title: Dual Stimuli-Responsive Hybrid Polymeric Nanoparticles Self-Assembled from POSS-Based Starlike Copolymer-Drug Conjugates for Efficient Intracellular Delivery of Hydrophobic Drugs.
abstract: To further fine tune drug release and enhance therapeutic effects of polyhedral oligomericsilsesquioxane (POSS)-based nanomedicine, a starlike organic-inorganic conjugate was synthesized by grafting semitelechelic N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers to a POSS rigid core through reductively degradable disulfide bonds. The hydrophobic docetaxel (DTX) was attached to the grafts by pH-sensitive hydrazone bonds and also encapsulated into the POSS core (SP-DTX). Thus, the final amphiphilic star-shaped conjugates could self-assemble into nanoparticles and exhibited conspicuous drug-loading capacity (20.1 wt %) based on the covalently conjugated accompanied by physically encapsulated DTX. The stimuli-responsive DTX release under acidic lysosomal and reducing cytoplasmic environments was verified, leading to enhanced cytotoxicity against PC-3 human prostate carcinoma cells. To evaluate the in vivo therapeutic effects of the DTX-loaded nanovehicles objectively, a stroma-rich, prostate xenograft tumor model was generated. SP-DTX displayed uniform tumor distribution and suppressed tumor growth to a more pronounced level (tumor inhibition of 78.9%) than nonredox-sensitive SP-DTX-A (67.4%), SP-DTX-C contained DTX only in the core (65.5%) or linear P-DTX (60.7%) through enhanced depletion of cancer-associated fibroblasts and induction of apoptosis. The hybrid POSS-based polymeric nanoparticles offer an efficient approach to transport hydrophobic drugs for cancer therapy.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University . No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P.R. China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University . No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P.R. China.
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University . No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University . No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P.R. China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University . No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011108:Polymers; D043823:Taxoids
keywords: high drug loading; hybrid nanoparticles; pH-responsive; redox-responsive; stroma-rich tumor