Bioreducible Shell-Cross-Linked Hyaluronic Acid Nanoparticles for Tumor-Targeted Drug Delivery Hwa Seung Han Thavasyappan Thambi Ki Young Choi Soyoung Son Hyewon Ko Min Chang Lee Dong-Gyu Jo Yee Soo Chae Young Mo Kang Jun Young Lee Jae Hyung Park 10.1021/bm5017755.s001 https://acs.figshare.com/articles/journal_contribution/Bioreducible_Shell_Cross_Linked_Hyaluronic_Acid_Nanoparticles_for_Tumor_Targeted_Drug_Delivery/2198476 The major issues of self-assembled nanoparticles as drug carriers for cancer therapy include biostability and tumor-targetability because the premature drug release from and nonspecific accumulation of the drug-loaded nanoparticles may cause undesirable toxicity to normal organs and lower therapeutic efficacy. In this study, we developed robust and tumor-targeted nanocarriers based on an amphiphilic hyaluronic acid (HA)-polycaprolactone (PCL) block copolymer, in which the HA shell was cross-linked via a bioreducible disulfide linkage. Doxorubicin (DOX), chosen as a model anticancer drug, was effectively encapsulated into the nanoparticles with high drug loading efficiency. The DOX-loaded bioreducible HA nanoparticles (DOX-HA-ss-NPs) greatly retarded the drug release under physiological conditions (pH 7.4), whereas the drug release rate was markedly enhanced in the presence of glutathione, a thiol-containing tripeptide capable of reducing disulfide bonds in the cytoplasm. Furthermore, DOX-HA-ss-NPs could effectively deliver the DOX into the nuclei of SCC7 cells in vitro as well as to tumors in vivo after systemic administration into SCC7 tumor-bearing mice, resulting in improved antitumor efficacy in tumor-bearing mice. Overall, it was demonstrated that bioreducible shell-cross-linked nanoparticles could be used as a potential carrier for cancer therapy. 2015-02-09 00:00:00 nanoparticle bioreducible disulfide linkage PCL DOX model anticancer drug SCC 7 cells drug release HA drug release rate drug loading efficiency cancer therapy