title: Design of a novel theranostic nanomedicine: synthesis and physicochemical properties of a biocompatible polyphosphazene-platinum(II) conjugate.
abstract: To develop a theranostic nanomedicine involving the antitumor-active moiety (dach)Pt(II) (dach: trans-(±)-1,2-diaminocyclohexane) of oxaliplatin (OX), a new biocompatible polyphosphazene carrier polymer was designed by grafting with a methoxy poly(ethylene glycol) (MPEG) to increase duration of circulation in the blood and with aminoethanol (AE) as a spacer group. The antitumor (dach)Pt moiety was conjugated to the carrier polymer using cis-aconitic acid (AA) as a linker, resulting in a polymer conjugate formulated as [NP(MPEG550)(AE-AA)Pt(dach)]n, named "Polyplatin" (PP). PP was found to self-assemble into very stable polymeric nanoparticles with a mean diameter of 55.1 nm and a critical aggregation concentration of 18.5 mg/L in saline. PP could easily be labeled with a fluorescence dye such as Cy5.5 for imaging studies. The time-dependent ex vivo image studies on organ distributions and clearance of Cy-labeled PP have shown that PP accumulated in the tumor with high selectivity by the enhanced permeability and retention effect but was cleared out from all the major organs including the liver in about 4 weeks postinjection. Another time-dependent bioimaging study on distribution and clearance of PP in mouse kidney using laser ablation inductively coupled plasma mass spectroscopy has shown that PP accumulates much less in kidney and is more rapidly excreted than monomeric OX, which is in accord with the very low acute toxicity of PP as shown by its high LD50 value of more than 2000 mg/kg. The pharmacokinetic study of PP has shown that it has a much longer half-life (t 1/2β) of 13.3 hours compared with the 5.21 hours of OX and about a 20 times higher area under the curve value of 42,850.8 ng h/mL compared with the 2,320.4 ng h/mL of OX. The nude mouse xenograft trials of PP against the gastric MKN-28 tumor cell line exhibited remarkably better tumor efficacy compared with OX at the higher tolerated dose, with lower systemic toxicity.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea; C & Pharm, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Avaji
authors.affiliation: Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jung Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: C & Pharm, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Yong Joo
authors.initials: YJ
authors.lastname: Jun
authors.affiliation: Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Kyung Su
authors.initials: KS
authors.lastname: Park
authors.affiliation: Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: Department of Food Science and Technology, Seoul Women's University, Seoul, Republic of Korea.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: C & Pharm, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Youn Soo
authors.initials: YS
authors.lastname: Sohn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001672:Biocompatible Materials / Q000737:chemistry* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D055598:Chemical Phenomena; D015195:Drug Design; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077150:Oxaliplatin; D011108:Polymers / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D000068936:Theranostic Nanomedicine; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D009943:Organophosphorus Compounds; D009944:Organoplatinum Compounds; D011108:Polymers; C108974:poly(phosphazene); D000077150:Oxaliplatin
keywords: anticancer agent; nanomedicine; oxaliplatin; polyphosphazene; theranostics