Intraliposomal conversion of lipophilic cis-bis-carboxylato-trans-R,R-1,2-diaminocyclohexane-platinum (II) complexes into cis-bis-dichloro-trans-R,R-1,2-diaminocyclohexane-platinum (II).
Cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP) is a lipophilic platinum complex (Pt complex) developed in a liposomal carrier. Prior studies have suggested that NDDP is a prodrug that exerts its biological activity through activation within the liposome bilayers containing dimyristoyl phosphatidylglycerol (DMPG) before in vivo administration. In order to understand the kinetics of the intraliposomal degradation/activation of different liposomal Pt complexes, we studied the effects of their structure, lipid composition, content of acidic phospholipids and size, and the effects of pH, temperature and the presence of residual chloroform on their stability, in vitro cytotoxicity, and in vivo antitumor activity. The following factors were found to enhance the intraliposomal degradation/activation of Pt complexes: (1) the size and spatial configuration of the Pt complex, (2) an acidic pH, (3) a high temperature, (4) the presence and amount of acidic phospholipids, and (5) the presence of residual chloroform. Liposome size did not affect the intraliposomal stability of different Pt complexes. Good inverse relationships between the extent of drug degradation and in vitro cytotoxicity and between the extent of drug degradation and in vivo antitumor potency were observed, thus confirming that the biological activity of these complexes is exerted through the intraliposomal formation of certain active intermediate(s). The only active intermediate that could be identified was cis-bis-dichloro-trans-R,R-1,2-diaminocyclohexane platinum(II) whose structure was confirmed by 1H, 13C, and 195Pt nuclear magnetic resonance (NMR) spectroscopy.
Han
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I
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Khokhar
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AR
Perez-Soler
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R
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D004337:Drug Carriers; D004355:Drug Stability; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007939:Leukemia L1210 / Q000188:drug therapy; D008081:Liposomes; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D009944:Organoplatinum Compounds; C054367:bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II); D002945:Cisplatin