title: Dual-pH responsive micelle platform for co-delivery of axitinib and doxorubicin.
abstract: While the complicated pathogenesis of cancer results in limited therapeutic efficacy of current mono-drug treatment, combination therapy by multiple drugs is becoming increasingly attractive due to the decreased side effects and synergistic anti-cancer activities. The recently emerging modality is the co-delivery of traditional chemotherapeutics and anti-angiogenesis agents. Although nanocarriers are frequently utilized for the co-delivery of different drugs, there are still concerns regarding their implementations. Most of the nanocarriers cannot release drugs separately into their different targeted sites of action. Therefore, we have developed a micellar platform for the co-delivery of an antiangiogenesis agent, axitinib (AXI) and a DNA intercalator, doxorubicin (DOX). Our results showed that this cross-linked micelle (DA-CM) could release AXI and DOX in tumor extracellular environment and intracellular lysosome compartments, respectively, in response to the dual pH stimulus. Notably, DA-CM exhibited remarkably improved tumor accumulation, cell internalization, tumor spheroids penetration and cytotoxicity. Ultimately, DA-CM reduced the number of immature vessels within xenograft tumors, demonstrating an effective antiangiogenesis effect. Meanwhile, they inhibited tumor growth by 88%. Our co-delivery micellar system with the dual-pH responsive feature might hold great promises for the combinatory 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, PR China, PR China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Xu
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, PR China, PR 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, PR China, PR 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, PR China, PR 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, PR China, PR China. Electronic address: huangyuan0@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000077784:Axitinib; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D007191:Indazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008823:Micelles; D011108:Polymers / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin; D000077784:Axitinib
keywords: Antiangiogenesis; Combination therapy; HPMA micelle; Synergistic effect; pH-responsive