title: Anti-tumor efficacy of polymer-platinum(II) complex micelles fabricated from folate conjugated PEG-graft-α,β-poly [(N-amino acidyl)-aspartamide] and cis-dichlorodiammine platinum(II) in tumor-bearing mice.
abstract: To develop a tumor-targeting nano-sized delivery system of cis-dichlorodiammine platinum(II) (CDDP), polymer-metal complex micelles were fabricated from folate-conjugated PEG-graft-α,β-poly [(N-amino acidyl)-aspartamide] (FA-PEG-g-PAAsp) and CDDP. The formation of polymer-metal complex micelles was confirmed by the measurements of critical aggregation concentration (CAC) and particle size, and the morphological observation. It was found that all the micelles showed spherical shapes with clear core-shell structures in narrow size distributions. The typical particle size measured by dynamic laser scattering (DLS) was ca. 105 nm, suggesting their passive targeting to tumor tissue and endocytosis potential. FA-PEG-g-PAAsp-CDDP micelles showed sustained drug release profiles over 40 h, and their accumulative drug release was ranked in the order of FA-PEG-g-PAsp-Ami-CDDP<FA-PEG-g-PAsp-Glu-CDDP<FA-PEG-g-PAsp-Asp-CDDP, depending on the category of used amino acid (Ami: potassium aminomalonate; Glu: glutamic acid; and Asp: aspartic acid). Cellular uptake of FA-PEG-g-PAsp-Ami-CDDP micelles was found to be higher than that of mPEG-g-PAsp-Ami-CDDP micelles because of folate receptor (FR)-mediated endocytosis, which is revealed by the cellular uptake image of Nile red-loaded micelles, and thereby provided higher cytotoxicity against FR-positive KB cells. Although the anti-tumor activity against KB cell-derived tumors was ordered at CDDP>FA-PEG-g-PAAsp-CDDP>mPEG-g-PAAsp-CDDP, the severe toxicity of CDDP in vivo limited its use as ideal anti-tumor drug. Furthermore, FA-PEG-g-PAAsp-CDDP and mPEG-g-PAAsp-CDDP showed rather low toxicity against mice, just similar to that of PBS. It indicated the great potential utilization of the FA-PEG-g-PAAsp-CDDP micelles as the tumor-targeted drug carriers of CDDP with improved anti-tumor efficacy.
authors: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, PR China.
authors: Yake
authors: Y
authors: Xue
authors: Xiaoxing
authors: X
authors: Tang
authors: Jin
authors: J
authors: Huang
authors: Xuzhu
authors: X
authors: Zhang
authors: Jiahui
authors: J
authors: Yu
authors: Yazhuo
authors: Y
authors: Zhang
authors: Songbai
authors: S
authors: Gui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D010455:Peptides; D011108:Polymers; C543071:mPEG-g-alpha,beta-poly((N-amino acidyl)-DL-aspartamide); D011092:Polyethylene Glycols; D005492:Folic Acid; D002945:Cisplatin