Dual Stimuli-Responsive Hybrid Polymeric Nanoparticles Self-Assembled from POSS-Based Starlike Copolymer-Drug Conjugates for Efficient Intracellular Delivery of Hydrophobic Drugs

To farther 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) methactylamide (HPMA) copolymers to a FOSS 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 FOSS 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.