title: Overcoming tumor resistance to cisplatin by cationic lipid-assisted prodrug nanoparticles.
abstract: Chemotherapy resistance has become a major challenge in the clinical treatment of lung cancer which is the leading cancer type for the estimated deaths. Recent studies have shown that nanoparticles as drug carriers can raise intracellular drug concentration by achieving effectively cellular uptake and rapid drug release, and therefore reverse the acquired chemoresistance of tumors. In this context, nanoparticles-based chemotherapy represents a promising strategy for treating malignancies with chemoresistance. In the present study, we developed cationic lipid assisted nanoparticles (CLAN) to deliver polylactide-cisplatin prodrugs to drug resistant lung cancer cells. The nanoparticles were formulated through self-assembly of a biodegradable poly(ethylene glycol)-block-poly(lactide) (PEG-PLA), a hydrophobic polylactide-cisplatin prodrug, and a cationic lipid. The cationic nanoparticles were proven to significantly improve cell uptake of cisplatin, leading to an increased DNA-Pt adduct and significantly promoted DNA damage in vitro. Moreover, our study reveals that cationic nanoparticles, although are slightly inferior in blood circulation and tumor accumulation, are more effective in blood vessel extravasation. The CLANs ultimately enhances the cellular drug availability and leads to the reversal of cisplatin resistance.
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Zhi-Ting
authors.initials: ZT
authors.lastname: Cao
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Zhi-Yao
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Sun
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Li
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Qin-Qin
authors.initials: QQ
authors.lastname: Cheng
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Zu-Qi
authors.initials: ZQ
authors.lastname: Zuo
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Yang-Zhong
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, PR China. Electronic address: yucaiwang@ustc.edu.cn.
authors.forename: Yu-Cai
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, PR China; CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, PR China; Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, Anhui 230027, PR China. Electronic address: jwang699@ustc.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002412:Cations; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D002412:Cations; D005229:Fatty Acids, Monounsaturated; D008055:Lipids; D011091:Polyesters; D011355:Prodrugs; D000644:Quaternary Ammonium Compounds; D011092:Polyethylene Glycols; C083464:poly(ethyleneglycol-lactide); C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane; D002945:Cisplatin
keywords: Cationic nanoparticle; Cisplatin resistance; Lung cancer; Pt(IV) prodrug