Perez-Soler R, Han I, al-Baker S, Khokhar A R
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Cancer Chemother Pharmacol. 1994;33(5):378-84. doi: 10.1007/BF00686266.
Lipophilic diaminocyclohexane (DACH) platinum complexes have shown significant promise in preclinical studies. One of these compounds, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP), which contains two branched leaving groups of 10 carbons, showed a favorable toxicity profile in a liposomal formulation in early clinical trials. However, like many other DACH platinum compounds with branched leaving groups, it is unstable within the liposomes, thus preventing its widespread clinical evaluation. We studied the effect of the configuration of leaving groups on intraliposomal complex stability by studying a series of DACH platinum complexes containing linear alkyl carboxylato leaving groups of 5-18 carbons. The entrapment efficiency was greater than 90% for all liposomal preparations of the complexes and was independent of lipid composition and length of the leaving group. The drug leakage from the liposomes was minimal, but was directly related to the length of the leaving group. Intraliposomal stability was inversely related to the length of the leaving group and the content of DMPG (dimyristoyl phosphatidylglycerol) in the liposomes. The effect of length of leaving group on intraliposomal stability was minimal in compounds with leaving groups smaller than 10 carbons, but very pronounced in compounds with longer leaving groups. Stable liposomal formulations of selected compounds with leaving groups of 6 and 10 carbons had significant in vivo antitumor activity against both L1210/S and L1210/PDD leukemias. The results indicate (1) that compounds with linear leaving groups are much more stable within DMPG-containing liposomes than compounds with branched leaving groups and (2) that DMPG is required for in vivo antitumor activity. Stable and active liposomal formulations of selected compounds with linear leaving groups have been identified. These formulations are candidates for clinical development.
亲脂性二氨基环己烷（DACH）铂配合物在临床前研究中已显示出巨大的前景。其中一种化合物，顺式 - 双新癸酸根 - 反式 - R，R - 1,2 - 二氨基环己烷铂（II）（NDDP），含有两个10个碳的支链离去基团，在早期临床试验的脂质体制剂中显示出良好的毒性特征。然而，与许多其他具有支链离去基团的DACH铂化合物一样，它在脂质体内不稳定，从而阻碍了其广泛的临床评估。我们通过研究一系列含有5 - 18个碳的线性烷基羧酸根离去基团的DACH铂配合物，研究了离去基团构型对脂质体内配合物稳定性的影响。所有配合物的脂质体制剂的包封率均大于90%，且与脂质组成和离去基团长度无关。脂质体中的药物泄漏极少，但与离去基团的长度直接相关。脂质体内稳定性与离去基团的长度以及脂质体中DMPG（二肉豆蔻酰磷脂酰甘油）的含量呈负相关。离去基团长度对脂质体内稳定性的影响在离去基团小于10个碳的化合物中最小，但在离去基团较长的化合物中非常明显。具有6个和10个碳离去基团的选定化合物的稳定脂质体制剂对L1210/S和L1210/PDD白血病均具有显著的体内抗肿瘤活性。结果表明：（1）具有线性离去基团的化合物在含DMPG的脂质体内比具有支链离去基团的化合物稳定得多；（2）体内抗肿瘤活性需要DMPG。已鉴定出具有线性离去基团的选定化合物的稳定且有活性的脂质体制剂。这些制剂是临床开发的候选药物。
