title: 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: Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Republic of Korea.
authors: Prakash G
authors: PG
authors: Avaji
authors: Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Republic of Korea.
authors: Hye In
authors: HI
authors: Joo
authors: Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Republic of Korea.
authors: Jung Hyun
authors: JH
authors: Park
authors: Advanced Analysis Center, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
authors: Kyung Su
authors: KS
authors: Park
authors: C & Pharm, Rm 211 Science Building B, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Republic of Korea.
authors: Yong Joo
authors: YJ
authors: Jun
authors: Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Republic of Korea. Electronic address: hwalee@ewha.ac.kr.
authors: Hwa Jeong
authors: HJ
authors: Lee
authors: C & Pharm, Rm 211 Science Building B, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-750, Republic of Korea. Electronic address: yssohn@ewha.ac.kr.
authors: Youn Soo
authors: YS
authors: Sohn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D017671:Platinum Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D009943:Organophosphorus Compounds; D017671:Platinum Compounds; D011108:Polymers; C108974:poly(phosphazene)
keywords: Oxaliplatin; Platinum drug; Polymer conjugate; Polymer micelle; Polyphosphazene