Polymer--cisplatin conjugate nanoparticles for acid-responsive drug delivery.
We report the synthesis of novel acid-responsive therapeutic nanoparticles (NPs) with sub-100 nm size consisting of polymer--cisplatin conjugates. The uniqueness of these drug delivery polymeric NPs lies in the covalent conjugation of each cisplatin drug to the hydrophobic segment of two biocompatible diblock copolymer chains through a hydrazone bond, resulting in highly differential drug release profile at different environmental acidity. We demonstrate that the synthesized polymer--cisplatin conjugates can readily precipitate to form sub-100 nm NPs in aqueous solution due to their very low critical micelle concentration (CMC). The resulting NPs show well-controlled cisplatin loading yield, excellent acid-responsive drug release kinetics, and enhanced in vitro cytotoxicity against ovarian cancer cells as compared to free cisplatin. As an environmentally sensitive drug delivery vehicle, these NPs can potentially minimize the drug loss during NP circulation in the blood, where the pH value is neutral, and trigger rapid intracellular drug release after the NPs are endocytosed by the target cells. This characteristic drug release profile holds the promise to suppress cancer cell chemoresistance by rapidly releasing a high dose of chemotherapy drugs inside the tumor cells, thereby improving the therapeutic efficacy of the drug payload.
Aryal
Santosh
S
Department of Nanoengineering and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
Hu
Che-Ming Jack
CM
Zhang
Liangfang
L
D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D004705:Endocytosis; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D007700:Kinetics; D007982:Levulinic Acids / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D004337:Drug Carriers; D006834:Hydrazines; D007982:Levulinic Acids; D011091:Polyesters; D011108:Polymers; D011355:Prodrugs; C029424:hydrazine; D011092:Polyethylene Glycols; C083464:poly(ethyleneglycol-lactide); D002945:Cisplatin; C032246:levulinic acid