title: Acid-Responsive Therapeutic Polymer for Prolonging Nanoparticle Circulation Lifetime and Destroying Drug-Resistant Tumors.
abstract: How to destroy drug-resistant tumor cells remains an ongoing challenge for cancer treatment. We herein report on a therapeutic nanoparticle, aHLP-PDA, which has an acid-activated hemolytic polymer (aHLP) grafted onto photothermal polydopamine (PDA) nanosphere via boronate ester bond, in efforts to ablate drug-resistant tumors. Upon exposure to oxidative stress and/or near-infrared laser irradiation, aHLP-PDA nanoparticle responsively releases aHLP, likely via responsive cleavage of boronate ester bond, and thus responsively exhibits acid-facilitated mammalian-membrane-disruptive activity. In vitro cell studies with drug-resistant and/or thermo-tolerant cancer cells show that the aHLP-PDA nanoparticle demonstrates preferential cytotoxicity at acidic pH over physiological pH. When administered intravenously, the aHLP-PDA nanoparticle exhibits significantly prolonged blood circulation lifetime and enhanced tumor uptake compared to bare PDA nanosphere, likely owing to aHLP's stealth effects conferred by its zwitterionic nature at blood pH. As a result, the aHLP-PDA nanoparticle effectively ablates drug-resistant tumors, leading to 100% mouse survival even on the 32nd day after suspension of photothermal treatment, as demonstrated with the mouse model. This work suggests that a combination of nanotechnology with lessons learned in bacterial antibiotic resistance may offer a feasible and effective strategy for treating drug-resistant cancers often found in relapsing patients.
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, ‡Department of Polymer Science and Engineering, and §Department of Materials Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
authors.forename: Ji-Gang
authors.initials: JG
authors.lastname: Piao
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, ‡Department of Polymer Science and Engineering, and §Department of Materials Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, ‡Department of Polymer Science and Engineering, and §Department of Materials Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006367:HeLa Cells; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy; D011108:Polymers / Q000627:therapeutic use*; D011109:Polymethacrylic Acids / Q000633:toxicity; D055672:Static Electricity; D013696:Temperature; D013997:Time Factors
chemical_list: D011108:Polymers; D011109:Polymethacrylic Acids; C030613:polymethacrylic acid
keywords: cancer; drug resistance; nanomedicine; pH-responsive; photothermal