ABSTRACT
The chemotherapeutic Parthenolide is an exciting new candidate for the treatment of acute lymphoblastic leukemia, but like many other small-molecule drugs, it has low aqueous solubility. As a consequence, Parthenolide can only be administered clinically in the presence of harmful cosolvents. Accordingly, we describe the synthesis, characterization, and testing of a range of biocompatible triblock copolymer micelles as particle-based delivery vectors for the hydrophobic drug Parthenolide. The drug-loaded particles are produced via an emulsion-to-micelle transition method, and the effects of introducing anionic and cationic surface charges on stability, drug sequestration, biocompatibility, and efficacy are investigated. Significantly, we demonstrate high levels of efficacy in the organic solvent-free systems against human mesenchymal stem cells and primary T-acute lymphoblastic leukemia patient cells, highlighting the effectiveness of the delivery vectors for the treatment of acute lymphoblastic leukemia.
Subject(s)
Drug Carriers/chemistry , Polymers/chemistry , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Biocompatible Materials/chemistry , Cells, Cultured , Drug Stability , Emulsions/chemistry , Humans , Mesenchymal Stem Cells/drug effects , Micelles , Solubility , Solvents/chemistryABSTRACT
Low intracellular delivery efficiency and multidrug resistance are among major barriers to effective cancer therapy. Herein, we report a novel, virus-mimicking, endosomolytic liposomal drug-delivery platform to address these two key challenges. The pH-responsive, comb-like pseudopeptides were prepared by grafting relatively long alkyl side chains onto a polyamide, poly(L-lysine isophthalamide), to mimic fusogenic peptides in viral spikes. The cholesterol-containing liposome, which mimics the viral envelope, was readily coated with these pseudopeptides due to their hydrophobic side chains acting as membrane anchors. These endosomolytic pseudopeptides displayed high adsorption onto the liposomal membrane and enabled the significantly higher cellular uptake. The virus-mimicking system showed a pH-triggered content-release profile which could be manipulated by varying the structure and concentration of the adsorbed polymers. The endosomolytic ability of the multifunctional liposome and its use for efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) were demonstrated. The virus-mimicking liposomal system with DOX encapsulation exhibited considerably higher potency against HeLa cervical cancer cells, A549 lung cancer cells, MES-SA uterus cancer cells, and MES-SA/DX5 multidrug-resistant cancer cells than DOX-loaded bare liposomes and free DOX. These results suggest its potential applications for enhanced cytoplasmic delivery and cancer treatment.