Oncology Institute and Nano-oncology Research Center, Shaare Zedek Medical Center, Jerusalem, Israel; Hebrew University-Faculty of Medicine, Jerusalem, Israel.
Oncology Institute and Nano-oncology Research Center, Shaare Zedek Medical Center, Jerusalem, Israel.
Adv Drug Deliv Rev. 2020;154-155:13-26. doi: 10.1016/j.addr.2020.07.027. Epub 2020 Aug 7.
Several liposome products have been approved for the treatment of cancer. In all of them, the active agents are encapsulated in the liposome water phase passively or by transmembrane ion gradients. An alternative approach in liposomal drug delivery consists of chemically modifying drugs to form lipophilic prodrugs with strong association to the liposomal bilayer. Based on this approach, we synthesized a mitomycin c-derived lipidic prodrug (MLP) which is entrapped in the bilayer of PEGylated liposomes (PL-MLP, Promitil®), and activated by thiolytic cleavage. PL-MLP is stable in plasma with thiolytic activation of MLP occurring exclusively in tissues and is more effective and less toxic than conventional chemotherapy in various tumor models. PL-MLP has completed phase I clinical development where it has shown a favorable safety profile and a 3-fold reduction in toxicity as compared to free mitomycin c. Clinical and pharmacokinetic studies in patients with advanced colo-rectal carcinoma have indicated a significant rate of disease stabilization (39%) in this chemo-refractory population and significant prolongation of median survival in patients attaining stable disease (13.9 months) versus progressive disease patients (6.35 months). The pharmacokinetics of MLP was typically stealth with long T½ (~1 day), slow clearance and small volume of distribution. Interestingly, a longer T½, and slower clearance were both correlated with disease stabilization and longer survival. This association of pharmacokinetic parameters with patient outcome suggests that arrest of tumor growth is related to the enhanced tumor localization of long-circulating liposomes and highlights the importance of personalized pharmacokinetic evaluation in the clinical use of nanomedicines. Another important area where PL-MLP may have an added value is in chemoradiotherapy, where it has shown a strong radiosensitizing effect in animal models based on a unique mechanism of enhanced prodrug activation and encouraging results in early human testing.
已有几种脂质体产品被批准用于癌症治疗。在所有这些产品中，活性药物成分都是通过跨膜离子梯度或被动地包裹在脂质体水相中。脂质体药物传递的另一种方法是通过化学修饰药物来形成与脂质体双层具有强结合的亲脂性前药。基于这种方法，我们合成了一种米托霉素 C 衍生的脂质前药 (MLP)，它被包裹在聚乙二醇化脂质体 (PL-MLP，Promitil®) 的双层中，并通过硫解切割激活。PL-MLP 在血浆中稳定，只有在组织中才会发生 MLP 的硫解激活，在各种肿瘤模型中比传统化疗更有效、毒性更低。PL-MLP 已完成 I 期临床开发，与游离米托霉素 C 相比，其表现出良好的安全性和毒性降低 3 倍。在晚期结直肠癌患者中的临床和药代动力学研究表明，在这种化疗耐药人群中，疾病稳定率（39%）显著，并且在达到稳定疾病的患者（13.9 个月）中中位生存时间显著延长，而进展性疾病患者（6.35 个月）。MLP 的药代动力学通常是隐匿的，具有较长的 T½（~1 天）、缓慢清除和较小的分布体积。有趣的是，较长的 T½和较慢的清除率均与疾病稳定和更长的生存时间相关。这些药代动力学参数与患者结局的相关性表明，肿瘤生长的停滞与长循环脂质体增强的肿瘤定位有关，突出了个性化药代动力学评估在纳米药物临床应用中的重要性。PL-MLP 可能具有附加值的另一个重要领域是化学放射治疗，它在动物模型中基于增强前药激活的独特机制显示出强烈的放射增敏作用，并在早期人体试验中取得了令人鼓舞的结果。
