Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
National Research Center "Kurchatov Institute", Moscow, Russian Federation.
Curr Drug Deliv. 2020;17(4):312-323. doi: 10.2174/1567201817666200214105357.
Recently we developed a scalable scheme of synthesis of melphalan ester conjugate with 1,2-dioleoyl--glycerol (MlphDG) and a protocol for the fabrication of its lyophilized liposomal formulation.
Herein we compared this new convenient in use formulation of MlphDG with parent drug Alkeran in rats concerning several toxicological parameters and evaluated its antitumor efficacy in the model of breast cancer in mice.
Liposomes of approximately 100 nm in diameter, consisting of egg phosphatidylcholine, soybean phosphatidylinositol, and MlphDG, or placebo liposomes without the drug were produced by extrusion and lyophilized. Alkeran or liposomes recovered by the addition of water were injected into the tail vein of animals. Clinical examination of rats consisted of detailed inspection of the behavior, general status, and hematological parameters. Mice with transplanted breast cancer WNT-1 were subjected to multiple treatments with the drugs; tumor growth inhibition was assessed, together with cellular immunity parameters.
Liposomes showed approximately two times lower acute toxicity and better tolerability than Alkeran in terms of behavioral criteria. The toxic effects of liposomes on hemopoiesis were manifested at higher doses than in the case of Alkeran, proportionally to the difference in LD50 values. The formulation inhibited tumor growth significantly more effectively than Alkeran, delaying the start of the exponential growth phase and exhibiting no additional toxic effects toward bone marrow.
Lower toxicity of the liposomal formulation of MlphDG promises improved quality of life for cancer patients in need of treatment with melphalan. Presumably, the list of indications for melphalan therapy could be extended.
最近，我们开发了一种可扩展的 1,2-二油酰基-sn-甘油（Dioleoyl-Glycerol，DioG）连接美法仑（Melfalan，Mlph）的前药偶联物（美法仑酯）的合成方案，并制定了其冻干脂质体制剂的制备方案。
本文旨在比较这种新型方便使用的美法仑酯制剂与原药阿霉素（Alkeran）在大鼠体内的几种毒理学参数，并在乳腺癌小鼠模型中评估其抗肿瘤疗效。
通过挤压和冻干制备了由卵磷酯、大豆磷酯酰肌醇和 MlphDG 组成的直径约为 100nm 的脂质体，或不含药物的安慰剂脂质体。将 Alkeran 或通过加水回收的脂质体注入动物尾静脉。大鼠的临床检查包括行为、一般状态和血液学参数的详细检查。对移植了乳腺癌 WNT-1 的小鼠进行了多次药物治疗；评估了肿瘤生长抑制情况，以及细胞免疫参数。
脂质体在行为标准方面的急性毒性比 Alkeran 低约 2 倍，且耐受性更好。与 Alkeran 相比，脂质体对造血系统的毒性作用在较高剂量时才表现出来，与 LD50 值的差异成正比。该制剂在抑制肿瘤生长方面的效果明显优于 Alkeran，延迟了肿瘤指数生长阶段的开始，且对骨髓没有额外的毒性作用。
美法仑酯脂质体制剂的低毒性有望提高需要接受美法仑治疗的癌症患者的生活质量。美法仑治疗的适应证范围可能会扩大。
