Synthesis and properties of a new micellar polyphosphazene-platinum(II) conjugate drug

Title
Synthesis and properties of a new micellar polyphosphazene-platinum(II) conjugate drug
Authors
Prakash G. Avaji주혜인박정현박경수전영주이화정손연수
Keywords
Platinum drug; Polymer conjugate; Polyphosphazene; Polymer micelle; Oxaliplatin
Issue Date
2014-11
Publisher
Journal of inorganic biochemistry
Citation
VOL 140, 45-52
Abstract
Aiming at tumor targeting delivery of oxaliplatin using polymer therapy, a new monomeric platinum(II) complex (dach)Pt[HEDM] (dach: trans-(±)-1,2-diaminocyclohexane; HEDM: 2-hydroxyethoxydiethylmalate) was designed to include the antitumor moiety (dach)Pt and HEDM as a linker to the polyphosphazene backbone. This monomeric Pt-complex could easily be grafted to the PEGylated polyphosphazene backbone to prepare a novel polyphosphazene–Pt conjugate, [NP(MPEG550)(dach)Pt(EM)]n [MPEG550: methoxy poly(ethylene glycol) with an average molecular weight of 550; EM: ethoxymalate]. This amphiphilic polyphosphazene–Pt conjugate was found to self-assemble into stable polymeric micelles of a mean diameter of 130 nm, which is suitable for passive tumor targeting by enhanced permeability and retention (EPR) effect. Pharmacokinetic study of this polymer conjugate exhibited long blood circulation as expected and longer half-life (t1/2β = 9.52 h) compared with oxaliplatin (3.47 h), and much larger AUC (area under the curve) value (25,831 ng·h/mL) compared with oxaliplatin (1194 ng·h/mL). Biodistribution study of the polymer conjugate has shown excellent tumor selectivity with the tumor to tissue ratio of 3.84 at 2 h post injection and 11.7 at 24 h post injection probably due to the EPR effect of the polymer conjugate while no tumor selectivity was observed for monomeric oxaliplatin. Furthermore, accumulation of this polymer conjugate in kidney was much lower compared with oxaliplatin. Also the nude mouse xenograft trial of the polymer conjugate has shown higher antitumor efficacy compared with oxaliplatin.
URI
http://pubs.kist.re.kr/handle/201004/47908
ISSN
01620134
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KIST Publication > Article
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