title: Pharmacokinetics, biodistribution and in vivo efficacy of cisplatin loaded poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) complex nanoparticles for tumor therapy.
abstract: Platinum-based polymeric nano-drugs, especially cisplatin-loaded polymeric nanoparticles (CDDP-NPs), have been extensively exploited for the treatment of solid tumors. However, it is still unclear what role the processing procedure and the properties of the polymeric carrier materials may play in influencing the plasma pharmacokinetics, biodistribution and in vivo efficacy of CDDP-NPs. In this study, a series of poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) copolymers were synthesized for the preparation of CDDP-loaded PLG-g-mPEG (CDDP/PLG-g-mPEG) nanoparticles. All of the parameters, including PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length, ultrafiltration purification and cisplatin loading content, were found to have a significant influence on the plasma pharmacokinetics of the CDDP/PLG-g-mPEG nanoparticles. The blood circulation time of the nanoparticles was prolonged with increases in PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and CDDP loading content. The use of ultrafiltration purification could prolong the blood circulation time of the nanoparticles as well. Experiments to measure the pharmacokinetics and biodistribution demonstrated that the selected CDDP/PLG-g-mPEG nanoparticles, NP10, had a long blood circulation time and could achieve selective and significant accumulation in Lewis lung carcinoma (LLC) tumors. The platinum plasma concentrations in the LLC tumor-bearing mice receiving NP10 remained up to 46-fold higher than that of mice receiving equivalent doses of free CDDP. In addition, the plasma area under the concentration time curve (AUC) of NP10 was 31-fold higher than that of free CDDP in 48h. The platinum concentration ratio of NP10 to free CDDP in tumors reached as high as 9.4. The tumor AUC ratio of NP10 to CDDP was 6. Using a mouse C26 tumor model, here we demonstrate that NP10 improves the safety and tolerance in vivo when compared to CDDP and effectively inhibits the growth of C26 tumors. Furthermore, increasing the dosage of NP10 by 2 or 3-fold of free CCDP improved its anticancer efficacy to comparable or higher levels. These results indicate that CDDP/PLG-g-mPEG nanoparticles have greater potential for the treatment of solid tumors in clinical application.
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China. Electronic address: ztang@ciac.ac.cn.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
authors.forename: Wantong
authors.initials: W
authors.lastname: Song
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun, 130012, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ahmad
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China. Electronic address: xschen@ciac.ac.cn.
authors.forename: Xuesi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002626:Chemistry, Pharmaceutical; D002945:Cisplatin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D050997:Nanomedicine; D053758:Nanoparticles; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D013678:Technology, Pharmaceutical / Q000379:methods; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; C579712:methoxypoly(ethylene glycol)-block-poly(glutamic acid); D011099:Polyglutamic Acid; D011092:Polyethylene Glycols; D002945:Cisplatin
keywords: Biodistribution; Cisplatin; Glutamic acid; Nanoparticle; Pharmacokinetics