Perez-Soler R, Khokhar A R
Departmentof Medical Oncology (Section of Head, Neck, and Thoracic Medical Oncology), University of Texas M.D. Anderson Cancer Center, Houston 77030.
Cancer Res. 1992 Nov 15;52(22):6341-7.
cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP), a lipophilic cisplatin analogue containing two branched leaving groups of 10 carbon atoms, is undergoing clinical evaluation in a liposomal formulation. In previous studies, NDDP entrapped in multilamellar vesicles composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a 7:3 molar ratio was non-nephrotoxic in humans, not cross-resistant with cisplatin in different in vitro and in vivo systems, and more active than cisplatin against murine models of experimental liver metastases whereas free NDDP was devoid of in vivo antitumor activity at the optimal dose of L-NDDP and barely active at higher doses. To elucidate the mechanisms by which the liposomal carrier enhances the biological properties to this class of antitumor agents, we studied the effect of the liposome composition, size of the branched leaving groups of the platinum compound, and pH and composition of the aqueous phase on the entrapment efficiency, drug leakage, drug stability, and in vivo toxicity and antitumor activity of different liposomal formulations of these agents. In experiments using normal saline as aqueous phase, the presence of DMPG in the lipid bilayer resulted in a decreased stability and an increased biological activity of NDDP, whereas NDDP entrapped in liposomes composed of DMPC alone (not containing DMPG) was stable but devoid of antitumor activity. In studies with structurally related analogues with branched leaving groups of 5, 6, 7, and 9 carbon atoms, similar trends were observed. In addition, the number of carbon atoms in the leaving groups was directly and inversely related to the entrapment efficiency and stability of the analogues, respectively, independently of lipid composition; increasing the size of the branched leaving groups resulted in an increased in situ degradation of the platinum compound and enhanced biological activity and potency. These results suggest that this class of platinum compounds exerts its biological activity through the formation of active intermediates in situ within the lipid bilayers and that the activation reaction is highly dependent on the presence of DMPG and the size of the lipophilic leaving group.
顺式 - 双 - 新癸酸根 - 反式 - R，R - 1,2 - 二氨基环己烷铂（II）（NDDP）是一种亲脂性顺铂类似物，含有两个10个碳原子的支链离去基团，目前正在以脂质体制剂形式进行临床评估。在先前的研究中，包裹在由二肉豆蔻酰磷脂酰胆碱（DMPC）和二肉豆蔻酰磷脂酰甘油（DMPG）以7:3摩尔比组成的多层囊泡中的NDDP对人类无肾毒性，在不同的体外和体内系统中与顺铂无交叉耐药性，并且在针对实验性肝转移的小鼠模型中比顺铂更具活性，而游离的NDDP在L - NDDP的最佳剂量下没有体内抗肿瘤活性，在更高剂量下几乎没有活性。为了阐明脂质体载体增强这类抗肿瘤药物生物学特性的机制，我们研究了脂质体组成、铂化合物支链离去基团的大小以及水相的pH值和组成对这些药物不同脂质体制剂的包封效率、药物泄漏、药物稳定性以及体内毒性和抗肿瘤活性的影响。在以生理盐水作为水相的实验中，脂质双层中DMPG的存在导致NDDP稳定性降低和生物活性增加，而包裹在仅由DMPC（不含DMPG）组成的脂质体中的NDDP是稳定的，但没有抗肿瘤活性。在用具有5、6、7和9个碳原子支链离去基团的结构相关类似物进行的研究中，观察到了类似的趋势。此外，离去基团中的碳原子数分别与类似物的包封效率和稳定性直接和反比相关，与脂质组成无关；增加支链离去基团的大小导致铂化合物的原位降解增加，并增强生物活性和效力。这些结果表明，这类铂化合物通过在脂质双层中原位形成活性中间体来发挥其生物学活性，并且活化反应高度依赖于DMPG的存在和亲脂性离去基团的大小。
