Shaare Zedek Medical Center, Jerusalem, Israel.
J Control Release. 2012 Jun 10;160(2):245-53. doi: 10.1016/j.jconrel.2011.11.019. Epub 2011 Nov 26.
A mitomycin-C lipid-based prodrug (MLP) formulated in pegylated liposomes (PL-MLP) was previously reported to have significant antitumor activity and reduced toxicity in mouse tumor models (Clin Cancer Res 12:1913-20, 2006). MLP is activated by thiolysis releasing mitomycin-C (MMC) which rapidly dissociates from liposomes. The purpose of this study was to examine the plasma stability, pharmacokinetics, and antitumor activity of PL-MLP in mouse models of human gastroentero-pancreatic tumors.
MLP was incorporated with almost 100% efficiency in pegylated liposomes composed of hydrogenated phosphatidylcholine, with or without cholesterol (Chol). Mean vesicle size was 45-65 nm for liposome preparations downsized by homogenization, and 80-100 nm when downsized by extrusion, the latter displaying narrower polydispersity. MLP to phospholipid mole ratio was 5% (~20 μg MMC-equivalents/μmol). Therapeutic studies were carried out in the N87 gastric carcinoma (Ca), HCT15 colon Ca, and Panc-1 pancreatic Ca models implanted s.c. in CD1 nude mice. Treatment was administered i.v. in mice with established tumors.
PL-MLP was very stable when incubated in plasma, and whole blood with a maximum of 5% release and activation to free MMC after 24 h. In the presence of a strong reducing agent (dithiotreitol), MLP was almost entirely activated to free MMC. Pharmacokinetic studies revealed major differences in plasma clearance between free MMC and PL-MLP. The longest half-lives were observed for extruded and Chol-containing preparations. Using a liposome radiolabel, it was found that the plasma levels of liposomes and prodrug were nearly superimposable confirming the absence of drug leakage in circulation. In vivo prodrug activation was significantly increased by co-injection of a large dose of a biocompatible reducing agent, N-acetylcysteine. PL-MLP was significantly more effective in delaying tumor growth and resulted in more tumor regressions than irinotecan in the N87 and HCT15 models, and than gemcitabine in the Panc-1 model. PL-MLP was ~3-fold less toxic than free MMC at MMC-equivalent doses, and displayed mild myelosuppression at therapeutic doses.
Delivery of MLP in pegylated liposomes is more effective than conventional chemotherapy in the treatment of gastroentero-pancreatic ectopic tumor models, and may represent an effective tool for treatment of these malignancies in the clinical setting with improved safety over free MMC. Reducing agents offer a tool for controlling in vivo prodrug release.
米托霉素脂质体前药（MLP）经聚乙二醇化脂质体（PL-MLP）包封，在小鼠肿瘤模型中具有显著的抗肿瘤活性和降低毒性（Clin Cancer Res 12:1913-20, 2006）。MLP 通过硫解激活，释放米托霉素-C（MMC），后者迅速从脂质体中解离。本研究的目的是研究 PL-MLP 在人胃肠胰腺肿瘤的小鼠模型中的血浆稳定性、药代动力学和抗肿瘤活性。
MLP 以接近 100%的效率掺入由氢化磷脂酰胆碱组成的聚乙二醇化脂质体中，无论是否含有胆固醇（Chol）。通过匀浆缩小的脂质体制剂的平均囊泡大小为 45-65nm，通过挤出缩小的脂质体制剂的平均囊泡大小为 80-100nm，后者显示出较窄的多分散性。MLP 与磷脂摩尔比为 5%（~20μg MMC 当量/μmol）。治疗研究在皮下植入 CD1 裸鼠的 N87 胃癌（Ca）、HCT15 结肠癌和 Panc-1 胰腺癌模型中进行。治疗采用静脉注射已建立肿瘤的小鼠。
PL-MLP 在血浆和含全血中非常稳定，最大释放和激活至游离 MMC 分别为 5%和 24 小时后。在存在强还原剂（二硫苏糖醇）的情况下，MLP 几乎完全被激活为游离 MMC。药代动力学研究显示游离 MMC 和 PL-MLP 在血浆清除率上存在显著差异。挤出物和含 Chol 的制剂的半衰期最长。使用脂质体放射性标记物，发现血浆中脂质体和前药的水平几乎完全重叠，证实药物在循环中无泄漏。通过共注射大剂量生物相容性还原剂 N-乙酰半胱氨酸，体内前药激活显著增加。PL-MLP 在 N87 和 HCT15 模型中延迟肿瘤生长的效果明显优于伊立替康，在 Panc-1 模型中延迟肿瘤生长的效果明显优于吉西他滨。PL-MLP 在 MMC 等效剂量下的毒性比游离 MMC 低约 3 倍，在治疗剂量下显示出轻度骨髓抑制。
聚乙二醇化脂质体递送 MLP 比传统化疗更有效治疗胃肠胰腺异位肿瘤模型，并且可能代表了一种有效的工具，可改善游离 MMC 的安全性，用于临床治疗这些恶性肿瘤。还原剂为控制体内前药释放提供了一种工具。
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