%0 Journal Article
%T Preparation and In Vivo Evaluation of Dichloro(1,2-Diaminocyclohexane)platinum(II)-Loaded Core Cross-Linked Polymer Micelles
%A Hardeep S. Oberoi
%A Natalia V. Nukolova
%A Yi Zhao
%A Samuel M. Cohen
%A Alexander V. Kabanov
%A Tatiana K. Bronich
%J Chemotherapy Research and Practice
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/905796
%X The therapeutic performance of oxaliplatin can be improved by incorporating the central cis-dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt) motif into the core cross-linked block copolymer micelles. We describe here the preparation, cellular uptake, and in vivo evaluation of core cross-linked micelles loaded with DACHPt. Stable drug-loaded micelles were prepared at high drug loading (~25£¿w/w%) and displayed a considerably increased in vitro cytotoxicity compared to free oxaliplatin against A2780 ovarian cancer cells. The DACHPt-loaded micelle formulation was well tolerated in mice and exhibited improved antitumor activity than oxaliplatin alone in an ovarian tumor xenograft model. 1. Introduction Since the introduction of cisplatin in clinical trials in 1970¡¯s and its successful approval for the treatment of testicular cancer and a number of other malignancies, a massive research effort has been dedicated towards finding new platinum complexes with improved therapeutic efficacy. Studies on second-generation platinum complexes, designed to reduce the dose-limiting toxicities associated with cisplatin treatment, saw the successful development of carboplatin with markedly reduced incidences of renal toxicity [1]. The design of third-generation platinum complexes was intended to overcome cellular resistance to cisplatin/carboplatin. Amongst the thousands of platinum complexes designed and evaluated, cis-dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt), containing the DACH modification at the amine ligands of cisplatin, was recognized as a potent anticancer agent [2]. The structural modification greatly altered the activity and toxicity of this platinum complex yielding a much broader spectrum of activity and more importantly a lack of cross-resistance with cisplatin. The issue of limited DACHPt solubility was dealt with oxalate modification at the leaving groups yielding oxaliplatin which gained worldwide clinical approval [3]. Although treatment with the third-generation platinum complex-oxaliplatin is relatively better tolerated than previous generation cisplatin and carboplatin treatment, various side effects still limit its effectiveness [4]. Neurotoxicity is the most severe toxicity associated with oxaliplatin regime and is observed clinically at two stages. A transient acute syndrome appears shortly after the first few infusions and causes distal and perioral paresthesias/dysesthesias, muscular cramps and spasms [5]. The more detrimental dose limiting cumulative sensory neuropathy develops gradually and results in persisting dysesthesias
%U http://www.hindawi.com/journals/cherp/2012/905796/