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

Prakash G. Avaji; Hye In Joo; Jung Hyun Park; Kyung Su Park; Yong Joo Jun; Hwa Jeong Lee; Youn Soo Sohn

doi:10.1016/j.jinorgbio.2014.06.014

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

Prakash G. Avaji, Hye In Joo, Jung Hyun Park, Kyung Su Park, Yong Joo Jun, Hwa Jeong Lee, Youn Soo Sohn

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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 (t_1/2β = 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.

Original language	English
Pages (from-to)	45-52
Number of pages	8
Journal	Journal of Inorganic Biochemistry
Volume	140
DOIs	https://doi.org/10.1016/j.jinorgbio.2014.06.014
State	Published - Nov 2014

Bibliographical note

Funding Information:
This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea ( HI11C0532 ) and by National Research Foundation of Korea (NRF) Grant funded by the Korean Government ( MEST ) ( NRF-2011-0013493 ).

Keywords

Oxaliplatin
Platinum drug
Polymer conjugate
Polymer micelle
Polyphosphazene

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10.1016/j.jinorgbio.2014.06.014

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@article{194c49af60784d99a433c814ad4245c8,

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 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.",

keywords = "Oxaliplatin, Platinum drug, Polymer conjugate, Polymer micelle, Polyphosphazene",

author = "Avaji, {Prakash G.} and Joo, {Hye In} and Park, {Jung Hyun} and Park, {Kyung Su} and Jun, {Yong Joo} and Lee, {Hwa Jeong} and Sohn, {Youn Soo}",

note = "Funding Information: This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea ( HI11C0532 ) and by National Research Foundation of Korea (NRF) Grant funded by the Korean Government ( MEST ) ( NRF-2011-0013493 ). ",

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doi = "10.1016/j.jinorgbio.2014.06.014",

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AU - Avaji, Prakash G.

AU - Joo, Hye In

AU - Park, Jung Hyun

AU - Park, Kyung Su

AU - Jun, Yong Joo

AU - Lee, Hwa Jeong

AU - Sohn, Youn Soo

N1 - Funding Information: This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea ( HI11C0532 ) and by National Research Foundation of Korea (NRF) Grant funded by the Korean Government ( MEST ) ( NRF-2011-0013493 ).

PY - 2014/11

Y1 - 2014/11

N2 - 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.

AB - 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.

KW - Oxaliplatin

KW - Platinum drug

KW - Polymer conjugate

KW - Polymer micelle

KW - Polyphosphazene

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ER -

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

Abstract

Bibliographical note

Keywords

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