title: ROP and ATRP Fabricated Dual Targeted Redox Sensitive Polymersomes Based on pPEGMA-PCL-ss-PCL-pPEGMA Triblock Copolymers for Breast Cancer Therapeutics.
abstract: To minimize cardiotoxicity and to increase the bioavailability of doxorubicin, polymersomes based on redox sensitive amphiphilic triblock copolymer poly(polyethylene glycol methacrylate)-poly(caprolactone)-s-s-poly(caprolactone)-poly(polyethylene glycol methacrylate) (pPEGMA-PCL-ss-PCL-pPEGMA) with disulfide linkage were designed and developed. The polymers were synthesized by ring opening polymerization (ROP) of ε-caprolactone followed by atom transfer radical polymerization (ATRP) of PEGMA. The triblock copolymers demonstrated various types of nanoparticle morphologies by varying hydrophobic/hydrophilic content of polymer blocks, with PEGMA content of ∼18% in the triblock copolymer leading to the formation of polymersomes in the size range ∼150 nm. High doxorubicin loading content of ∼21% was achieved in the polymersomes. Disulfide linkages were incorporated in the polymeric backbone to facilitate degradation of the nanoparticles by the intracellular tripeptide glutathione (GSH), leading to intracellular drug release. Release studies showed ∼59% drug release in pH 5.5 in the presence of 10 mM GSH, whereas only ∼19% was released in pH 7.4. In cellular uptake studies, dual targeted polymersomes showed ∼22-fold increase in cellular uptake efficiency in breast cancer cell lines (BT474 and MCF-7) as compared to nontargeted polymersomes with higher apoptosis rates. In vivo studies on Ehrlich's ascites tumor (EAT) bearing Swiss albino mouse model showed ∼85% tumor regression as compared to free doxorubicin (∼42%) without any significant cardiotoxicity associated with doxorubicin. The results indicate enhanced antitumor efficacy of the redox sensitive biocompatible nanosystem and shows promise as a potential drug nanocarrier in cancer therapeutics.
authors.affiliation: §Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Kumar
authors.affiliation: §Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India.
authors.forename: Shantanu V
authors.initials: SV
authors.lastname: Lale
authors.affiliation: §Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India.
authors.forename: Shveta
authors.initials: S
authors.lastname: Mahajan
authors.forename: Veena
authors.initials: V
authors.lastname: Choudhary
authors.affiliation: §Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India.
authors.forename: Veena
authors.initials: V
authors.lastname: Koul
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004058:Diffusion; D005492:Folic Acid / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D053761:Nanocomposites / Q000737:chemistry* / Q000648:ultrastructure; D010084:Oxidation-Reduction; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011109:Polymethacrylic Acids; D000068878:Trastuzumab / Q000008:administration & dosage / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D008689:Methacrylates; D053769:Nanocapsules; D011091:Polyesters; D011109:Polymethacrylic Acids; C528061:poly(poly(ethylene glycol)methacrylate); C016240:polycaprolactone; D011092:Polyethylene Glycols; D005492:Folic Acid; D000068878:Trastuzumab
keywords: Ehrlich’s ascites tumor; cellular uptake; folate; redox sensitive polymersomes; trastuzumab