Liposome-based approaches to overcome anticancer drug resistance.
ABSTRACT Drug resistance remains an important obstacle towards better outcomes in the treatment of cancer. One general approach to overcome this problem has been to inhibit specific resistance mechanisms, such as P-glycoprotein (PGP)-mediated drug efflux, using small molecule agents or other therapeutic strategies. Alternatively, drug delivery approaches using liposomes or other carriers can in principle target drugs to tumor tissue, tumor cells, or even compartments within tumor cells. By increasing bioavailability of drugs at sites of action, these approaches may provide therapeutic advantages, including enhanced efficacy against resistant tumors. Current liposomal anthracyclines have achieved clinical use in cancer treatment by providing efficient encapsulation of drug in stable and non-reactive carriers, and there is evidence indicating potential benefit in some clinical settings involving resistant tumors. Other liposome-based strategies include constructs designed to be taken up by tumor cells, as well as further modifications to allow triggered drug release. These approaches seek to overcome drug resistance by more efficient delivery to tumor cells, and in some cases by concomitant avoidance or inhibition of drug efflux mechanisms. Newer agents employ molecular targeting, such as immunoliposomes using antibody-directed binding and internalization. These agents selectively deliver drug to tumor cells, can efficiently internalize for intracellular drug release, and can potentially enhance both efficacy and safety.
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ABSTRACT: Conjugation of anti-neoplastic agents with human proteins is a strategy to diminish the toxic side effects of anthracycline antibiotics. We have developed a novel doxorubicin-transferrin (DOX-TRF) conjugate aimed to direct anticancer drugs against therapeutic targets that display altered levels of expression in malignant versus normal cells. Our previous work has shown that the cellular bio-distribution of the conjugate is dependent on a dynamic balance between influx and efflux processes. Here, we set out to investigate whether P-glycoprotein (P-gp) expression may affect DOX-TRF conjugate-induced cellular drug accumulation and cytotoxicity. All experiments were carried out on human erythromyeloblastoid cells exhibiting P-gp over-expression (K562/DOX) and its drug sensitive parental line (K562). MTT cytotoxicity, flow cytometry, fluorescence microscopy and RT-PCR assessments revealed that the investigated conjugate (DOX-TRF) possesses a greater cytotoxic potential than free DOX. Our data suggest that the newly developed DOX-TRF conjugate is a less P-gp dependent substrate than free DOX and, consequently, may be used in a clinical setting to increase treatment efficacy in resistant human tumors.Cellular Oncology 11/2014; · 2.12 Impact Factor
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ABSTRACT: The purpose of this study was to investigate the effect of liposome composition, which affects the nature of vesicular membrane on the cytotoxic efficacy of bleomycin. Formulation A comprised phosphatidylcholine (PC), cholesterol (CH), and dicetylphosphate (DCP). Formulation B employed PC, CH with dioleoylphosphatidylethanolamine (DOPE) as the fusogenic component. Formulation C consisted of rigid liposomes comprising dipalmitoylphosphatidylcholine (DPPC), CH, and DCP. Preparation D contained dioleoylphosphatidylcholine (DOPC), CH, and DCP. Formulation E employed the same components of B, with PC being replaced with Pegylated PC. The cytotoxic efficacy was monitored using the Daudi cell line obtained from Burkitt's lymphoma. Formulations A and B significantly increased the cell death via necrosis compared with drug solution. Formulation D produced marginal increase in the efficacy of bleomycin with the rigid vesicles being similar to the control. Pegylated liposomes (E) were as effective as A and B, but the cytotoxic effect was via apoptosis. In conclusion, the efficacy of liposomes depended on the composition with fusogenic, flexible, or Pegylated vesicles being superior. Drug Dev Res 72: 265–273, 2011. © 2010 Wiley-Liss, Inc.Drug Development Research 05/2011; 72(3). · 0.87 Impact Factor
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ABSTRACT: The field of cancer nanomedicine is considered a promising area for improved delivery of bioactive molecules including drugs, pharmaceutical agents and nucleic acids. Among these, drug delivery technology has made discernible progress in recent years and the areas that warrant further focus and consideration towards technological developments have also been recognized. Development of viable methods for on-demand spatial and temporal release of entrapped drugs from the nanocarriers is an arena that is likely to enhance the clinical suitability of drug-loaded nanocarriers. One such approach, which utilizes light as the external stimulus to disrupt and/or destabilize drug-loaded nanoparticles, will be the discussion platform of this article. Although several phototriggerable nanocarriers are currently under development, I will limit this review to the phototriggerable liposomes that have demonstrated promise in the cell culture systems at least (but not the last). The topics covered in this review include (i) a brief summary of various phototriggerable nanocarriers; (ii) an overview of the application of liposomes to deliver payload of photosensitizers and associated technologies; (iii) the design considerations of photoactivable lipid molecules and the chemical considerations and mechanisms of phototriggering of liposomal lipids; (iv) limitations and future directions for in vivo, clinically viable triggered drug delivery approaches and potential novel photoactivation strategies will be discussed.Pharmaceutics 03/2013; 6(1):1-25.