effectors of HER signaling by promoting anti-apoptotic and pro-proliferative effects in cancer cells. As a result, many anti-HER drugs have been developed and patented for use in cancer therapy. One such drug that was recently approved for clinical trials is lapatinib (Tykerb, GW572016). Lapatinib is a small molecule inhibitor that is active at the ATP binding site of the tyrosine kinase involved in HER signaling. Importantly, this drug has dual specificity acting at the ATP binding sites of both HER-2 and HER-1 (EGFR). This review therefore summarizes the current knowledge based on pre-clinical and clinical evidence of the therapeutic effects of lapatinib against cancer and the promising strategy of combination therapy with the possibility of circumventing the problems of drug resistance commonly faced by chemotherapeutic drugs. PMID:19522695

  11. Progress in aptamer-mediated drug delivery vehicles for cancer targeting and its implications in addressing chemotherapeutic challenges.

    PubMed

    Zhu, Jie; Huang, He; Dong, Shiwu; Ge, Liang; Zhang, Yuan

    2014-01-01

    Aptamers are novel oligonucleotides with flexible three-dimensional configurations that recognize and bind to their cognate targets, including tumor surface receptors, in a high-affinity and highly specific manner. Because of their unique intrinsic properties, a variety of aptamer-mediated nanovehicles have been developed to directionally transport anti-cancer drugs to tumor sites to minimize systemic cytotoxicity and to enhance permeation by these tumoricidal agents. Despite advances in the selection and synthesis of aptamers and in the conjugation and self-assembly of nanotechnologies, current chemotherapy and drug delivery systems face great challenges. These challenges are due to the limitations of aptamers and vehicles and because of complicated tumor mechanisms, including heterogeneity, anti-cancer drug resistance, and hypoxia-induced aberrances. In this review, we will summarize current approaches utilizing tumor surface hallmarks and aptamers and their roles and mechanisms in therapeutic nanovehicles targeting tumors. Delivery forms include nanoparticles, nanotubes, nanogels, aptamer-drug conjugates, and novel molecular trains. Moreover, the obstacles posed by the aforementioned issues will be highlighted, and possible solutions will be acknowledged. Furthermore, future perspectives will be presented, including cutting-edge integration with RNA interference nanotechnology and personalized chemotherapy, which will facilitate innovative approaches to aptamer-based therapeutics. PMID:25057317

  12. Progress in Aptamer-Mediated Drug Delivery Vehicles for Cancer Targeting and Its Implications in Addressing Chemotherapeutic Challenges

    PubMed Central

    Zhu, Jie; Huang, He; Dong, Shiwu; Ge, Liang; Zhang, Yuan

    2014-01-01

    Aptamers are novel oligonucleotides with flexible three-dimensional configurations that recognize and bind to their cognate targets, including tumor surface receptors, in a high-affinity and highly specific manner. Because of their unique intrinsic properties, a variety of aptamer-mediated nanovehicles have been developed to directionally transport anti-cancer drugs to tumor sites to minimize systemic cytotoxicity and to enhance permeation by these tumoricidal agents. Despite advances in the selection and synthesis of aptamers and in the conjugation and self-assembly of nanotechnologies, current chemotherapy and drug delivery systems face great challenges. These challenges are due to the limitations of aptamers and vehicles and because of complicated tumor mechanisms, including heterogeneity, anti-cancer drug resistance, and hypoxia-induced aberrances. In this review, we will summarize current approaches utilizing tumor surface hallmarks and aptamers and their roles and mechanisms in therapeutic nanovehicles targeting tumors. Delivery forms include nanoparticles, nanotubes, nanogels, aptamer-drug conjugates, and novel molecular trains. Moreover, the obstacles posed by the aforementioned issues will be highlighted, and possible solutions will be acknowledged. Furthermore, future perspectives will be presented, including cutting-edge integration with RNA interference nanotechnology and personalized chemotherapy, which will facilitate innovative approaches to aptamer-based therapeutics. PMID:25057317

  13. Tumour suppressor genes in chemotherapeutic drug response

    PubMed Central

    Lai, Dulcie; Visser-Grieve, Stacy; Yang, Xiaolong

    2012-01-01

    Since cancer is one of the leading causes of death worldwide, there is an urgent need to find better treatments. Currently, the use of chemotherapeutics remains the predominant option for cancer therapy. However, one of the major obstacles for successful cancer therapy using these chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. Therefore identification of genes involved in chemotherapeutic response is critical for predicting tumour response and treating drug-resistant cancer patients. A group of genes commonly lost or inactivated are tumour suppressor genes, which can promote the initiation and progression of cancer through regulation of various biological processes such as cell proliferation, cell death and cell migration/invasion. Recently, mounting evidence suggests that these tumour suppressor genes also play a very important role in the response of cancers to a variety of chemotherapeutic drugs. In the present review, we will provide a comprehensive overview on how major tumour suppressor genes [Rb (retinoblastoma), p53 family, cyclin-dependent kinase inhibitors, BRCA1 (breast-cancer susceptibility gene 1), PTEN (phosphatase and tensin homologue deleted on chromosome 10), Hippo pathway, etc.] are involved in chemotherapeutic drug response and discuss their applications in predicting the clinical outcome of chemotherapy for cancer patients. We also propose that tumour suppressor genes are critical chemotherapeutic targets for the successful treatment of drug-resistant cancer patients in future applications. PMID:22762204

  14. Cisplatin@US-tube Carbon Nanocapsules For Enhanced Chemotherapeutic Delivery

    PubMed Central

    Guven, Adem; Rusakova, Irene A.; Lewis, Michael T.; Wilson, Lon J.

    2012-01-01

    The use of chemotherapeutic drugs in cancer therapy is often limited by problems with administration such as insolubility, inefficient biodistribution, lack of selectivity, and inability of the drug to cross cellular barriers. To overcome these limitations, various types of drug delivery systems have been explored, and recently, carbon nanotube (CNT) materials have also garnered attention in the area of drug delivery. In this study, we describe the preparation, characterization, and in vitro testing of a new ultra-short single-walled carbon nanotube (US-tube)-based drug delivery system for the treatment of cancer. In particular, the encapsulation of cisplatin (CDDP), a widely-used anticancer drug, within US-tubes has been achieved, and the resulting CDDP@US-tube material characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and inductively-coupled optical emission spectrometry (ICP-OES). Dialysis studies performed in phosphate-buffered saline (PBS) at 37 °C have demonstrated that CDDP release from CDDP@US-tubes can be controlled (retarded) by wrapping the CDDP@US-tubes with Pluronic-F108 surfactant. Finally, the anticancer activity of pluronic-wrapped CDDP@US-tubes has been evaluated against two different breast cancer cell lines, MCF-7 and MDA-MB-231, and found to exhibit enhanced cytotoxicity over free CDDP after 24 hours. These studies have laid the foundation for developing US-tube-based delivery of chemotherapeutics, with drug release mainly limited to within cancer cells only. PMID:22078812

  15. Direct chemotherapeutic dual drug delivery through intra-articular injection for synergistic enhancement of rheumatoid arthritis treatment

    PubMed Central

    Reum Son, A; Kim, Da Yeon; Hun Park, Seung; Yong Jang, Ja; Kim, Kyungsook; Ju Kim, Byoung; Yun Yin, Xiang; Ho Kim, Jae; Hyun Min, Byoung; Keun Han, Dong; Suk Kim, Moon

    2015-01-01

    The effectiveness of systemic rheumatoid arthritis (RA) treatments is limited by difficulties in achieving therapeutic doses within articular joints. We evaluated the ability of intra-articular administration of injectable formulations to synergistically enhance repair of RA joints. Methotrexate-loaded hyaluronic acid (Met-HA), dexamethasone-loaded microcapsules (Dex-M), and Dex-M dispersed inside Met-HA were prepared as viscous emulsions and injected into articular joints using a needle to form a drug depot. By near-infrared (NIR) fluorescence imaging, we confirmed the local release of NIR from the depot injected into the articular joint over an extended period. In comparison with the subjects treated with Met-HA or Dex-M alone, subjects treated simultaneously with Met-HA and Dex-M exhibited faster and more significant RA repair. Collectively, these results indicated that the drug depot formed after intra-articular injection of Met-HA/Dex-M induced long-lasting drug release and allowed Met and Dex to effectively act in the articular joint, resulting in enhanced RA repair. PMID:26424611

  16. Co-delivery of chemotherapeutic drugs with vitamin E TPGS by porous PLGA nanoparticles for enhanced chemotherapy against multi-drug resistance.

    PubMed

    Zhu, Huijun; Chen, Hongbo; Zeng, Xiaowei; Wang, Zhongyuan; Zhang, Xudong; Wu, Yanping; Gao, Yongfeng; Zhang, Jinxie; Liu, Kewei; Liu, Ranyi; Cai, Lintao; Mei, Lin; Feng, Si-Shen

    2014-02-01

    We report a strategy to make use of poly(lactic-co-glycolic acid) nanoparticle (PLGA NPs) for co-delivery of docetaxel (DTX) as a model anticancer drug together with vitamin E TPGS. The latter plays a dual role as a pore-forming agent in the nanoparticles that may result in smaller particle size, higher drug encapsulation efficiency and faster drug release, and also as a bioactive agent that could inhibit P-glycoprotein to overcome multi-drug resistance of the cancer cells, The DTX-loaded PLGA NPs of 0, 10, 20 and 40% TPGS were prepared by the nanoprecipitation method and then characterized for their size and size distribution, surface morphology, physical status and encapsulation efficiency of the drug in the NPs. All four NPs were found of size ranged 100-120 nm and EE ranged 85-95% at drug loading level around 10%. The in vitro evaluation showed that the 48 h IC50 values of the free DTX and the DTX-loaded PLGA NPs of 0, 10, 20% TPGS were 2.619 and 0.474, 0.040, 0.009 μg/mL respectively, which means that the PLGA NPs formulation could be 5.57 fold effective than the free DTX and that the DTX-loaded PLGA NPs of 10 or 20% TPGS further be 11.85 and 52.7 fold effective than the DTX-loaded PLGA NPs of no TPGS (therefore, 66.0 and 284 fold effective than the free DTX). Xenograft tumor model and immunohistological staining analysis further confirmed the advantages of the strategy of co-delivery of anticancer drugs with TPGS by PLGA NPs. PMID:24360574

  17. Multiphysics and Multiscale Analysis for Chemotherapeutic Drug

    PubMed Central

    Zhang, Linan; Kim, Sung Youb; Kim, Dongchoul

    2015-01-01

    This paper presents a three-dimensional dynamic model for the chemotherapy design based on a multiphysics and multiscale approach. The model incorporates cancer cells, matrix degrading enzymes (MDEs) secreted by cancer cells, degrading extracellular matrix (ECM), and chemotherapeutic drug. Multiple mechanisms related to each component possible in chemotherapy are systematically integrated for high reliability of computational analysis of chemotherapy. Moreover, the fidelity of the estimated efficacy of chemotherapy is enhanced by atomic information associated with the diffusion characteristics of chemotherapeutic drug, which is obtained from atomic simulations. With the developed model, the invasion process of cancer cells in chemotherapy treatment is quantitatively investigated. The performed simulations suggest a substantial potential of the presented model for a reliable design technology of chemotherapy treatment. PMID:26491672

  18. Efficacy of combined photothermal therapy and chemotherapeutic drugs

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Shih, En-Chung; Hirschberg, Henry

    2015-03-01

    Hyperthermia has been shown to enhance the effects of chemotherapeutic agents in a wide variety of cancers. The purpose of this study was to investigate the combined effects of a number of commonly used chemotherapeutic drugs (bleomycin, doxorubicin and cisplatin) with photothermal therapy (PTT)-induced hyperthermia in an in vitro system consisting of human head and neck squamous carcinoma cells and murine lymphocytic monocytes which were used as delivery vehicles for gold-silica nanoshells (AuNS). PTT was accomplished via near infra-red (NIR) irradiation of AuNS. The results showed that PTT combined with cisplatin resulted in only a mild degree of synergism while additive effects were observed for concurrent treatments of PTT and doxorubicin and PTT and bleomycin.

  19. Smart Approach for In Situ One-Step Encapsulation and Controlled Delivery of a Chemotherapeutic Drug using Metal-Organic Framework-Drug Composites in Aqueous Media.

    PubMed

    Adhikari, Chandan; Chakraborty, Anjan

    2016-04-01

    Controlled release of an anticancer drug, doxorubicin (dox), from metal-organic framework (MOF)-drug composites is demonstrated under different external stimuli. 1,3,5-Benzenetricarboxylic acid (H3 BTC) is used as an organic ligand, and iron acetate and zinc nitrate are used as metal sources to synthesize Fe-BTC and Zn-BTC MOFs, which are known to be biocompatible. The in situ formation of MOF-drug composites demonstrates high drug loading capacity compared to conventional methods. The present methodology is devoid of any extra steps for loading the drug after synthesis. Moreover, the drug loading is also independent of pore size of the MOF as the drug molecules are embedded inside the MOF during their in situ formation. The drug release was monitored under external stimuli including change to acidic pH and the presence of biocompatible liposomes for a period of more than 72 h. Steady-state fluorescence spectroscopy is used to monitor the drug release as a function of time and confocal laser scanning microscopy is used to unravel the post-release fate of doxorubicin in the presence of liposomes. It is found that drug release rate is higher for the Zn-BTC-dox composite than for the Fe-BTC-dox composite. This is attributed to the stronger binding between dox and Fe-BTC than that between dox and Zn-BTC. This study highlights a novel approach for the preparation of MOF-drug composites in an aqueous medium for future biomedical applications. PMID:26752093

  20. Ultrasound-Guided Delivery of siRNA and a Chemotherapeutic Drug by Using Microbubble Complexes: In Vitro and In Vivo Evaluations in a Prostate Cancer Model

    PubMed Central

    Bae, Yun Jung; Yoon, Young Il; Yoon, Tae-Jong

    2016-01-01

    Objective To evaluate the effectiveness of ultrasound and microbubble-liposome complex (MLC)-mediated delivery of siRNA and doxorubicin into prostate cancer cells and its therapeutic capabilities both in vitro and in vivo. Materials and Methods Microbubble-liposome complexes conjugated with anti-human epidermal growth factor receptor type 2 (Her2) antibodies were developed to target human prostate cancer cell lines PC-3 and LNCaP. Intracellular delivery of MLC was observed by confocal microscopy. We loaded MLC with survivin-targeted small interfering RNA (siRNA) and doxorubicin, and delivered it into prostate cancer cells. The release of these agents was facilitated by ultrasound application. Cell viability was analyzed by MTT assay after the delivery of siRNA and doxorubicin. Survivin-targeted siRNA loaded MLC was delivered into the xenograft mouse tumor model. Western blotting was performed to quantify the expression of survivin in vivo. Results Confocal microscopy demonstrated substantial intracellular uptake of MLCs in LNCaP, which expresses higher levels of Her2 than PC-3. The viability of LNCaP cells was significantly reduced after the delivery of MLCs loaded with siRNA and doxorubicin (85.0 ± 2.9%), which was further potentiated by application of ultrasound (55.0 ± 3.5%, p = 0.009). Survivin expression was suppressed in vivo in LNCaP tumor xenograft model following the ultrasound and MLC-guided delivery of siRNA (77.4 ± 4.90% to 36.7 ± 1.34%, p = 0.027). Conclusion Microbubble-liposome complex can effectively target prostate cancer cells, enabling intracellular delivery of the treatment agents with the use of ultrasound. Ultrasound and MLC-mediated delivery of survivin-targeted siRNA and doxorubicin can induce prostate cell apoptosis and block survivin expression in vitro and in vivo. PMID:27390541

  1. Adsorption of doxorubicin on citrate-capped gold nanoparticles: insights into engineering potent chemotherapeutic delivery systems

    NASA Astrophysics Data System (ADS)

    Curry, Dennis; Cameron, Amanda; MacDonald, Bruce; Nganou, Collins; Scheller, Hope; Marsh, James; Beale, Stefanie; Lu, Mingsheng; Shan, Zhi; Kaliaperumal, Rajendran; Xu, Heping; Servos, Mark; Bennett, Craig; Macquarrie, Stephanie; Oakes, Ken D.; Mkandawire, Martin; Zhang, Xu

    2015-11-01

    Gold nanomaterials have received great interest for their use in cancer theranostic applications over the past two decades. Many gold nanoparticle-based drug delivery system designs rely on adsorbed ligands such as DNA or cleavable linkers to load therapeutic cargo. The heightened research interest was recently demonstrated in the simple design of nanoparticle-drug conjugates wherein drug molecules are directly adsorbed onto the as-synthesized nanoparticle surface. The potent chemotherapeutic, doxorubicin often serves as a model drug for gold nanoparticle-based delivery platforms; however, the specific interaction facilitating adsorption in this system remains understudied. Here, for the first time, we propose empirical and theoretical evidence suggestive of the main adsorption process where (1) hydrophobic forces drive doxorubicin towards the gold nanoparticle surface before (2) cation-π interactions and gold-carbonyl coordination between the drug molecule and the cations on AuNP surface facilitate DOX adsorption. In addition, biologically relevant compounds, such as serum albumin and glutathione, were shown to enhance desorption of loaded drug molecules from AuNP at physiologically relevant concentrations, providing insight into the drug release and in vivo stability of such drug conjugates.Gold nanomaterials have received great interest for their use in cancer theranostic applications over the past two decades. Many gold nanoparticle-based drug delivery system designs rely on adsorbed ligands such as DNA or cleavable linkers to load therapeutic cargo. The heightened research interest was recently demonstrated in the simple design of nanoparticle-drug conjugates wherein drug molecules are directly adsorbed onto the as-synthesized nanoparticle surface. The potent chemotherapeutic, doxorubicin often serves as a model drug for gold nanoparticle-based delivery platforms; however, the specific interaction facilitating adsorption in this system remains understudied

  2. ADVANCED MOLECULAR DESIGN OF BIOPOLYMERS FOR TRANSMUCOSAL AND INTRACELLULAR DELIVERY OF CHEMOTHERAPEUTIC AGENTS AND BIOLOGICAL THERAPEUTICS

    PubMed Central

    Liechty, William B.; Caldorera-Moore, Mary; Phillips, Margaret A.; Schoener, Cody; Peppas, Nicholas A.

    2011-01-01

    Hydrogels have been instrumental in the development of polymeric systems for controlled release of therapeutic agents. These materials are attractive for transmucosal and intracellular drug delivery because of their facile synthesis, inherent biocompatibility, tunable physicochemical properties, and capacity to respond to various physiological stimuli. In this contribution, we outline a multifaceted hydrogel-based approach for expanding the range of therapeutics in oral formulations from classical small-molecule drugs to include proteins, chemotherapeutics, and nucleic acids. Through judicious materials selection and careful design of copolymer composition and molecular architecture, we can engineer systems capable of responding to distinct physiological cues, with tunable physicochemical properties that are optimized to load, protect, and deliver valuable macromolecular payloads to their intended site of action. These hydrogel carriers, including complexation hydrogels, tethered hydrogels, interpenetrating networks, nanoscale hydrogels, and hydrogels with decorated structures are investigated for their ability respond to changes in pH, to load and release insulin and fluorescein, and remain non-toxic to Caco-2 cells. Our results suggest these novel hydrogel networks have great potential for controlled delivery of proteins, chemotherapeutics, and nucleic acids. PMID:21699934

  3. Advanced molecular design of biopolymers for transmucosal and intracellular delivery of chemotherapeutic agents and biological therapeutics.

    PubMed

    Liechty, William B; Caldorera-Moore, Mary; Phillips, Margaret A; Schoener, Cody; Peppas, Nicholas A

    2011-10-30

    Hydrogels have been instrumental in the development of polymeric systems for controlled release of therapeutic agents. These materials are attractive for transmucosal and intracellular drug delivery because of their facile synthesis, inherent biocompatibility, tunable physicochemical properties, and capacity to respond to various physiological stimuli. In this contribution, we outline a multifaceted hydrogel-based approach for expanding the range of therapeutics in oral formulations from classical small-molecule drugs to include proteins, chemotherapeutics, and nucleic acids. Through judicious material selection and careful design of copolymer composition and molecular architecture, we can engineer systems capable of responding to distinct physiological cues, with tunable physicochemical properties that are optimized to load, protect, and deliver valuable macromolecular payloads to their intended site of action. These hydrogel carriers, including complexation hydrogels, tethered hydrogels, interpenetrating networks, nanoscale hydrogels, and hydrogels with decorated structures are investigated for their ability to respond to changes in pH, to load and release insulin and fluorescein, and remain non-toxic to Caco-2 cells. Our results suggest these novel hydrogel networks have great potential for controlled delivery of proteins, chemotherapeutics, and nucleic acids. PMID:21699934

  4. Alterations of chemotherapeutic pharmacokinetic profiles by drug–drug interactions

    PubMed Central

    Ghalib, Mohammed; Chaudhary, Imran; Goel, Sanjay

    2012-01-01

    Background Drug interactions in oncology are common place and largely ignored as we tolerate high thresholds of ‘toxic’ drug responses in these patients. However, in the era of ‘targeted’ or seemingly ‘less toxic’ therapy, these interactions are more commonly flagged and contribute significantly towards poor ‘quality of life’ and medical fatalities. Objective This review and opinion article focuses on alteration of chemotherapeutic pharmacokinetic profiles by drug interactions in the setting of polypharmacy. The assumption is that the drugs, with changes in their pharmacokinetics, will contribute towards changes in their pharmacodynamics. Methods The examples cited for such drug–drug interactions are culled from published literature with an emphasis on those interactions that have been well characterized at the molecular level. Results Although very few drug interaction studies have been performed on approved oncology based drugs, it is clear that drugs whose pharmacokinetics profiles are closely related to their pharmacodynamics will indeed result in clinically important drug interactions. Some newer mechanisms are described that involve interactions at the level of gene transcription, whereby, drug metabolism is significantly altered. However, for any given drug interaction, there does not seem to be a comprehensive model describing interactions. Conclusions Mechanisms based drug interactions are plentiful in oncology; however, there is an absolute lack of a comprehensive model that would predict drug–drug interactions. PMID:19239394

  5. Effective delivery of chemotherapeutic nanoparticles by depleting host Kupffer cells.

    PubMed

    Ohara, Yusuke; Oda, Tatsuya; Yamada, Keiichi; Hashimoto, Shinji; Akashi, Yoshimasa; Miyamoto, Ryoichi; Kobayashi, Akihiko; Fukunaga, Kiyoshi; Sasaki, Ryoko; Ohkohchi, Nobuhiro

    2012-11-15

    Although chemotherapeutic nanoparticles would confer various advantages, the majority of administrated nanoparticles are known to be spoiled by the reticuloendothelial system (RES). Intending to more effectively deliver therapeutic nanoparticles to target regions in vivo, host RES, especially Kupffer cells in the liver, have been depleted ahead of drug administration. To demonstrate this hypothesis, clodronate liposomes were preinjected into BALB/c nude mice for depletion of Kupffer cells 2 days before, and pegylated liposomal doxorubicin (Doxil) at the doses of 1.25, 2.5 and 5.0 mg/kg was administered. As a result, doxorubicin accumulation in the liver was decreased from 36 to 26% injected dose/organ by the Kupffer cells depletion, and consequently, the plasma concentration of doxorubicin was significantly enhanced threefold (from 11 to 33 μg/mL) on day 1 at 1.25 mg/kg-dose group. Doxorubicin accumulation in the tumor was increased from 0.78 to 3.0 μg/g-tissue on day 3, and tumor growth inhibition by Doxil was significantly boosted (tumor volumes from 751 to 482 mm(3) on day 24) by the Kupffer cells depletion. In conclusion, Kupffer cells depletion by clodronate liposomes enhanced the plasma concentration and antitumor effects of Doxil, and would be widely applicable for various clinical cancer chemotherapies using nanoparticles. PMID:22362271

  6. Local bacteria affect the efficacy of chemotherapeutic drugs

    PubMed Central

    Lehouritis, Panos; Cummins, Joanne; Stanton, Michael; Murphy, Carola T.; McCarthy, Florence O.; Reid, Gregor; Urbaniak, Camilla; Byrne, William L.; Tangney, Mark

    2015-01-01

    In this study, the potential effects of bacteria on the efficacy of frequently used chemotherapies was examined. Bacteria and cancer cell lines were examined in vitro and in vivo for changes in the efficacy of cancer cell killing mediated by chemotherapeutic agents. Of 30 drugs examined in vitro, the efficacy of 10 was found to be significantly inhibited by certain bacteria, while the same bacteria improved the efficacy of six others. HPLC and mass spectrometry analyses of sample drugs (gemcitabine, fludarabine, cladribine, CB1954) demonstrated modification of drug chemical structure. The chemoresistance or increased cytotoxicity observed in vitro with sample drugs (gemcitabine and CB1954) was replicated in in vivo murine subcutaneous tumour models. These findings suggest that bacterial presence in the body due to systemic or local infection may influence tumour responses or off-target toxicity during chemotherapy. PMID:26416623

  7. The use of ultrasound to release chemotherapeutic drugs from micelles and liposomes.

    PubMed

    Ahmed, Salma E; Martins, Ana M; Husseini, Ghaleb A

    2015-01-01

    Several drug delivery systems have been investigated to reduce the side effects of chemotherapy by encapsulating the therapeutic agent in a nanosized carrier until it reaches the tumor site. Many of these particles are designed to be responsive to the mechanical and thermal perturbations delivered by ultrasound. Once the nanoparticle reaches the desired location, ultrasound is applied to release the chemotherapy drug only in the vicinity of the targeted (cancer) site, thus avoiding any detrimental interaction with healthy cells in the body. Studies using liposomes and micelles have shown promising results in this area, as these nanoparticles with simple, yet effective structures, showed high efficiency as drug delivery vehicles both in vitro and in vivo. This article reviews the design and application of two novel nanosized chemotherapeutic carriers (i.e. micelles and liposomes) intended to be actuated by ultrasound. PMID:25203857

  8. A novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells

    PubMed Central

    Wang, Si; Placzek, William J.; Stebbins, John L.; Mitra, Sayantan; Noberini, Roberta; Koolpe, Mitchell; Zhang, Ziming; Dahl, Russell; Pasquale, Elena B.; Pellecchia, Maurizio

    2012-01-01

    The efficacy of anti-cancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is over-expressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anti-cancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We found that the peptide-drug conjugate is dramatically more effective than paclitaxel alone at inhibiting tumor growth in a prostate cancer xenograft model, delivering significantly higher levels of drug to the tumor site. We believe these studies open the way to the development of a new class of therapeutic compounds that exploit the EphA2 receptor for drug delivery to cancer cells. PMID:22329578

  9. Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

    NASA Astrophysics Data System (ADS)

    Roy Chaudhuri, Tista

    An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

  10. Drug delivery systems.

    PubMed

    Robinson, D H; Mauger, J W

    1991-10-01

    New and emerging drug delivery systems for traditional drugs and the products of biotechnology are discussed, and the role of the pharmacist in ensuring the appropriate use of these systems is outlined. Advantages of advanced drug delivery systems over traditional systems are the ability to deliver a drug more selectively to a specific site; easier, more accurate, less frequent dosing; decreased variability in systemic drug concentrations; absorption that is more consistent with the site and mechanism of action; and reductions in toxic metabolites. Four basic strategies govern the mechanisms of advanced drug delivery: physical, chemical, biological, and mechanical. Oral drug delivery systems use natural and synthetic polymers to deliver the product to a specific region in the gastrointestinal tract in a timely manner that minimizes adverse effects and increases drug efficacy. Innovations in injectable and implantable delivery systems include emulsions, particulate delivery systems, micromolecular products and macromolecular drug adducts, and enzymatic-controlled delivery. Options for noninvasive drug delivery include the transdermal, respiratory, intranasal, ophthalmic, lymphatic, rectal, intravaginal, and intrauterine routes as well as topical application. Rapid growth is projected in the drug delivery systems market worldwide in the next five years. Genetic engineering has mandated the development of new strategies to deliver biotechnologically derived protein and peptide drugs and chemoimmunoconjugates. The role of the pharmacist in the era of advanced drug delivery systems will be broad based, including administering drugs, compounding, calculating dosages based on pharmacokinetic and pharmacodynamic monitoring, counseling, and research. The advent of advanced drug delivery systems offers pharmacists a new opportunity to assume an active role in patient care. PMID:1772110

  11. Nanotransporters for drug delivery.

    PubMed

    Lühmann, Tessa; Meinel, Lorenz

    2016-06-01

    Soluble nanotransporters for drugs can be profiled for targeted delivery particularly to maximize the efficacy of highly potent drugs while minimizing off target effects. This article outlines on the use of biological carrier molecules with a focus on albumin, various drug linkers for site specific release of the drug payload from the nanotransporter and strategies to combine these in various ways to meet different drug delivery demands particularly the optimization of the payload per nanotransporter. PMID:26773302

  12. Ocular drug delivery.

    PubMed

    Gaudana, Ripal; Ananthula, Hari Krishna; Parenky, Ashwin; Mitra, Ashim K

    2010-09-01

    Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aqueous and blood-retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases. PMID:20437123

  13. Transdermal drug delivery

    PubMed Central

    Prausnitz, Mark R.; Langer, Robert

    2009-01-01

    Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase impact on medicine. PMID:18997767

  14. Old drugs, novel ways out: Drug resistance toward cytotoxic chemotherapeutics.

    PubMed

    Wijdeven, Ruud H; Pang, Baoxu; Assaraf, Yehuda G; Neefjes, Jacques

    2016-09-01

    Efficacy of chemotherapy in the treatment of distinct malignancies is often hampered by drug resistance arising in the tumor. Understanding the molecular basis of drug resistance and translating this knowledge into personalized treatment decisions can enhance therapeutic efficacy and even curative outcome. Over the years, multiple drug resistance mechanisms have been identified that enable tumors to cope with the damage instigated by a specific drug or group of anti-tumor agents. Here we provide an overview of the molecular pathways leading to resistance against conventional anti-cancer drugs, with emphasis on the utility of these pathways for rational selection of treatments for individual cancer patients. We further complement the review by discussing the pitfalls and difficulties in translating these findings into novel treatment strategies for cancer patients. PMID:27620955

  15. Ultrasonic Drug Delivery – A General Review

    PubMed Central

    Pitt, William G.; Husseini, Ghaleb A.; Staples, Bryant J.

    2006-01-01

    Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles. PMID:16296719

  16. Pharmacological telomerase inhibition can sensitize drug-resistant and drug-sensitive cells to chemotherapeutic treatment.

    PubMed

    Ward, Ryan J; Autexier, Chantal

    2005-09-01

    Effective strategies to reverse or prevent chemotherapeutic resistance are required before cancer therapies can be curative. Telomerase is the ribonucleoprotein responsible for de novo synthesis and maintenance of telomeres, and its activity is predominantly observed in cancer cells. The telomerase enzyme has been successfully inhibited or inactivated to sensitize cells to cellular stresses; however, no studies have determined yet the effect of combining a pharmacological inhibitor of telomerase catalysis and traditional chemotherapeutics for the treatment of drug-sensitive or drug-resistant cancers. Here, we describe the effect of 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small-molecule inhibitor of telomerase catalytic activity, on drug-resistant leukemia and breast cancer cells and their parental counterparts when treated in combination with chemotherapeutics. We observed that BIBR1532-treated cells show progressive telomere shortening, decreased proliferative capacity, and sensitization to chemotherapeutic treatment. These effects are telomere length-dependent, because cells insensitive to BIBR1532 or cells released from telomerase inhibition did not demonstrate changes in growth ability or drug sensitivity. Our novel observations suggest that pharmacological telomerase inhibition in combination therapy may be a valid strategy for the treatment of both drug-sensitive and drug-resistant cancers. PMID:15939802

  17. Intracochlear Drug Delivery Systems

    PubMed Central

    Borenstein, Jeffrey T.

    2011-01-01

    Introduction Advances in molecular biology and in the basic understanding of the mechanisms associated with sensorineural hearing loss and other diseases of the inner ear, are paving the way towards new approaches for treatments for millions of patients. However, the cochlea is a particularly challenging target for drug therapy, and new technologies will be required to provide safe and efficacious delivery of these compounds. Emerging delivery systems based on microfluidic technologies are showing promise as a means for direct intracochlear delivery. Ultimately, these systems may serve as a means for extended delivery of regenerative compounds to restore hearing in patients suffering from a host of auditory diseases. Areas covered in this review Recent progress in the development of drug delivery systems capable of direct intracochlear delivery is reviewed, including passive systems such as osmotic pumps, active microfluidic devices, and systems combined with currently available devices such as cochlear implants. The aim of this article is to provide a concise review of intracochlear drug delivery systems currently under development, and ultimately capable of being combined with emerging therapeutic compounds for the treatment of inner ear diseases. Expert Opinion Safe and efficacious treatment of auditory diseases will require the development of microscale delivery devices, capable of extended operation and direct application to the inner ear. These advances will require miniaturization and integration of multiple functions, including drug storage, delivery, power management and sensing, ultimately enabling closed-loop control and timed-sequence delivery devices for treatment of these diseases. PMID:21615213

  18. Dual-Crosslinked Methacrylated Alginate Sub-Microspheres for Intracellular Chemotherapeutic Delivery

    PubMed Central

    Scherrer, Ryan M.; Oldinski, Rachael A.

    2016-01-01

    Intracellular delivery vehicles comprised of methacrylated alginate (Alg-MA) were developed for the internalization and release of doxorubicin hydrochloride (DOX). Alg-MA was synthesized via an anhydrous reaction, and a mixture of Alg-MA and DOX was formed into sub-microspheres using a water/oil emulsion. Covalently crosslinked sub-microspheres were formed via exposure to green light, in order to investigate effects of crosslinking on drug release and cell internalization, compared to traditional techniques such as ultra violet (UV) light. Crosslinking was performed using light exposure alone, or in combination with ionic crosslinking using calcium chloride (CaCl2). Alg-MA sub-microsphere diameters were between 88 – 617 nm, and zeta-potentials were between −20 and −37 mV. Using human lung epithelial carcinoma cells (A549s) as a model, cellular internalization was confirmed using flow cytometry; different sub-microsphere formulations varied the efficiency of internalization, with UV-crosslinked sub-microspheres achieving the highest internalization percentages. While blank (non-loaded) Alg-MA sub-microspheres were non-cytotoxic to A549s, DOX-loaded sub-microspheres significantly reduced mitochondrial activity after five days of culture. Photo-crosslinked Alg-MA sub-microspheres may be a potential chemotherapeutic delivery system for cancer treatment. PMID:27378419

  19. Dual-Cross-Linked Methacrylated Alginate Sub-Microspheres for Intracellular Chemotherapeutic Delivery.

    PubMed

    Fenn, Spencer L; Miao, Tianxin; Scherrer, Ryan M; Oldinski, Rachael A

    2016-07-20

    Intracellular delivery vehicles comprised of methacrylated alginate (Alg-MA) were developed for the internalization and release of doxorubicin hydrochloride (DOX). Alg-MA was synthesized via an anhydrous reaction, and a mixture of Alg-MA and DOX was formed into sub-microspheres using a water/oil emulsion. Covalently cross-linked sub-microspheres were formed via exposure to green light, in order to investigate effects of cross-linking on drug release and cell internalization, compared to traditional techniques, such as ultraviolet (UV) light irradiation. Cross-linking was performed using light exposure alone or in combination with ionic cross-linking using calcium chloride (CaCl2). Alg-MA sub-microsphere diameters were between 88 and 617 nm, and ζ-potentials were between -20 and -37 mV. Using human lung epithelial carcinoma cells (A549) as a model, cellular internalization was confirmed using flow cytometry; different sub-microsphere formulations varied the efficiency of internalization, with UV-cross-linked sub-microspheres achieving the highest internalization percentages. While blank (nonloaded) Alg-MA submicrospheres were noncytotoxic to A549 cells, DOX-loaded sub-microspheres significantly reduced mitochondrial activity after 5 days of culture. Photo-cross-linked Alg-MA sub-microspheres may be a potential chemotherapeutic delivery system for cancer treatment. PMID:27378419

  20. Antibody–drug conjugates as novel anti-cancer chemotherapeutics

    PubMed Central

    Peters, Christina; Brown, Stuart

    2015-01-01

    Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics. PMID:26182432

  1. Ikaros expression sensitizes leukemic cells to the chemotherapeutic drug doxorubicin

    PubMed Central

    He, Licai; Gao, Shenmeng; Zhu, Zhenfeng; Chen, Shang; Gu, Haihua

    2016-01-01

    Ikaros is an important transcription factor involved in the development and differentiation of hematopoietic cells. However, its role in the treatment of hematopoietic malignancies such as leukemia is less well understood. In the present study, it was observed by data mining of the Oncomine database that high expression levels of full-length Ikaros (IK1) is correlated with increased sensitivity of cancer cells to treatments with chemotherapeutic drugs, including doxorubicin (DOX). To examine the functional significance of this observation, the expression of IK1 in a leukemia cell line was altered, and the response of leukemic cells to DOX treatment was analyzed. It was observed that overexpression of IK1 could enhance DOX-induced apoptosis, while knockdown of IK1 attenuated DOX-induced apoptosis in leukemic cells. Further experiments demonstrated that IK1 sensitized leukemic cells to DOX-induced apoptosis, probably through upregulation of caspase-9. These data suggest that high expression levels of IK1 may be a potential biomarker to predict responses of leukemia patients to treatment with chemotherapy.

  2. Metrology for drug delivery.

    PubMed

    Lucas, Peter; Klein, Stephan

    2015-08-01

    In various recently published studies, it is argued that there are underestimated risks with infusion technology, i.e., adverse incidents believed to be caused by inadequate administration of the drugs. This is particularly the case for applications involving very low-flow rates, i.e., <1 ml/h and applications involving drug delivery by means of multiple pumps. The risks in infusing are caused by a lack of awareness, incompletely understood properties of the complete drug delivery system and a lack of a proper metrological infrastructure for low-flow rates. Technical challenges such as these were the reason a European research project "Metrology for Drug Delivery" was started in 2011. In this special issue of Biomedical Engineering, the results of that project are discussed. PMID:25879307

  3. PECTIN IN CONTROLLED DRUG DELIVERY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Controlled drug delivery remains a research focus for public health to enhance patient compliance, drug efficiency and to reduce the side effects of drugs. Pectin, an edible plant polysaccharide, has shown potential for the construction of drug delivery systems for site-specific drug delivery. Sev...

  4. Single compartment drug delivery

    PubMed Central

    Cima, Michael J.; Lee, Heejin; Daniel, Karen; Tanenbaum, Laura M.; Mantzavinou, Aikaterini; Spencer, Kevin C.; Ong, Qunya; Sy, Jay C.; Santini, John; Schoellhammer, Carl M.; Blankschtein, Daniel; Langer, Robert S.

    2014-01-01

    Drug design is built on the concept that key molecular targets of disease are isolated in the diseased tissue. Systemic drug administration would be sufficient for targeting in such a case. It is, however, common for enzymes or receptors that are integral to disease to be structurally similar or identical to those that play important biological roles in normal tissues of the body. Additionally, systemic administration may not lead to local drug concentrations high enough to yield disease modification because of rapid systemic metabolism or lack of sufficient partitioning into the diseased tissue compartment. This review focuses on drug delivery methods that physically target drugs to individual compartments of the body. Compartments such as the bladder, peritoneum, brain, eye and skin are often sites of disease and can sometimes be viewed as “privileged,” since they intrinsically hinder partitioning of systemically administered agents. These compartments have become the focus of a wide array of procedures and devices for direct administration of drugs. We discuss the rationale behind single compartment drug delivery for each of these compartments, and give an overview of examples at different development stages, from the lab bench to phase III clinical trials to clinical practice. We approach single compartment drug delivery from both a translational and a technological perspective. PMID:24798478

  5. Mucoadhesive drug delivery systems

    PubMed Central

    Shaikh, Rahamatullah; Raj Singh, Thakur Raghu; Garland, Martin James; Woolfson, A David; Donnelly, Ryan F.

    2011-01-01

    Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Over the past few decades, mucosal drug delivery has received a great deal of attention. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal). PMID:21430958

  6. Optically generated ultrasound for enhanced drug delivery

    DOEpatents

    Visuri, Steven R.; Campbell, Heather L.; Da Silva, Luiz

    2002-01-01

    High frequency acoustic waves, analogous to ultrasound, can enhance the delivery of therapeutic compounds into cells. The compounds delivered may be chemotherapeutic drugs, antibiotics, photodynamic drugs or gene therapies. The therapeutic compounds are administered systemically, or preferably locally to the targeted site. Local delivery can be accomplished through a needle, cannula, or through a variety of vascular catheters, depending on the location of routes of access. To enhance the systemic or local delivery of the therapeutic compounds, high frequency acoustic waves are generated locally near the target site, and preferably near the site of compound administration. The acoustic waves are produced via laser radiation interaction with an absorbing media and can be produced via thermoelastic expansion, thermodynamic vaporization, material ablation, or plasma formation. Acoustic waves have the effect of temporarily permeabilizing the membranes of local cells, increasing the diffusion of the therapeutic compound into the cells, allowing for decreased total body dosages, decreased side effects, and enabling new therapies.

  7. Nanotopography applications in drug delivery.

    PubMed

    Walsh, Laura A; Allen, Jessica L; Desai, Tejal A

    2015-01-01

    Refinement of micro- and nanofabrication in the semiconductor field has led to innovations in biomedical technologies. Nanotopography, in particular, shows great potential in facilitating drug delivery. The flexibility of fabrication techniques has created a diverse array of topographies that have been developed for drug delivery applications. Nanowires and nanostraws deliver drug cytosolically for in vitro and ex vivo applications. In vivo drug delivery is limited by the barrier function of the epithelium. Nanowires on microspheres increase adhesion and residence time for oral drug delivery, while also increasing permeability of the epithelium. Low aspect ratio nanocolumns increase paracellular permeability, and in conjunction with microneedles increase transdermal drug delivery of biologics in vivo. In summary, nanotopography is a versatile tool for drug delivery. It can deliver directly to cells or be used for in vivo delivery across epithelial barriers. This editorial highlights the application of nanotopography in the field of drug delivery. PMID:26512871

  8. Photomechanical drug delivery

    NASA Astrophysics Data System (ADS)

    Doukas, Apostolos G.; Lee, Shun

    2000-05-01

    Photomechanical waves (PW) are generated by Q-switched or mode-locked lasers. Ablation is a reliable method for generating PWs with consistent characteristics. Depending on the laser wavelength and target material, PWs with different parameters can be generated which allows the investigation of PWs with cells and tissue. PWs have been shown to permeabilize the stratum corneum (SC) in vivo and facilitate the transport of drugs into the skin. Once a drug has diffused into the dermis it can enter the vasculature, thus producing a systemic effect. Fluorescence microscopy of biopsies show that 40-kDa molecules can be delivered to a depth of > 300 micrometers into the viable skin of rats. Many important drugs such as insulin, and erythropoietin are smaller or comparable in size, making the PWs attractive for transdermal drug delivery. There are three possible pathways through the SC: Transappendageal via hair follicles or other appendages, transcellular through the corneocytes, and intercellular via the extracellular matrix. The intracellular route appears to be the most likely pathway of drug delivery through the SC.

  9. MEMS: Enabled Drug Delivery Systems.

    PubMed

    Cobo, Angelica; Sheybani, Roya; Meng, Ellis

    2015-05-01

    Drug delivery systems play a crucial role in the treatment and management of medical conditions. Microelectromechanical systems (MEMS) technologies have allowed the development of advanced miniaturized devices for medical and biological applications. This Review presents the use of MEMS technologies to produce drug delivery devices detailing the delivery mechanisms, device formats employed, and various biomedical applications. The integration of dosing control systems, examples of commercially available microtechnology-enabled drug delivery devices, remaining challenges, and future outlook are also discussed. PMID:25703045

  10. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

    PubMed

    Alimoradi, Houman; Matikonda, Siddharth S; Gamble, Allan B; Giles, Gregory I; Greish, Khaled

    2016-01-01

    Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems. PMID:26898739

  11. Polymers for Drug Delivery Systems

    PubMed Central

    Liechty, William B.; Kryscio, David R.; Slaughter, Brandon V.; Peppas, Nicholas A.

    2012-01-01

    Polymers have played an integral role in the advancement of drug delivery technology by providing controlled release of therapeutic agents in constant doses over long periods, cyclic dosage, and tunable release of both hydrophilic and hydrophobic drugs. From early beginnings using off-the-shelf materials, the field has grown tremendously, driven in part by the innovations of chemical engineers. Modern advances in drug delivery are now predicated upon the rational design of polymers tailored for specific cargo and engineered to exert distinct biological functions. In this review, we highlight the fundamental drug delivery systems and their mathematical foundations and discuss the physiological barriers to drug delivery. We review the origins and applications of stimuli-responsive polymer systems and polymer therapeutics such as polymer-protein and polymer-drug conjugates. The latest developments in polymers capable of molecular recognition or directing intracellular delivery are surveyed to illustrate areas of research advancing the frontiers of drug delivery. PMID:22432577

  12. Effect of Paullinia cupana on MCF-7 breast cancer cell response to chemotherapeutic drugs.

    PubMed

    Hertz, Everaldo; Cadoná, Francine Carla; Machado, Alencar Kolinski; Azzolin, Verônica; Holmrich, Sabrina; Assmann, Charles; Ledur, Pauline; Ribeiro, Euler Esteves; DE Souza Filho, Olmiro Cezimbra; Mânica-Cattani, Maria Fernanda; DA Cruz, Ivana Beatrice Mânica

    2015-01-01

    Previous studies suggested that certain plants, such as guarana (Paullinia cupana), exert a protective effect against cancer-related fatigue in breast cancer patients undergoing chemotherapy. However, guarana possesses bioactive molecules, such as caffeine and catechin, which may affect the pharmacological properties of antitumor drugs. Therefore, the aim of this study was to evaluate the effects of guarana on breast cancer cell response to 7 chemotherapeutic agents currently used in the treatment of breast cancer. To perform this study, MCF-7 breast cancer cells were cultured under controlled conditions and exposed to 1, 5 and 10 µg/ml guarana concentrations, with and without chemotherapeutics (gemcitabine, vinorelbine, methotrexate, 5-fluorouracil, paclitaxel, doxorubicin and cyclophosphamide). The effect of these treatments on MCF-7 cell viability and proliferation was spectrophotometrically analyzed with the MTT assay. The main results demonstrated an antiproliferative effect of guarana at concentrations of 5 and 10 µg/ml and a significant effect on chemotherapeutic drug action. In general, guarana improved the antiproliferative effect of chemotherapeutic agents, causing a decrease of >40% in cell growth after 72 h of exposure. The results suggested an interaction of guarana with the chemotherapeutic drugs, which requires confirmation by in vivo complementary studies. PMID:25469267

  13. Effect of Paullinia cupana on MCF-7 breast cancer cell response to chemotherapeutic drugs

    PubMed Central

    HERTZ, EVERALDO; CADONÁ, FRANCINE CARLA; MACHADO, ALENCAR KOLINSKI; AZZOLIN, VERÔNICA; HOLMRICH, SABRINA; ASSMANN, CHARLES; LEDUR, PAULINE; RIBEIRO, EULER ESTEVES; DE SOUZA FILHO, OLMIRO CEZIMBRA; MÂNICA-CATTANI, MARIA FERNANDA; DA CRUZ, IVANA BEATRICE MÂNICA

    2015-01-01

    Previous studies suggested that certain plants, such as guarana (Paullinia cupana), exert a protective effect against cancer-related fatigue in breast cancer patients undergoing chemotherapy. However, guarana possesses bioactive molecules, such as caffeine and catechin, which may affect the pharmacological properties of antitumor drugs. Therefore, the aim of this study was to evaluate the effects of guarana on breast cancer cell response to 7 chemotherapeutic agents currently used in the treatment of breast cancer. To perform this study, MCF-7 breast cancer cells were cultured under controlled conditions and exposed to 1, 5 and 10 µg/ml guarana concentrations, with and without chemotherapeutics (gemcitabine, vinorelbine, methotrexate, 5-fluorouracil, paclitaxel, doxorubicin and cyclophosphamide). The effect of these treatments on MCF-7 cell viability and proliferation was spectrophotometrically analyzed with the MTT assay. The main results demonstrated an antiproliferative effect of guarana at concentrations of 5 and 10 µg/ml and a significant effect on chemotherapeutic drug action. In general, guarana improved the antiproliferative effect of chemotherapeutic agents, causing a decrease of >40% in cell growth after 72 h of exposure. The results suggested an interaction of guarana with the chemotherapeutic drugs, which requires confirmation by in vivo complementary studies. PMID:25469267

  14. Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs.

    PubMed

    Jackson, Rebecca A; Chen, Ee Sin

    2016-06-01

    The recent advances in pharmacogenomics have made personalized medicine no longer a pipedream but a precise and powerful way to tailor individualized cancer treatment strategies. Cancer is a devastating disease, and contemporary chemotherapeutic strategies now integrate several agents in the treatment of some types of cancer, with the intent to block more than one target simultaneously. This constitutes the premise of synthetic lethality, an attractive therapeutic strategy already demonstrating clinical success in patients with breast and ovarian cancers. Synthetic lethal combinations offer the potential to also target the hitherto "undruggable" mutations that have challenged the cancer field for decades. However, synthetic lethality in clinical cancer therapy is very much still in its infancy, and selecting the most appropriate combinations-or synthetic lethal pairs-is not always an intuitive process. Here, we review some of the recent progress in identifying synthetic lethal combinations and their potential for therapy and highlight some of the tools through which synthetic lethal pairs are identified. PMID:26803999

  15. Exploiting the Tumor Phenotype Using Biodegradable Submicron Carriers of Chemotherapeutic Drugs

    PubMed Central

    Geary, Sean M.; Salem, Aliasger K.

    2014-01-01

    Tumor tissues possess characteristics that distinguish them from healthy tissues and make them attractive targets for submicron carriers of chemotherapeutic drugs (CTX). CTX are generally administered systemically in free form to cancer patients resulting in unwanted cytotoxic effects and placing limitations on the deliverable CTX dose. In an effort to raise the therapeutic index of CTX there are now liposome-based CTX formulations in clinical use that are more tumor specific than the free form of CTX. However, progression to liposome-based chemotherapy in the clinic has been slow and there have been no approved formulations introduced in the last decade. Alternative carrier systems such as those made from the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA) have been investigated in preclinical settings with promising outcomes. Here we review the principle behind biodegradable submicron carriers as CTX delivery vehicles for solid tumors with a specific focUS on liposomes and PLGA-based carriers, highlighting the strengths and weaknesses of each system. PMID:25271435

  16. Improving drug delivery to solid tumors: priming the tumor microenvironment.

    PubMed

    Khawar, Iftikhar Ali; Kim, Jung Ho; Kuh, Hyo-Jeong

    2015-03-10

    Malignant transformation and growth of the tumor mass tend to induce changes in the surrounding microenvironment. Abnormality of the tumor microenvironment provides a driving force leading not only to tumor progression, including invasion and metastasis, but also to acquisition of drug resistance, including pharmacokinetic (drug delivery-related) and pharmacodynamic (sensitivity-related) resistance. Drug delivery systems exploiting the enhanced permeability and retention (EPR) effect and active targeting moieties were expected to be able to cope with delivery-related drug resistance. However, recent evidence supports a considerable barrier role of tumors via various mechanisms, which results in imperfect or inefficient EPR and/or targeting effect. The components of the tumor microenvironment such as abnormal tumor vascular system, deregulated composition of the extracellular matrix, and interstitial hypertension (elevated interstitial fluid pressure) collectively or cooperatively hinder the drug distribution, which is prerequisite to the efficacy of nanoparticles and small-molecule drugs used in cancer medicine. Hence, the abnormal tumor microenvironment has recently been suggested to be a promising target for the improvement of drug delivery to improve therapeutic efficacy. Strategies to modulate the abnormal tumor microenvironment, referred to here as "solid tumor priming" (vascular normalization and/or solid stress alleviation leading to improvement in blood perfusion and convective molecular movement), have shown promising results in the enhancement of drug delivery and anticancer efficacy. These strategies may provide a novel avenue for the development of new chemotherapeutics and combination chemotherapeutic regimens as well as reassessment of previously ineffective agents. PMID:25526702

  17. Apical ABC transporters and cancer chemotherapeutic drug disposition.

    PubMed

    Durmus, Selvi; Hendrikx, Jeroen J M A; Schinkel, Alfred H

    2015-01-01

    ATP-binding cassette (ABC) transporters are transmembrane efflux transporters that mediate cellular extrusion of a broad range of substrates ranging from amino acids, lipids, and ions to xenobiotics including many anticancer drugs. ABCB1 (P-GP) and ABCG2 (BCRP) are the most extensively studied apical ABC drug efflux transporters. They are highly expressed in apical membranes of many pharmacokinetically relevant tissues such as epithelial cells of the small intestine and endothelial cells of the blood capillaries in brain and testis, and in the placental maternal-fetal barrier. In these tissues, they have a protective function as they efflux their substrates back to the intestinal lumen or blood and thus restrict the intestinal uptake and tissue disposition of many compounds. This presents a major challenge for the use of many (anticancer) drugs, as most currently used anticancer drugs are substrates of these transporters. Herein, we review the latest findings on the role of apical ABC transporters in the disposition of anticancer drugs. We discuss that many new, rationally designed anticancer drugs are substrates of these transporters and that their oral availability and/or brain disposition are affected by this interaction. We also summarize studies that investigate the improvement of oral availability and brain disposition of many cytotoxic (e.g., taxanes) and rationally designed (e.g., tyrosine kinase inhibitor) anticancer drugs, using chemical inhibitors of these transporters. These findings provide a better understanding of the importance of apical ABC transporters in chemotherapy and may therefore advance translation of promising preclinical insights and approaches to clinical studies. PMID:25640265

  18. ATP-triggered anticancer drug delivery

    NASA Astrophysics Data System (ADS)

    Mo, Ran; Jiang, Tianyue; Disanto, Rocco; Tai, Wanyi; Gu, Zhen

    2014-03-01

    Stimuli-triggered drug delivery systems have been increasingly used to promote physiological specificity and on-demand therapeutic efficacy of anticancer drugs. Here we utilize adenosine-5'-triphosphate (ATP) as a trigger for the controlled release of anticancer drugs. We demonstrate that polymeric nanocarriers functionalized with an ATP-binding aptamer-incorporated DNA motif can selectively release the intercalating doxorubicin via a conformational switch when in an ATP-rich environment. The half-maximal inhibitory concentration of ATP-responsive nanovehicles is 0.24 μM in MDA-MB-231 cells, a 3.6-fold increase in the cytotoxicity compared with that of non-ATP-responsive nanovehicles. Equipped with an outer shell crosslinked by hyaluronic acid, a specific tumour-targeting ligand, the ATP-responsive nanocarriers present an improvement in the chemotherapeutic inhibition of tumour growth using xenograft MDA-MB-231 tumour-bearing mice. This ATP-triggered drug release system provides a more sophisticated drug delivery system, which can differentiate ATP levels to facilitate the selective release of drugs.

  19. In vivo enhancement of anticancer therapy using bare or chemotherapeutic drug-bearing nanodiamond particles

    PubMed Central

    Li, Yingqi; Tong, Yaoli; Cao, Ruixia; Tian, Zhimei; Yang, Binsheng; Yang, Pin

    2014-01-01

    Background This study investigated the use of nanodiamond particles (NDs) as a promising material for drug delivery in vivo and in vitro. Methods HepG2 cells (a human hepatic carcinoma cell line) were used to determine the characteristics of a nanodiamond-doxorubicin complex (ND-DOX) when taken up by cells in vitro using laser scanning confocal microscopy and dialysis experiments. We also compared the survival rate and histopathology of tumor-bearing mice after treatment with NDs or ND-DOX in vivo. Results In vitro investigation showed that ND-DOX has slow and sustained drug release characteristics compared with free doxorubicin. In vivo, the survival rate of tumor-bearing mice treated with ND-DOX was four times greater than that of mice treated with free doxorubicin. Interestingly, the survival rate in mice treated with NDs alone was close to that of mice treated with free doxorubicin. This indicates that treatment with ND-DOX can prolong the lifespan of tumor-bearing mice significantly compared with conventional doxorubicin and that NDs can have this effect as well. Histopathological analysis showed that neither the NDs nor ND-DOX were toxic to the kidney, liver, or spleen in contrast with the well-known toxic effects of free doxorubicin on the kidney and liver. Further, both the bare NDs and ND-DOX could suppress tumor growth effectively. Conclusion NDs can potentially prolong survival, and ND-DOX may act as a nanodrug with promising chemotherapeutic efficacy and safety. PMID:24591828

  20. Nanocarrier mediated Delivery of siRNA/miRNA in Combination with Chemotherapeutic Agents for Cancer Therapy: Current Progress and Advances

    PubMed Central

    Gandhi, Nishant S.; Tekade, Rakesh K.; Chougule, Mahavir B.

    2014-01-01

    Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibits drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), Multidrug resistant protein 1(MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer. PMID:25204288

  1. Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer.

    PubMed

    Fujita, Ken-ichi; Kubota, Yutaro; Ishida, Hiroo; Sasaki, Yasutsuna

    2015-11-21

    Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy. PMID:26604633

  2. Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer

    PubMed Central

    Fujita, Ken-ichi; Kubota, Yutaro; Ishida, Hiroo; Sasaki, Yasutsuna

    2015-01-01

    Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy. PMID:26604633

  3. Polymer Particulates in Drug Delivery.

    PubMed

    Kaur, Harmeet; Kumar, Virender; Kumar, Krishan; Rathor, Sandeep; Kumari, Parveen; Singh, Jasbir

    2016-01-01

    Development of effective drug delivery systems is important for medicine and healthcare. Polymer particulates (micro- and nanoparticles) have opened new opportunities in the field of drug delivery by overcoming various limitations of conventional delivery methods. The properties of polymeric particles can be readily tuned by precisely engineering the constituent blocks of polymers for improving drug loading, release rate, pharmacokinetics, targeting, etc. The end-groups of various polymers can be readily modified with ligands making them suitable for recognizing by cell-specific receptors, providing cellular specificity, and superior intracellular delivery. This review will mainly cover delivery of many potential drugs and biomolecules by means of polymeric microparticles, nanoparticles and copolymer micelles or assemblies. An overview about formulation methods of polymer particulates has also been addressed. Attempt has been made to cover all the potential polymers that are well known in pharmaceutical history. PMID:26898740

  4. Osmotic micropumps for drug delivery.

    PubMed

    Herrlich, Simon; Spieth, Sven; Messner, Stephan; Zengerle, Roland

    2012-11-01

    This paper reviews miniaturized drug delivery systems applying osmotic principles for pumping. Osmotic micropumps require no electrical energy and consequently enable drug delivery systems of smallest size for a broad field of new applications. In contrast to common tablets, these pumps provide constant (zero-order) drug release rates. This facilitates systems for long term use not limited by gastrointestinal transit time and first-pass metabolism. The review focuses on parenteral routes of administration targeting drug delivery either in a site-specific or systemic way. Osmotic pumps consist of three building blocks: osmotic agent, solvent, and drug. This is used to categorize pumps into (i) single compartment systems using water from body fluids as solvent and the drug itself as the osmotic agent, (ii) two compartment systems employing a separate osmotic agent, and (iii) multi-compartment architectures employing solvent, drug and osmotic agent separately. In parallel to the micropumps, relevant applications and therapies are discussed. PMID:22370615

  5. Bioresponsive matrices in drug delivery

    PubMed Central

    2010-01-01

    For years, the field of drug delivery has focused on (1) controlling the release of a therapeutic and (2) targeting the therapeutic to a specific cell type. These research endeavors have concentrated mainly on the development of new degradable polymers and molecule-labeled drug delivery vehicles. Recent interest in biomaterials that respond to their environment have opened new methods to trigger the release of drugs and localize the therapeutic within a particular site. These novel biomaterials, usually termed "smart" or "intelligent", are able to deliver a therapeutic agent based on either environmental cues or a remote stimulus. Stimuli-responsive materials could potentially elicit a therapeutically effective dose without adverse side effects. Polymers responding to different stimuli, such as pH, light, temperature, ultrasound, magnetism, or biomolecules have been investigated as potential drug delivery vehicles. This review describes the most recent advances in "smart" drug delivery systems that respond to one or multiple stimuli. PMID:21114841

  6. Beta-lactams and their potential use as novel anticancer chemotherapeutics drugs.

    PubMed

    Kuhn, Deborah; Coates, Cristina; Daniel, Kenyon; Chen, Di; Bhuiyan, Mohammad; Kazi, Aslamuzzaman; Turos, Edward; Dou, Q Ping

    2004-09-01

    The discovery of natural and synthetic antibiotics is one of the most important medical breakthroughs in human history. Many diseases, such as bacterial meningitis, pneumonia, and septicemia, are now curable with the use of antibiotics. Antibiotics are efficacious, generally well tolerated in patients, and have a low toxicity level. It is for these reasons antibiotics remain an attractive target for drug discovery. Traditional beta-lactam antibiotics (e.g. penicillins, penems, cephalosporins) have a bicyclic ring structure that is conformationally rigid and functions to inhibit bacterial cell wall synthesis. In addition to the bactericidal action of antibiotics, it has been discovered that many antibiotics are capable of inhibiting tumor cell growth. There are currently many antitumor antibiotics approved for cancer therapy, which work to inhibit tumor cell growth by DNA intercalation. The use of beta-lactams as prodrugs has also met with success by aiding delivery of the chemotherapeutic directly to tumor sites. Recently, a novel class of N-thiolated monobactams, so termed because they possess a monocyclic ring instead of the bicyclic ring, has been found to induce apoptosis potently and specifically in many tumor cell lines but not in normal, non-transformed cell lines. Other beta-lactams, such as the polyaromatics, have been found to slow or inhibit tumor cell growth, and the 4-alkylidene beta-lactams are capable of inhibiting matrix metalloproteinases and leukocyte elactase activity. These data indicate that synthesis and evaluation of beta-lactams are a promising area for further development in anticancer research. PMID:15358584

  7. Assessment of urinary excretion of antimalarial drugs in large-scale chemotherapeutic eradication projects.

    PubMed

    BRUCE-CHWATT, L J

    1959-01-01

    Assessment of the urinary excretion of an antimalarial drug is a useful means of checking the amount of drug administered and the regularity of intake. The author describes the various methods available for the qualitative and quantitative estimation of antimalarial drugs in urine and discusses their relative merits, with special reference to their suitability for use in the field. He points out the difficulties involved in estimating the urinary excretion of antimalarials in large-scale chemotherapeutic eradication projects and stress the importance of simplifying testing techniques as far as possible. PMID:13805135

  8. Nanoencapsulation for drug delivery

    PubMed Central

    Kumari, Avnesh; Singla, Rubbel; Guliani, Anika; Yadav, Sudesh Kumar

    2014-01-01

    Nanoencapsulation of drug/small molecules in nanocarriers (NCs) is a very promising approach for development of nanomedicine. Modern drug encapsulation methods allow efficient loading of drug molecules inside the NCs thereby reducing systemic toxicity associated with drugs. Targeting of NCs can enhance the accumulation of nanonencapsulated drug at the diseased site. This article focussed on the synthesis methods, drug loading, drug release mechanism and cellular response of nanoencapsulated drugs on liposomes, micelles, carbon nanotubes, dendrimers, and magnetic NCs. Also the uses of these various NCs have been highlighted in the field of nanotechnology. PMID:26417260

  9. Photoresponsive nanoparticles for drug delivery

    PubMed Central

    Rwei, Alina Y.; Wang, Weiping; Kohane, Daniel S.

    2015-01-01

    Summary Externally triggerable drug delivery systems provide a strategy for the delivery of therapeutic agents preferentially to a target site, presenting the ability to enhance therapeutic efficacy while reducing side effects. Light is a versatile and easily tuned external stimulus that can provide spatiotemporal control. Here we will review the use of nanoparticles in which light triggers drug release or induces particle binding to tissues (phototargeting). PMID:26644797

  10. The Role of Transporters in the Toxicity of Chemotherapeutic Drugs: Focus on Transporters for Organic Cations.

    PubMed

    Hucke, Anna; Ciarimboli, Giuliano

    2016-07-01

    The introduction of chemotherapy in the treatment of cancer is one of the most important achievements of modern medicine, even allowing the cure of some lethal diseases such as testicular cancer and other malignant neoplasms. The number and type of chemotherapeutic agents available have steadily increased and have developed until the introduction of targeted tumor therapy. It is now evident that transporters play an important role for determining toxicity of chemotherapeutic drugs not only against target but also against nontarget cells. This is of special importance for intracellularly active hydrophilic drugs, which cannot freely penetrate the plasma membrane. Because many important chemotherapeutic agents are substrates of transporters for organic cations, this review discusses the known interaction of these substances with these transporters. A particular focus is given to the role of transporters for organic cations in the development of side effects of chemotherapy with platinum derivatives and in the efficacy of recently developed tyrosine kinase inhibitors to specifically target cancer cells. It is evident that specific inhibition of uptake transporters may be a possible strategy to protect against undesired side effects of platinum derivatives without compromising their antitumor efficacy. These transporters are also important for efficient targeting of tyrosine kinase inhibitors to cancer cells. However, in order to achieve the aims of protecting from undesired toxicities and improving the specificity of uptake by tumor cells, an exact knowledge of transporter expression, function, regulation under normal and pathologic conditions, and of genetically and epigenetically regulation is mandatory. PMID:27385173

  11. Hypoxia suppresses chemotherapeutic drug-induced p53 Serine 46 phosphorylation by triggering HIPK2 degradation.

    PubMed

    Moehlenbrink, Jutta; Bitomsky, Nadja; Hofmann, Thomas G

    2010-06-01

    The molecular mechanisms by which hypoxic tumor cells escape radio- and chemotherapy are largely unclear. Homeodomain-interacting protein kinase 2 (HIPK2) drives the apoptotic program in response to DNA-damaging chemotherapeutic drug treatment by phosphorylating the tumor suppressor protein p53 at Ser46. HIPK2 is kept inactive in unstressed cells through ubiquitination and degradation facilitated by the ubiquitin ligases WSB1 and Siah1. Here, we demonstrate that HIPK2 is degraded during hypoxia in a proteasome-dependent and partially Siah1-dependent fashion. Concordantly, hypoxic tumor cells show an impaired p53 Ser46 phosphorylation in response to treatment with the chemotherapeutic Adriamycin. Remarkably, proteasome-inhibition rescues HIPK2 expression in hypoxic hepatoma cells and restores p53 Ser46 phosphorylation and caspase activity after Adriamycin treatment. Our findings suggest a molecular mechanism by which hypoxic cancer cells can escape chemotherapeutic drug treatment and suggest proteasome-inhibition as a promising approach to sensitise hypoxic cancer cells to therapy. PMID:20018442

  12. Nanoscale coordination polymers for anticancer drug delivery

    NASA Astrophysics Data System (ADS)

    Phillips, Rachel Huxford

    This dissertation reports the synthesis and characterization of nanoscale coordination polymers (NCPs) for anticancer drug delivery. Nanoparticles have been explored in order to address the limitations of small molecule chemotherapeutics. NCPs have been investigated as drug delivery vehicles as they can exhibit the same beneficial properties as the bulk metal-organic frameworks as well as interesting characteristics that are unique to nanomaterials. Gd-MTX (MTX = methotrexate) NCPs with a MTX loading of 71.6 wt% were synthesized and stabilized by encapsulation within a lipid bilayer containing anisamide (AA), a small molecule that targets sigma receptors which are overexpressed in many cancer tissues. Functionalization with AA allows for targeted delivery and controlled release to cancer cells, as shown by enhanced efficacy against leukemia cells. The NCPs were doped with Ru(bpy)32+ (bpy = 2,2'-bipyridine), and this formulation was utilized as an optical imaging agent by confocal microscopy. NCPs containing the chemotherapeutic pemetrexed (PMX) were synthesized using different binding metals. Zr-based materials could not be stabilized by encapsulation with a lipid bilayer, and Gd-based materials showed that PMX had degraded during synthesis. However, Hf-based NCPs containing 19.7 wt% PMX were stabilized by a lipid coating and showed in vitro efficacy against non-small cell lung cancer (NSCLC) cell lines. Enhanced efficacy was observed for formulations containing AA. Additionally, NCP formulations containing the cisplatin prodrug disuccinatocisplatin were prepared; one of these formulations could be stabilized by encapsulation within a lipid layer. Coating with a lipid layer doped with AA rendered this formulation an active targeting agent. The resulting formulation proved more potent than free cisplatin in NSCLC cell lines. Improved NCP uptake was demonstrated by confocal microscopy and competitive binding assays. Finally, a Pt(IV) oxaliplatin prodrug was

  13. Synthesis and characterization of transferrin-targeted chemotherapeutic delivery systems prepared via RAFT copolymerization of high molecular weight PEG macromonomers

    PubMed Central

    Roy, Debashish; Berguig, Geoffrey Y; Ghosn, Bilal; Lane, Daniel; Braswell, Scott; Stayton, Patrick S; Convertine, Anthony J

    2014-01-01

    Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a nanoparticulate drug delivery system for chemotherapeutics. The nanoparticles contain a PEG “stealth” corona as well as reactive anhydride functionality designed for conjugating targeting proteins. The multifunctional carrier functionality was achieved by controlling the copolymerization of the hydrophobic monomer lauryl methacrylate (LMA), with a reactive anhydride functional methacrylate (TMA), and a large polyethyleneglycol methacrylate monomer (Mn~950 Da) (O950). RAFT polymerization kinetics of O950 were evaluated as a function of target degrees of polymerization (DP), initial chain transfer agent to initiator ratio ([CTA]o/[I]o), and solvent concentration. Excellent control over the polymerization was observed for target DPs of 25 and 50 at [CTA]o/[I]o ratio of 10 as evidenced by narrow and symmetric molecular weight distributions and the ability to prepare block copolymers. The TMA-functional copolymers were conjugated to the tumor targeting protein transferrin (Tf). The targeted copolymer was shown to encapsulate docetaxel at concentrations comparable to the commercial single vial formulation of docetaxel (Taxotere). In vitro cytotoxicity studies conducted in HeLa cells show that the Tf targeting enhances the cancer killing properties relative to the polymer encapsulated docetaxel formulation. PMID:25221630

  14. Insight to drug delivery aspects for colorectal cancer

    PubMed Central

    Gulbake, Arvind; Jain, Aviral; Jain, Ashish; Jain, Ankit; Jain, Sanjay K

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide in human beings. Surgery, chemotherapy, radiotherapy and targeted therapies are the conventional four approaches which are currently used for the treatment of CRC. The site specific delivery of chemotherapeutics to their site of action would increase effectiveness with reducing side effects. Targeted oral drug delivery systems based on polysaccharides are being investigated to target and deliver chemotherapeutic and chemopreventive agents directly to colon and rectum. Site-specific drug delivery to colon increases its concentration at the target site, and thus requires a lower dose and hence abridged side effects. Some novel therapies are also briefly discussed in article such as receptor (epidermal growth factor receptor, folate receptor, wheat germ agglutinin, VEGF receptor, hyaluronic acid receptor) based targeting therapy; colon targeted proapoptotic anticancer drug delivery system, gene therapy. Even though good treatment options are available for CRC, the ultimate therapeutic approach is to avert the incidence of CRC. It was also found that CRCs could be prevented by diet and nutrition such as calcium, vitamin D, curcumin, quercetin and fish oil supplements. Immunotherapy and vaccination are used nowadays which are showing better results against CRC. PMID:26811609

  15. Insight to drug delivery aspects for colorectal cancer.

    PubMed

    Gulbake, Arvind; Jain, Aviral; Jain, Ashish; Jain, Ankit; Jain, Sanjay K

    2016-01-14

    Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide in human beings. Surgery, chemotherapy, radiotherapy and targeted therapies are the conventional four approaches which are currently used for the treatment of CRC. The site specific delivery of chemotherapeutics to their site of action would increase effectiveness with reducing side effects. Targeted oral drug delivery systems based on polysaccharides are being investigated to target and deliver chemotherapeutic and chemopreventive agents directly to colon and rectum. Site-specific drug delivery to colon increases its concentration at the target site, and thus requires a lower dose and hence abridged side effects. Some novel therapies are also briefly discussed in article such as receptor (epidermal growth factor receptor, folate receptor, wheat germ agglutinin, VEGF receptor, hyaluronic acid receptor) based targeting therapy; colon targeted proapoptotic anticancer drug delivery system, gene therapy. Even though good treatment options are available for CRC, the ultimate therapeutic approach is to avert the incidence of CRC. It was also found that CRCs could be prevented by diet and nutrition such as calcium, vitamin D, curcumin, quercetin and fish oil supplements. Immunotherapy and vaccination are used nowadays which are showing better results against CRC. PMID:26811609

  16. Enhanced delivery of the RAPTA-C macromolecular chemotherapeutic by conjugation to degradable polymeric micelles.

    PubMed

    Blunden, Bianca M; Lu, Hongxu; Stenzel, Martina H

    2013-12-01

    Macromolecular ruthenium complexes are a promising avenue to better and more selective chemotherapeutics. We have previously shown that RAPTA-C [RuCl2(p-cymene)(PTA)], with the water-soluble 1,3,5-phosphaadamantane (PTA) ligand, could be attached to a polymer moiety via nucleophilic substitution of an available iodide with an amide in the PTA ligand. To increase the cell uptake of this macromolecule, we designed an amphiphilic block copolymer capable of self-assembling into polymeric micelles. The block copolymer was prepared by ring-opening polymerization of d,l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) using a RAFT agent with an additional hydroxyl functionality, followed by the RAFT copolymerization of 2-hydroxyethyl acrylate (HEA) and 2-chloroethyl methacrylate (CEMA). The Finkelstein reaction and reaction with PTA led to polymers that can readily react with the dimer of RuCl2(p-cymene) to create a macromolecular RAPTA-C drug. RAPTA-C conjugation, micellization, and subsequent cytotoxicity and cell uptake of these polymeric moieties was tested on ovarian cancer A2780, A2780cis, and Ovcar-3 cell lines. Confocal microscopy images confirmed cell uptake of the micelles into the lysosome of the cells, indicative of an endocytic pathway. On average, a 10-fold increase in toxicity was found for the macromolecular drugs when compared to the RAPTA-C molecule. Furthermore, the cell uptake of ruthenium was analyzed and a significant increase was found for the micelles compared to RAPTA-C. Notably, micelles prepared from the polymer containing fewer HEA units had the highest cytotoxicity, the best cell uptake of ruthenium and were highly effective in suppressing the colony-forming ability of cells. PMID:24266669

  17. Targeted drug delivery using genetically engineered diatom biosilica.

    PubMed

    Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

    2015-01-01

    The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites. PMID:26556723

  18. Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells

    PubMed Central

    Carstens, Matthew R.; Fisher, Robert C.; Acharya, Abhinav P.; Butterworth, Elizabeth A.; Scott, Edward; Huang, Emina H.; Keselowsky, Benjamin G.

    2015-01-01

    A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneous phenotypes within a tumor. The cancer stem cell hypothesis postulates that a minute fraction of cells within a tumor, termed cancer stem cells (CSCs), have a tumor-initiating capacity that propels tumor growth. An application of this discovery is to target this critical cell population using chemotherapy; however, the process of isolating these cells is arduous, and the rarity of CSCs makes it difficult to test potential drug candidates in a robust fashion, particularly for individual patients. To address the challenge of screening drug libraries on patient-derived populations of rare cells, such as CSCs, we have developed a drug-eluting microarray, a miniaturized platform onto which a minimal quantity of cells can adhere and be exposed to unique treatment conditions. Hundreds of drug-loaded polymer islands acting as drug depots colocalized with adherent cells are surrounded by a nonfouling background, creating isolated culture environments on a solid substrate. Significant results can be obtained by testing <6% of the cells required for a typical 96-well plate. Reliability was demonstrated by an average coefficient of variation of 14% between all of the microarrays and 13% between identical conditions within a single microarray. Using the drug-eluting array, colorectal CSCs isolated from two patients exhibited unique responses to drug combinations when cultured on the drug-eluting microarray, highlighting the potential as a prognostic tool to identify personalized chemotherapeutic regimens targeting CSCs. PMID:26124098

  19. New chemotherapeutic drug sensitivity assay for colon carcinomas in monolayer culture.

    PubMed

    Schroy, P C; Cohen, A; Winawer, S J; Friedman, E A

    1988-06-01

    Ten previously untreated colon carcinomas were tested for chemotherapeutic drug sensitivity in primary monolayer culture. Colon carcinomas were partly digested to groups of epithelial cells which plated with a mean efficiency of 42 +/- 9% (SE) on a collagen I-bovine serum albumin substrate in serum-free medium, producing patches of tightly adherent epithelial cells. The cultured cells were judged epithelial by the presence of cytokeratins, an epithelial cell surface epitope, junctional complexes, and brush borders. Each carcinoma was plated in 40 to 60 Petri dishes (35 mm), yielding a mean of 28 +/- 8 (SE) colonies per dish (6832 +/- 1952 cells). Drugs tested in duplicate plates were mitomycin C, cisplatin, streptozotocin, and 5-fluorouracil at 0.1, 1, 10, and 100 micrograms/ml, and at 0.1, 1, and 2x the peak tolerated drug concentration in serum. Twenty-four h after plating, any nonadherent cells were removed, and the adherent tumor cells were continuously exposed to the drugs for 3 days. Each drug induced colony lysis in a dose-dependent manner in responsive tumors. Drug-resistant, cycling cells were identified by [3H]thymidine incorporation in colonies which were not lysed by drug treatment. Each of the ten carcinomas exhibited inherent resistance to one or more chemotherapy drugs within the concentration ranges clinically achievable. PMID:2966672

  20. Protein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in Cancer Cells.

    PubMed

    Bellini, Michela; Mazzucchelli, Serena; Galbiati, Elisabetta; Sommaruga, Silvia; Fiandra, Luisa; Truffi, Marta; Rizzuto, Maria A; Colombo, Miriam; Tortora, Paolo; Corsi, Fabio; Prosperi, Davide

    2014-12-28

    A genetically engineered apoferritin variant consisting of 24 heavy-chain subunits (HFn) was produced to achieve a cumulative delivery of an antitumor drug, which exerts its cytotoxic action by targeting the DNA at the nucleus of human cancer cells with subcellular precision. The rationale of our approach is based on exploiting the natural arsenal of defense of cancer cells to stimulate them to recruit large amounts of HFn nanoparticles loaded with doxorubicin inside their nucleus in response to a DNA damage, which leads to a programmed cell death. After demonstrating the selectivity of HFn for representative cancer cells compared to healthy fibroblasts, doxorubicin-loaded HFn was used to treat the cancer cells. The results from confocal microscopy and DNA damage assays proved that loading of doxorubicin in HFn nanoparticles increased the nuclear delivery of the drug, thus enhancing doxorubicin efficacy. Doxorubicin-loaded HFn acts as a "Trojan Horse": HFn was internalized in cancer cells faster and more efficiently compared to free doxorubicin, then promptly translocated into the nucleus following the DNA damage caused by the partial release in the cytoplasm of encapsulated doxorubicin. This self-triggered translocation mechanism allowed the drug to be directly released in the nuclear compartment, where it exerted its toxic action. This approach was reliable and straightforward providing an antiproliferative effect with high reproducibility. The particular self-assembling nature of HFn nanocage makes it a versatile and tunable nanovector for a broad range of molecules suitable both for detection and treatment of cancer cells. PMID:25312541

  1. Nanoparticles for Brain Drug Delivery

    PubMed Central

    Masserini, Massimo

    2013-01-01

    The central nervous system, one of the most delicate microenvironments of the body, is protected by the blood-brain barrier (BBB) regulating its homeostasis. BBB is a highly complex structure that tightly regulates the movement of ions of a limited number of small molecules and of an even more restricted number of macromolecules from the blood to the brain, protecting it from injuries and diseases. However, the BBB also significantly precludes the delivery of drugs to the brain, thus, preventing the therapy of a number of neurological disorders. As a consequence, several strategies are currently being sought after to enhance the delivery of drugs across the BBB. Within this review, the recently born strategy of brain drug delivery based on the use of nanoparticles, multifunctional drug delivery systems with size in the order of one-billionth of meters, is described. The review also includes a brief description of the structural and physiological features of the barrier and of the most utilized nanoparticles for medical use. Finally, the potential neurotoxicity of nanoparticles is discussed, and future technological approaches are described. The strong efforts to allow the translation from preclinical to concrete clinical applications are worth the economic investments. PMID:25937958

  2. The role of MAPK pathways in the action of chemotherapeutic drugs.

    PubMed

    Boldt, Simone; Weidle, Ulrich H; Kolch, Walter

    2002-11-01

    In this study we have investigated the role of mitogen-induced and stress-activated MAP kinase pathways in the cellular response to taxol, etoposide and ceramide in three different human cancer cell lines: HeLa cervical carcinoma, MCF7 breast cancer and A431 squamous carcinoma cells. The mitogen-induced ERK MAPKs were linked to cell proliferation and survival, whereas the stress-activated MAPKs, p38 and JNK, were connected with apoptosis. Our results show that all drugs activated MAPKs, but that the extent and kinetics of activation were different. In order to assay the biological consequences of drug-induced MAPK activation we employed selective MAPK inhibitors and measured both long-term clonogenic survival as well as short-term parameters including apoptosis, mitochondrial metabolic integrity and cell cycle progression. Our results show that drug induced toxicity is not correlated with any singular parameter, but rather a combination of effects on cell cycle and apoptosis. In certain constellations the modulation of MAPK pathways could enhance or decrease drug efficacies. These effects mainly pertained to the regulation of apoptosis and clonogenic survival, but they were highly dependent on the combination of drug and cell line without any clear patterns of correlations emerging. These results suggest that the modulation of MAPK pathways to enhance the efficacy of chemotherapeutic drugs is of limited value unless it is tailored to the specific combination of drug and cancer. PMID:12419831

  3. Mucoadhesive vaginal drug delivery systems.

    PubMed

    Acartürk, Füsun

    2009-11-01

    Vaginal delivery is an important route of drug administration for both local and systemic diseases. The vaginal route has some advantages due to its large surface area, rich blood supply, avoidance of the first-pass effect, relatively high permeability to many drugs and self-insertion. The traditional commercial preparations, such as creams, foams, gels, irrigations and tablets, are known to reside in the vaginal cavity for a relatively short period of time owing to the self-cleaning action of the vaginal tract, and often require multiple daily doses to ensure the desired therapeutic effect. The vaginal route appears to be highly appropriate for bioadhesive drug delivery systems in order to retain drugs for treating largely local conditions, or for use in contraception. In particular, protection against sexually-transmitted diseases is critical. To prolong the residence time in the vaginal cavity, bioadhesive therapeutic systems have been developed in the form of semi-solid and solid dosage forms. The most commonly used mucoadhesive polymers that are capable of forming hydrogels are synthetic polyacrylates, polycarbophil, chitosan, cellulose derivatives (hydroxyethycellulose, hydroxy-propylcellulose and hydroxypropylmethylcellulose), hyaluronic acid derivatives, pectin, tragacanth, carrageenan and sodium alginate. The present article is a comprehensive review of the patents related to mucoadhesive vaginal drug delivery systems. PMID:19925443

  4. Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone.

    PubMed

    Damiani, Roberto Marques; Moura, Dinara Jaqueline; Viau, Cassiana Macagnan; Caceres, Rafael Andrade; Henriques, João Antonio Pêgas; Saffi, Jenifer

    2016-09-01

    Anthracyclines, e.g., doxorubicin (DOX), and anthracenediones, e.g., mitoxantrone (MTX), are drugs used in the chemotherapy of several cancer types, including solid and non-solid malignancies such as breast cancer, leukemia, lymphomas, and sarcomas. Although they are effective in tumor therapy, treatment with these two drugs may lead to side effects such as arrhythmia and heart failure. At the same clinically equivalent dose, MTX causes slightly reduced cardiotoxicity compared with DOX. These drugs interact with iron to generate reactive oxygen species (ROS), target topoisomerase 2 (Top2), and impair mitochondria. These are some of the mechanisms through which these drugs induce late cardiomyopathy. In this review, we compare the cardiotoxicities of these two chemotherapeutic drugs, DOX and MTX. As described here, even though they share similarities in their modes of toxicant action, DOX and MTX seem to differ in a key aspect. DOX is a more redox-interfering drug, while MTX induces energy imbalance. In addition, DOX toxicity can be explained by underlying mechanisms that include targeting of Top2 beta, mitochondrial impairment, and increases in ROS generation. These modes of action have not yet been demonstrated for MTX, and this knowledge gap needs to be filled. PMID:27342245

  5. Nanostructures for protein drug delivery.

    PubMed

    Pachioni-Vasconcelos, Juliana de Almeida; Lopes, André Moreni; Apolinário, Alexsandra Conceição; Valenzuela-Oses, Johanna Karina; Costa, Juliana Souza Ribeiro; Nascimento, Laura de Oliveira; Pessoa, Adalberto; Barbosa, Leandro Ramos Souza; Rangel-Yagui, Carlota de Oliveira

    2016-02-01

    Use of nanoscale devices as carriers for drugs and imaging agents has been extensively investigated and successful examples can already be found in therapy. In parallel, recombinant DNA technology together with molecular biology has opened up numerous possibilities for the large-scale production of many proteins of pharmaceutical interest, reflecting in the exponentially growing number of drugs of biotechnological origin. When we consider protein drugs, however, there are specific criteria to take into account to select adequate nanostructured systems as drug carriers. In this review, we highlight the main features, advantages, drawbacks and recent developments of nanostructures for protein encapsulation, such as nanoemulsions, liposomes, polymersomes, single-protein nanocapsules and hydrogel nanoparticles. We also discuss the importance of nanoparticle stabilization, as well as future opportunities and challenges in nanostructures for protein drug delivery. PMID:26580477

  6. Microfabricated injectable drug delivery system

    DOEpatents

    Krulevitch, Peter A.; Wang, Amy W.

    2002-01-01

    A microfabricated, fully integrated drug delivery system capable of secreting controlled dosages of multiple drugs over long periods of time (up to a year). The device includes a long and narrow shaped implant with a sharp leading edge for implantation under the skin of a human in a manner analogous to a sliver. The implant includes: 1) one or more micromachined, integrated, zero power, high and constant pressure generating osmotic engine; 2) low power addressable one-shot shape memory polymer (SMP) valves for switching on the osmotic engine, and for opening drug outlet ports; 3) microfabricated polymer pistons for isolating the pressure source from drug-filled microchannels; 4) multiple drug/multiple dosage capacity, and 5) anisotropically-etched, atomically-sharp silicon leading edge for penetrating the skin during implantation. The device includes an externally mounted controller for controlling on-board electronics which activates the SMP microvalves, etc. of the implant.

  7. Nanothermodynamics mediates drug delivery.

    PubMed

    Stefi, Aikaterina L; Sarantopoulou, Evangelia; Kollia, Zoe; Spyropoulos-Antonakakis, Nikolaos; Bourkoula, Athanasia; Petrou, Panagiota S; Kakabakos, Sotirios; Soras, Georgios; Trohopoulos, Panagiotis N; Nizamutdinov, Alexey S; Semashko, Vadim V; Cefalas, Alkiviadis Constantinos

    2015-01-01

    The efficiency of penetration of nanodrugs through cell membranes imposes further complexity due to nanothermodynamic and entropic potentials at interfaces. Action of nanodrugs is effective after cell membrane penetration. Contrary to diffusion of water diluted common molecular drugs, nanosize imposes an increasing transport complexity at boundaries and interfaces (e.g., cell membrane). Indeed, tiny dimensional systems brought the concept of "nanothermodynamic potential," which is proportional to the number of nanoentities in a macroscopic system, from either the presence of surface and edge effects at the boundaries of nanoentities or the restriction of the translational and rotational degrees of freedom of molecules within them. The core element of nanothermodynamic theory is based on the assumption that the contribution of a nanosize ensemble to the free energy of a macroscopic system has its origin at the excess interaction energy between the nanostructured entities. As the size of a system is increasing, the contribution of the nanothermodynamic potential to the free energy of the system becomes negligible. Furthermore, concentration gradients at boundaries, morphological distribution of nanoentities, and restriction of the translational motion from trapping sites are the source of strong entropic potentials at the interfaces. It is evident therefore that nanothermodynamic and entropic potentials either prevent or allow enhanced concentration very close to interfaces and thus strongly modulate nanoparticle penetration within the intracellular region. In this work, it is shown that nano-sized polynuclear iron (III)-hydroxide in sucrose nanoparticles have a nonuniform concentration around the cell membrane of macrophages in vivo, compared to uniform concentration at hydrophobic prototype surfaces. The difference is attributed to the presence of entropic and nanothermodynamic potentials at interfaces. PMID:25416996

  8. Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance

    PubMed Central

    Shi, Zhi; Tiwari, Amit K; Shukla, Suneet; Robey, Robert W.; Singh, Satyakam; Kim, In-Wha; Bates, Susan E.; Peng, Xingxiang; Abraham, Ioana; Ambudkar, Suresh V.; Talele, Tanaji T.; Fu, Li-Wu; Chen, Zhe-Sheng

    2011-01-01

    Sildenafil is a potent and selective inhibitor of the type 5 cGMP-specific phosphodiesterase that is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. Here we report that sildenafil has differential effects on cell surface ABC transporters such as ABCB1, ABCC1 and ABCG2 that modulate intracompartmental and intracellular concentrations of chemotherapeutic drugs. In ABCB1-overexpressing cells, non-toxic doses of sildenafil inhibited resistance and increased the effective intracellular concentration of ABCB1 substrate drugs, such as paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil inhibited resistance to ABCG2 substrate anticancer drugs, for example, increasing the effective intracellular concentration of mitoxantrone or the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of E217βG and methotrexate by the ABCG2 transporter. Mechanistic investigations revealed that sildenafil stimulated ABCB1 ATPase activity and inhibited photolabeling of ABCB1 with [125I]-IAAP, whereas it only slightly stimulated ABCG2 ATPase activity and inhibited photolabeling of ABCG2 with [125I]-IAAP. In contrast, Sildenafil did not alter the sensitivity of parental, ABCB1- or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drugs, nor did sildenafil affect the function of another ABC drug transporter ABCC1. Homology modeling predicted the binding conformation of sildenafil within the large cavity of the transmembrane region of ABCB1. Overall, we found that sildenafil inhibits the transporter function of ABCB1 and ABCG2, with a stronger effect on ABCB1. Our findings suggest a possible strategy to enhance the distribution and potentially the activity of anti-cancer drugs by jointly using a clinically approved drug with known side effects and drug-drug interactions. PMID:21402712

  9. Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance.

    PubMed

    Shi, Zhi; Tiwari, Amit K; Shukla, Suneet; Robey, Robert W; Singh, Satyakam; Kim, In-Wha; Bates, Susan E; Peng, Xingxiang; Abraham, Ioana; Ambudkar, Suresh V; Talele, Tanaji T; Fu, Li-Wu; Chen, Zhe-Sheng

    2011-04-15

    Sildenafil is a potent and selective inhibitor of the type 5 cGMP (cyclic guanosine 3',5'-monophosphate)-specific phosphodiesterase that is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. Here, we report that sildenafil has differential effects on cell surface ABC transporters such as ABCB1, ABCC1, and ABCG2 that modulate intracompartmental and intracellular concentrations of chemotherapeutic drugs. In ABCB1-overexpressing cells, nontoxic doses of sildenafil inhibited resistance and increased the effective intracellular concentration of ABCB1 substrate drugs such as paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil inhibited resistance to ABCG2 substrate anticancer drugs, for example, increasing the effective intracellular concentration of mitoxantrone or the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of E(2)17βG and methotrexate by the ABCG2 transporter. Mechanistic investigations revealed that sildenafil stimulated ABCB1 ATPase activity and inhibited photolabeling of ABCB1 with [(125)I]-iodoarylazidoprazosin (IAAP), whereas it only slightly stimulated ABCG2 ATPase activity and inhibited photolabeling of ABCG2 with [(125)I]-IAAP. In contrast, sildenafil did not alter the sensitivity of parental, ABCB1-, or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drugs, nor did sildenafil affect the function of another ABC drug transporter, ABCC1. Homology modeling predicted the binding conformation of sildenafil within the large cavity of the transmembrane region of ABCB1. Overall, we found that sildenafil inhibits the transporter function of ABCB1 and ABCG2, with a stronger effect on ABCB1. Our findings suggest a possible strategy to enhance the distribution and potentially the activity of anticancer drugs by jointly using a clinically approved drug with known side effects and drug-drug interactions. PMID:21402712

  10. Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug.

    PubMed

    Guillermet-Guibert, Julie; Davenne, Lise; Pchejetski, Dimitri; Saint-Laurent, Nathalie; Brizuela, Leyre; Guilbeau-Frugier, Céline; Delisle, Marie-Bernadette; Cuvillier, Olivier; Susini, Christiane; Bousquet, Corinne

    2009-04-01

    Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug. PMID:19372554

  11. Role of Cytochrome P450 Monooxygenase in Carcinogen and Chemotherapeutic Drug Metabolism.

    PubMed

    Wahlang, B; Falkner, K Cameron; Cave, Matt C; Prough, Russell A

    2015-01-01

    The purpose of this chapter is to provide insight into which human cytochromes P450 (CYPs) may be involved in metabolism of chemical carcinogens and anticancer drugs. A historical overview of this field and the development of literature using relevant animal models and expressed human CYPs have provided information about which specific CYPs may be involved in carcinogen metabolism. Definition of the biochemical properties of CYP activity came from several groups who studied the reaction stoichiometry of butter yellow and benzo[α]pyrene, including their role in induction of these enzyme systems. This chapter will list as much as is known about the human CYPs involved in carcinogen and anticancer drug metabolism, as well as summarize studies with rodent CYPs. A review of three major classes of anticancer drugs and their metabolism in humans is covered for cyclophosphamide, procarbazine, and anthracycline antibiotics, cancer chemotherapeutic compounds extensively metabolized by CYPs. The emerging information about human CYP gene polymorphisms as well as other enzymes involved in foreign compound metabolism provides considerable information about how these genetic variants affect carcinogen and anticancer drug metabolism. With information available from individual's genomic sequences, consideration of populations who may be at risk due to environmental exposure to carcinogens or how to optimize their cancer therapy regimens to enhance efficacy of the anticancer drugs appears to be an important field of study to benefit individuals in the future. PMID:26233902

  12. Protease-mediated drug delivery

    NASA Astrophysics Data System (ADS)

    Dickson, Eva F.; Goyan, Rebecca L.; Kennedy, James C.; Mackay, M.; Mendes, M. A. K.; Pottier, Roy H.

    2003-12-01

    Drugs used in disease treatment can cause damage to both malignant and normal tissue. This toxicity limits the maximum therapeutic dose. Drug targeting is of high interest to increase the therapeutic efficacy of the drug without increasing systemic toxicity. Certain tissue abnormalities, disease processes, cancers, and infections are characterized by high levels of activity of specific extracellular and/or intracellular proteases. Abnormally high activity levels of specific proteases are present at sites of physical or chemical trauma, blood clots, malignant tumors, rheumatoid arthritis, inflammatory bowel disease, gingival disease, glomerulonerphritis, and acute pancreatitis. Abnormal protease activity is suspected in development of liver thrombosis, pulmonary emphysema, atherosclerosis, and muscular dystrophy. Inactiviating disease-associated proteases by the administration of appropriate protease inhibitors has had limited success. Instead, one could use such proteases to target drugs to treat the condition. Protease mediated drug delivery offers such a possibility. Solubilizing groups are attached to insoluble drugs via a polypeptide chain which is specifically cleavable by certian proteases. When the solubilized drug enounters the protease, the solubilizing moieties are cleaved, and the drug precipitates at the disease location. Thus, a smaller systemic dosage could result in a therapeutic drug concentration at the treatment site with less systemic toxicity.

  13. The Targeted-liposome Delivery System of Antitumor Drugs.

    PubMed

    Wu, Wei-dang; Yi, Xiu-lin; Jiang, Li-xin; Li, Ya-zhuo; Gao, Jing; Zeng, Yong; Yi, Rong-da; Dai, Li-peng; Li, Wei; Ci, Xiao-yan; Si, Duan-yun; Liu, Chang-xiao

    2015-01-01

    The liposome delivery system has been intensively explored as novel drug delivery system (DDS) for antitumor drugs, due to its safety, selective cytotoxicity, long circulation and slow elimination in blood, which is favorable for cancer therapy. The liposome-based chemotherapeutics are used to treat a variety of cancers to enhance the therapeutic index of antitumor drugs. Here, the author reviewed the important targets for cancer therapy and the pharmacokinetic behavior of liposomal drugs in vivo, as well as the application of the targeting liposomal system in cancer therapy. Considering further application for clinical use, the great challenges of the liposome-based delivery system were also proposed as follows: 1) prepare stealth liposome with steric stabilization and further enhance the therapeutic effects and safety; 2) explore more safe clinical targets and complementary or different types of targeting liposome; 3) thirdly, more investment is needed on the research of pharmacokinetics of the elements such as the ligands (antibody), PEG and lipids of liposome delivery system as well as safety evaluation. Considering the complex process of the liposomal encapsulation drugs in vivo, the author inferred that there are maybe different forms of the encapsulation drug to be internalized by the tumor tissues at the same time and space, although there are little reports on it. PMID:26652257

  14. Peptide and protein delivery using new drug delivery systems.

    PubMed

    Jain, Ashish; Jain, Aviral; Gulbake, Arvind; Shilpi, Satish; Hurkat, Pooja; Jain, Sanjay K

    2013-01-01

    Pharmaceutical and biotechnological research sorts protein drug delivery systems by importance based on their various therapeutic applications. The effective and potent action of the proteins/peptides makes them the drugs of choice for the treatment of numerous diseases. Major research issues in protein delivery include the stabilization of proteins in delivery devices and the design of appropriate target-specific protein carriers. Many efforts have been made for effective delivery of proteins/peptidal drugs through various routes of administrations for successful therapeutic effects. Nanoparticles made of biodegradable polymers such as poly lactic acid, polycaprolactone, poly(lactic-co-glycolic acid), the poly(fumaric-co-sebacic) anhydride chitosan, and modified chitosan, as well as solid lipids, have shown great potential in the delivery of proteins/peptidal drugs. Moreover, scientists also have used liposomes, PEGylated liposomes, niosomes, and aquasomes, among others, for peptidal drug delivery. They also have developed hydrogels and transdermal drug delivery systems for peptidal drug delivery. A receptor-mediated delivery system is another attractive strategy to overcome the limitation in drug absorption that enables the transcytosis of the protein across the epithelial barrier. Modification such as PEGnology is applied to various proteins and peptides of the desired protein and peptides also increases the circulating life, solubility and stability, pharmacokinetic properties, and antigenicity of protein. This review focuses on various approaches for effective protein/peptidal drug delivery, with special emphasis on insulin delivery. PMID:23662604

  15. Ultrasound mediated nanoparticle drug delivery

    NASA Astrophysics Data System (ADS)

    Mullin, Lee B.

    Ultrasound is not only a powerful diagnostic tool, but also a promising therapeutic technology that can be used to improve localized drug delivery. Microbubble contrast agents are micron sized encapsulated gas filled bubbles that are administered intravenously. Originally developed to enhance ultrasound images, microbubbles are highly echogenic due to the gas core that provides a detectable impedance difference from the surrounding medium. The core also allows for controlled response of the microbubbles to ultrasound pulses. Microbubbles can be pushed using acoustic radiation force and ruptured using high pressures. Destruction of microbubbles can increase permeability at the cellular and vascular level, which can be advantageous for drug delivery. Advances in drug delivery methods have been seen with the introduction of nanoparticles, nanometer sized objects often carrying a drug payload. In chemotherapy, nanoparticles can deliver drugs to tumors while limiting systemic exposure due to abnormalities in tumor vasculature such large gaps between endothelial cells that allow nanoparticles to enter into the interstitial space; this is referred to as the enhanced permeability and retention (EPR) effect. However, this effect may be overestimated in many tumors. Additionally, only a small percentage of the injected dose accumulates in the tumor, which most the nanoparticles accumulating in the liver and spleen. It is hypothesized that combining the acoustic activity of an ultrasound contrast agent with the high payload and extravasation ability of a nanoparticle, localized delivery to the tumor with reduced systemic toxicity can be achieved. This method can be accomplished by either loading nanoparticles onto the shell of the microbubble or through a coadministration method of both nanoparticles and microbubbles. The work presented in this dissertation utilizes novel and commercial nanoparticle formulations, combined with microbubbles and a variety of ultrasound systems

  16. Opportunities in respiratory drug delivery.

    PubMed

    Pritchard, John N; Giles, Rachael D

    2014-12-01

    A wide range of asthma and chronic obstructive pulmonary disease products are soon to be released onto the inhaled therapies market and differentiation between these devices will help them to gain market share over their competitors. Current legislation is directing healthcare towards being more efficient and cost-effective in order to continually provide quality care despite the challenges of aging populations and fewer resources. Devices and drugs that can be differentiated by producing improved patient outcomes would, therefore, be likely to win market share. In this perspective article, the current and potential opportunities for the successful delivery and differentiation of new inhaled drug products are discussed. PMID:25531928

  17. Nasal drug delivery in humans.

    PubMed

    Bitter, Christoph; Suter-Zimmermann, Katja; Surber, Christian

    2011-01-01

    Intranasal administration is an attractive option for local and systemic delivery of many therapeutic agents. The nasal mucosa is--compared to other mucosae--easily accessible. Intranasal drug administration is noninvasive, essentially painless and particularly suited for children. Application can be performed easily by patients or by physicians in emergency settings. Intranasal drug delivery offers a rapid onset of therapeutic effects (local or systemic). Nasal application circumvents gastrointestinal degradation and hepatic first-pass metabolism of the drug. The drug, the vehicle and the application device form an undividable triad. Its selection is therefore essential for the successful development of effective nasal products. This paper discusses the feasibility and potential of intranasal administration. A series of questions regarding (a) the intended use (therapeutic considerations), (b) the drug, (c) the vehicle and (d) the application device (pharmaceutical considerations) are addressed with a view to their impact on the development of products for nasal application. Current and future trends and perspectives are discussed. PMID:21325837

  18. Pharmacokinetics of Chemotherapeutic Drugs in Pediatric Patients With Down Syndrome and Leukemia.

    PubMed

    Hefti, Erik; Blanco, Javier G

    2016-05-01

    Children with Down syndrome (DS) have a 10- to 30-fold increased risk of developing acute myeloid leukemia or acute lymphoblastic leukemia. Patients with DS and leukemia are treated with the same chemotherapeutic agents as patients without DS. Treatment regimens for pediatric leukemia comprise multiple cytotoxic drugs including methotrexate, doxorubicin, vincristine, cytarabine, and etoposide. There have been reports of increased toxicity, as well as altered therapeutic outcomes in pediatric patients with DS and leukemia. This review is focused on the pharmacokinetics of cytotoxic drugs in pediatric patients with leukemia and DS. The available literature suggests that methotrexate and thioguanine display altered pharmacokinetic parameters in pediatric patients with DS. It has been hypothesized that the variable pharmacokinetics of these drugs may contribute to the increased incidence of treatment-related toxicities seen in DS. Data from a small number of studies suggest that the pharmacokinetics of vincristine, etoposide, doxorubicin, and busulfan are similar between patients with and without DS. Definitive conclusions regarding the pharmacokinetics of cytotoxic drugs in pediatric patients with leukemia and DS are difficult to reach due to limitations in the available studies. PMID:26907658

  19. Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy

    PubMed Central

    Hong, Zai-Fa; Zhao, Wen-Xiu; Yin, Zhen-Yu; Xie, Cheng-Rong; Xu, Ya-Ping; Chi, Xiao-Qin; Zhang, Sheng; Wang, Xiao-Min

    2015-01-01

    Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA. PMID:25933112

  20. Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy.

    PubMed

    Hong, Zai-Fa; Zhao, Wen-Xiu; Yin, Zhen-Yu; Xie, Cheng-Rong; Xu, Ya-Ping; Chi, Xiao-Qin; Zhang, Sheng; Wang, Xiao-Min

    2015-01-01

    Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA. PMID:25933112

  1. STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs.

    PubMed

    Walch-Rückheim, Barbara; Pahne-Zeppenfeld, Jennifer; Fischbach, Jil; Wickenhauser, Claudia; Horn, Lars Christian; Tharun, Lars; Büttner, Reinhard; Mallmann, Peter; Stern, Peter; Kim, Yoo-Jin; Bohle, Rainer Maria; Rübe, Christian; Ströder, Russalina; Juhasz-Böss, Ingolf; Solomayer, Erich-Franz; Smola, Sigrun

    2016-07-01

    Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from low-grade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872-83. ©2016 AACR. PMID:27216197

  2. Development of lattice-inserted 5-Fluorouracil-hydroxyapatite nanoparticles as a chemotherapeutic delivery system.

    PubMed

    Tseng, Ching-Li; Chen, Jung-Chih; Wu, Yu-Chun; Fang, Hsu-Wei; Lin, Feng-Huei; Tang, Tzu-Piao

    2015-10-01

    Developing an effective vehicle for cancer treatment, hydroxyapatite nanoparticles were fabricated for drug delivery. When 5-Fluorouracil, a major chemoagent, is combined with hydroxyapatite nanocarriers by interclay insertion, the modified hydroxyapatite nanoparticles have superior lysosomal degradation profiles, which could be leveraged as controlled drug release. The decomposition of the hydroxyapatite nanocarriers facilitates the release of 5-Fluorouracil into the cytoplasm causing cell death. Hydroxyapatite nanoparticles with/without 5-Fluorouracil were synthesized and analyzed in this study. Their crystallization properties and chemical composition were examined by X-ray diffraction and Fourier transforms infrared spectroscopy. The 5-Fluorouracil release rate was determined by UV spectroscopy. The biocompatibility of hydroxyapatite-5-Fluorouracil extraction solution was assessed using 3T3 cells via a WST-8 assay. The effect of hydroxyapatite-5-Fluorouracil particles which directly work on the human lung adenocarcinoma (A549) cells was evaluated by a lactate dehydrogenase assay via contact cultivation. A 5-Fluorouracil-absorbed hydroxyapatite particles were also tested. Overall, hydroxyapatite-5-Fluorouracils were prepared using a co-precipitation method wherein 5-Fluorouracil was intercalated in the hydroxyapatite lattice as determined by X-ray diffraction. Energy dispersive scanning examination showed the 5-Fluorouracil content was higher in hydroxyapatite-5-Fluorouracil than in a prepared absorption formulation. With 5-Fluorouracil insertion in the lattice, the widths of the a and c axial constants of the hydroxyapatite crystal increased. The extraction solution of hydroxyapatite-5-Fluorouracil was nontoxic to 3T3 cells, in which 5-Fluorouracil was not released in a neutral phosphate buffer solution. In contrast, at a lower pH value (2.5), 5-Fluorouracil was released by the acidic decomposition of hydroxyapatite. Finally, the results of the lactate

  3. Superhydrophobic materials for drug delivery

    NASA Astrophysics Data System (ADS)

    Yohe, Stefan Thomas

    Superhydrophobicity is a property of material surfaces reflecting the ability to maintain air at the solid-liquid interface when in contact with water. These surfaces have characteristically high apparent contact angles, by definition exceeding 150°, as a result of the composite material-air surface formed under an applied water droplet. Superhydrophobic surfaces were first discovered on naturally occurring substrates, and have subsequently been fabricated in the last several decades to harness these favorable surface properties for a number of emerging applications, including their use in biomedical settings. This work describes fabrication and characterization of superhydrophobic 3D materials, as well as their use as drug delivery devices. Superhydrophobic 3D materials are distinct from 2D superhydrophobic surfaces in that air is maintained not just at the surface of the material, but also within the bulk. When the superhydrophobic 3D materials are submerged in water, water infiltrates slowly and continuously as a new water-air-material interface is formed with controlled displacement of air. Electrospinning and electrospraying are used to fabricate superhydrophobic 3D materials utilizing blends of the biocompatible polymers poly(epsilon-caprolactone) and poly(caprolactone-co-glycerol monostearate) (PGC-C18). PGC-C18 is significantly more hydrophobic than PCL (contact angle of 116° versus 83° for flat materials), and further additions of PGC-C18 into electrospun meshes and electrosprayed coatings affords increased stability of the entrapped air layer. For example, PCL meshes alone (500 mum thick) take 10 days to fully wet, and with 10% or 30% PGC-C18 addition wetting rates are dramatically slowed to 60% wetted by 77 days and 4% by 75 days, respectively. Stability of the superhydrophobic materials can be further probed with a variety of physio-chemical techniques, including pressure, surfactant containing solutions, and solvents of varying surface tension

  4. Chemotherapeutic response to cisplatin-like drugs in human breast cancer cells probed by vibrational microspectroscopy.

    PubMed

    Batista de Carvalho, A L M; Pilling, M; Gardner, P; Doherty, J; Cinque, G; Wehbe, K; Kelley, C; Batista de Carvalho, L A E; Marques, M P M

    2016-06-23

    Studies of drug-cell interactions in cancer model systems are essential in the preclinical stage of rational drug design, which relies on a thorough understanding of the mechanisms underlying cytotoxic activity and biological effects, at a molecular level. This study aimed at applying complementary vibrational spectroscopy methods to evaluate the cellular impact of two Pt(ii) and Pd(ii) dinuclear chelates with spermine (Pt2Spm and Pd2Spm), using cisplatin (cis-Pt(NH3)2Cl2) as a reference compound. Their effects on cellular metabolism were monitored in a human triple-negative metastatic breast cancer cell line (MDA-MB-231) by Raman and synchrotron-radiation infrared microspectroscopies, for different drug concentrations (2-8 μM) at 48 h exposure. Multivariate data analysis was applied (unsupervised PCA), unveiling drug- and concentration-dependent effects: apart from discrimination between control and drug-treated cells, a clear separation was obtained for the different agents studied - mononuclear vs. polynuclear, and Pt(ii) vs. Pd(ii). Spectral biomarkers of drug action were identified, as well as the cellular response to the chemotherapeutic insult. The main effect of the tested compounds was found to be on DNA, lipids and proteins, the Pd(ii) agent having a more significant impact on proteins while its Pt(ii) homologue affected the cellular lipid content at lower concentrations, which suggests the occurrence of distinct and unconventional pathways of cytotoxicity for these dinuclear polyamine complexes. Raman and FTIR microspectroscopies were confirmed as powerful non-invasive techniques to obtain unique spectral signatures of the biochemical impact and physiological reaction of cells to anticancer agents. PMID:27063935

  5. Carrier Deformability in Drug Delivery.

    PubMed

    Morilla, Maria Jose; Romero, Eder Lilia

    2016-01-01

    Deformability is a key property of drug carriers used to increase the mass penetration across the skin without disrupting the lipid barrier. Highly deformable vesicles proved to be more effective than conventional liposomes in delivering drugs into and across the mammalian skin upon topical non occlusive application. In the past five years, highly deformable vesicles have been used for local delivery of drugs on joint diseases, skin cancer, atopic dermatitis, would healing, psoriasis, scar treatment, fungal, bacteria and protozoa infections. Promising topical vaccination strategies rely also in this type of carriers. Here we provide an overview on the main structural and mechanical features of deformable vesicles, to finish with an extensive update on their latest preclinical applications. PMID:26675226

  6. Microspheres and Nanotechnology for Drug Delivery.

    PubMed

    Jóhannesson, Gauti; Stefánsson, Einar; Loftsson, Thorsteinn

    2016-01-01

    Ocular drug delivery to the posterior segment of the eye can be accomplished by invasive drug injections into different tissues of the eye and noninvasive topical treatment. Invasive treatment involves the risks of surgical trauma and infection, and conventional topical treatments are ineffective in delivering drugs to the posterior segment of the eye. In recent years, nanotechnology has become an ever-increasing part of ocular drug delivery. In the following, we briefly review microspheres and nanotechnology for drug delivery to the eye, including different forms of nanotechnology such as nanoparticles, microparticles, liposomes, microemulsions and micromachines. The permeation barriers and anatomical considerations linked to ocular drug delivery are discussed and a theoretical overview on drug delivery through biological membranes is given. Finally, in vitro, in vivo and human studies of x03B3;-cyclodextrin nanoparticle eyedrop suspensions are discussed as an example of nanotechnology used for drug delivery to the eye. PMID:26501994

  7. Therapeutic applications of hydrogels in oral drug delivery

    PubMed Central

    Sharpe, Lindsey A; Daily, Adam M; Horava, Sarena D; Peppas, Nicholas A

    2015-01-01

    Introduction Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications. Areas covered This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed. Expert opinion Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest. PMID:24848309

  8. Tocol emulsions for drug solubilization and parenteral delivery.

    PubMed

    Constantinides, Panayiotis P; Tustian, Alex; Kessler, Dean R

    2004-05-01

    Tocols represent a family of tocopherols, tocotrienols, and their derivatives, and are fundamentally derived from the simplest tocopherol, 6-hydroxy-2-methyl-2-phytylchroman, which is referred to as "tocol". The most common tocol is D-alpha-tocopherol, also known as vitamin E. Tocols can be excellent solvents for water insoluble drugs and are compatible with other cosolvents, oils and surfactants. This review highlights the major developments in the use of tocols in parenteral emulsions for drug delivery, with a focus on drug solubilization, physicochemical properties, and biopharmaceutical applications. Tocol emulsions offer an appealing alternative for the parenteral administration of poorly soluble drugs, including major chemotherapeutics such as paclitaxel. Data will be presented on solubilization of paclitaxel, a key chemotherapeutic agent, and its corresponding formulation development, toxicity, efficacy and pharmacokinetic studies in animal models and humans. The breadth of the utility of tocol-based emulsions will be discussed and examples of specific therapeutic drugs and applications will be provided. As these formulations progress further in the clinic, the therapeutic utility of tocol emulsions is anticipated to expand. PMID:15109767

  9. Ocular drug delivery systems: An overview

    PubMed Central

    Patel, Ashaben; Cholkar, Kishore; Agrahari, Vibhuti; Mitra, Ashim K

    2014-01-01

    The major challenge faced by today’s pharmacologist and formulation scientist is ocular drug delivery. Topical eye drop is the most convenient and patient compliant route of drug administration, especially for the treatment of anterior segment diseases. Delivery of drugs to the targeted ocular tissues is restricted by various precorneal, dynamic and static ocular barriers. Also, therapeutic drug levels are not maintained for longer duration in target tissues. In the past two decades, ocular drug delivery research acceleratedly advanced towards developing a novel, safe and patient compliant formulation and drug delivery devices/techniques, which may surpass these barriers and maintain drug levels in tissues. Anterior segment drug delivery advances are witnessed by modulation of conventional topical solutions with permeation and viscosity enhancers. Also, it includes development of conventional topical formulations such as suspensions, emulsions and ointments. Various nanoformulations have also been introduced for anterior segment ocular drug delivery. On the other hand, for posterior ocular delivery, research has been immensely focused towards development of drug releasing devices and nanoformulations for treating chronic vitreoretinal diseases. These novel devices and/or formulations may help to surpass ocular barriers and associated side effects with conventional topical drops. Also, these novel devices and/or formulations are easy to formulate, no/negligibly irritating, possess high precorneal residence time, sustain the drug release, and enhance ocular bioavailability of therapeutics. An update of current research advancement in ocular drug delivery necessitates and helps drug delivery scientists to modulate their think process and develop novel and safe drug delivery strategies. Current review intends to summarize the existing conventional formulations for ocular delivery and their advancements followed by current nanotechnology based formulation developments

  10. Molecular aptamers for drug delivery.

    PubMed

    Tan, Weihong; Wang, Hui; Chen, Yan; Zhang, Xiaobing; Zhu, Haizhen; Yang, Chaoyong; Yang, Ronghua; Liu, Chen

    2011-12-01

    The active targeting of drugs in a cell-, tissue- or disease-specific manner represents a potentially powerful technology with widespread applications in medicine, including the treatment of cancers. Aptamers have properties such as high affinity and specificity for targets, easy chemical synthesis and modification, and rapid tissue penetration. They have become attractive molecules in diagnostics and therapeutics rivaling and, in some cases, surpassing other molecular probes, such as antibodies. In this review, we highlight the recent progress in aptamer-mediated delivery for therapeutics and disease-targeting based on aptamer integration with a variety of nanomaterials, such as gold nanorods, DNA micelles, DNA hydrogels and carbon nanotubes. PMID:21821299

  11. Repurposing the FDA-Approved Pinworm Drug Pyrvinium as a Novel Chemotherapeutic Agent for Intestinal Polyposis

    PubMed Central

    Giambelli, Camilla; Fei, Dennis Liang; Han, Lu; Hang, Brian I.; Bai, Feng; Pei, Xin-Hai; Nose, Vania; Burlingame, Oname; Capobianco, Anthony J.; Orton, Darren; Lee, Ethan; Robbins, David J.

    2014-01-01

    Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes. PMID:25003333

  12. Fibrin Glue as a Drug Delivery System

    PubMed Central

    Spicer, Patrick P.; Mikos, Antonios G.

    2010-01-01

    Fibrin glue has been used surgically for decades for hemostasis as well as a sealant. It has also been researched as both a gel for cell delivery and a vehicle for drug delivery. The drug delivery applications for fibrin glue span tissue engineering to chemotherapy and involve several mechanisms for drug matrix interactions and control of release kinetics. Additionally, drugs or factors can be loaded in the gel via impregnation and tethering to the gel through covalent linkages or affinity based systems. This review highlights recent research of fibrin glue as a drug delivery vehicle. PMID:20637815

  13. Modeling Expression Plasticity of Genes that Differentiate Drug-sensitive from Drug-resistant Cells to Chemotherapeutic Treatment

    PubMed Central

    Wang, Ningtao; Wang, Yaqun; Han, Hao; Huber, Kathryn J; Yang, Jin-Ming; Li, Runze; Wu, Rongling

    2014-01-01

    By measuring gene expression at an unprecedented resolution and throughput, RNA-seq has played a pivotal role in studying biological functions. Its typical application in clinical medicine is to identify the discrepancies of gene expression between two different types of cancer cells, sensitive and resistant to chemotherapeutic treatment, in a hope to predict drug response. Here we modified and used a mechanistic model to identify distinct patterns of gene expression in response of different types of breast cancer cell lines to chemotherapeutic treatment. This model was founded on a mixture likelihood of Poisson-distributed transcript read data, with each mixture component specified by the Skellam function. By estimating and comparing the amount of gene expression in each environment, the model can test how genes alter their expression in response to environment and how different genes interact with each other in the responsive process. Using the modified model, we identified the alternations of gene expression between two cell lines of breast cancer, resistant and sensitive to tamoxifen, which allows us to interpret the expression mechanism of how genes respond to metabolic differences between the two cell types. The model can have a general implication for studying the plastic pattern of gene expression across different environments measured by RNA-seq. PMID:25435798

  14. Fluorescent graphene quantum dots as traceable, pH-sensitive drug delivery systems

    PubMed Central

    Qiu, Jichuan; Zhang, Ruibin; Li, Jianhua; Sang, Yuanhua; Tang, Wei; Rivera Gil, Pilar; Liu, Hong

    2015-01-01

    Graphene quantum dots (GQDs) were rationally fabricated as a traceable drug delivery system for the targeted, pH-sensitive delivery of a chemotherapeutic drug into cancer cells. The GQDs served as fluorescent carriers for a well-known anticancer drug, doxorubicin (Dox). The whole system has the capacity for simultaneous tracking of the carrier and of drug release. Dox release is triggered upon acidification of the intracellular vesicles, where the carriers are located after their uptake by cancer cells. Further functionalization of the loaded carriers with targeting moieties such as arginine-glycine-aspartic acid (RGD) peptides enhanced their uptake by cancer cells. DU-145 and PC-3 human prostate cancer cell lines were used to evaluate the anticancer ability of Dox-loaded RGD-modified GQDs (Dox-RGD-GQDs). The results demonstrated the feasibility of using GQDs as traceable drug delivery systems with the ability for the pH-triggered delivery of drugs into target cells. PMID:26604747

  15. Ungual and transungual drug delivery.

    PubMed

    Shivakumar, H N; Juluri, Abhishek; Desai, B G; Murthy, S Narasimha

    2012-08-01

    Topical therapy is desirable in treatment of nail diseases like onychomycosis (fungal infection of nail) and psoriasis. The topical treatment avoids the adverse effects associated with systemic therapy, thereby enhancing the patient compliance and reducing the treatment cost. However the effectiveness of the topical therapies has been limited due to the poor permeability of the nail plate to topically applied therapeutic agents. Research over the past one decade has been focused on improving the transungual permeability by means of chemical treatment, penetration enhancers, mechanical and physical methods. The present review is an attempt to discuss the different physical and chemical methods employed to increase the permeability of the nail plate. Minimally invasive electrically mediated techniques such as iontophoresis have gained success in facilitating the transungual delivery of actives. In addition drug transport across the nail plate has been improved by filing the dorsal surface of the nail plate prior to application of topical formulation. But attempts to improve the trans-nail permeation using transdermal chemical enhancers have failed so far. Attempts are on to search suitable physical enhancement techniques and chemical transungual enhancers in view to maximize the drug delivery across the nail plate. PMID:22149347

  16. C8-glycosphingolipids preferentially insert into tumor cell membranes and promote chemotherapeutic drug uptake.

    PubMed

    Cordeiro Pedrosa, Lília R; van Cappellen, Wiggert A; Steurer, Barbara; Ciceri, Dalila; ten Hagen, Timo L M; Eggermont, Alexander M M; Verheij, Marcel; Goñi, Felix María; Koning, Gerben A; Contreras, F-Xabier

    2015-08-01

    Insufficient drug delivery into tumor cells limits the therapeutic efficacy of chemotherapy. Co-delivery of liposome-encapsulated drug and synthetic short-chain glycosphingolipids (SC-GSLs) significantly improved drug bioavailability by enhancing intracellular drug uptake. Investigating the mechanisms underlying this SC-GSL-mediated drug uptake enhancement is the aim of this study. Fluorescence microscopy was used to visualize the cell membrane lipid transfer intracellular fate of fluorescently labeled C6-NBD-GalCer incorporated in liposomes in tumor and non-tumor cells. Additionally click chemistry was applied to image and quantify native SC-GSLs in tumor and non-tumor cell membranes. SC-GSL-mediated flip-flop was investigated in model membranes to confirm membrane-incorporation of SC-GSL and its effect on membrane remodeling. SC-GSL enriched liposomes containing doxorubicin (Dox) were incubated at 4°C and 37°C and intracellular drug uptake was studied in comparison to standard liposomes and free Dox. SC-GSL transfer to the cell membrane was independent of liposomal uptake and the majority of the transferred lipid remained in the plasma membrane. The transfer of SC-GSL was tumor cell-specific and induced membrane rearrangement as evidenced by a transbilayer flip-flop of pyrene-SM. However, pore formation was measured, as leakage of hydrophilic fluorescent probes was not observed. Moreover, drug uptake appeared to be mediated by SC-GSLs. SC-GSLs enhanced the interaction of doxorubicin (Dox) with the outer leaflet of the plasma membrane of tumor cells at 4°C. Our results demonstrate that SC-GSLs preferentially insert into tumor cell plasma membranes enhancing cell intrinsic capacity to translocate amphiphilic drugs such as Dox across the membrane via a biophysical process. PMID:25917957

  17. Polymeric conjugates for drug delivery

    PubMed Central

    Larson, Nate; Ghandehari, Hamidreza

    2012-01-01

    The field of polymer therapeutics has evolved over the past decade and has resulted in the development of polymer-drug conjugates with a wide variety of architectures and chemical properties. Whereas traditional non-degradable polymeric carriers such as poly(ethylene glycol) (PEG) and N-(2-hydroxypropyl methacrylamide) (HPMA) copolymers have been translated to use in the clinic, functionalized polymer-drug conjugates are increasingly being utilized to obtain biodegradable, stimuli-sensitive, and targeted systems in an attempt to further enhance localized drug delivery and ease of elimination. In addition, the study of conjugates bearing both therapeutic and diagnostic agents has resulted in multifunctional carriers with the potential to both “see and treat” patients. In this paper, the rational design of polymer-drug conjugates will be discussed followed by a review of different classes of conjugates currently under investigation. The design and chemistry used for the synthesis of various conjugates will be presented with additional comments on their potential applications and current developmental status. PMID:22707853

  18. Physically facilitating drug-delivery systems

    PubMed Central

    Rodriguez-Devora, Jorge I; Ambure, Sunny; Shi, Zhi-Dong; Yuan, Yuyu; Sun, Wei; Xu, Tao

    2012-01-01

    Facilitated/modulated drug-delivery systems have emerged as a possible solution for delivery of drugs of interest to pre-allocated sites at predetermined doses for predefined periods of time. Over the past decade, the use of different physical methods and mechanisms to mediate drug release and delivery has grown significantly. This emerging area of research has important implications for development of new therapeutic drugs for efficient treatments. This review aims to introduce and describe different modalities of physically facilitating drug-delivery systems that are currently in use for cancer and other diseases therapy. In particular, delivery methods based on ultrasound, electrical, magnetic and photo modulations are highlighted. Current uses and areas of improvement for these different physically facilitating drug-delivery systems are discussed. Furthermore, the main advantages and drawbacks of these technologies reviewed are compared. The review ends with a speculative viewpoint of how research is expected to evolve in the upcoming years. PMID:22485192

  19. Novel central nervous system drug delivery systems.

    PubMed

    Stockwell, Jocelyn; Abdi, Nabiha; Lu, Xiaofan; Maheshwari, Oshin; Taghibiglou, Changiz

    2014-05-01

    For decades, biomedical and pharmaceutical researchers have worked to devise new and more effective therapeutics to treat diseases affecting the central nervous system. The blood-brain barrier effectively protects the brain, but poses a profound challenge to drug delivery across this barrier. Many traditional drugs cannot cross the blood-brain barrier in appreciable concentrations, with less than 1% of most drugs reaching the central nervous system, leading to a lack of available treatments for many central nervous system diseases, such as stroke, neurodegenerative disorders, and brain tumors. Due to the ineffective nature of most treatments for central nervous system disorders, the development of novel drug delivery systems is an area of great interest and active research. Multiple novel strategies show promise for effective central nervous system drug delivery, giving potential for more effective and safer therapies in the future. This review outlines several novel drug delivery techniques, including intranasal drug delivery, nanoparticles, drug modifications, convection-enhanced infusion, and ultrasound-mediated drug delivery. It also assesses possible clinical applications, limitations, and examples of current clinical and preclinical research for each of these drug delivery approaches. Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous system diseases, causing improved therapies for those who are affected by central nervous system diseases. PMID:24325540

  20. Polymers for Colon Targeted Drug Delivery

    PubMed Central

    Rajpurohit, H.; Sharma, P.; Sharma, S.; Bhandari, A.

    2010-01-01

    The colon targeted drug delivery has a number of important implications in the field of pharmacotherapy. Oral colon targeted drug delivery systems have recently gained importance for delivering a variety of therapeutic agents for both local and systemic administration. Targeting of drugs to the colon via oral administration protect the drug from degradation or release in the stomach and small intestine. It also ensures abrupt or controlled release of the drug in the proximal colon. Various drug delivery systems have been designed that deliver the drug quantitatively to the colon and then trigger the release of drug. This review will cover different types of polymers which can be used in formulation of colon targeted drug delivery systems. PMID:21969739

  1. Silica-based mesoporous nanoparticles for controlled drug delivery.

    PubMed

    Kwon, Sooyeon; Singh, Rajendra K; Perez, Roman A; Abou Neel, Ensanya A; Kim, Hae-Won; Chrzanowski, Wojciech

    2013-01-01

    Drug molecules with lack of specificity and solubility lead patients to take high doses of the drug to achieve sufficient therapeutic effects. This is a leading cause of adverse drug reactions, particularly for drugs with narrow therapeutic window or cytotoxic chemotherapeutics. To address these problems, there are various functional biocompatible drug carriers available in the market, which can deliver therapeutic agents to the target site in a controlled manner. Among the carriers developed thus far, mesoporous materials emerged as a promising candidate that can deliver a variety of drug molecules in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles are widely used as a delivery reagent because silica possesses favourable chemical properties, thermal stability and biocompatibility. Currently, sol-gel-derived mesoporous silica nanoparticles in soft conditions are of main interest due to simplicity in production and modification and the capacity to maintain function of bioactive agents. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release. The properties of mesopores, including pore size and porosity as well as the surface properties, can be altered depending on additives used to fabricate mesoporous silica nanoparticles. Active surface enables functionalisation to modify surface properties and link therapeutic molecules. The tuneable mesopore structure and modifiable surface of mesoporous silica nanoparticle allow incorporation of various classes of drug molecules and controlled delivery to the target sites. This review aims to present the state of knowledge of currently available drug delivery system and identify properties of an ideal drug carrier for specific application, focusing on mesoporous silica nanoparticles. PMID:24020012

  2. Silica-based mesoporous nanoparticles for controlled drug delivery

    PubMed Central

    Kwon, Sooyeon; Singh, Rajendra K; Perez, Roman A; Abou Neel, Ensanya A

    2013-01-01

    Drug molecules with lack of specificity and solubility lead patients to take high doses of the drug to achieve sufficient therapeutic effects. This is a leading cause of adverse drug reactions, particularly for drugs with narrow therapeutic window or cytotoxic chemotherapeutics. To address these problems, there are various functional biocompatible drug carriers available in the market, which can deliver therapeutic agents to the target site in a controlled manner. Among the carriers developed thus far, mesoporous materials emerged as a promising candidate that can deliver a variety of drug molecules in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles are widely used as a delivery reagent because silica possesses favourable chemical properties, thermal stability and biocompatibility. Currently, sol-gel-derived mesoporous silica nanoparticles in soft conditions are of main interest due to simplicity in production and modification and the capacity to maintain function of bioactive agents. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release. The properties of mesopores, including pore size and porosity as well as the surface properties, can be altered depending on additives used to fabricate mesoporous silica nanoparticles. Active surface enables functionalisation to modify surface properties and link therapeutic molecules. The tuneable mesopore structure and modifiable surface of mesoporous silica nanoparticle allow incorporation of various classes of drug molecules and controlled delivery to the target sites. This review aims to present the state of knowledge of currently available drug delivery system and identify properties of an ideal drug carrier for specific application, focusing on mesoporous silica nanoparticles. PMID:24020012

  3. Drug Delivery Innovations for Enhancing the Anticancer Potential of Vitamin E Isoforms and Their Derivatives

    PubMed Central

    Neophytou, Christiana M.; Constantinou, Andreas I.

    2015-01-01

    Vitamin E isoforms have been extensively studied for their anticancer properties. Novel drug delivery systems (DDS) that include liposomes, nanoparticles, and micelles are actively being developed to improve Vitamin E delivery. Furthermore, several drug delivery systems that incorporate Vitamin E isoforms have been synthesized in order to increase the bioavailability of chemotherapeutic agents or to provide a synergistic effect. D-alpha-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) is a synthetic derivative of natural alpha-tocopherol which is gaining increasing interest in the development of drug delivery systems and has also shown promising anticancer effect as a single agent. This review provides a summary of the properties and anticancer effects of the most potent Vitamin E isoforms and an overview of the various formulations developed to improve their efficacy, with an emphasis on the use of TPGS in drug delivery approaches. PMID:26137487

  4. Breathable Medicine: Pulmonary Mode of Drug Delivery.

    PubMed

    Gandhimathi, Chinnasamy; Venugopal, Jayarama Reddy; Sundarrajan, Subramanian; Sridhar, Radhakrishnan; Tay, Samuel Sam Wah; Ramakrishna, Seeram; Kumar, Srinivasan Dinesh

    2015-04-01

    Pharmaceutically active compounds require different modes of drug delivery systems to accomplish therapeutic activity without loss of its activity and lead to exhibit no adverse effects. Originating from ancient days, pulmonary mode of drug delivery is gaining much importance compared to other modes of drug delivery systems with respect to specific diseases. Pulmonary drug delivery is a non-invasive route for local and systemic therapies together with more patient convenience, compliance and is a needleless system. In this review, we addressed the vaccine delivery via non- or minimally invasive routes. Polymeric nanoparticles are preferred for use in the pulmonary delivery devices owing to a prolonged retention in lungs. Small site for absorption, mucociliary clearance, short residence time and low bioavailability are some of the limitations in pulmonary drug delivery have been resolved by generating micro- and nano-sized aerosol particles. We have classified the breathable medicine on the basis of available devices for inhalation and also prominent diseases treated through pulmonary mode of drug delivery. Owing to increasing toxicity of pharmacological drugs, the use of natural medicines has been rapidly gaining importance recently. The review article describes breathability of medicines or the pulmonary mode of drug delivery system and their drug release profile, absorption, distribution and efficacy to cure asthma and diabetes. PMID:26353470

  5. Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro

    PubMed Central

    2014-01-01

    Background Given the importance of complementary and alternative medicine (CAM) to cancer patients, there is an increasing need to learn more about possible interactions between CAM and anticancer drugs. Mistletoe (Viscum album L.) belongs to the medicinal herbs that are used as supportive care during chemotherapy. In the in vitro study presented here the effect of standardized mistletoe preparations on the cytostatic and cytotoxic activity of several common conventional chemotherapeutic drugs was investigated using different cancer cell lines. Methods Human breast carcinoma cell lines HCC1937 and HCC1143 were treated with doxorubicin hydrochloride, pancreas adenocarcinoma cell line PA-TU-8902 with gemcitabine hydrochloride, prostate carcinoma cell line DU145 with docetaxel and mitoxantrone hydrochloride and lung carcinoma cell line NCI-H460 was treated with docetaxel and cisplatin. Each dose of the respective chemotherapeutic drug was combined with Viscum album extract (VAE) in clinically relevant concentrations and proliferation and apoptosis were measured. Results VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect. Conclusions Our in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the exposition of cancer cells to chemotherapeutic drugs and VAE simultaneously. PMID:24397864

  6. Simultaneous cytosolic delivery of a chemotherapeutic and siRNA using nanoparticle-stabilized nanocapsules

    NASA Astrophysics Data System (ADS)

    Hardie, Joseph; Jiang, Ying; Tetrault, Emily R.; Ghazi, Phaedra C.; Yesilbag Tonga, Gulen; Farkas, Michelle E.; Rotello, Vincent M.

    2016-09-01

    We report on nanoparticle-stabilized capsules (NPSCs) as a platform for the co-delivery of survivin-targeted siRNA and tamoxifen. These capsules feature an inner oil core that provides a carrier for tamoxifen, and is coated on the surface with positively charged nanoparticles self-assembled with siRNA. The multifaceted chemical nature of the NPSC system enables the simultaneous delivery of both payloads directly into the cytosol in vitro. The NPSC co-delivery of tamoxifen and survivin-targeted siRNA into breast cancer cells disables the pathways that inhibit apoptosis, resulting in enhanced breast cell death.

  7. Simultaneous cytosolic delivery of a chemotherapeutic and siRNA using nanoparticle-stabilized nanocapsules.

    PubMed

    Hardie, Joseph; Jiang, Ying; Tetrault, Emily R; Ghazi, Phaedra C; Tonga, Gulen Yesilbag; Farkas, Michelle E; Rotello, Vincent M

    2016-09-16

    We report on nanoparticle-stabilized capsules (NPSCs) as a platform for the co-delivery of survivin-targeted siRNA and tamoxifen. These capsules feature an inner oil core that provides a carrier for tamoxifen, and is coated on the surface with positively charged nanoparticles self-assembled with siRNA. The multifaceted chemical nature of the NPSC system enables the simultaneous delivery of both payloads directly into the cytosol in vitro. The NPSC co-delivery of tamoxifen and survivin-targeted siRNA into breast cancer cells disables the pathways that inhibit apoptosis, resulting in enhanced breast cell death. PMID:27505356

  8. Drug delivery systems: An updated review

    PubMed Central

    Tiwari, Gaurav; Tiwari, Ruchi; Sriwastawa, Birendra; Bhati, L; Pandey, S; Pandey, P; Bannerjee, Saurabh K

    2012-01-01

    Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. For the treatment of human diseases, nasal and pulmonary routes of drug delivery are gaining increasing importance. These routes provide promising alternatives to parenteral drug delivery particularly for peptide and protein therapeutics. For this purpose, several drug delivery systems have been formulated and are being investigated for nasal and pulmonary delivery. These include liposomes, proliposomes, microspheres, gels, prodrugs, cyclodextrins, among others. Nanoparticles composed of biodegradable polymers show assurance in fulfilling the stringent requirements placed on these delivery systems, such as ability to be transferred into an aerosol, stability against forces generated during aerosolization, biocompatibility, targeting of specific sites or cell populations in the lung, release of the drug in a predetermined manner, and degradation within an acceptable period of time. PMID:23071954

  9. Multifunctional Particles for Melanoma-Targeted Drug Delivery

    PubMed Central

    Wadajkar, Aniket S.; Bhavsar, Zarna; Ko, Cheng-Yu; Koppolu, Bhanuprasanth; Cui, Weina; Tang, Liping; Nguyen, Kytai T.

    2012-01-01

    New magnetic-based core-shell particles (MBCSP) were developed to target skin cancer cells while delivering chemotherapeutic drugs in a controlled fashion. MBCSP consist of a thermo-responsive shell of poly(N-isopropylacrylamide-acrylamide-allylamine) and a core of poly(lactic-co-glycolic acid) (PLGA) embedded with magnetite nanoparticles. To target melanoma cancer cells, MBCSP were conjugated with Gly-Arg-Gly-Asp-Ser (GRGDS) peptides that specifically bind to the α5β3+ receptor of melanoma cell. MBCSP consist of unique multifunctional and controlled drug delivery characteristics. Specially, they can provide dual drug release mechanisms (a sustained release of drugs through degradation of PLGA core and a controlled release in response to changes in temperature via thermo-responsive polymer shell), and dual targeting mechanisms (magnetic localization and receptor-mediated targeting). Results from in vitro studies indicate that GRGDS-conjugated MBCSP has an average diameter of 296 nm and exhibit no cytotoxicity towards human dermal fibroblasts up to 500 μg ml−1. Further, a sustained release of curcumin from the core and a temperature-dependent release of doxorubicin from the shell of MBCSP were observed. The particles also produced a dark contrast signal in magnetic resonance imaging. Finally, the particles were accumulated at the tumor site in a B16F10 melanoma orthotopic mouse model, especially in presence of a magnet. Results indicate great potential of MBCSP as a platform technology to target, treat, and monitor melanoma for targeted drug delivery to reduce side effects of chemotherapeutic reagents. PMID:22561668

  10. Microfluidic Manipulation of Core/Shell Nanoparticles for Oral Delivery of Chemotherapeutics: A New Treatment Approach for Colorectal Cancer.

    PubMed

    Hasani-Sadrabadi, Mohammad Mahdi; Taranejoo, Shahrouz; Dashtimoghadam, Erfan; Bahlakeh, Ghasem; Majedi, Fatemeh Sadat; VanDersarl, Jules John; Janmaleki, Mohsen; Sharifi, Fatemeh; Bertsch, Arnaud; Hourigan, Kerry; Tayebi, Lobat; Renaud, Philippe; Jacob, Karl I

    2016-06-01

    A microfluidics approach to synthesize core-shell nanocarriers with high pH tunability is described. The sacrificial shell protects the core layer with the drugs and prevents their release in the severe pH conditions of the gastrointestinal tract, while allowing for drug release in the proximity of a tumor. The proposed nanoparticulate drug-delivery system is designed for the oral administration of cancer therapeutics. PMID:27001745

  11. Molecular aptamers for drug delivery

    PubMed Central

    Tan, Weihong; Wang, Hui; Chen, Yan; Zhang, Xiaobing; Zhu, Haizhen; Yang, Chaoyong; Yang, Ronghua

    2011-01-01

    The active targeting of drugs in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology with widespread applications in medicine, including the treatment of cancers. Aptamers, with properties such as high affinity and specificity to their targets, easy chemical synthesis and modification, as well as rapid tissue penetration, have become attractive molecules in diagnostics and therapeutics. They rival and, in some cases, surpass other molecular probes, such as antibodies. In this review, we highlight the recent progress in aptamer-mediated delivery for therapeutics and disease-targeting based on aptamer integration with a variety of nanomaterials, such as gold nanorods, DNA-micelles, DNA-hydrogels and carbon nanotubes. PMID:21821299

  12. Implantable Devices for Sustained, Intravesical Drug Delivery

    PubMed Central

    2016-01-01

    In clinical settings, intravesical instillation of a drug bolus is often performed for the treatment of bladder diseases. However, it requires repeated instillations to extend drug efficacy, which may result in poor patient compliance. To alleviate this challenge, implantable devices have been developed for the purpose of sustained, intravesical drug delivery. In this review, we briefly summarize the current trend in the development of intravesical drug-delivery devices. We also introduce the most recently developed devices with strong potential for intravesical drug-delivery applications. PMID:27377941

  13. Targeted Drug Delivery in Pancreatic Cancer

    PubMed Central

    Yu, Xianjun; Zhang, Yuqing; Chen, Changyi; Yao, Qizhi; Li, Min

    2009-01-01

    Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor and antibody has been a success in recent pre-clinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer, and provides important information on potential therapeutic targets for pancreatic cancer treatment. PMID:19853645

  14. Permeation enhancer strategies in transdermal drug delivery.

    PubMed

    Marwah, Harneet; Garg, Tarun; Goyal, Amit K; Rath, Goutam

    2016-01-01

    Today, ∼74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system. PMID:25006687

  15. Enhanced anticancer efficacy by ATP-mediated liposomal drug delivery.

    PubMed

    Mo, Ran; Jiang, Tianyue; Gu, Zhen

    2014-06-01

    A liposome-based co-delivery system composed of a fusogenic liposome encapsulating ATP-responsive elements with chemotherapeutics and a liposome containing ATP was developed for ATP-mediated drug release triggered by liposomal fusion. The fusogenic liposome had a protein-DNA complex core containing an ATP-responsive DNA scaffold with doxorubicin (DOX) and could release DOX through a conformational change from the duplex to the aptamer/ATP complex in the presence of ATP. A cell-penetrating peptide-modified fusogenic liposomal membrane was coated on the core, which had an acid-triggered fusogenic potential with the ATP-loaded liposomes or endosomes/lysosomes. Directly delivering extrinsic liposomal ATP promoted the drug release from the fusogenic liposome in the acidic intracellular compartments upon a pH-sensitive membrane fusion and anticancer efficacy was enhanced both in vitro and in vivo. PMID:24764317

  16. Development of an Acoustic Droplet Vaporization, Ultrasound Drug Delivery Emulsion

    NASA Astrophysics Data System (ADS)

    Fabiilli, Mario L.; Sebastian, Ian E.; Fowlkes, J. Brian

    2010-03-01

    Many therapeutic applications of ultrasound (US) include the use of pefluorocarbon (PFC) microbubbles or emulsions. These colloidal systems can be activated in the presence of US, which in the case of emulsions, results in the production of bubbles—a process known as acoustic droplet vaporization (ADV). ADV can be used as a drug delivery mechanism, thereby yielding the localized release of toxic agents such a chemotherapeutics. In this work, emulsions that contain PFC and chlorambucil, a chemotherapy drug, are formulated using albumin or lipid shells. For albumin droplets, the oil phase—which contained CHL—clearly enveloped the PFC phase. The albumin emulsion also displayed better retention of CHL in the absence of US, which was evaluated by incubating Chinese hamster ovary cells with the various formulations. Thus, the developed emulsions are suitable for further testing in ADV-induced release of CHL.

  17. Ultrasound-triggered drug delivery using acoustic droplet vaporization

    NASA Astrophysics Data System (ADS)

    Fabiilli, Mario Leonardo

    The goal of targeted drug delivery is the spatial and temporal localization of a therapeutic agent and its associated bioeffects. One method of drug localization is acoustic droplet vaporization (ADV), whereby drug-laden perfluorocarbon (PFC) emulsions are vaporized into gas bubbles using ultrasound, thereby releasing drug locally. Transpulmonary droplets are converted into bubbles that occlude capillaries, sequestering the released drug within an organ or tumor. This research investigates the relationship between the ADV and inertial cavitation (IC) thresholds---relevant for drug delivery due to the bioffects generated by IC---and explores the delivery of lipophilic and hydrophilic compounds using PFC double emulsions. IC can positively and negatively affect ultrasound mediated drug delivery. The ADV and IC thresholds were determined for various bulk fluid, droplet, and acoustic parameters. At 3.5 MHz, the ADV threshold occurred at a lower rarefactional pressure than the IC threshold. The results suggest that ADV is a distinct phenomenon from IC, the ADV nucleus is internal to the droplet, and the IC nucleus is the bubble generated by ADV. The ADV triggered release of a lipophilic chemotherapeutic agent, chlorambucil (CHL), from a PFC-in-oil-in-water emulsion was explored using plated cells. Cells exposed to a CHL-loaded emulsion, without ADV, displayed 44% less growth inhibition than cells exposed to an equal concentration of CHL in solution. Upon ADV of the CHL-loaded emulsion, the growth inhibition increased to the same level as cells exposed to CHL in solution. A triblock copolymer was synthesized which enabled the formulation of stable water-in-PFC-in-water (W1/PFC/W2) emulsions. The encapsulation of fluorescein in the W1 phase significantly decreased the mass flux of fluorescein; ADV was shown to completely release the fluorescein from the emulsions. ADV was also shown to release thrombin, dissolved in the W1 phase, which could be used in vivo to extend

  18. pH-Responsive Hydrogels with Dispersed Hydrophobic Nanoparticles for the Oral Delivery of Chemotherapeutics

    PubMed Central

    Schoener, Cody A.; Hutson, Heather N.; Peppas, Nicholas A.

    2012-01-01

    Amphiphilic polymer carriers were formed by polymerizing a hydrophilic, pH-responsive hydrogel composed of poly(methacrylic – grafted – ethylene glycol) (P(MAA-g-EG)) in the presence of hydrophobic PMMA nanoparticles. These polymer carriers were varied in PMMA nanoparticle content to elicit a variety of physiochemical properties which would preferentially load doxorubicin, a hydrophobic chemotherapeutic, and release doxorubicin locally in the colon for the treatment of colon cancers. Loading levels ranged from 49% to 64% and increased with increasing nanoparticle content. Doxorubicin loaded polymers were released in a physiological model where low pH was used to simulate the stomach and then stepped to more neutral conditions to simulate the upper small intestine. P(MAA-g-EG) containing nanoparticles were less mucoadhesive as determined using a tensile tester, polymer samples, and fresh porcine small intestine. The cytocompatibility of the polymer materials were assessed using cell lines representing the GI tract and colon cancer and were non-cytotoxic at varying concentrations and exposure times. PMID:23281185

  19. Nanoparticles for intracellular-targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Paulo, Cristiana S. O.; Pires das Neves, Ricardo; Ferreira, Lino S.

    2011-12-01

    Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.

  20. Recent advances in ocular drug delivery.

    PubMed

    Achouri, Djamila; Alhanout, Kamel; Piccerelle, Philippe; Andrieu, Véronique

    2013-11-01

    Amongst the various routes of drug delivery, the field of ocular drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. Recent research has focused on the characteristic advantages and limitations of the various drug delivery systems, and further research will be required before the ideal system can be developed. Administration of drugs to the ocular region with conventional delivery systems leads to short contact time of the formulations on the epithelium and fast elimination of drugs. This transient residence time involves poor bioavailability of drugs which can be explained by the tear production, non-productive absorption and impermeability of corneal epithelium. Anatomy of the eye is shortly presented and is connected with ophthalmic delivery and bioavailability of drugs. In the present update on ocular dosage forms, chemical delivery systems such as prodrugs, the use of cyclodextrins to increase solubility of various drugs, the concept of penetration enhancers and other ocular drug delivery systems such as polymeric gels, bioadhesive hydrogels, in-situ forming gels with temperature-, pH-, or osmotically induced gelation, combination of polymers and colloidal systems such as liposomes, niosomes, cubosomes, microemulsions, nanoemulsions and nanoparticles are discussed. Novel ophthalmic delivery systems propose the use of many excipients to increase the viscosity or the bioadhesion of the product. New formulations like gels or colloidal systems have been tested with numerous active substances by in vitro and in vivo studies. Sustained drug release and increase in drug bioavailability have been obtained, offering the promise of innovation in drug delivery systems for ocular administration. Combining different properties of pharmaceutical formulations appears to offer a genuine synergy in bioavailability and sustained release. Promising results are obtained with colloidal systems which present very comfortable

  1. State-of-the-Art Materials for Ultrasound-Triggered Drug Delivery

    PubMed Central

    Sirsi, Shashank; Borden, Mark

    2014-01-01

    Ultrasound is a unique and exciting theranostic modality that can be used to track drug carriers, trigger drug release and improve drug deposition with high spatial precision. In this review, we briefly describe the mechanisms of interaction between drug carriers and ultrasound waves, including cavitation, streaming and hyperthermia, and how those interactions can promote drug release and tissue uptake. We then discuss the rational design of some state-of-the-art materials for ultrasound-triggered drug delivery and review recent progress for each drug carrier, focusing on the delivery of chemotherapeutic agents such as doxorubicin. These materials include nanocarrier formulations, such as liposomes and micelles, designed specifically for ultrasound-triggered drug release, as well as microbubbles, microbubble-nanocarrier hybrids, microbubble-seeded hydrogels and phase-change agents. PMID:24389162

  2. Magnetic nanoparticles for gene and drug delivery

    PubMed Central

    McBain, Stuart C; Yiu, Humphrey HP; Dobson, Jon

    2008-01-01

    Investigations of magnetic micro- and nanoparticles for targeted drug delivery began over 30 years ago. Since that time, major progress has been made in particle design and synthesis techniques, however, very few clinical trials have taken place. Here we review advances in magnetic nanoparticle design, in vitro and animal experiments with magnetic nanoparticle-based drug and gene delivery, and clinical trials of drug targeting. PMID:18686777

  3. Co-administration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs

    PubMed Central

    Beyer, Ines; Cao, Hua; Persson, Jonas; Song, Hui; Richter, Maximilian; Feng, Qinghua; Yumul, Roma; van Rensburg, Ruan; Li, Zongyi; Berenson, Ronald; Carter, Darrick; Roffler, Steve; Drescher, Charles; Lieber, André

    2013-01-01

    Purpose Epithelial junctions between tumor cells inhibit the penetration of anti-cancer drugs into tumors. We previously reported on recombinant adenovirus serotype 3 derived protein (JO-1), which triggers transient opening of intercellular junctions in epithelial tumors through binding to desmoglein 2 (DSG2), and enhances the anti-tumor effects of several therapeutic monoclonal antibodies. The goal of this study was to evaluate whether JO-1 co-therapy can also improve the efficacy of chemotherapeutic drugs. Experimental Design The effect of intravenous application of JO-1 in combination with several chemotherapy drugs including paclitaxel/Taxol™, nanoparticle albumin bound paclitaxel/Abraxane™, liposomal doxorubicin/Doxil™ and irinotecan/Camptosar™, was tested in xenograft models for breast, colon, ovarian, gastric and lung cancer. Because JO-1 does not bind to mouse cells, for safety studies with JO-1, we also used human DSG2 (hDSG2) transgenic mice with tumors that overexpressed human DSG2. Results JO-1 increased the efficacy of chemotherapeutic drugs, and in several models overcame drug resistance. JO-1 treatment also allowed for the reduction of drug doses required to achieve anti-tumor effects. Importantly, JO-1 co-admininstration protected normal tissues, including bone marrow and intestinal epithelium, against toxic effects that are normally associated with chemotherapeutic agents. Using the hDSG2 transgenic mouse model, we demonstrated that JO-1 predominantly accumulates in tumors. Except for a mild, transient diarrhea, intravenous injection of JO-1 (2mg/kg) had no critical side effects on other tissues or hematological parameters in hDSG2-transgenic mice. Conclusions Our preliminary data suggest that JO-1 co-therapy has the potential to improve the therapeutic outcome of cancer chemotherapy. PMID:22535153

  4. Smart Polymers in Nasal Drug Delivery

    PubMed Central

    Chonkar, Ankita; Nayak, Usha; Udupa, N.

    2015-01-01

    Nasal drug delivery has now been recognized as a promising route for drug delivery due to its capability of transporting a drug to systemic circulation and central nervous system. Though nasal mucosa offers improved bioavailability and quick onset of action of the drug, main disadvantage associated with nasal drug delivery is mucocilliary clearance due to which drug particles get cleared from the nose before complete absorption through nasal mucosa. Therefore, mucoadhesive polymeric approach can be successfully used to enhance the retention of the drug on nasal mucosal surface. Here, some of the aspects of the stimuli responsive polymers have been discussed which possess liquid state at the room temperature and in response to nasal temperature, pH and ions present in mucous, can undergo in situ gelation in nasal cavity. In this review, several temperature responsive, pH responsive and ion responsive polymers used in nasal delivery, their gelling mechanisms have been discussed. Smart polymers not only able to enhance the retention of the drug in nasal cavity but also provide controlled release, ease of administration, enhanced permeation of the drug and protection of the drug from mucosal enzymes. Thus smart polymeric approach can be effectively used for nasal delivery of peptide drugs, central nervous system dugs and hormones. PMID:26664051

  5. Nanoscale drug delivery for targeted chemotherapy.

    PubMed

    Xin, Yong; Huang, Qian; Tang, Jian-Qin; Hou, Xiao-Yang; Zhang, Pei; Zhang, Long Zhen; Jiang, Guan

    2016-08-28

    Despite significant improvements in diagnostic methods and innovations in therapies for specific cancers, effective treatments for neoplastic diseases still represent major challenges. Nanotechnology as an emerging technology has been widely used in many fields and also provides a new opportunity for the targeted delivery of cancer drugs. Nanoscale delivery of chemotherapy drugs to the tumor site is highly desirable. Recent studies have shown that nanoscale drug delivery systems not only have the ability to destroy cancer cells but may also be carriers for chemotherapy drugs. Some studies have demonstrated that delivery of chemotherapy via nanoscale carriers has greater therapeutic benefit than either treatment modality alone. In this review, novel approaches to nanoscale delivery of chemotherapy are described and recent progress in this field is discussed. PMID:27235607

  6. Recent Advances in Delivery of Drug-Nucleic Acid Combinations for Cancer Treatment

    PubMed Central

    Li, Jing; Wang, Yan; Zhu, Yu; Oupický, David

    2013-01-01

    Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations. PMID:23624358

  7. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

    NASA Astrophysics Data System (ADS)

    Pandey, Ambarish; Sarangi, Sasmit; Chien, Kelly; Sengupta, Poulomi; Papa, Anne-Laure; Basu, Sudipta; Sengupta, Shiladitya

    2014-11-01

    Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

  8. Hypoxia Responsive, Tumor Penetrating Lipid Nanoparticles for Delivery of Chemotherapeutics to Pancreatic Cancer Cell Spheroids.

    PubMed

    Kulkarni, Prajakta; Haldar, Manas K; Katti, Preeya; Dawes, Courtney; You, Seungyong; Choi, Yongki; Mallik, Sanku

    2016-08-17

    Solid tumors are often poorly irrigated due to structurally compromised microcirculation. Uncontrolled multiplication of cancer cells, insufficient blood flow, and the lack of enough oxygen and nutrients lead to the development of hypoxic regions in the tumor tissues. As the partial pressure of oxygen drops below the necessary level (10 psi), the cancer cells modulate their genetic makeup to survive. Hypoxia triggers tumor progression by enhancing angiogenesis, cancer stem cell production, remodeling of the extracellular matrix, and epigenetic changes in the cancer cells. However, the hypoxic regions are usually located deep in the tumors and are usually inaccessible to the intravenously injected drug carrier or the drug. Considering the designs of the reported nanoparticles, it is likely that the drug is delivered to the peripheral tumor tissues, close to the blood vessels. In this study, we prepared lipid nanoparticles (LNs) comprising the synthesized hypoxia-responsive lipid and a peptide-lipid conjugate. We observed that the resultant LNs penetrated to the hypoxic regions of the tumors. Under low oxygen partial pressure, the hypoxia-responsive lipid undergoes reduction, destabilizing the lipid membrane, and releasing encapsulated drugs from the nanoparticles. We demonstrated the results employing spheroidal cultures of the pancreatic cancer cells BxPC-3. We observed that the peptide-decorated, drug encapsulated LNs reduced the viability of pancreatic cancer cells of the spheroids to 35% under hypoxic conditions. PMID:27391789

  9. Inorganic Nanomaterials as Carriers for Drug Delivery.

    PubMed

    Chen, Shizhu; Hao, Xiaohong; Liang, Xingjie; Zhang, Qun; Zhang, Cuimiao; Zhou, Guoqiang; Shen, Shigang; Jia, Guang; Zhang, Jinchao

    2016-01-01

    For safe and effective therapy, drugs must be delivered efficiently and with minimal systemic side effects. Nanostructured drug carriers enable the delivery of small-molecule drugs as well as nucleic acids and proteins. Inorganic nanomaterials are ideal for drug delivery platforms due to their unique physicochemical properties, such as facile preparation, good storage stability and biocompatibility. Many inorganic nanostructure-based drug delivery platforms have been prepared. Although there are still many obstacles to overcome, significant advances have been made in recent years. This review focuses on the status and development of inorganic nanostructures, including silica, quantum dots, gold, carbon-based and magnetic iron oxide-based nanostructures, as carriers for chemical and biological drugs. We specifically highlight the extensive use of these inorganic drug carriers for cancer therapy. Finally, we discuss the most important areas in the field that urgently require further study. PMID:27301169

  10. Radiation sterilization of new drug delivery systems

    PubMed Central

    Abuhanoğlu, Gürhan

    2014-01-01

    Radiation sterilization has now become a commonly used method for sterilization of several active ingredients in drugs or drug delivery systems containing these substances. In this context, many applications have been performed on the human products that are required to be sterile, as well as on pharmaceutical products prepared to be developed. The new drug delivery systems designed to deliver the medication to the target tissue or organ, such as microspheres, nanospheres, microemulsion, and liposomal systems, have been sterilized by gamma (γ) and beta (β) rays, and more recently, by e-beam sterilization. In this review, the sterilization of new drug delivery systems was discussed other than conventional drug delivery systems by γ irradiation. PMID:24936306

  11. Modeling of diffusion controlled drug delivery.

    PubMed

    Siepmann, Juergen; Siepmann, Florence

    2012-07-20

    Mathematical modeling of drug release can be very helpful to speed up product development and to better understand the mechanisms controlling drug release from advanced delivery systems. Ideally, in silico simulations can quantitatively predict the impact of formulation and processing parameters on the resulting drug release kinetics. The aim of this article is to give an overview on the current state of the art of modeling drug release from delivery systems, which are predominantly controlled by diffusional mass transport. The inner structure of the device, the ratio "initial drug concentration:drug solubility" as well as the device geometry determine which type of mathematical equation must be applied. A straightforward "road map" is given, explaining how to identify the appropriate equation for a particular type of drug delivery system. The respective equations for a broad range of devices are indicated, including reservoir and matrix systems, exhibiting or not an initial excess of drug and the geometry of slabs, spheres and cylinders. The assumptions the models are based on as well as their limitations are pointed out. Practical examples illustrate the usefulness of mathematical modeling of diffusion controlled drug delivery. Due to the advances in information technology the importance of in silico optimization of advanced drug delivery systems can be expected to significantly increase in the future. PMID:22019555

  12. Potential of magnetic nanoparticles for targeted drug delivery

    PubMed Central

    Yang, Hung-Wei; Hua, Mu-Yi; Liu, Hao-Li; Huang, Chiung-Yin; Wei, Kuo-Chen

    2012-01-01

    Nanoparticles (NPs) play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs) with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some newly developed methods to synthesize and modify the surfaces of MNPs and their biomedical applications. PMID:24198498

  13. Perspectives on transdermal ultrasound mediated drug delivery

    PubMed Central

    Smith, Nadine Barrie

    2007-01-01

    The use of needles for multiple injection of drugs, such as insulin for diabetes, can be painful. As a result, prescribed drug noncompliance can result in severe medical complications. Several noninvasive methods exist for transdermal drug delivery. These include chemical mediation using liposomes and chemical enhancers or physical mechanisms such as microneedles, iontophoresis, electroporation, and ultrasound. Ultrasound enhanced transdermal drug delivery offers advantages over traditional drug delivery methods which are often invasive and painful. A broad review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for noninvasive drug administration. From a clinical perspective, few drugs, proteins or peptides have been successfully administered transdermally because of the low skin permeability to these relatively large molecules, although much work is underway to resolve this problem. The proposed mechanism of ultrasound has been suggested to be the result of cavitation, which is discussed along with the bioeffects from therapeutic ultrasound. For low frequencies, potential transducers which can be used for drug delivery are discussed, along with cautions regarding ultrasound safety versus efficacy. PMID:18203426

  14. The Benefits and Challenges Associated with the Use of Drug Delivery Systems in Cancer Therapy

    PubMed Central

    Cukierman, Edna; Khan, David R.

    2010-01-01

    The use of Drug Delivery Systems as nanocarriers for chemotherapeutic agents can improve the pharmacological properties of drugs by altering drug pharmacokinetics and biodistribution. Among the many drug delivery systems available, both micelles and liposomes have gained the most attention in recent years due to their clinical success. There are several formulations of these nanocarrier systems in various stages of clinical trials, as well as currently clinically approved liposomal-based drugs. In this review, we discuss these drug carrier systems, as well as current efforts that are being made in order to further improve their delivery efficacy through the incorporation of targeting ligands. In addition, this review discusses aspects of drug resistance attributed to the remodeling of the extracellular matrix that occurs during tumor development and progression, as well as to the acidic, hypoxic, and glucose deprived tumor microenvironment. Finally, we address future prospective approaches to overcoming drug resistance by further modifications made to these drug delivery systems, as well as the possibility of coencapsulation/coadministration of various drugs aimed to surmount some of these microenvironmental-influenced obstacles for efficacious drug delivery in chemotherapy. PMID:20417189

  15. Recent advances in ophthalmic drug delivery

    PubMed Central

    Kompella, Uday B; Kadam, Rajendra S; Lee, Vincent HL

    2011-01-01

    Topical ocular drug bioavailability is notoriously poor, in the order of 5% or less. This is a consequence of effective multiple barriers to drug entry, comprising nasolacrimal drainage, epithelial drug transport barriers and clearance from the vasculature in the conjunctiva. While sustained drug delivery to the back of the eye is now feasible with intravitreal implants such as Vitrasert™ (~6 months), Retisert™ (~3 years) and Iluvien™ (~3 years), currently there are no marketed delivery systems for long-term drug delivery to the anterior segment of the eye. The purpose of this article is to summarize the resurgence in interest to prolong and improve drug entry from topical administration. These approaches include mucoadhesives, viscous polymer vehicles, transporter-targeted prodrug design, receptor-targeted functionalized nanoparticles, iontophoresis, punctal plug and contact lens delivery systems. A few of these delivery systems might be useful in treating diseases affecting the back of the eye. Their effectiveness will be compared against intravitreal implants (upper bound of effectiveness) and trans-scleral systems (lower bound of effectiveness). Refining the animal model by incorporating the latest advances in microdialysis and imaging technology is key to expanding the knowledge central to the design, testing and evaluation of the next generation of innovative ocular drug delivery systems. PMID:21399724

  16. Synthetic micro/nanomotors in drug delivery.

    PubMed

    Gao, Wei; Wang, Joseph

    2014-09-21

    Nanomachines offer considerable promise for the treatment of diseases. The ability of man-made nanomotors to rapidly deliver therapeutic payloads to their target destination represents a novel nanomedicine approach. Synthetic nanomotors, based on a multitude of propulsion mechanisms, have been developed over the past decade toward diverse biomedical applications. In this review article, we journey from the use of chemically powered drug-delivery nanovehicles to externally actuated (fuel-free) drug-delivery nanomachine platforms, and conclude with future prospects and challenges for such practical propelling drug-delivery systems. As future micro/nanomachines become more powerful and functional, these tiny devices are expected to perform more demanding biomedical tasks and benefit different drug delivery applications. PMID:25096021

  17. Chitosan Microspheres in Novel Drug Delivery Systems

    PubMed Central

    Mitra, Analava; Dey, Baishakhi

    2011-01-01

    The main aim in the drug therapy of any disease is to attain the desired therapeutic concentration of the drug in plasma or at the site of action and maintain it for the entire duration of treatment. A drug on being used in conventional dosage forms leads to unavoidable fluctuations in the drug concentration leading to under medication or overmedication and increased frequency of dose administration as well as poor patient compliance. To minimize drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability various drug delivery and drug targeting systems are currently under development. Handling the treatment of severe disease conditions has necessitated the development of innovative ideas to modify drug delivery techniques. Drug targeting means delivery of the drug-loaded system to the site of interest. Drug carrier systems include polymers, micelles, microcapsules, liposomes and lipoproteins to name some. Different polymer carriers exert different effects on drug delivery. Synthetic polymers are usually non-biocompatible, non-biodegradable and expensive. Natural polymers such as chitin and chitosan are devoid of such problems. Chitosan comes from the deacetylation of chitin, a natural biopolymer originating from crustacean shells. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with excellent film-forming ability. Being of cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Hence chitosan has become a promising natural polymer for the preparation of microspheres/nanospheres and microcapsules. The techniques employed to microencapsulate with chitosan include ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation. This review focuses on the preparation, characterization of chitosan microspheres and their role in novel drug delivery systems. PMID:22707817

  18. Drug Delivery Systems: Entering the Mainstream

    NASA Astrophysics Data System (ADS)

    Allen, Theresa M.; Cullis, Pieter R.

    2004-03-01

    Drug delivery systems (DDS) such as lipid- or polymer-based nanoparticles can be designed to improve the pharmacological and therapeutic properties of drugs administered parenterally. Many of the early problems that hindered the clinical applications of particulate DDS have been overcome, with several DDS formulations of anticancer and antifungal drugs now approved for clinical use. Furthermore, there is considerable interest in exploiting the advantages of DDS for in vivo delivery of new drugs derived from proteomics or genomics research and for their use in ligand-targeted therapeutics.

  19. Vesicular carriers for dermal drug delivery.

    PubMed

    Sinico, Chiara; Fadda, Anna Maria

    2009-08-01

    The skin can offer several advantages as a route of drug administration although its barrier nature makes it difficult for most drugs to penetrate into and permeate through it. During the past decades there has been a lot of interest in lipid vesicles as a tool to improve drug topical delivery. Vesicular systems such as liposomes, niosomes, ethosomes and elastic, deformable vesicles provide an alternative for improved skin drug delivery. The function of vesicles as topical delivery systems is controversial with variable effects being reported in relation to the type of vesicles and their composition. In fact, vesicles can act as drug carriers controlling active release; they can provide a localized depot in the skin for dermally active compounds and enhance transdermal drug delivery. A wide variety of lipids and surfactants can be used to prepare vesicles, which are commonly composed of phospholipids (liposomes) or non-ionic surfactants (niosomes). Vesicle composition and preparation method influence their physicochemical properties (size, charge, lamellarity, thermodynamic state, deformability) and therefore their efficacy as drug delivery systems. A review of vesicle value in localizing drugs within the skin at the site of action will be provided with emphasis on their potential mechanism of action. PMID:19569979

  20. Methods of Drug Delivery in Neurotrauma.

    PubMed

    Deng-Bryant, Ying; Readnower, Ryan; Leung, Lai Yee; Tortella, Frank; Shear, Deborah

    2016-01-01

    The central nervous system (CNS) is protected by blood-brain barrier (BBB) and blood-cerebrospinal-fluid (CSF) barrier that limit toxic agents and most molecules from penetrating the brain and spinal cord. However, these barriers also prevent most pharmaceuticals from entering into the CNS. Drug delivery to the CNS following neurotrauma is complicated. Although studies have shown BBB permeability increases in various TBI models, it remains as the key mitigating factor for delivering drugs into the CNS. The commonly used methods for drug delivery in preclinical neurotrauma studies include intraperitoneal, subcutaneous, intravenous, and intracerebroventricular delivery. It should be noted that for a drug to be successfully translated into the clinic, it needs to be administered preclinically as it would be anticipated to be administered to patients. And this likely leads to better dose selection of the drug, as well as recognition of any possible side effects, prior to transition into a clinical trial. Additionally, novel approach that is noninvasive and yet circumvents BBB, such as drug delivery through nerve pathways innervating the nasal passages, needs to be investigated in animal models, as it may provide a viable drug delivery method for patients who sustain mild CNS injury or require chronic treatments. Therefore, the focus of this chapter is to present rationales and methods for delivering drugs by IV infusion via the jugular vein, and intranasally in preclinical studies. PMID:27604714

  1. [Progression of drug delivery system for glaucoma].

    PubMed

    Xu, Yan; Lyu, Liu

    2014-12-01

    Reduction of intraocular pressure (IOP) by drugs is a major treatment for glaucoma. Clinically, diverse antiglaucoma drugs take effect to decrease the IOP through different mechanisms.However, due to limitations of traditional form of eye drops, the bioavailability of the drug and the patient compliance is lowered, the clinical efficacy is not good and also some toxic and side-effects come out.Otherwise, traditional medication is not suitable for neuroprotective drugs to work on both retina and optic nerve. Drug delivery system has the potential to improve the bioavailability of the drug, prolong the time of drug action, decrease the dosage and frequency of drugs, reduce the side-effects, and improve the patient compliance and efficacy.It is one of the most important studies in glaucoma medication development because it is valuable for patients' neuroprotection.Nowadays, several novel delivery systems have been designed. This review will focus on the progressions of some of the sustained-release antiglaucoma eye drops, polymeric gels, colloidal systems, membrane-controlled drug delivery system, ocular implants, and transscleral drug delivery systems. PMID:25619186

  2. Role of microemuslsions in advanced drug delivery.

    PubMed

    Sharma, Aman Kumar; Garg, Tarun; Goyal, Amit K; Rath, Goutam

    2016-06-01

    Microemulsions have gained significant attention from formulation scientists since the time they have been discovered, because of their excellent properties related to their stability, solubility, simplicity, and formulation aspects. The application of microemulsions is not limited to drug delivery via the oral, topical or ocular routes, but may also be seen in cosmetics, immunology, sensor devices, coating, textiles, analytical chemistry, and spermicide. Finally, the objective of this review is to discuss briefly the applications of microemulsions in advanced drug delivery. PMID:25711493

  3. Osmotically controlled drug delivery system with associated drugs.

    PubMed

    Gupta, Brahma Prakash; Thakur, Navneet; Jain, Nishi P; Banweer, Jitendra; Jain, Surendra

    2010-01-01

    Conventional drug delivery systems have slight control over their drug release and almost no control over the effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the controlled or modified release drug delivery systems. They include dosage forms for oral and transdermal administration as well as injectable and implantable systems. For most of drugs, oral route remains as the most acceptable route of administration. Certain molecules may have low oral bioavailability because of solubility or permeability limitations. Development of an extended release dosage form also requires reasonable absorption throughout the gastro-intestinal tract (GIT). Among the available techniques to improve the bioavailability of these drugs fabrication of osmotic drug delivery system is the most appropriate one. Osmotic drug delivery systems release the drug with the zero order kinetics which does not depend on the initial concentration and the physiological factors of GIT. This review brings out new technologies, fabrication and recent clinical research in osmotic drug delivery. PMID:21486532

  4. The application of prodrug-based nano-drug delivery strategy in cancer combination therapy.

    PubMed

    Ge, Yanxiu; Ma, Yakun; Li, Lingbing

    2016-10-01

    Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. PMID:27400243

  5. Double layered hydroxides as potential anti-cancer drug delivery agents.

    PubMed

    Riaz, Ufana; Ashraf, S M

    2013-04-01

    The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug-LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed. PMID:23170959

  6. BMX Negatively Regulates BAK Function, Thereby Increasing Apoptotic Resistance to Chemotherapeutic Drugs.

    PubMed

    Fox, Joanna L; Storey, Alan

    2015-04-01

    The ability of chemotherapeutic agents to induce apoptosis, predominantly via the mitochondrial (intrinsic) apoptotic pathway, is thought to be a major determinant of the sensitivity of a given cancer to treatment. Intrinsic apoptosis, regulated by the BCL2 family, integrates diverse apoptotic signals to determine cell death commitment and then activates the nodal effector protein BAK to initiate the apoptotic cascade. In this study, we identified the tyrosine kinase BMX as a direct negative regulator of BAK function. BMX associates with BAK in viable cells and is the first kinase to phosphorylate the key tyrosine residue needed to maintain BAK in an inactive conformation. Importantly, elevated BMX expression prevents BAK activation in tumor cells treated with chemotherapeutic agents and is associated with increased resistance to apoptosis and decreased patient survival. Accordingly, BMX expression was elevated in prostate, breast, and colon cancers compared with normal tissue, including in aggressive triple-negative breast cancers where BMX overexpression may be a novel biomarker. Furthermore, BMX silencing potentiated BAK activation, rendering tumor cells hypersensitive to otherwise sublethal doses of clinically relevant chemotherapeutic agents. Our finding that BMX directly inhibits a core component of the intrinsic apoptosis machinery opens opportunities to improve the efficacy of existing chemotherapy by potentiating BAK-driven cell death in cancer cells. PMID:25649765

  7. Microneedles for drug and vaccine delivery

    PubMed Central

    Kim, Yeu-Chun; Park, Jung-Hwan; Prausnitz, Mark R.

    2012-01-01

    Microneedles were first conceptualized for drug delivery many decades ago, but only became the subject of significant research starting in the mid-1990’s when microfabrication technology enabled their manufacture as (i) solid microneedles for skin pretreatment to increase skin permeability, (ii) microneedles coated with drug that dissolves off in the skin, (iii) polymer microneedles that encapsulate drug and fully dissolve in the skin and (iv) hollow microneedles for drug infusion into the skin. As shown in more than 350 papers now published in the field, microneedles have been used to deliver a broad range of different low molecular weight drugs, biotherapeutics and vaccines, including published human studies with a number of small-molecule and protein drugs and vaccines. Influenza vaccination using a hollow microneedle is in widespread clinical use and a number of solid microneedle products are sold for cosmetic purposes. In addition to applications in the skin, microneedles have also been adapted for delivery of bioactives into the eye and into cells. Successful application of microneedles depends on device function that facilitates microneedle insertion and possible infusion into skin, skin recovery after microneedle removal, and drug stability during manufacturing, storage and delivery, and on patient outcomes, including lack of pain, skin irritation and skin infection, in addition to drug efficacy and safety. Building off a strong technology base and multiple demonstrations of successful drug delivery, microneedles are poised to advance further into clinical practice to enable better pharmaceutical therapies, vaccination and other applications. PMID:22575858

  8. Progress in antiretroviral drug delivery using nanotechnology

    PubMed Central

    Mallipeddi, Rama; Rohan, Lisa Cencia

    2010-01-01

    There are currently a number of antiretroviral drugs that have been approved by the Food and Drug Administration for use in the treatment of human immunodeficiency virus (HIV). More recently, antiretrovirals are being evaluated in the clinic for prevention of HIV infection. Due to the challenging nature of treatment and prevention of this disease, the use of nanocarriers to achieve more efficient delivery of antiretroviral drugs has been studied. Various forms of nanocarriers, such as nanoparticles (polymeric, inorganic, and solid lipid), liposomes, polymeric micelles, dendrimers, cyclodextrins, and cell-based nanoformulations have been studied for delivery of drugs intended for HIV prevention or therapy. The aim of this review is to provide a summary of the application of nanocarrier systems to the delivery of anti-HIV drugs, specifically antiretrovirals. For anti-HIV drugs to be effective, adequate distribution to specific sites in the body must be achieved, and effective drug concentrations must be maintained at those sites for the required period of time. Nanocarriers provide a means to overcome cellular and anatomical barriers to drug delivery. Their application in the area of HIV prevention and therapy may lead to the development of more effective drug products for combating this pandemic disease. PMID:20957115

  9. Calcium phosphate ceramics in drug delivery

    NASA Astrophysics Data System (ADS)

    Bose, Susmita; Tarafder, Solaiman; Edgington, Joe; Bandyopadhyay, Amit

    2011-04-01

    Calcium phosphate (CaP) particulates, cements and scaffolds have attracted significant interest as drug delivery vehicles. CaP systems, including both hydroxyapaptite and tricalcium phosphates, possess variable stoichiometry, functionality and dissolution properties which make them suitable for cellular delivery. Their chemical similarity to bone and thus biocompatibility, as well as variable surface charge density contribute to their controlled release properties. Among specific research areas, nanoparticle size, morphology, surface area due to porosity, and chemistry controlled release kinetics are the most active. This article discusses CaP systems in their particulate, cements, and scaffold forms for drug, protein, and growth factor delivery toward orthopedic and dental applications.

  10. Transpapillary Drug Delivery to the Breast

    PubMed Central

    Dave, Kaushalkumar; Averineni, Ranjith; Sahdev, Preety; Perumal, Omathanu

    2014-01-01

    The study was aimed at investigating localized topical drug delivery to the breast via mammary papilla (nipple). 5-fluorouracil (5-FU) and estradiol (EST) were used as model hydrophilic and hydrophobic compounds respectively. Porcine and human nipple were used for in-vitro penetration studies. The removal of keratin plug enhanced the drug transport through the nipple. The drug penetration was significantly higher through the nipple compared to breast skin. The drug’s lipophilicity had a significant influence on drug penetration through nipple. The ducts in the nipple served as a major transport pathway to the underlying breast tissue. Results showed that porcine nipple could be a potential model for human nipple. The topical application of 5-FU on the rat nipple resulted in high drug concentration in the breast and minimal drug levels in plasma and other organs. Overall, the findings from this study demonstrate the feasibility of localized drug delivery to the breast through nipple. PMID:25545150

  11. Chemotherapeutic Drugs Induce ATP Release via Caspase-gated Pannexin-1 Channels and a Caspase/Pannexin-1-independent Mechanism*

    PubMed Central

    Boyd-Tressler, Andrea; Penuela, Silvia; Laird, Dale W.; Dubyak, George R.

    2014-01-01

    Anti-tumor immune responses have been linked to the regulated release of ATP from apoptotic cancer cells to engage P2 purinergic receptor signaling cascades in nearby leukocytes. We used the Jurkat T cell acute lymphocytic leukemia model to characterize the role of pannexin-1 (Panx1) channels in the release of nucleotides during chemotherapeutic drug-induced apoptosis. Diverse pro-apoptotic drugs, including topoisomerase II inhibitors, kinase inhibitors, and proteosome inhibitors, induced functional activation of Panx1 channels via caspase-3-mediated cleavage of the Panx1 autoinhibitory C-terminal domain. The caspase-activated Panx1 channels mediated efflux of ATP, but also ADP and AMP, with the latter two comprising >90% of the released adenine nucleotide pool as cells transitioned from the early to late stages of apoptosis. Chemotherapeutic drugs also activated an alternative caspase- and Panx1-independent pathway for ATP release from Jurkat cells in the presence of benzyloxycarbonyl-VAD, a pan-caspase inhibitor. Comparison of Panx1 levels indicated much higher expression in leukemic T lymphocytes than in normal, untransformed T lymphoblasts. This suggests that signaling roles for Panx1 may be amplified in leukemic leukocytes. Together, these results identify chemotherapy-activated pannexin-1 channels and ATP release as possible mediators of paracrine interaction between dying tumor cells and the effector leukocytes that mediate immunogenic anti-tumor responses. PMID:25112874

  12. Novel drug delivery systems for glaucoma

    PubMed Central

    Lavik, E; Kuehn, M H; Kwon, Y H

    2011-01-01

    Reduction of intraocular pressure (IOP) by pharmaceutical or surgical means has long been the standard treatment for glaucoma. A number of excellent drugs are available that are effective in reducing IOP. These drugs are typically applied as eye drops. However, patient adherence can be poor, thus reducing the clinical efficacy of the drugs. Several novel delivery systems designed to address the issue of adherence and to ensure consistent reduction of IOP are currently under development. These delivery systems include contact lenses-releasing glaucoma medications, injectables such as biodegradable micro- and nanoparticles, and surgically implanted systems. These new technologies are aimed at increasing clinical efficacy by offering multiple delivery options and are capable of managing IOP for several months. There is also a desire to have complementary neuroprotective approaches for those who continue to show progression, despite IOP reduction. Many potential neuroprotective agents are not suitable for traditional oral or drop formulations. Their potential is dependent on developing suitable delivery systems that can provide the drugs in a sustained, local manner to the retina and optic nerve. Drug delivery systems have the potential to improve patient adherence, reduce side effects, increase efficacy, and ultimately, preserve sight for glaucoma patients. In this review, we discuss benefits and limitations of the current systems of delivery and application, as well as those on the horizon. PMID:21475311

  13. Microfluidic device for drug delivery

    NASA Technical Reports Server (NTRS)

    Beebe, David J. (Inventor); MacDonald, Michael J. (Inventor); Eddington, David T. (Inventor); Mensing, Glennys A. (Inventor)

    2010-01-01

    A microfluidic device is provided for delivering a drug to an individual. The microfluidic device includes a body that defines a reservoir for receiving the drug therein. A valve interconnects the reservoir to an output needle that is insertable into the skin of an individual. A pressure source urges the drug from the reservoir toward the needle. The valve is movable between a closed position preventing the flow of the drug from the reservoir to the output needle and an open position allowing for the flow of the drug from the reservoir to the output needle in response to a predetermined condition in the physiological fluids of the individual.

  14. Learning from Biology: Synthetic Lipoproteins for Drug Delivery

    PubMed Central

    Huang, Huang; Cruz, William; Chen, Juan; Zheng, Gang

    2014-01-01

    Synthetic lipoproteins represent a relevant tool for targeted delivery of biological/chemical agents (chemotherapeutics, siRNAs, photosensitizers and imaging contrast agents) into various cell types. These nanoparticles offer a number of advantages on drugs delivery over their native counterparts while retaining their natural characteristics and biological functions. Their ultra-small size (<30nm), high biocompatibility, favorable circulation half-life and natural ability to bind specific lipoprotein receptors i.e. low-density lipoprotein receptor (LDLR) and Scavenger receptor class B member 1 (SRB1) that are found in a number of pathological conditions (e.g. cancer, atherosclerosis), make them superior delivery strategies when compared to other nanoparticle systems. We review the various approaches that have been developed for the generation of synthetic lipoproteins and their respective applications in vitro and in vivo. More specifically, we summarize the way to address the limitation on use of reconstituted lipoproteins by means of natural or recombinant apolipoproteins, as well as apolipoprotein mimetic molecules. Finally, we provide an overview of the advantages and disadvantages of these approaches and discuss future perspectives for clinical translation of these nanoparticles. PMID:25346461

  15. Implication of nanofibers in oral drug delivery.

    PubMed

    Kapahi, Himani; Khan, Nikhat Mansoor; Bhardwaj, Ankur; Mishra, Neeraj

    2015-01-01

    Nanofibers has gained significant prominence in recent years due to its wide applications in medicinal pharmacy, textile, tissue engineering and in various drug delivery system. In oral drug delivery system (DDS), nanofibers can be delivered as Nanofiber scaffolds, electrosponge nanofibers as oral fast delivery system, multilayered nanofiber loaded mashes, surface modified cross-linked electrospun nanofibers. Nanofibers are of 50- 1000 nm size fibres having large surface area, high porosity, small pore size, low density. Various approaches for formulation of nanofibers are molecular assembly, thermally induced phase separation, electrospining. Most commonly used by using electrospining polymer nanofibres with different range can be produced collective usage of electro spinning with pharmaceutical polymers offers novel tactics for developing drug delivery system (DDS). Different polymers used in preparation of nanofibers include biodegradable hydrophilic polymers, hydrophobic polymers and amphiphilic polymers. Electrospun nanofibers are often used to load insoluble drugs for enhancing their dissolution properties due to their high surface area per unit mass. Besides the water insoluble drugs freely water soluble sodium can also spun into the fibers. The most commonly polymers used for nanofibers are gelatin, dextran, nylon, polystyrene, polyacrylonitrile, polycarbonate, polyimides, poly vinyl alchol, polybenzimidazole. Delivery systems reviewed rely on temporal control, changes in pH along the GIT, the action of local enzymes to trigger drug release, and changes in intraluminal pressure. Dissolution of enteric polymer coatings due to a change in local pH and reduction of azo-bonds to release an active agent are both used in commercially marketed products. In vitro and in vivo studies have demonstrated that the release rates of drugs from these nanofiber formulations are enhanced compared to those from original drug substance. This review is focused on the different

  16. Electroresponsive nanoparticles for drug delivery on demand.

    PubMed

    Samanta, Devleena; Hosseini-Nassab, Niloufar; Zare, Richard N

    2016-04-28

    The potential of electroresponsive conducting polymer nanoparticles to be used as general drug delivery systems that allow electrically pulsed, linearly scalable, and on demand release of incorporated drugs is demonstrated. As examples, facile release from polypyrrole nanoparticles is shown for fluorescein, a highly water-soluble model compound, piroxicam, a lipophilic small molecule drug, and insulin, a large hydrophilic peptide hormone. The drug loading is about 13 wt% and release is accomplished in a few seconds by applying a weak constant current or voltage. To identify the parameters that should be finely tuned to tailor the carrier system for the release of the therapeutic molecule of interest, a systematic study of the factors that affect drug delivery is performed, using fluorescein as a model compound. The parameters studied include current, time, voltage, pH, temperature, particle concentration, and ionic strength. Results indicate that there are several degrees of freedom that can be optimized for efficient drug delivery. The ability to modulate linearly drug release from conducting polymers with the applied stimulus can be utilized to design programmable and minimally invasive drug delivery devices. PMID:27088543

  17. Electroresponsive nanoparticles for drug delivery on demand

    NASA Astrophysics Data System (ADS)

    Samanta, Devleena; Hosseini-Nassab, Niloufar; Zare, Richard N.

    2016-04-01

    The potential of electroresponsive conducting polymer nanoparticles to be used as general drug delivery systems that allow electrically pulsed, linearly scalable, and on demand release of incorporated drugs is demonstrated. As examples, facile release from polypyrrole nanoparticles is shown for fluorescein, a highly water-soluble model compound, piroxicam, a lipophilic small molecule drug, and insulin, a large hydrophilic peptide hormone. The drug loading is about 13 wt% and release is accomplished in a few seconds by applying a weak constant current or voltage. To identify the parameters that should be finely tuned to tailor the carrier system for the release of the therapeutic molecule of interest, a systematic study of the factors that affect drug delivery is performed, using fluorescein as a model compound. The parameters studied include current, time, voltage, pH, temperature, particle concentration, and ionic strength. Results indicate that there are several degrees of freedom that can be optimized for efficient drug delivery. The ability to modulate linearly drug release from conducting polymers with the applied stimulus can be utilized to design programmable and minimally invasive drug delivery devices.

  18. Lipid-Based Drug Delivery Systems

    PubMed Central

    Shrestha, Hina; Bala, Rajni; Arora, Sandeep

    2014-01-01

    The principle objective of formulation of lipid-based drugs is to enhance their bioavailability. The use of lipids in drug delivery is no more a new trend now but is still the promising concept. Lipid-based drug delivery systems (LBDDS) are one of the emerging technologies designed to address challenges like the solubility and bioavailability of poorly water-soluble drugs. Lipid-based formulations can be tailored to meet a wide range of product requirements dictated by disease indication, route of administration, cost consideration, product stability, toxicity, and efficacy. These formulations are also a commercially viable strategy to formulate pharmaceuticals, for topical, oral, pulmonary, or parenteral delivery. In addition, lipid-based formulations have been shown to reduce the toxicity of various drugs by changing the biodistribution of the drug away from sensitive organs. However, the number of applications for lipid-based formulations has expanded as the nature and type of active drugs under investigation have become more varied. This paper mainly focuses on novel lipid-based formulations, namely, emulsions, vesicular systems, and lipid particulate systems and their subcategories as well as on their prominent applications in pharmaceutical drug delivery. PMID:26556202

  19. Electronics will transform drug delivery devices.

    PubMed

    Mazzoni, Paolo

    2004-03-01

    The drug delivery device sector will be transformed by electronically controlled alternatives that will maximise user safety and medical effectiveness and open the way to the introduction of high-power, next-generation drugs. Current business partnerships will need to change to allow this to happen. PMID:15154333

  20. A pulsed mode electrolytic drug delivery device

    NASA Astrophysics Data System (ADS)

    Yi, Ying; Buttner, Ulrich; Carreno, Armando A. A.; Conchouso, David; Foulds, Ian G.

    2015-10-01

    This paper reports the design of a proof-of-concept drug delivery device that is actuated using the bubbles formed during electrolysis. The device uses a platinum (Pt) coated nickel (Ni) metal foam and a solid drug in reservoir (SDR) approach to improve the device’s performance. This electrochemically-driven pump has many features that are unlike conventional drug delivery devices: it is capable of pumping periodically and being refilled automatically; it features drug release control; and it enables targeted delivery. Pt-coated metal foam is used as a catalytic reforming element, which reduces the period of each delivery cycle. Two methods were used for fabricating the Pt-coated metal: sputtering and electroplating. Of these two methods, the sputtered Pt-coated metal foam has a higher pumping rate; it also has a comparable recombination rate when compared to the electroplated Pt-coated metal foam. The only drawback of this catalytic reformer is that it consumes nickel scaffold. Considering long-term applications, the electroplated Pt metal foam was selected for drug delivery, where a controlled drug release rate of 2.2 μg  ±  0.3 μg per actuation pulse was achieved using 4 mW of power.

  1. Microfabrication Technologies for Oral Drug Delivery

    PubMed Central

    Sant, Shilpa; Tao, Sarah L.; Fisher, Omar; Xu, Qiaobing; Peppas, Nicholas A.; Khademhosseini, Ali

    2012-01-01

    Micro-/nanoscale technologies such as lithographic techniques and microfluidics offer promising avenues to revolutionalize the fields of tissue engineering, drug discovery, diagnostics and personalized medicine. Microfabrication techniques are being explored for drug delivery applications due to their ability to combine several features such as precise shape and size into a single drug delivery vehicle. They also offer to create unique asymmetrical features incorporated into single or multiple reservoir systems maximizing contact area with the intestinal lining. Combined with intelligent materials, such microfabricated platforms can be designed to be bioadhesive and stimuli-responsive. Apart from drug delivery devices, microfabrication technologies offer exciting opportunities to create biomimetic gastrointestinal tract models incorporating physiological cell types, flow patterns and brush-border like structures. Here we review the recent developments in this field with a focus on the applications of microfabrication in the development of oral drug delivery devices and biomimetic gastrointestinal tract models that can be used to evaluate the drug delivery efficacy. PMID:22166590

  2. 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

  3. Brain drug delivery systems for neurodegenerative disorders.

    PubMed

    Garbayo, E; Ansorena, E; Blanco-Prieto, M J

    2012-09-01

    Neurodegenerative disorders (NDs) are rapidly increasing as population ages. However, successful treatments for NDs have so far been limited and drug delivery to the brain remains one of the major challenges to overcome. There has recently been growing interest in the development of drug delivery systems (DDS) for local or systemic brain administration. DDS are able to improve the pharmacological and therapeutic properties of conventional drugs and reduce their side effects. The present review provides a concise overview of the recent advances made in the field of brain drug delivery for treating neurodegenerative disorders. Examples include polymeric micro and nanoparticles, lipidic nanoparticles, pegylated liposomes, microemulsions and nanogels that have been tested in experimental models of Parkinson's, Alzheimer's and Huntington's disease. Overall, the results reviewed here show that DDS have great potential for NDs treatment. PMID:23016644

  4. Amorphous powders for inhalation drug delivery.

    PubMed

    Chen, Lan; Okuda, Tomoyuki; Lu, Xiang-Yun; Chan, Hak-Kim

    2016-05-01

    For inhalation drug delivery, amorphous powder formulations offer the benefits of increased bioavailability for poorly soluble drugs, improved biochemical stability for biologics, and expanded options of using various drugs and their combinations. However, amorphous formulations usually have poor physicochemical stability. This review focuses on inhalable amorphous powders, including the production methods, the active pharmaceutical ingredients and the excipients with a highlight on stabilization of the particles. PMID:26780404

  5. Targeted Delivery of Chemotherapeutic Agents Using Improved Radiosensitive Liquid Core Microcapsules and Assessment of Their Antitumor Effect

    SciTech Connect

    Harada, Satoshi Ehara, Shigeru; Ishii, Keizo; Yamazaki, Hiromichi; Matsuyama, Shigeo; Sato, Takahiro; Oikawa, Shyoichi; Kamiya, Tomihiro; Arakawa, Kazuo; Yokota, Wataru; Sera, Koichiro; Ito, Jyun

    2009-10-01

    Purpose: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. Methods and Materials: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 {mu}g) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl{sub 2} solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy {sup 60}Co {gamma}-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. Results: Microcapsules that had been polymerized using a 4.34% CaCl{sub 2} solution supplemented with 5.0 x 10{sup -3}% (10{sup -3}% meant or 10%{sup -3}) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. Conclusion: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

  6. Drug Delivery Research: The Invention Cycle.

    PubMed

    Park, Kinam

    2016-07-01

    Controlled drug delivery systems have been successful in introducing improved formulations for better use of existing drugs and novel delivery of biologicals. The initial success of producing many oral products and some injectable depot formulations, however, reached a plateau, and the progress over the past three decades has been slow. This is likely due to the difficulties of formulating hydrophilic, high molecular weight drugs, such as proteins and nucleic acids, for targeting specific cells, month-long sustained delivery, and pulsatile release. Since the approaches that have served well for delivery of small molecules are not applicable to large molecules, it is time to develop new methods for biologicals. The process of developing future drug delivery systems, termed as the invention cycle, is proposed, and it starts with clearly defining the problems for developing certain formulations. Once the problems are well-defined, creative imagination examines all potential options and selects the best answer and alternatives. Then, innovation takes over to generate unique solutions for developing new formulations that resolve the previously identified problems. Ultimately, the new delivery systems will have to go through a translational process to produce the final formulations for clinical use. The invention cycle also emphasizes examining the reasons for success of certain formulations, not just the reasons for failure of many systems. Implementation of the new invention cycle requires new mechanisms of funding the younger generation of scientists and a new way of identifying their achievements, thereby releasing them from the burden of short-termism. PMID:26962897

  7. Inhaled nano- and microparticles for drug delivery

    PubMed Central

    El-Sherbiny, Ibrahim M.; El-Baz, Nancy M.; Yacoub, Magdi H.

    2015-01-01

    The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems. PMID:26779496

  8. Applications of chitosan nanoparticles in drug delivery.

    PubMed

    Tajmir-Riahi, H A; Nafisi, Sh; Sanyakamdhorn, S; Agudelo, D; Chanphai, P

    2014-01-01

    We have reviewed the binding affinities of several antitumor drugs doxorubicin (Dox), N-(trifluoroacetyl) doxorubicin (FDox), tamoxifen (Tam), 4-hydroxytamoxifen (4-Hydroxytam), and endoxifen (Endox) with chitosan nanoparticles of different sizes (chitosan-15, chitosan-100, and chitosan-200 KD) in order to evaluate the efficacy of chitosan nanocarriers in drug delivery systems. Spectroscopic and molecular modeling studies showed the binding sites and the stability of drug-polymer complexes. Drug-chitosan complexation occurred via hydrophobic and hydrophilic contacts as well as H-bonding network. Chitosan-100 KD was the more effective drug carrier than the chitosan-15 and chitosan-200 KD. PMID:24567139

  9. The therapeutic potential of vaginal drug delivery in the treatment of cervical cancer.

    PubMed

    McConville, Christopher

    2015-01-01

    Cervical cancer is usually treated by surgery, with the more advanced cancers requiring adjuvant chemo or radiotherapy. Its location makes it easily accessible through the vagina for the localized delivery of chemotherapeutic drugs. Localized delivery has the advantage of direct delivery to the site of action resulting in a lower dose being required and a reduction in systemic side effects. This approach would be advantageous in fertility-sparing surgery, where by localized delivery could be used to reduce tumor size allowing for a much smaller tumor to be removed, reducing the risk of preterm birth. Furthermore, localized delivery could be used after surgery to reduce the risk of recurrence, which is significantly higher in fertility-sparing surgery compared with standard surgery. PMID:26001173

  10. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    NASA Astrophysics Data System (ADS)

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2011-03-01

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  11. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    SciTech Connect

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2014-09-24

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  12. Drug Delivery Strategies of Chemical CDK Inhibitors.

    PubMed

    Alvira, Daniel; Mondragón, Laura

    2016-01-01

    The pharmacological use of new therapeutics is often limited by a safe and effective drug-delivery system. In this sense, new chemical CDK inhibitors are not an exception. Nanotechnology may be able to solve some of the main problems limiting cancer treatments such as more specific delivery of therapeutics and reduction of toxic secondary effects. It provides new delivery systems able to specifically target cancer cells and release the active molecules in a controlled fashion. Specifically, silica mesoporous supports (SMPS) have emerged as an alternative for more classical drug delivery systems based on polymers. In this chapter, we describe the synthesis of a SMPS containing the CDK inhibitor roscovitine as cargo molecule and the protocols for confirmation of the proper cargo release of the nanoparticles in cell culture employing cell viability, cellular internalization, and cell death induction studies. PMID:26231714

  13. A Novel Combined Approach of Short-Chain Sphingolipids and Thermosensitive Liposomes for Improved Drug Delivery to Tumor Cells.

    PubMed

    Haeri, Azadeh; Pedrosa, Lilia R C; Ten Hagen, Timo L M; Dadashzadeh, Simin; Koning, Gerben A

    2016-04-01

    Despite the advantages of liposomal drug delivery, the bioavailability of the chemotherapeutic drugs to tumor cells is limited by their slow release from nanocarriers and low drug permeability across cell membranes. Drug encapsulation into stealth thermosensitive liposomes can improve drug delivery to tumors by combining efficient accumulation at tumors and the active release of the payload following remote heat triggering. Short-chain sphingolipids are known to enhance cellular uptake of amphiphilic drugs. We hypothesized that short-chain sphingolipids could be utilized to further improve intracellular drug delivery from a thermoresponsive formulation by enhancing the cell membrane passage of released drug. The following two strategies were investigated: (1) co-delivery of C8-glucosylceramide and doxorubicin within the thermosensitive liposomes and (2) pretreatment with glucosylceramide-enriched drug-free liposomes and subsequent treatment with doxorubicin loaded thermosensitive liposomes. Liposomes were prepared and extensively characterized. Drug uptake, cell cytotoxicity and live cell imaging were performed under normothermic and hyperthermic conditions in melanoma cells. In these studies, hyperthermia improved drug delivery from doxorubicin loaded thermosensitive formulations. However, the results from cell experiments indicated that there was no additional benefit in the co-delivery strategy using doxorubicin loaded glucosylceramide-enriched thermosensitive liposomes. In contrast, cellular studies showed significantly higher doxorubicin internalization in the pretreatment strategy. One-hour exposure of the cells to C8-glucosylceramide before applying hyperthermia caused improved doxorubicin uptake and cytotoxicity as well as an almost instantaneous cellular entry of the doxorubicin released from thermosensitive liposomes. This novel, two-step drug delivery approach can be potentially beneficial for the intracellular delivery of cell impermeable

  14. Engineered Polymers for Advanced Drug Delivery

    PubMed Central

    Kim, Sungwon; Kim, Jong-Ho; Jeon, Oju; Kwon, Ick Chan; Park, Kinam

    2009-01-01

    Engineered polymers have been utilized for developing advanced drug delivery systems. The development of such polymers has caused advances in polymer chemistry, which, in turn, has resulted in smart polymers that can respond to changes in environmental condition, such as temperature, pH, and biomolecules. The responses vary widely from swelling/deswelling to degradation. Drug-polymer conjugates and drug-containing nano/micro-particles have been used for drug targeting. Engineered polymers and polymeric systems have also been used in new areas, such as molecular imaging as well as in nanotechnology. This review examines the engineered polymers that have been used as traditional drug delivery and as more recent applications in nanotechnology. PMID:18977434

  15. 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.

  16. Engineered inorganic nanoparticles for drug delivery applications.

    PubMed

    Ojea-Jiménez, Isaac; Comenge, Joan; García-Fernández, Lorena; Megson, Zoë A; Casals, Eudald; Puntes, Victor F

    2013-06-01

    Inorganic nanoparticles (NPs) currently have immense potential as drug delivery vectors due to their unique physicochemical properties such as high surface area per unit volume, their optical and magnetic uniqueness and the ability to be functionalized with a large number of ligands to enhance their affinity towards target molecules. These features, together with the therapeutic activity of some drugs, render the combination of these two entities (NP-drug) as an attractive alternative in the area of drug delivery. One of the major advantages of these conjugates is the possibility to have a local delivery of the drug, thus reducing systemic side effects and enabling a higher efficiency of the therapeutic molecule. This review highlights the direct implications of nanoscale particles in the development of drug delivery systems. In more detail, it is also remarked the extensive use of inorganic NPs for targeted cancer therapies. As the range of nanoparticles and their applications continues to increase, human safety concerns are gaining importance, which makes it necessary to better understand the potential toxicity hazards of these materials. PMID:23116108

  17. Chitosan: a propitious biopolymer for drug delivery.

    PubMed

    Duttagupta, Dibyangana S; Jadhav, Varsha M; Kadam, Vilasrao J

    2015-01-01

    Scientists have always been interested in the use of natural polymers for drug delivery. Chitosan, being a natural cationic polysaccharide has received a great deal of attention in the past few years. It is obtained by deacetylation of chitin and is regarded as the second most ubiquitous polymer subsequent to cellulose on earth. Unlike other natural polymers, the cationic charge possessed by chitosan is accountable for imparting interesting physical and chemical properties. Chitosan has been widely exploited for its mucoadhesive character, permeation enhancing properties and controlled release of drugs. Moreover it's non-toxic, biocompatible and biodegradable properties make it a good candidate for novel drug delivery system. This review provides an insight on various chitosan based formulations for drug delivery. Some of the current applications of chitosan in areas like ophthalmic, nasal, buccal, sublingual, gastro-retentive, pulmonary, transdermal, colon-specific and vaginal drug delivery have been discussed. In addition, active targeting of drugs to tumor cells using chitosan has been described. Lastly a brief section covering the safety aspects of chitosan has also been reviewed. PMID:25761010

  18. Trojan Microparticles for Drug Delivery

    PubMed Central

    Anton, Nicolas; Jakhmola, Anshuman; Vandamme, Thierry F.

    2012-01-01

    During the last decade, the US Food and Drug Administration (FDA) have regulated a wide range of products, (foods, cosmetics, drugs, devices, veterinary, and tobacco) which may utilize micro and nanotechnology or contain nanomaterials. Nanotechnology allows scientists to create, explore, and manipulate materials in nano-regime. Such materials have chemical, physical, and biological properties that are quite different from their bulk counterparts. For pharmaceutical applications and in order to improve their administration (oral, pulmonary and dermal), the nanocarriers can be spread into microparticles. These supramolecular associations can also modulate the kinetic releases of drugs entrapped in the nanoparticles. Different strategies to produce these hybrid particles and to optimize the release kinetics of encapsulated drugs are discussed in this review. PMID:24300177

  19. Nanoparticles in the ocular drug delivery

    PubMed Central

    Zhou, Hong-Yan; Hao, Ji-Long; Wang, Shuang; Zheng, Yu; Zhang, Wen-Song

    2013-01-01

    Ocular drug transport barriers pose a challenge for drug delivery comprising the ocular surface epithelium, the tear film and internal barriers of the blood-aqueous and blood-retina barriers. Ocular drug delivery efficiency depends on the barriers and the clearance from the choroidal, conjunctival vessels and lymphatic. Traditional drug administration reduces the clinical efficacy especially for poor water soluble molecules and for the posterior segment of the eye. Nanoparticles (NPs) have been designed to overcome the barriers, increase the drug penetration at the target site and prolong the drug levels by few internals of drug administrations in lower doses without any toxicity compared to the conventional eye drops. With the aid of high specificity and multifunctionality, DNA NPs can be resulted in higher transfection efficiency for gene therapy. NPs could target at cornea, retina and choroid by surficial applications and intravitreal injection. This review is concerned with recent findings and applications of NPs drug delivery systems for the treatment of different eye diseases. PMID:23826539

  20. Genetically engineered nanocarriers for drug delivery

    PubMed Central

    Shi, Pu; Gustafson, Joshua A; MacKay, J Andrew

    2014-01-01

    Cytotoxicity, low water solubility, rapid clearance from circulation, and off-target side-effects are common drawbacks of conventional small-molecule drugs. To overcome these shortcomings, many multifunctional nanocarriers have been proposed to enhance drug delivery. In concept, multifunctional nanoparticles might carry multiple agents, control release rate, biodegrade, and utilize target-mediated drug delivery; however, the design of these particles presents many challenges at the stage of pharmaceutical development. An emerging solution to improve control over these particles is to turn to genetic engineering. Genetically engineered nanocarriers are precisely controlled in size and structure and can provide specific control over sites for chemical attachment of drugs. Genetically engineered drug carriers that assemble nanostructures including nanoparticles and nanofibers can be polymeric or non-polymeric. This review summarizes the recent development of applications in drug and gene delivery utilizing nanostructures of polymeric genetically engineered drug carriers such as elastin-like polypeptides, silk-like polypeptides, and silk-elastin-like protein polymers, and non-polymeric genetically engineered drug carriers such as vault proteins and viral proteins. PMID:24741309

  1. Barriers to drug delivery in solid tumors

    PubMed Central

    Sriraman, Shravan Kumar; Aryasomayajula, Bhawani; Torchilin, Vladimir P

    2014-01-01

    Over the last decade, significant progress has been made in the field of drug delivery. The advent of engineered nanoparticles has allowed us to circumvent the initial limitations to drug delivery such as pharmacokinetics and solubility. However, in spite of significant advances to tumor targeting, an effective treatment strategy for malignant tumors still remains elusive. Tumors possess distinct physiological features which allow them to resist traditional treatment approaches. This combined with the complexity of the biological system presents significant hurdles to the site-specific delivery of therapeutic drugs. One of the key features of engineered nanoparticles is that these can be tailored to execute specific functions. With this review, we hope to provide the reader with a clear understanding and knowledge of biological barriers and the methods to exploit these characteristics to design multifunctional nanocarriers, effect useful dosing regimens and subsequently improve therapeutic outcomes in the clinic. PMID:25068098

  2. Current perspectives on intrathecal drug delivery

    PubMed Central

    Bottros, Michael M; Christo, Paul J

    2014-01-01

    Advances in intrathecal analgesia and intrathecal drug delivery systems have allowed for a range of medications to be used in the control of pain and spasticity. This technique allows for reduced medication doses that can decrease the side effects typically associated with oral or parenteral drug delivery. Recent expert panel consensus guidelines have provided care paths in the treatment of nociceptive, neuropathic, and mixed pain syndromes. While the data for pain relief, adverse effect reduction, and cost-effectiveness with cancer pain control are compelling, the evidence is less clear for noncancer pain, other than spasticity. Physicians should be aware of mechanical, pharmacological, surgical, and patient-specific complications, including possible granuloma formation. Newer intrathecal drug delivery systems may allow for better safety and quality of life outcomes. PMID:25395870

  3. Targeting the brain: advances in drug delivery.

    PubMed

    Blumling Iii, James P; Silva, Gabriel A

    2012-09-01

    The blood-brain barrier (BBB) represents a significant obstacle for drug delivery to the brain. Many therapeutics with potential for treating neurological conditions prove incompatible with intravenous delivery simply because of this barrier. Rather than modifying drugs to penetrate the BBB directly, it has proven more efficacious to either physically bypass the barrier or to use specialized delivery vehicles that circumvent BBB regulatory mechanisms. Controlled-release intracranial polymer implants and particle injections are the clinical state of the art with regard to localized delivery, although these approaches can impose significant surgical risks. Focused ultrasound provides a non-invasive alternative that may prove more desirable for acute treatment of brain tumors and other conditions requiring local tissue necrosis. For targeting the brain as a whole, cell-penetrating peptides (CPPs) and molecular trojan horses (MTHs) have demonstrated particular ability as delivery molecules and will likely see increased application. CPPs are not brain specific but offer the potential for efficient traversal of the BBB, and tandem systems with targeting molecules may produce extremely effective brain drug delivery tools. Molecular trojan horses utilize receptor-mediated transcytosis to transport cargo and are thus limited by the quantity of relevant receptors; however, they can be very selective for the BBB endothelium and have shown promise in gene therapy. PMID:23016646

  4. Ultrasound-mediated gastrointestinal drug delivery

    PubMed Central

    Schoellhammer, Carl M.; Schroeder, Avi; Maa, Ruby; Lauwers, Gregory Yves; Swiston, Albert; Zervas, Michael; Barman, Ross; DiCiccio, Angela M.; Brugge, William R.; Anderson, Daniel G.; Blankschtein, Daniel; Langer, Robert; Traverso, Giovanni

    2016-01-01

    There is a significant clinical need for rapid and efficient delivery of drugs directly to the site of diseased tissues for the treatment of gastrointestinal (GI) pathologies, in particular, Crohn’s and ulcerative colitis. However, complex therapeutic molecules cannot easily be delivered through the GI tract because of physiologic and structural barriers. We report the use of ultrasound as a modality for enhanced drug delivery to the GI tract, with an emphasis on rectal delivery. Ultrasound increased the absorption of model therapeutics inulin, hydrocortisone, and mesalamine two- to tenfold in ex vivo tissue, depending on location in the GI tract. In pigs, ultrasound induced transient cavitation with negligible heating, leading to an order of magnitude enhancement in the delivery of mesalamine, as well as successful systemic delivery of a macromolecule, insulin, with the expected hypoglycemic response. In a rodent model of chemically induced acute colitis, the addition of ultrasound to a daily mesalamine enema (compared to enema alone) resulted in superior clinical and histological scores of disease activity. In both animal models, ultrasound treatment was well tolerated and resulted in minimal tissue disruption, and in mice, there was no significant effect on histology, fecal score, or tissue inflammatory cytokine levels. The use of ultrasound to enhance GI drug delivery is safe in animals and could augment the efficacy of GI therapies and broaden the scope of agents that could be delivered locally and systemically through the GI tract for chronic conditions such as inflammatory bowel disease. PMID:26491078

  5. Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery

    PubMed Central

    Fang, Yi-Ping; Wu, Pao-Chu; Huang, Yaw-Bin; Tzeng, Cherng-Chyi; Chen, Yeh-Long; Hung, Yu-Han; Tsai, Ming-Jun; Tsai, Yi-Hung

    2012-01-01

    Background The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenyl) amino]furo[2,3-b]quinoline (PK-L4) is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection. Aims To utilize solid lipid nanoparticles (SLNs) modified with polyethylene glycol (PEG) to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration. Results The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE%) of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%–64% in the human lung carcinoma cell line (A549), 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7), and 95% in the human breast adenocarcinoma cell line (MDA-MB-231). The amount of PK-L4 released by SLNs with PEG was significantly higher than that from the PK-L4 solution (P < 0.05). After intravenous bolus of the PK-L4-loaded SLNs with PEG, there was a marked significant difference in half-life alpha (0.136 ± 0.046 hours) when compared with the PK-L4 solution (0.078 ± 0.023 hours); also the area under the curve from zero to infinity did not change in plasma when compared to the PK-L4 solution. This demonstrated that PK-L4-loaded SLNs were rapidly distributed from central areas to tissues and exhibited higher accumulation in specific organs. The highest deposition of PK-L4-loaded SLNs

  6. Drug delivery and nanoparticles: Applications and hazards

    PubMed Central

    De Jong, Wim H; Borm, Paul JA

    2008-01-01

    The use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. Interestingly pharmaceutical sciences are using nanoparticles to reduce toxicity and side effects of drugs and up to recently did not realize that carrier systems themselves may impose risks to the patient. The kind of hazards that are introduced by using nanoparticles for drug delivery are beyond that posed by conventional hazards imposed by chemicals in classical delivery matrices. For nanoparticles the knowledge on particle toxicity as obtained in inhalation toxicity shows the way how to investigate the potential hazards of nanoparticles. The toxicology of particulate matter differs from toxicology of substances as the composing chemical(s) may or may not be soluble in biological matrices, thus influencing greatly the potential exposure of various internal organs. This may vary from a rather high local exposure in the lungs and a low or neglectable exposure for other organ systems after inhalation. However, absorbed species may also influence the potential toxicity of the inhaled particles. For nanoparticles the situation is different as their size opens the potential for crossing the various biological barriers within the body. From a positive viewpoint, especially the potential to cross the blood brain barrier may open new ways for drug delivery into the brain. In addition, the nanosize also allows for access into the cell and various cellular compartments including the nucleus. A multitude of substances are currently under investigation for the preparation of nanoparticles for drug delivery, varying from biological substances like albumin, gelatine and phospholipids for liposomes, and more substances of a chemical nature like various polymers and solid metal containing nanoparticles. It is obvious that the potential interaction with tissues and cells

  7. Drug delivery system and breast cancer cells

    NASA Astrophysics Data System (ADS)

    Colone, Marisa; Kaliappan, Subramanian; Calcabrini, Annarica; Tortora, Mariarosaria; Cavalieri, Francesca; Stringaro, Annarita

    2016-06-01

    Recently, nanomedicine has received increasing attention for its ability to improve the efficacy of cancer therapeutics. Nanosized polymer therapeutic agents offer the advantage of prolonged circulation in the blood stream, targeting to specific sites, improved efficacy and reduced side effects. In this way, local, controlled delivery of the drug will be achieved with the advantage of a high concentration of drug release at the target site while keeping the systemic concentration of the drug low, thus reducing side effects due to bioaccumulation. Various drug delivery systems such as nanoparticles, liposomes, microparticles and implants have been demonstrated to significantly enhance the preventive/therapeutic efficacy of many drugs by increasing their bioavailability and targetability. As these carriers significantly increase the therapeutic effect of drugs, their administration would become less cost effective in the near future. The purpose of our research work is to develop a delivery system for breast cancer cells using a microvector of drugs. These results highlight the potential uses of these responsive platforms suited for biomedical and pharmaceutical applications. At the request of all authors of the paper an updated version was published on 12 July 2016. The manuscript was prepared and submitted without Dr. Francesca Cavalieri's contribution and her name was added without her consent. Her name has been removed in the updated and re-published article.

  8. 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.

  9. Recent technologies in pulsatile drug delivery systems

    PubMed Central

    Jain, Deepika; Raturi, Richa; Jain, Vikas; Bansal, Praveen; Singh, Ranjit

    2011-01-01

    Pulsatile drug delivery systems (PDDS) have attracted attraction because of their multiple benefits over conventional dosage forms. They deliver the drug at the right time, at the right site of action and in the right amount, which provides more benefit than conventional dosages and increased patient compliance. These systems are designed according to the circadian rhythm of the body, and the drug is released rapidly and completely as a pulse after a lag time. These products follow the sigmoid release profile characterized by a time period. These systems are beneficial for drugs with chronopharmacological behavior, where nocturnal dosing is required, and for drugs that show the first-pass effect. This review covers methods and marketed technologies that have been developed to achieve pulsatile delivery. Marketed technologies, such as PulsincapTM, Diffucaps®, CODAS®, OROS® and PULSYSTM, follow the above mechanism to render a sigmoidal drug release profile. Diseases wherein PDDS are promising include asthma, peptic ulcers, cardiovascular ailments, arthritis and attention deficit syndrome in children and hypercholesterolemia. Pulsatile drug delivery systems have the potential to bring new developments in the therapy of many diseases. PMID:23507727

  10. Drug delivery system and breast cancer cells

    NASA Astrophysics Data System (ADS)

    Colone, Marisa; Kaliappan, Subramanian; Calcabrini, Annarica; Tortora, Mariarosaria; Cavalieri, Francesca; Stringaro, Annarita

    2016-06-01

    Recently, nanomedicine has received increasing attention for its ability to improve the efficacy of cancer therapeutics. Nanosized polymer therapeutic agents offer the advantage of prolonged circulation in the blood stream, targeting to specific sites, improved efficacy and reduced side effects. In this way, local, controlled delivery of the drug will be achieved with the advantage of a high concentration of drug release at the target site while keeping the systemic concentration of the drug low, thus reducing side effects due to bioaccumulation. Various drug delivery systems such as nanoparticles, liposomes, microparticles and implants have been demonstrated to significantly enhance the preventive/therapeutic efficacy of many drugs by increasing their bioavailability and targetability. As these carriers significantly increase the therapeutic effect of drugs, their administration would become less cost effective in the near future. The purpose of our research work is to develop a delivery system for breast cancer cells using a microvector of drugs. These results highlight the potential uses of these responsive platforms suited for biomedical and pharmaceutical applications.

  11. Transungual drug delivery: current status.

    PubMed

    Elkeeb, Rania; AliKhan, Ali; Elkeeb, Laila; Hui, Xiaoying; Maibach, Howard I

    2010-01-15

    Topical therapy is highly desirable in treating nail disorders due to its localized effects, which results in minimal adverse systemic events and possibly improved adherence. However, the effectiveness of topical therapies is limited by minimal drug permeability through the nail plate. Current research on nail permeation that focuses on altering the nail plate barrier by means of chemical treatments, penetration enhancers as well as physical and mechanical methods is reviewed. A new method of nail sampling is examined. Finally limitations of current ungual drug permeability studies are briefly discussed. PMID:19819318

  12. Disulfide-based multifunctional conjugates for targeted theranostic drug delivery.

    PubMed

    Lee, Min Hee; Sessler, Jonathan L; Kim, Jong Seung

    2015-11-17

    Theranostics, chemical entities designed to combine therapeutic effects and imaging capability within one molecular system, have received considerable attention in recent years. Much of this interest reflects the promise inherent in personalized medicine, including disease-targeted treatments for cancer patients. One important approach to realizing this latter promise involves the development of so-called theranostic conjugates, multicomponent constructs that selectively target cancer cells and deliver cytotoxic agents while producing a readily detectable signal that can be monitored both in vitro and in vivo. This requires the synthesis of relatively complex systems comprising imaging reporters, masked chemotherapeutic drugs, cleavable linkers, and cancer targeting ligands. Ideally, the cleavage process should take place within or near cancer cells and be activated by cellular components that are associated with cancer states or specifically expressed at a higher level in cancer cells. Among the cleavable linkers currently being explored for the construction of such localizing conjugates, disulfide bonds are particularly attractive. This is because disulfide bonds are stable in most blood pools but are efficiently cleaved by cellular thiols, including glutathione (GSH) and thioredoxin (Trx), which are generally found at elevated levels in tumors. When disulfide bonds are linked to fluorophores, changes in emission intensity or shifts in the emission maxima are typically seen upon cleavage as the result of perturbations to internal charge transfer (ICT) processes. In well-designed systems, this allows for facile imaging. In this Account, we summarize our recent studies involving disulfide-based fluorescent drug delivery conjugates, including preliminary tests of their biological utility in vitro and in vivo. To date, a variety of chemotherapeutic agents, such as doxorubicin, gemcitabine, and camptothecin, have been used to create disulfide-based conjugates, as have

  13. Nanotechnology-Based Drug Delivery Systems for Melanoma Antitumoral Therapy: A Review

    PubMed Central

    Rigon, Roberta Balansin; Oyafuso, Márcia Helena; Fujimura, Andressa Terumi; do Prado, Alice Haddad; Gremião, Maria Palmira Daflon

    2015-01-01

    Melanoma (MEL) is a less common type of skin cancer, but it is more aggressive with a high mortality rate. The World Cancer Research Fund International (GLOBOCAN 2012) estimates that there were 230,000 new cases of MEL in the world in 2012. Conventional MEL treatment includes surgery and chemotherapy, but many of the chemotherapeutic agents used present undesirable properties. Drug delivery systems are an alternative strategy by which to carry antineoplastic agents. Encapsulated drugs are advantageous due to such properties as high stability, better bioavailability, controlled drug release, a long blood circulation time, selective organ or tissue distribution, a lower total required dose, and minimal toxic side effects. This review of scientific research supports applying a nanotechnology-based drug delivery system for MEL therapy. PMID:26078967

  14. Nanotechnology-Based Drug Delivery Systems for Melanoma Antitumoral Therapy: A Review.

    PubMed

    Rigon, Roberta Balansin; Oyafuso, Márcia Helena; Fujimura, Andressa Terumi; Gonçalez, Maíra Lima; do Prado, Alice Haddad; Gremião, Maria Palmira Daflon; Chorilli, Marlus

    2015-01-01

    Melanoma (MEL) is a less common type of skin cancer, but it is more aggressive with a high mortality rate. The World Cancer Research Fund International (GLOBOCAN 2012) estimates that there were 230,000 new cases of MEL in the world in 2012. Conventional MEL treatment includes surgery and chemotherapy, but many of the chemotherapeutic agents used present undesirable properties. Drug delivery systems are an alternative strategy by which to carry antineoplastic agents. Encapsulated drugs are advantageous due to such properties as high stability, better bioavailability, controlled drug release, a long blood circulation time, selective organ or tissue distribution, a lower total required dose, and minimal toxic side effects. This review of scientific research supports applying a nanotechnology-based drug delivery system for MEL therapy. PMID:26078967

  15. Aptamers for Targeted Drug Delivery

    PubMed Central

    Ray, Partha; White, Rebekah R.

    2010-01-01

    Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX). SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery.

  16. PH responsive polypeptide based polymeric micelles for anticancer drug delivery.

    PubMed

    Zhao, Dongping; Li, Bingqiang; Han, Jiaming; Yang, Yue; Zhang, Xinchen; Wu, Guolin

    2015-09-01

    A pH-responsive polymeric micelle based on poly(aspartamide) derivative was explored as an efficient acid-triggered anticancer drug delivery system. Poly(α,β-l-asparthydrazide) (PAHy) was prepared by aminolysis reaction of polysuccinimide with hydrazine hydrate. Poly(ethylene glycol) and aliphatic chain (C18) were conjugated onto PAHy to afford an amphiphilic copolymer with acid-liable hydrazone bonds. The structure of the resulting copolymer and its self-assembled micelles were confirmed by (1) H NMR, FTIR, DLS, and TEM. Furthermore, doxorubicin (DOX) was loaded into the polymeric micelles via the hydrophobic interaction between the C18 group and DOX molecules, and the π-π staking between the hydrazone conjugated DOX and free DOX molecules. Results showed that the DOX loaded nanoparticle (NP) was relatively stable under physiological conditions, while the DOX was quickly released in response to acidity due to the shedding of mPEG shells and dissociating of C18 segments because of the pH-cleavage of intermediate hydrazone bonds. In addition, the DOX loaded micelles presented a high cytotoxic activity against tumor cells in vitro. This pH responsive NP has appeared highly promising for the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy. PMID:25689362

  17. A Fibrous Localized Drug Delivery Platform with NIR-Triggered and Optically Monitored Drug Release.

    PubMed

    Liu, Heng; Fu, Yike; Li, Yangyang; Ren, Zhaohui; Li, Xiang; Han, Gaorong; Mao, Chuanbin

    2016-09-01

    Implantable localized drug delivery systems (LDDSs) with intelligent functionalities have emerged as a powerful chemotherapeutic platform in curing cancer. Developing LDDSs with rationally controlled drug release and real-time monitoring functionalities holds promise for personalized therapeutic protocols but suffers daunting challenges. To overcome such challenges, a series of porous Yb(3+)/Er(3+) codoped CaTiO3 (CTO:Yb,Er) nanofibers, with specifically designed surface functionalization, were synthesized for doxorubicin (DOX) delivery. The content of DOX released could be optically monitored by increase in the intensity ratio of green to red emission (I550/I660) of upconversion photoluminescent nanofibers under 980 nm near-infrared (NIR) excitation owing to the fluorescence resonance energy transfer (FRET) effect between DOX molecules and the nanofibers. More importantly, the 808 nm NIR irradiation enabled markedly accelerated DOX release, confirming representative NIR-triggered drug release properties. In consequence, such CTO:Yb,Er nanofibers presented significantly enhanced in vitro anticancer efficacy under NIR irradiation. This study has thus inspired another promising fibrous LDDS platform with NIR-triggered and optics-monitored DOX releasing for personalized tumor chemotherapy. PMID:27557281

  18. Sericin/Dextran Injectable Hydrogel as an Optically Trackable Drug Delivery System for Malignant Melanoma Treatment.

    PubMed

    Liu, Jia; Qi, Chao; Tao, Kaixiong; Zhang, Jinxiang; Zhang, Jian; Xu, Luming; Jiang, Xulin; Zhang, Yunti; Huang, Lei; Li, Qilin; Xie, Hongjian; Gao, Jinbo; Shuai, Xiaoming; Wang, Guobin; Wang, Zheng; Wang, Lin

    2016-03-01

    Severe side effects of cancer chemotherapy prompt developing better drug delivery systems. Injectable hydrogels are an effective site-target system. For most of injectable hydrogels, once delivered in vivo, some properties including drug release and degradation, which are critical to chemotherapeutic effects and safety, are challenging to monitor. Developing a drug delivery system for effective cancer therapy with in vivo real-time noninvasive trackability is highly desired. Although fluorescence dyes are used for imaging hydrogels, the cytotoxicity limits their applications. By using sericin, a natural photoluminescent protein from silk, we successfully synthesized a hydrazone cross-linked sericin/dextran injectable hydrogel. This hydrogel is biodegradable and biocompatible. It achieves efficient drug loading and controlled release of both macromolecular and small molecular drugs. Notably, sericin's photoluminescence from this hydrogel is directly and stably correlated with its degradation, enabling long-term in vivo imaging and real-time monitoring of the remaining drug. The hydrogel loaded with Doxorubicin significantly suppresses tumor growth. Together, the work demonstrates the efficacy of this drug delivery system, and the in vivo effectiveness of this sericin-based optical monitoring strategy, providing a potential approach for improving hydrogel design toward optimal efficiency and safety of chemotherapies, which may be widely applicable to other drug delivery systems. PMID:26900631

  19. Drug delivery applications with ethosomes.

    PubMed

    Ainbinder, D; Paolino, D; Fresta, M; Touitou, E

    2010-10-01

    Ethosomes are specially tailored vesicular carriers able to efficiently deliver various molecules with different physicochemical properties into deep skin layers and across the skin. This paper reviews the unique characteristics of the ethosomal carriers, focusing on work carried out with drug containing ethosomal systems in animal models and in clinical studies. The paper concludes with a discussion on the safety of the ethosomal system applications. PMID:21329048

  20. Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles.

    PubMed

    Ma, Jingwei; Zhang, Yi; Tang, Ke; Zhang, Huafeng; Yin, Xiaonan; Li, Yong; Xu, Pingwei; Sun, Yanling; Ma, Ruihua; Ji, Tiantian; Chen, Junwei; Zhang, Shuang; Zhang, Tianzhen; Luo, Shunqun; Jin, Yang; Luo, Xiuli; Li, Chengyin; Gong, Hongwei; Long, Zhixiong; Lu, Jinzhi; Hu, Zhuowei; Cao, Xuetao; Wang, Ning; Yang, Xiangliang; Huang, Bo

    2016-06-01

    Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications. PMID:27167569

  1. Poly(hydroxy acids) in drug delivery.

    PubMed

    Juni, K; Nakano, M

    1987-01-01

    Poly(hydroxy acids) so far have been examined for use in drug delivery in limited number, while the advantageous use of the polymers has been recognized due to their biodegradability and biocompatibility. Homo- and copolymers of lactic acid and glycolic acid have been studied in drug delivery by many workers, while homo- and copolymers of epsilon-caprolactone have been studied by only one group of workers. Although poly-hydroxybutyric acid had been found to be a naturally occurring polymer, examination as to the use of the polymer in drug delivery is rather recent and reports are still limited. In the present article, the use of poly(hydroxy acids) including homo- and copolymers of lactic acid and glycolic acid, polycaprolactone, and poly-beta-hydroxybutyric acid in drug delivery is reviewed. Physicochemical properties, biodegradability, and biocompatibility of the polymers, and evaluations in vitro and in vivo of specific dosage forms using the polymers, are included. The most recent work in our laboratories on the use of polyactic acid and poly-beta-hydroxybutyric acid is also included. PMID:3549007

  2. Recent Perspectives in Ocular Drug Delivery

    PubMed Central

    Gaudana, Ripal; Jwala, J.; Boddu, Sai H. S.; Mitra, Ashim K.

    2015-01-01

    Anatomy and physiology of the eye makes it a highly protected organ. Designing an effective therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable task. Limitations of topical and intravitreal route of administration have challenged scientists to find alternative mode of administration like periocular routes. Transporter targeted drug delivery has generated a great deal of interest in the field because of its potential to overcome many barriers associated with current therapy. Application of nanotechnology has been very promising in the treatment of a gamut of diseases. In this review, we have briefly discussed several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels. Potential for ocular gene therapy has also been described in this article. In near future, a great deal of attention will be paid to develop non-invasive sustained drug release for both anterior and posterior segment eye disorders. A better understanding of nature of ocular diseases, barriers and factors affecting in vivo performance, would greatly drive the development of new delivery systems. Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders. PMID:18758924

  3. Suppression of PRKAR1A expression enhances anti-proliferative and apoptotic effects of protein kinase inhibitors and chemotherapeutic drugs on cholangiocarcinoma cells.

    PubMed

    Loilome, Watcharin; Juntana, Sirinun; Pinitsoontorn, Chadamas; Namwat, Nisana; Tassaneeyakul, Wichittra; Yongvanit, Puangrat

    2012-01-01

    Suppression of protein kinase A regulatory subunit 1 alpha (PRKAR1A) has been proven to inhibit cholangiocarcinoma (CCA) cell growth and enhance apoptosis. In the present study, we aimed to determine synergistic and/or additive effects of chemotherapeutic agents, including protein kinase inhibitors (i.e. sorafenib, sunitinib, gefitinib, Met inhibitor) and conventional chemotherapeutic drugs (i.e. 5-fluorouracil, doxorubicin, paclitaxel, gemcitabine), in PRKARIA knockdown CCA cell lines. The results revealed that PRKAR1A suppressed CCA cell lines demonstrated enhanced sensitivity to some chemotherapeutic drugs when compared to control cells. Moreover, PRKAR1A knockdown in combination with either sorafenib or 5-fluorouracil increased apoptotic effects on CCA cell lines. Therefore, selective inhibition of PRKAR1A appears to enhance the growth inhibitory effects of chemotherapeutic drugs as well as induce apoptotic cell death. Our findings suggest that additional suppression of PRKAR1A expression may increase the efficacy of conventional CCA chemotherapeutic treatment. Clinical studies in CCA patients now need to be conducted. PMID:23480756

  4. Chemotherapeutic efficiency of drugs in vitro: Comparison of doxorubicin exposure in 3D and 2D culture matrices.

    PubMed

    Casey, A; Gargotti, M; Bonnier, F; Byrne, H J

    2016-06-01

    The interest in the use of 3D matrices for in vitro analysis, with a view to increasing the relevance of in vitro studies and reducing the dependence on in vivo studies, has been growing in recent years. Cells grown in a 3D in vitro matrix environment have been reported to exhibit significantly different properties to those in a conventional 2D culture environment. However, comparison of 2D and 3D cell culture models have recently been noted to result in differing responses of cytotoxic assays, without any associated change in viability. The effect was attributed to differing conversion rates and effective concentrations of the resazurin assay in 2D and 3D environments, rather than differences in cellular metabolism. In this study, the efficacy of a chemotherapeutic agent, doxorubicin, is monitored and compared in conventional 2D and 3D collagen gel exposures of immortalized human cervical cells. Viability was monitored with the aid of the Alamar Blue assay and drug internalisation was verified using confocal microscopy. Drug uptake and retention within the collagen matrix was monitored by absorption spectroscopy. The viability studies showed apparent differences between the 2D and 3D culture systems, the differences attributed in part to the physical transition from 2D to a 3D environment causing alterations to dye resazurin uptake and conversion rates. The use of 3D culture matrices has widely been interpreted to result in "reduced" toxicity or cellular "resistance" to the chemotherapeutic agent. The results of this study show that the reduced efficiency of the drug to cells grown in the 3D environment can be accounted for by a sequential reduction of the effective concentration of the test compound and assay. This is due to absorption within the collagen gel inducing a higher uptake of both drug and assay thereby influencing the toxic impact of the drug and conversion rate of resazurin, and. The increased effective surface area of the cell exposed to the drug

  5. Strategies for antimicrobial drug delivery to biofilm.

    PubMed

    Martin, Claire; Low, Wan Li; Gupta, Abhishek; Amin, Mohd Cairul Iqbal Mohd; Radecka, Iza; Britland, Stephen T; Raj, Prem; Kenward, Ken M A

    2015-01-01

    Biofilms are formed by the attachment of single or mixed microbial communities to a variety of biological and/or synthetic surfaces. Biofilm micro-organisms benefit from many advantages of the polymicrobial environment including increased resistance against antimicrobials and protection against the host organism's defence mechanisms. These benefits stem from a number of structural and physiological differences between planktonic and biofilm-resident microbes, but two main factors are the presence of extracellular polymeric substances (EPS) and quorum sensing communication. Once formed, biofilms begin to synthesise EPS, a complex viscous matrix composed of a variety of macromolecules including proteins, lipids and polysaccharides. In terms of drug delivery strategies, it is the EPS that presents the greatest barrier to diffusion for drug delivery systems and free antimicrobial agents alike. In addition to EPS synthesis, biofilm-based micro-organisms can also produce small, diffusible signalling molecules involved in cell density-dependent intercellular communication, or quorum sensing. Not only does quorum sensing allow microbes to detect critical cell density numbers, but it also permits co-ordinated behaviour within the biofilm, such as iron chelation and defensive antibiotic activities. Against this backdrop of microbial defence and cell density-specific communication, a variety of drug delivery systems have been developed to deliver antimicrobial agents and antibiotics to extracellular and/or intracellular targets, or more recently, to interfere with the specific mechanisms of quorum sensing. Successful delivery strategies have employed lipidic and polymeric-based formulations such as liposomes and cyclodextrins respectively, in addition to inorganic carriers e.g. metal nanoparticles. This review will examine a range of drug delivery systems and their application to biofilm delivery, as well as pharmaceutical formulations with innate antimicrobial properties

  6. The Interaction of the Chemotherapeutic Drug Chlorambucil with Human Glutathione Transferase A1-1: Kinetic and Structural Analysis

    PubMed Central

    Karpusas, Michael; Axarli, Irine; Chiniadis, Lykourgos; Papakyriakou, Athanasios; Bethanis, Kostas; Scopelitou, Katholiki; Clonis, Yannis D.; Labrou, Nikolaos E.

    2013-01-01

    Glutathione transferases (GSTs) are enzymes that contribute to cellular detoxification by catalysing the nucleophilic attack of glutathione (GSH) on the electrophilic centre of a number of xenobiotic compounds, including several chemotherapeutic drugs. In the present work we investigated the interaction of the chemotherapeutic drug chlorambucil (CBL) with human GSTA1-1 (hGSTA1-1) using kinetic analysis, protein crystallography and molecular dynamics. In the presence of GSH, CBL behaves as an efficient substrate for hGSTA1-1. The rate-limiting step of the catalytic reaction between CBL and GSH is viscosity-dependent and kinetic data suggest that product release is rate-limiting. The crystal structure of the hGSTA1-1/CBL-GSH complex was solved at 2.1 Å resolution by molecular replacement. CBL is bound at the H-site attached to the thiol group of GSH, is partially ordered and exposed to the solvent, making specific interactions with the enzyme. Molecular dynamics simulations based on the crystal structure indicated high mobility of the CBL moiety and stabilization of the C-terminal helix due to the presence of the adduct. In the absence of GSH, CBL is shown to be an alkylating irreversible inhibitor for hGSTA1-1. Inactivation of the enzyme by CBL followed a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of CBL per mol of dimeric enzyme being incorporated. Structural analysis suggested that the modifying residue is Cys112 which is located at the entrance of the H-site. The results are indicative of a structural communication between the subunits on the basis of mutually exclusive modification of Cys112, indicating that the two enzyme active sites are presumably coordinated. PMID:23460799

  7. Involvement of Akt and mTOR in chemotherapeutic and hormonal-based drug resistance and response to radiation in breast cancer cells

    PubMed Central

    Steelman, Linda S; Navolanic, Patrick; Chappell, William H; Abrams, Stephen L; Wong, Ellis WT; Martelli, Alberto M; Cocco, Lucio; Stivala, Franca; Libra, Massimo; Nicoletti, Ferdinando; Drobot, Lyudmyla B; Franklin, Richard A

    2011-01-01

    Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs and radiation is clearly important as these are common treatment approaches. Signaling cascades often involved in chemo-, hormonal- and radiation resistance are the Ras/PI3K/PTE N/Akt/mTO R, Ras/Raf/MEK/ERK and p53 pathways. In the following studies we have examined the effects of activation of the Ras/PI3K/PTE N/Akt/mTO R cascade in the response of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs and radiation. Activation of Akt by introduction of conditionally-activated Akt-1 gene could result in resistance to chemotherapeutic and hormonal based drugs as well as radiation. We have determined that chemotherapeutic drugs such as doxorubicin or the hormone based drug tamoxifen, both used to treat breast cancer, resulted in the activation of the Raf/MEK/ERK pathway which is often associated with a proproliferative, anti-apoptotic response. In drug sensitive MCF-7 cells which have wild-type p53; ERK, p53 and downstream p21Cip-1 were induced upon exposure to doxorubicin. In contrast, in the drug resistant cells which expressed activated Akt-1, much lower levels of p53 and p21Cip1 were induced upon exposure to doxorubicin. These results indicate the involvement of the Ras/PI3K/PTE N/Akt/mTO R, Ras/Raf/MEK/ERK and p53 pathways in the response to chemotherapeutic and hormonal based drugs. Understanding how breast cancers respond to chemo- and hormonal-based therapies and radiation may enhance the ability to treat breast cancer more effectively. PMID:21869603

  8. Nano carriers that enable co-delivery of chemotherapy and RNAi agents for treatment of drug-resistant cancers.

    PubMed

    Tsouris, Vasilios; Joo, Min Kyung; Kim, Sun Hwa; Kwon, Ick Chan; Won, You-Yeon

    2014-01-01

    Tumor cells exhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. The drug resistance has a genetic basis that is caused by an abnormal gene expression. There are several types of drug resistance: efflux pumps reducing the cellular concentration of the drug, alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolic alteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cycle checkpoints (Gottesman et al., 2002; Holohan et al., 2013). siRNA is used to silence the drug resistant phenotype and prevent this drug resistance response. Of the listed types of drug resistance, pump-type resistance (e.g., high expression of ATP-binding cassette transporter proteins such as P-glycoproteins (Pgp; also known as multi-drug resistance protein 1 or MDR1, encoded by the ATP-Binding Cassette Sub-Family B Member 1 (ABCB1) gene)) and apoptosis inhibition (e.g., expression of anti-apoptotic proteins such as Bcl-2) are the most frequently targeted for gene silencing. The co-delivery of siRNA and chemotherapeutic drugs has a synergistic effect, but many of the current projects do not control the drug release from the nanocarrier. This means that the drug payload is released before the drug resistance proteins have degraded and the drug resistance phenotype has been silenced. Current research focuses on cross-linking the carrier's polymers to prevent premature drug release, but these carriers still rely on environmental cues to release the drug payload, and the drug may be released too early. In this review, we studied the release kinetics of siRNA and chemotherapeutic drugs from a broad range of carriers. We also give examples of carriers used to co-deliver siRNA and drugs to drug-resistant tumor cells, and we examine how modifications to the carrier affect the delivery. Lastly, we give our recommendations for the future directions of the co-delivery of si

  9. Fluorescence optical imaging in anticancer drug delivery.

    PubMed

    Etrych, Tomáš; Lucas, Henrike; Janoušková, Olga; Chytil, Petr; Mueller, Thomas; Mäder, Karsten

    2016-03-28

    In the past several decades, nanosized drug delivery systems with various targeting functions and controlled drug release capabilities inside targeted tissues or cells have been intensively studied. Understanding their pharmacokinetic properties is crucial for the successful transition of this research into clinical practice. Among others, fluorescence imaging has become one of the most commonly used imaging tools in pre-clinical research. The development of increasing numbers of suitable fluorescent dyes excitable in the visible to near-infrared wavelengths of the spectrum has significantly expanded the applicability of fluorescence imaging. This paper focuses on the potential applications and limitations of non-invasive imaging techniques in the field of drug delivery, especially in anticancer therapy. Fluorescent imaging at both the cellular and systemic levels is discussed in detail. Additionally, we explore the possibility for simultaneous treatment and imaging using theranostics and combinations of different imaging techniques, e.g., fluorescence imaging with computed tomography. PMID:26892751

  10. Matrix metalloproteases: Underutilized targets for drug delivery

    PubMed Central

    Vartak, Deepali G.; Gemeinhart, Richard A.

    2013-01-01

    Pathophysiological molecules in the extracellular environment offer excellent targets that can be exploited for designing drug targeting systems. Matrix metalloproteases (MMPs) are a family of extracellular proteolytic enzymes that are characterized by their overexpression or overactivity in several pathologies. Over the last two decades, the MMP literature reveals heightened interest in the research involving MMP biology, pathology, and targeting. This review describes various strategies that have been designed to utilize MMPs for targeting therapeutic entities. Key factors that need to be considered in the successful design of such systems have been identified based on the analyses of these strategies. Development of targeted drug delivery using MMPs has been steadily pursued; however, drug delivery efforts using these targets need to be intensified and focused to realize the clinical application of the fast developing fundamental MMP research. PMID:17365270

  11. A Molecular Communications Model for Drug Delivery.

    PubMed

    Femminella, Mauro; Reali, Gianluca; Vasilakos, Athanasios V

    2015-12-01

    This paper considers the scenario of a targeted drug delivery system, which consists of deploying a number of biological nanomachines close to a biological target (e.g., a tumor), able to deliver drug molecules in the diseased area. Suitably located transmitters are designed to release a continuous flow of drug molecules in the surrounding environment, where they diffuse and reach the target. These molecules are received when they chemically react with compliant receptors deployed on the receiver surface. In these conditions, if the release rate is relatively high and the drug absorption time is significant, congestion may happen, essentially at the receiver site. This phenomenon limits the drug absorption rate and makes the signal transmission ineffective, with an undesired diffusion of drug molecules elsewhere in the body. The original contribution of this paper consists of a theoretical analysis of the causes of congestion in diffusion-based molecular communications. For this purpose, it is proposed a reception model consisting of a set of pure loss queuing systems. The proposed model exhibits an excellent agreement with the results of a simulation campaign made by using the Biological and Nano-Scale communication simulator version 2 (BiNS2), a well-known simulator for molecular communications, whose reliability has been assessed through in vitro experiments. The obtained results can be used in rate control algorithms to optimally determine the optimal release rate of molecules in drug delivery applications. PMID:26529770

  12. Ultrasound-Mediated Polymeric Micelle Drug Delivery.

    PubMed

    Xia, Hesheng; Zhao, Yue; Tong, Rui

    2016-01-01

    The synthesis of multi-functional nanocarriers and the design of new stimuli-responsive means are equally important for drug delivery. Ultrasound can be used as a remote, non-invasive and controllable trigger for the stimuli-responsive release of nanocarriers. Polymeric micelles are one kind of potential drug nanocarrier. By combining ultrasound and polymeric micelles, a new modality (i.e., ultrasound-mediated polymeric micelle drug delivery) has been developed and has recently received increasing attention. A major challenge remaining in developing ultrasound-responsive polymeric micelles is the improvement of the sensitivity or responsiveness of polymeric micelles to ultrasound. This chapter reviews the recent advance in this field. In order to understand the interaction mechanism between ultrasound stimulus and polymeric micelles, ultrasound effects, such as thermal effect, cavitation effect, ultrasound sonochemistry (including ultrasonic degradation, ultrasound-initiated polymerization, ultrasonic in-situ polymerization and ultrasound site-specific degradation), as well as basic micellar knowledge are introduced. Ultrasound-mediated polymeric micelle drug delivery has been classified into two main streams based on the different interaction mechanism between ultrasound and polymeric micelles; one is based on the ultrasound-induced physical disruption of the micelle and reversible release of payload. The other is based on micellar ultrasound mechanochemical disruption and irreversible release of payload. PMID:26486348

  13. Drug Delivery Nanoparticles in Skin Cancers

    PubMed Central

    Dianzani, Chiara; Zara, Gian Paolo; Maina, Giovanni; Pettazzoni, Piergiorgio; Pizzimenti, Stefania; Rossi, Federica; Gigliotti, Casimiro Luca; Ciamporcero, Eric Stefano; Daga, Martina; Barrera, Giuseppina

    2014-01-01

    Nanotechnology involves the engineering of functional systems at nanoscale, thus being attractive for disciplines ranging from materials science to biomedicine. One of the most active research areas of the nanotechnology is nanomedicine, which applies nanotechnology to highly specific medical interventions for prevention, diagnosis, and treatment of diseases, including cancer disease. Over the past two decades, the rapid developments in nanotechnology have allowed the incorporation of multiple therapeutic, sensing, and targeting agents into nanoparticles, for detection, prevention, and treatment of cancer diseases. Nanoparticles offer many advantages as drug carrier systems since they can improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase drug half-life by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. They can also enable a tunable release of therapeutic compounds and the simultaneous delivery of two or more drugs for combination therapy. In this review, we discuss the recent advances in the use of different types of nanoparticles for systemic and topical drug delivery in the treatment of skin cancer. In particular, the progress in the treatment with nanocarriers of basal cell carcinoma, squamous cell carcinoma, and melanoma has been reported. PMID:25101298

  14. A novel in vitro three-dimensional retinoblastoma model for evaluating chemotherapeutic drugs

    PubMed Central

    Mitra, Moutushy; Mohanty, Chandana; Harilal, Anju; Maheswari, Uma K.; Sahoo, Sanjeeb Kumar

    2012-01-01

    Purpose Novel strategies are being applied for creating better in vitro models that simulate in vivo conditions for testing the efficacy of anticancer drugs. In the present study we developed surface-engineered, large and porous, biodegradable, polymeric microparticles as a scaffold for three dimensional (3-D) growth of a Y79 retinoblastoma (RB) cell line. We evaluated the effect of three anticancer drugs in naïve and nanoparticle-loaded forms on a 3-D versus a two-dimensional (2-D) model. We also studied the influence of microparticles on extracellular matrix (ECM) synthesis and whole genome miRNA-gene expression profiling to identify 3D-responsive genes that are implicated in oncogenesis in RB cells. Methods Poly(D,L)-lactide-co-glycolide (PLGA) microparticles were prepared by the solvent evaporation method. RB cell line Y79 was grown alone or with PLGA–gelatin microparticles. Antiproliferative activity, drug diffusion, and cellular uptake were studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a yellow tetrazole (MTT) assay, fluorescent microscope, and flow cytometry. Extra cellular matrix (ECM) synthesis was observed by collagenase assay and whole genome miRNA-microarray profiling by using an Agilent chip. Results With optimized composition of microparticles and cell culture conditions, an eightfold increase from the seeding density was achieved in 5 days of culture. The antiproliferative effect of the drugs in the 3-D model was significantly lower than in the 2-D suspension, which was evident from the 4.5 to 21.8 fold differences in their IC50 values. Using doxorubicin, the flow cytometry data demonstrated a 4.4 fold lower drug accumulation in the cells grown in the 3-D model at 4 h. The collagen content of the cells grown in the 3-D model was 2.3 fold greater than that of the cells grown in the 2-D model, suggesting greater synthesis of the extracellular matrix in the 3-D model as the extracellular matrix acted as a barrier to drug

  15. Intracarotid Delivery of Drugs: The Potential and the Pitfalls

    PubMed Central

    Joshi, Shailendra; Meyers, Phillip M.; Ornstein, Eugene

    2014-01-01

    The major efforts to selectively deliver drugs to the brain in the last decade have relied on smart molecular techniques to penetrate the blood brain barrier while intraarterial drug delivery has drawn relatively little attention. In the last decade there have been rapid advances in endovascular techniques. Modern endovascular procedures can permit highly targeted drug delivery by intracarotid route. Intracarotid drug delivery can be the primary route of drug delivery or it could be used to facilitate the delivery of smart-neuropharmaceuticals. There have been few attempts to systematically understand the kinetics of intracarotid drugs. Anecdotal data suggests that intracarotid drug delivery is effective in the treatment of cerebral vasospasm, thromboembolic strokes, and neoplasms. Neuroanesthesiologists are frequently involved in the care of such high-risk patients. Therefore, it is necessary to understand the applications of intracarotid drug delivery and the unusual kinetics of intracarotid drugs. PMID:18719453

  16. Methionine depletion with recombinant methioninase: In vitro and in vivo efficacy against neuroblastoma and its synergism with chemotherapeutic drugs

    PubMed Central

    Hu, Jian; Cheung, Nai-Kong V.

    2009-01-01

    Methionine starvation can modulate gene methylation, cell cycle transition, and pathways related to survival following DNA damage. Methionine depletion by recombinant methioninase (rMETase) may have in vitro and in vivo efficacy against neuroblastoma (NB), especially when combined with chemotherapeutic drugs. rMETase from Pseudomonas Putida was produced in E. Coli and purified by ion-exchange chromatography. rMETase alone inhibited the proliferation of 15/15 NB cell lines in vitro. Among these 15 cell lines, only 66N demonstrated rMETase-induced apoptosis. rMETase alone suppressed LAN-1 and NMB-7 xenografts (p<0.01) and no toxicities were noted other than reversible weight loss. In vitro efficacy experiments combining rMETase and chemotherapeutic agents were carried out using SK-N-LD and SK-N-BE(1)N established at diagnosis, as well as LAN-1, SK-N-BE(2)C, and NMB-7 established at relapse. Microtubule depolymerization agents including vincristine, vinorelbine, vinblatine, and mebendazole showed synergism when tested in combination with rMETase in all 5 cell lines. Among DNA damaging agents, synergy with rMETase was observed only in cell lines established at diagnosis, and not at relapse. Cell cycle analysis showed that rMETase arrested G2 phase, and not M phase. In vivo efficacy experiments using LAN-1 and NMB-7 xenografts showed that rMETase rendered vincristine more effective than vincristine alone in tumor growth suppression (p<0.001). In conclusion, methionine depletion inhibited NB proliferation and arrested tumor cells at G2 phase. rMETase synergized with microtubule depolymerization agents. Moreover, synergism between rMETase and DNA damaging agents was dependent on whether cell lines were established at diagnosis or at relapse. PMID:19089915

  17. Drug delivery to the lymphatic system: importance in future cancer diagnosis and therapies

    PubMed Central

    Xie, Yumei; Bagby, Taryn R; Cohen, MS

    2011-01-01

    Cancer is the second leading cause of death in the US. Currently, protocols for cancer treatment include surgery to remove diseased and suspect tissues, focused radiation, systemic chemotherapy, immunotherapy and their combinations. With conventional chemotherapy, it is almost impossible to deliver anticancer drugs specifically to the tumor cells without damaging healthy organs or tissues. Over the past several decades, efforts have been made to improve drug delivery technologies that target anticancer drugs specifically to tumor cells. It has been known for over four decades that the lymphatics are the first site of metastasis for most solid cancers; however, few efforts have been made to localize chemotherapies to lymphatic tissues. Trials of several systemic targeted drug delivery systems based on nanoparticles containing chemotherapeutic agents (e.g., liposomal doxorubicin) have shown similar antitumor activity but better patient tolerance compared with conventional formulations. Animal studies have demonstrated that nanoparticles made of natural or synthetic polymers and liposomal carriers have higher accumulation in the lymph nodes and surrounding lymphatics compared to conventional intravenous therapies. This combination has the potential to both reduce nonspecific organ toxicities and increase the chemotherapeutic dose to the most likely sites of locoregional cancer metastasis. PMID:19563270

  18. Zwitterionic drug nanocarriers: a biomimetic strategy for drug delivery.

    PubMed

    Jin, Qiao; Chen, Yangjun; Wang, Yin; Ji, Jian

    2014-12-01

    Nanomaterials self-assembled from amphiphilic functional copolymers have emerged as safe and efficient nanocarriers for delivery of therapeutics. Surface engineering of the nanocarriers is extremely important for the design of drug delivery systems. Bioinspired zwitterions are considered as novel nonfouling materials to construct biocompatible and bioinert nanocarriers. As an alternative to poly(ethylene glycol) (PEG), zwitterions exhibit some unique properties that PEG do not have. In this review, we highlight recent progress of the design of drug nanocarriers using a zwitterionic strategy. The possible mechanism of stealth properties of zwitterions was proposed. The advantages of zwitterionic drug nanocarriers deriving from phosphorylcholine (PC), carboxybetaine (CB), and sulfobetaine (SB) are also discussed. PMID:25092584

  19. Inhalation drug delivery devices: technology update

    PubMed Central

    Ibrahim, Mariam; Verma, Rahul; Garcia-Contreras, Lucila

    2015-01-01

    The pulmonary route of administration has proven to be effective in local and systemic delivery of miscellaneous drugs and biopharmaceuticals to treat pulmonary and non-pulmonary diseases. A successful pulmonary administration requires a harmonic interaction between the drug formulation, the inhaler device, and the patient. However, the biggest single problem that accounts for the lack of desired effect or adverse outcomes is the incorrect use of the device due to lack of training in how to use the device or how to coordinate actuation and aerosol inhalation. This review summarizes the structural and mechanical features of aerosol delivery devices with respect to mechanisms of aerosol generation, their use with different formulations, and their advantages and limitations. A technological update of the current state-of-the-art designs proposed to overcome current challenges of existing devices is also provided. PMID:25709510

  20. Polysaccharide-Based Micelles for Drug Delivery

    PubMed Central

    Zhang, Nan; Wardwell, Patricia R.; Bader, Rebecca A.

    2013-01-01

    Delivery of hydrophobic molecules and proteins has been an issue due to poor bioavailability following administration. Thus, micelle carrier systems are being investigated to improve drug solubility and stability. Due to problems with toxicity and immunogenicity, natural polysaccharides are being explored as substitutes for synthetic polymers in the development of new micelle systems. By grafting hydrophobic moieties to the polysaccharide backbone, self-assembled micelles can be readily formed in aqueous solution. Many polysaccharides also possess inherent bioactivity that can facilitate mucoadhesion, enhanced targeting of specific tissues, and a reduction in the inflammatory response. Furthermore, the hydrophilic nature of some polysaccharides can be exploited to enhance circulatory stability. This review will highlight the advantages of polysaccharide use in the development of drug delivery systems and will provide an overview of the polysaccharide-based micelles that have been developed to date. PMID:24300453

  1. Caged Protein Nanoparticles for Drug Delivery

    PubMed Central

    Molino, Nicholas M.; Wang, Szu-Wen

    2014-01-01

    Caged protein nanoparticles possess many desirable features for drug delivery, such as ideal sizes for endocytosis, non-toxic biodegradability, and the ability to functionalize at three distinct interfaces (external, internal, and inter-subunit) using the tools of protein engineering. Researchers have harnessed these attributes by covalently and non-covalently loading therapeutic molecules through mechanisms that facilitate release within specific microenvironments. Effective delivery depends on several factors, including specific targeting, cell uptake, release kinetics, and systemic clearance. The innate ability of the immune system to recognize and respond to proteins has recently been exploited to deliver therapeutic compounds with these platforms for immunomodulation. The diversity of drugs, loading/release mechanisms, therapeutic targets, and therapeutic efficacy are discussed in this review. PMID:24832078

  2. Nanotechnology Approaches for Ocular Drug Delivery

    PubMed Central

    Xu, Qingguo; Kambhampati, Siva P.; Kannan, Rangaramanujam M.

    2013-01-01

    Blindness is a major health concern worldwide that has a powerful impact on afflicted individuals and their families, and is associated with enormous socio-economical consequences. The Middle East is heavily impacted by blindness, and the problem there is augmented by an increasing incidence of diabetes in the population. An appropriate drug/gene delivery system that can sustain and deliver therapeutics to the target tissues and cells is a key need for ocular therapies. The application of nanotechnology in medicine is undergoing rapid progress, and the recent developments in nanomedicine-based therapeutic approaches may bring significant benefits to address the leading causes of blindness associated with cataract, glaucoma, diabetic retinopathy and retinal degeneration. In this brief review, we highlight some promising nanomedicine-based therapeutic approaches for drug and gene delivery to the anterior and posterior segments. PMID:23580849

  3. Diatomite silica nanoparticles for drug delivery

    NASA Astrophysics Data System (ADS)

    Ruggiero, Immacolata; Terracciano, Monica; Martucci, Nicola M.; De Stefano, Luca; Migliaccio, Nunzia; Tatè, Rosarita; Rendina, Ivo; Arcari, Paolo; Lamberti, Annalisa; Rea, Ilaria

    2014-07-01

    Diatomite is a natural fossil material of sedimentary origin, constituted by fragments of diatom siliceous skeletons. In this preliminary work, the properties of diatomite nanoparticles as potential system for the delivery of drugs in cancer cells were exploited. A purification procedure, based on thermal treatments in strong acid solutions, was used to remove inorganic and organic impurities from diatomite and to make them a safe material for medical applications. The micrometric diatomite powder was reduced in nanoparticles by mechanical crushing, sonication, and filtering. Morphological analysis performed by dynamic light scattering and transmission electron microscopy reveals a particles size included between 100 and 300 nm. Diatomite nanoparticles were functionalized by 3-aminopropyltriethoxysilane and labeled by tetramethylrhodamine isothiocyanate. Different concentrations of chemically modified nanoparticles were incubated with cancer cells and confocal microscopy was performed. Imaging analysis showed an efficient cellular uptake and homogeneous distribution of nanoparticles in cytoplasm and nucleus, thus suggesting their potentiality as nanocarriers for drug delivery.

  4. Microneedle Coating Techniques for Transdermal Drug Delivery

    PubMed Central

    Haj-Ahmad, Rita; Khan, Hashim; Arshad, Muhammad Sohail; Rasekh, Manoochehr; Hussain, Amjad; Walsh, Susannah; Li, Xiang; Chang, Ming-Wei; Ahmad, Zeeshan

    2015-01-01

    Drug administration via the transdermal route is an evolving field that provides an alternative to oral and parenteral routes of therapy. Several microneedle (MN) based approaches have been developed. Among these, coated MNs (typically where drug is deposited on MN tips) are a minimally invasive method to deliver drugs and vaccines through the skin. In this review, we describe several processes to coat MNs. These include dip coating, gas jet drying, spray coating, electrohydrodynamic atomisation (EHDA) based processes and piezoelectric inkjet printing. Examples of process mechanisms, conditions and tested formulations are provided. As these processes are independent techniques, modifications to facilitate MN coatings are elucidated. In summary, the outcomes and potential value for each technique provides opportunities to overcome formulation or dosage form limitations. While there are significant developments in solid degradable MNs, coated MNs (through the various techniques described) have potential to be utilized in personalized drug delivery via controlled deposition onto MN templates. PMID:26556364

  5. Microneedle Coating Techniques for Transdermal Drug Delivery.

    PubMed

    Haj-Ahmad, Rita; Khan, Hashim; Arshad, Muhammad Sohail; Rasekh, Manoochehr; Hussain, Amjad; Walsh, Susannah; Li, Xiang; Chang, Ming-Wei; Ahmad, Zeeshan

    2015-01-01

    Drug administration via the transdermal route is an evolving field that provides an alternative to oral and parenteral routes of therapy. Several microneedle (MN) based approaches have been developed. Among these, coated MNs (typically where drug is deposited on MN tips) are a minimally invasive method to deliver drugs and vaccines through the skin. In this review, we describe several processes to coat MNs. These include dip coating, gas jet drying, spray coating, electrohydrodynamic atomisation (EHDA) based processes and piezoelectric inkjet printing. Examples of process mechanisms, conditions and tested formulations are provided. As these processes are independent techniques, modifications to facilitate MN coatings are elucidated. In summary, the outcomes and potential value for each technique provides opportunities to overcome formulation or dosage form limitations. While there are significant developments in solid degradable MNs, coated MNs (through the various techniques described) have potential to be utilized in personalized drug delivery via controlled deposition onto MN templates. PMID:26556364

  6. Intratumoral Drug Delivery with Nanoparticulate Carriers

    PubMed Central

    Holback, Hillary

    2011-01-01

    Stiff extracellular matrix, elevated interstitial fluid pressure, and the affinity for the tumor cells in the peripheral region of a solid tumor mass have long been recognized as significant barriers to diffusion of small-molecular-weight drugs and antibodies. However, their impacts on nanoparticle-based drug delivery have begun to receive due attention only recently. This article reviews biological features of many solid tumors that influence transport of drugs and nanoparticles and properties of nanoparticles relevant to their intratumoral transport, studied in various tumor models. We also discuss several experimental approaches employed to date for enhancement of intratumoral nanoparticle penetration. The impact of nanoparticle distribution on the effectiveness of chemotherapy remains to be investigated and should be considered in the design of new nanoparticulate drug carriers. PMID:21213021

  7. Injected nanocrystals for targeted drug delivery

    PubMed Central

    Lu, Yi; Li, Ye; Wu, Wei

    2016-01-01

    Nanocrystals are pure drug crystals with sizes in the nanometer range. Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs. Nanocrystals in the blood stream can be recognized and sequestered as exogenous materials by mononuclear phagocytic system (MPS) cells, leading to passive accumulation in MPS-rich organs, such as liver, spleen and lung. Particle size, morphology and surface modification affect the biodistribution of nanocrystals. Ligand conjugation and stimuli-responsive polymers can also be used to target nanocrystals to specific pathogenic sites. In this review, the progress on injected nanocrystals for targeted drug delivery is discussed following a brief introduction to nanocrystal preparation methods, i.e., top-down and bottom-up technologies. PMID:27006893

  8. Nanogel Carrier Design for Targeted Drug Delivery

    PubMed Central

    Eckmann, D. M.; Composto, R. J.; Tsourkas, A.; Muzykantov, V. R.

    2014-01-01

    Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanogel drug carrier design. In particular, we highlight published studies of nanogel design, descriptions of nanogel functional characteristics and their behavior in biological models. These studies form a compendium of information that supports the scientific and clinical rationale for development of this carrier for targeted therapeutic interventions. PMID:25485112

  9. Advanced drug delivery approaches against periodontitis.

    PubMed

    Joshi, Deeksha; Garg, Tarun; Goyal, Amit K; Rath, Goutam

    2016-01-01

    Periodontitis is an inflammatory disease of gums involving the degeneration of periodontal ligaments, creation of periodontal pocket and resorption of alveolar bone, resulting in the disruption of the support structure of teeth. According to WHO, 10-15% of the global population suffers from severe periodontitis. The disease results from the growth of a diverse microflora (especially anaerobes) in the pockets and release of toxins, enzymes and stimulation of body's immune response. Various local or systemic approaches were used for an effective treatment of periodontitis. Currently, controlled local drug delivery approach is more favorable as compared to systemic approach because it mainly focuses on improving the therapeutic outcomes by achieving factors like site-specific delivery, low dose requirement, bypass of first-pass metabolism, reduction in gastrointestinal side effects and decrease in dosing frequency. Overall it provides a safe and effective mode of treatment, which enhances patient compliance. Complete eradication of the organisms from the sites was not achieved by using various surgical and mechanical treatments. So a number of polymer-based delivery systems like fibers, films, chips, strips, microparticles, nanoparticles and nanofibers made from a variety of natural and synthetic materials have been successfully tested to deliver a variety of drugs. These systems are biocompatible and biodegradable, completely fill the pockets, and have strong retention on the target site due to excellent mucoadhesion properties. The review summarizes various available and recently developing targeted delivery devices for the treatment of periodontitis. PMID:25005586

  10. Stemness and chemotherapeutic drug resistance induced by EIF5A2 overexpression in esophageal squamous cell carcinoma

    PubMed Central

    Yang, Hong; Li, Xiao-dong; Zhou, Ying; Ban, Xiaojiao; Zeng, Ting-ting; Li, Lei; Zhang, Bao-zhu; Yun, Jingping; Xie, Dan; Guan, Xin-Yuan; Li, Yan

    2015-01-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies of the digestive tract in East Asian countries. Multimodal therapies, including adjuvant chemotherapy and neo-adjuvant chemotherapy, have become more often used for patients with advanced ESCC. However, the chemotherapy effect is often limited by patients' drug resistance. This study demonstrated that EIF5A2 (eukaryotic translation initiation factor 5A2) overexpression induced stemness and chemoresistance in ESCC cells. We showed that EIF5A2 overexpression in ESCC cells resulted in increased chemoresistance to 5-fluorouracil (5-FU), docetaxel and taxol. In contrast, shRNAs suppressing eIF5A2 increased tumor sensitivity to these chemotherapeutic drugs. In addition, EIF5A2 overexpression was correlated with a poorer overall survival in patients with ESCC who underwent taxane-based chemotherapy after esophagectomy (P < 0.05). Based on these results, we suggest that EIF5A2 could be a predictive biomarker for selecting appropriate chemo-treatment for ESCC patients and EIF5A2 inhibitors might be considered as combination therapy to enhance chemosensitivity in patients with ESCC. PMID:26317793