title: Co-delivery of cisplatin and paclitaxel by folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles for the treatment of non-small lung cancer.
abstract: An amphiphilic copolymer, folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) was prepared and explored as a nanometer carrier for the co-delivery of cisplatin (cis-diaminodichloroplatinum, CDDP) and paclitaxel (PTX). CDDP and PTX were encapsulated inside the hydrophobic inner core and chelated to the middle shell, respectively. PEG provided the outer corona for prolonged circulation. An in vitro release profile of the CDDP + PTX-encapsulated nanoparticles revealed that the PTX chelation cross-link prevented an initial burst release of CDDP. After an incubation period of 24 hours, the CDDP+PTX-encapsulated nanoparticles exhibited a highly synergistic effect for the inhibition of A549 (FA receptor negative) and M109 (FA receptor positive) lung cancer cell line proliferation. Pharmacokinetic experiment and distribution research shows that nanoparticles have longer circulation time in the blood and can prolong the treatment times of chemotherapeutic drugs. For the in vivo treatment of A549 cells xeno-graft lung tumor, the CDDP+PTX-encapsulated nanoparticles displayed an obvious tumor inhibiting effect with an 89.96% tumor suppression rate (TSR). This TSR was significantly higher than that of free chemotherapy drug combination or nanoparticles with a single drug. For M109 cells xeno-graft tumor, the TSR was 95.03%. In vitro and in vivo experiments have all shown that the CDDP+PTX-encapsulated nanoparticles have better targeting and antitumor effects in M109 cells than CDDP+PTX-loaded PEG-PLGA nanoparticles (p < 0.05). In addition, more importantly, the enhanced anti-tumor efficacy of the CDDP+PTX-encapsulated nanoparticles came with reduced side-effects. No obvious body weight loss or functional changes occurred within blood components, liver, or kidneys during the treatment of A549 and M109 tumor-bearing mice with the CDDP+PTX-encapsulated nanoparticles. Thus, the FA modified amphiphilic copolymer-based combination of CDDP and PTX may provide useful guidance for effective and safe cancer chemotherapy, especially in tumors with high FA receptor expression.
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.|The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Zelai
authors.initials: Z
authors.lastname: He
authors.affiliation: The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Teng
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Can
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cardio-thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D014018:Tissue Distribution; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011091:Polyesters; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011092:Polyethylene Glycols; D005492:Folic Acid; D017239:Paclitaxel; D002945:Cisplatin
keywords: PLGA; biocompatibility; chemotherapy; cytotoxicity; nanoparticles