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

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 130nm, 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=9.52h) compared with oxaliplatin (3.47h), and much larger AUC (area under the curve) value (25,831ng·h/mL) compared with oxaliplatin (1194ng·h/mL). Biodistribution study of the polymer conjugate has shown excellent tumor selectivity with the tumor to tissue ratio of 3.84 at 2h post injection and 11.7 at 24h 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.

• Authors: Prakash G Avaji, Hye In Joo, Jung Hyun Park, Kyung Su Park, Yong Joo Jun, Hwa Jeong Lee, Youn Soo Sohn
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 140 Pg. 45-52 (Nov 2014) ISSN: 1873-3344 [Electronic] United States
• PMID: 25061690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Micelles
• Organophosphorus Compounds
• Platinum Compounds
• Polymers
• poly(phosphazene)

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Humans
• Magnetic Resonance Spectroscopy
• Micelles
• Organophosphorus Compounds (chemical synthesis, chemistry)
• Platinum Compounds (chemical synthesis, chemistry)
• Polymers (chemical synthesis, chemistry)
• Rats
• Rats, Sprague-Dawley
• Tissue Distribution