title: Structure-directing star-shaped block copolymers: supramolecular vesicles for the delivery of anticancer drugs.
abstract: Amphiphilic polycarbonate/PEG copolymer with a star-like architecture was designed to facilitate a unique supramolecular transformation of micelles to vesicles in aqueous solution for the efficient delivery of anticancer drugs. The star-shaped amphipilic block copolymer was synthesized by initiating the ring-opening polymerization of trimethylene carbonate (TMC) from methyl cholate through a combination of metal-free organo-catalytic living ring-opening polymerization and post-polymerization chain-end derivatization strategies. Subsequently, the self-assembly of the star-like polymer in aqueous solution into nanosized vesicles for anti-cancer drug delivery was studied. DOX was physically encapsulated into vesicles by dialysis and drug loading level was significant (22.5% in weight) for DOX. Importantly, DOX-loaded nanoparticles self-assembled from the star-like copolymer exhibited greater kinetic stability and higher DOX loading capacity than micelles prepared from cholesterol-initiated diblock analogue. The advantageous disparity is believed to be due to the transformation of micelles (diblock copolymer) to vesicles (star-like block copolymer) that possess greater core space for drug loading as well as the ability of such supramolecular structures to encapsulate DOX. DOX-loaded vesicles effectively inhibited the proliferation of 4T1, MDA-MB-231 and BT-474 cells, with IC50 values of 10, 1.5 and 1.0mg/L, respectively. DOX-loaded vesicles injected into 4T1 tumor-bearing mice exhibited enhanced accumulation in tumor tissue due to the enhanced permeation and retention (EPR) effect. Importantly, DOX-loaded vesicles demonstrated greater tumor growth inhibition than free DOX without causing significant body weight loss or cardiotoxicity. The unique ability of the star-like copolymer emanating from the methyl cholate core provided the requisite modification in the block copolymer interfacial curvature to generate vesicles of high loading capacity for DOX with significant kinetic stability that have potential for use as an anti-cancer drug delivery carrier for cancer therapy.
authors: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669, Singapore.
authors: Chuan
authors: C
authors: Yang
authors: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669, Singapore.
authors: Shao Qiong
authors: SQ
authors: Liu
authors: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669, Singapore.
authors: Shrinivas
authors: S
authors: Venkataraman
authors: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669, Singapore.
authors: Shu Jun
authors: SJ
authors: Gao
authors: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669, Singapore.
authors: Xiyu
authors: X
authors: Ke
authors: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669, Singapore.
authors: Xin Tian
authors: XT
authors: Chia
authors: IBM Almaden Research Center, 650 Harry Road, San Jose, CA 95120, USA.
authors: James L
authors: JL
authors: Hedrick
authors: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669, Singapore. Electronic address: yyyang@ibn.a-star.edu.sg.
authors: Yi Yan
authors: YY
authors: Yang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D020355:Cholates / Q000737:chemistry; D003692:Delayed-Action Preparations; D004146:Dioxanes; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D053758:Nanoparticles; D011076:Polycarboxylate Cement; D011092:Polyethylene Glycols; D058105:Polymerization; D011108:Polymers / Q000737:chemistry*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D020355:Cholates; D003692:Delayed-Action Preparations; D004146:Dioxanes; D011076:Polycarboxylate Cement; D011108:Polymers; C005506:polycarbonate; D011092:Polyethylene Glycols; C443643:trimethylene carbonate; D004317:Doxorubicin; C037034:methyl cholate
keywords: Anti-tumor activity; Biodistribution; Doxorubicin; Star-like polycarbonate; Vesicles