title: Subcellular co-delivery of two different site-oriented payloads for tumor therapy.
abstract: Co-delivery of multiple agents via nanocarriers is of great interest in cancer therapy, but subcellular delivery to the corresponding site of action remains challenging. Here we report a smart nanovehicle which enables two different site-oriented payloads to reach their targeted organelles based on stimulus-responsive release and nucleus-targeted modification. First, all trans retinoic acid (RA) conjugated camptothecin (RA-CPT) was loaded in a polyhedral oligomericsilsesquioxane (POSS)-based core; docetaxel (DTX) was grafted on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. The POSS core grafted with semitelechelic HPMA copolymers then self-assembled into micelles. Once internalized into the cell, the two drugs were unleashed environment-responsively, and nuclear targeted RA remarkably facilitated the nuclear transport of CPT. Compared with single drug-loaded micelles, the dual drug-loaded platform showed superior synergic cytotoxicity, which was further strengthened by the involvement of RA. The ability to induce DNA damage and apoptosis was also enhanced by nucleus-targeted modification. Finally, dual drug-loaded micelles exhibited much better in vivo tumor inhibition (87.1%) and less systemic toxicity than the combination of single drug-loaded systems or the dual drug-loaded micelles without RA. Therefore, our study provides a novel "one platform, two targets" strategy in combinatory anti-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, Sichuan 610041, P.R. China. huangyuan0@163.com.
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, Sichuan 610041, P.R. China. huangyuan0@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
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, Sichuan 610041, P.R. China. huangyuan0@163.com.
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, Sichuan 610041, P.R. China. huangyuan0@163.com.
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, Sichuan 610041, P.R. China. huangyuan0@163.com.
authors.forename: Yuan
authors.identifier: http://orcid.org/0000-0003-3410-8602
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000178:Acrylamides; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D002166:Camptothecin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004249:DNA Damage; D000077143:Docetaxel; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy*; D017646:Organosilicon Compounds; D011108:Polymers; D043823:Taxoids / Q000008:administration & dosage; D014212:Tretinoin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D008823:Micelles; D017646:Organosilicon Compounds; D011108:Polymers; D043823:Taxoids; C521417:polyhedraloligosilsesquioxane; D000077143:Docetaxel; D014212:Tretinoin; C032976:N-(2-hydroxypropyl)methacrylamide; D002166:Camptothecin