Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research , 101 College Street, Suite 800, Toronto, Ontario, M5G 0A3, Canada.
Mol Pharm. 2013 Dec 2;10(12):4499-508. doi: 10.1021/mp400321e. Epub 2013 Nov 11.
The majority of ultrafast temperature sensitive liposome (uTSL) formulations reported in the literature deliver the highly membrane permeable drug, doxorubicin (DOX). Here we report on the study of the uTSL formulation, HaT (Heat activated cytoToxic, composed of the phospholipid DPPC and the surfactant Brij78) loaded with the water-soluble, but poorly membrane permeable anticancer drugs, gemcitabine (GEM) and oxaliplatin (OXA). The HaT formulation displayed ultrafast release of these drugs in response to temperature, whereas attempts with LTSL (Lyso-lipid Temperature Sensitive Liposome, composed of DPPC, MSPC, and DSPE-PEG) were unsuccessful. HaT-GEM and HaT-OXA both released >80% of the encapsulated drug within 2 min at 40-42 °C, with <5% drug leakage at 37 °C after 30 min in serum. The pharmacokinetic profile of both drugs was improved by formulating with HaT relative to the free drug, with clearance reduced by 50-fold for GEM and 3-fold for OXA. HaT-GEM and HaT-OXA both displayed improved drug uptake in the heated tumor relative to the unheated tumor (by 9-fold and 3-fold, respectively). In particular, HaT-GEM showed 25-fold improved delivery to the heated tumor relative to free GEM and significantly enhanced antitumor efficacy with complete tumor regression after a single dose of HaT-GEM. These data suggest that uTSL technology can also be used to deliver nonmembrane permeable drugs via an intravascular ultrafast release mechanism to great effect.
大多数文献中报道的超快温度敏感脂质体（uTSL）制剂都能传递高度膜渗透性的药物，阿霉素（DOX）。在这里，我们报告了超快温度敏感脂质体（HaT）制剂的研究，该制剂由磷脂 DPPC 和表面活性剂 Brij78 组成，负载水溶性但膜渗透性差的抗癌药物，吉西他滨（GEM）和奥沙利铂（OXA）。HaT 制剂在温度响应下表现出这些药物的超快释放，而 Lyso-lipid Temperature Sensitive Liposome（LTSL）制剂（由 DPPC、MSPC 和 DSPE-PEG 组成）则未能成功。HaT-GEM 和 HaT-OXA 在 40-42°C 下 2 分钟内释放超过 80%的包裹药物，在 37°C 血清中 30 分钟后药物泄漏率<5%。与游离药物相比，用 HaT 制剂对两种药物的药代动力学特征都有改善，吉西他滨的清除率降低了 50 倍，奥沙利铂的清除率降低了 3 倍。与未加热肿瘤相比，HaT-GEM 和 HaT-OXA 都在加热肿瘤中显示出更好的药物摄取（分别提高了 9 倍和 3 倍）。特别是，HaT-GEM 与游离 GEM 相比，对加热肿瘤的递送增加了 25 倍，单次给予 HaT-GEM 后，肿瘤完全消退，显著提高了抗肿瘤疗效。这些数据表明，uTSL 技术也可以通过血管内超快释放机制传递非膜渗透性药物，效果显著。
