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.