A Lipophilic Pt(IV) Oxaliplatin Derivative Enhances Antitumor Activity

Aiman Abu Ammar; Raji Raveendran; Dan Gibson; Taher Nassar; Simon Benita

doi:https://doi.org/10.1021/acs.jmedchem.6b00955

A Lipophilic Pt(IV) Oxaliplatin Derivative Enhances Antitumor Activity

Aiman Abu Ammar, Raji Raveendran, Dan Gibson, Taher Nassar, Simon Benita

School of Pharmacy

The Hebrew University of Jerusalem

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

Abstract

Side effects and acquired resistance by cancer cells limit the use of platinum anticancer drugs. Modification of oxaliplatin (OXA) into a lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)] (1), containing both lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles. Complex 1 exhibited unique potency against a panel of cancer cells, including cisplatin-resistant tumor cells. [Pt(DACH)(OAc)(OPal)(ox)] incorporated nanoparticles (2) presented a mean diameter of 146 nm with encapsulation yields above 95% as determined by HPLC. Complexes 1 and 2 showed enhanced in vitro cellular Pt accumulation, DNA platination, and antiproliferative effect compared to OXA. Results of an orthotopic intraperitoneal model of metastatic ovarian cancer (SKOV-3) and a xenograft subcutaneous model of colon (HCT-116) tumor in SCID-bg mice showed that the activity of 1 and 2 significantly decreased tumor growth rates compared to control and OXA treatment groups. Consequently, these findings warrant further development toward clinical translation.

Original language	English
Pages (from-to)	9035-9046
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	19
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00955
State	Published - 13 Oct 2016

All Science Journal Classification (ASJC) codes

Drug Discovery
Molecular Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.1021/acs.jmedchem.6b00955

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title = "A Lipophilic Pt(IV) Oxaliplatin Derivative Enhances Antitumor Activity",

abstract = "Side effects and acquired resistance by cancer cells limit the use of platinum anticancer drugs. Modification of oxaliplatin (OXA) into a lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)] (1), containing both lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles. Complex 1 exhibited unique potency against a panel of cancer cells, including cisplatin-resistant tumor cells. [Pt(DACH)(OAc)(OPal)(ox)] incorporated nanoparticles (2) presented a mean diameter of 146 nm with encapsulation yields above 95% as determined by HPLC. Complexes 1 and 2 showed enhanced in vitro cellular Pt accumulation, DNA platination, and antiproliferative effect compared to OXA. Results of an orthotopic intraperitoneal model of metastatic ovarian cancer (SKOV-3) and a xenograft subcutaneous model of colon (HCT-116) tumor in SCID-bg mice showed that the activity of 1 and 2 significantly decreased tumor growth rates compared to control and OXA treatment groups. Consequently, these findings warrant further development toward clinical translation.",

author = "{Abu Ammar}, Aiman and Raji Raveendran and Dan Gibson and Taher Nassar and Simon Benita",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

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doi = "https://doi.org/10.1021/acs.jmedchem.6b00955",

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AU - Abu Ammar, Aiman

AU - Raveendran, Raji

AU - Gibson, Dan

AU - Nassar, Taher

AU - Benita, Simon

PY - 2016/10/13

Y1 - 2016/10/13

N2 - Side effects and acquired resistance by cancer cells limit the use of platinum anticancer drugs. Modification of oxaliplatin (OXA) into a lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)] (1), containing both lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles. Complex 1 exhibited unique potency against a panel of cancer cells, including cisplatin-resistant tumor cells. [Pt(DACH)(OAc)(OPal)(ox)] incorporated nanoparticles (2) presented a mean diameter of 146 nm with encapsulation yields above 95% as determined by HPLC. Complexes 1 and 2 showed enhanced in vitro cellular Pt accumulation, DNA platination, and antiproliferative effect compared to OXA. Results of an orthotopic intraperitoneal model of metastatic ovarian cancer (SKOV-3) and a xenograft subcutaneous model of colon (HCT-116) tumor in SCID-bg mice showed that the activity of 1 and 2 significantly decreased tumor growth rates compared to control and OXA treatment groups. Consequently, these findings warrant further development toward clinical translation.

AB - Side effects and acquired resistance by cancer cells limit the use of platinum anticancer drugs. Modification of oxaliplatin (OXA) into a lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)] (1), containing both lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles. Complex 1 exhibited unique potency against a panel of cancer cells, including cisplatin-resistant tumor cells. [Pt(DACH)(OAc)(OPal)(ox)] incorporated nanoparticles (2) presented a mean diameter of 146 nm with encapsulation yields above 95% as determined by HPLC. Complexes 1 and 2 showed enhanced in vitro cellular Pt accumulation, DNA platination, and antiproliferative effect compared to OXA. Results of an orthotopic intraperitoneal model of metastatic ovarian cancer (SKOV-3) and a xenograft subcutaneous model of colon (HCT-116) tumor in SCID-bg mice showed that the activity of 1 and 2 significantly decreased tumor growth rates compared to control and OXA treatment groups. Consequently, these findings warrant further development toward clinical translation.

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M3 - مقالة

C2 - 27603506

SN - 0022-2623

VL - 59

SP - 9035

EP - 9046

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 19

ER -

A Lipophilic Pt(IV) Oxaliplatin Derivative Enhances Antitumor Activity

Abstract

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