Drug Delivery and Formulation, Medicinal Chemistry Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario, Canada M5G 0A3.
J Control Release. 2011 Sep 25;154(3):290-7. doi: 10.1016/j.jconrel.2011.05.020. Epub 2011 May 26.
The combination of thermosensitive liposomes and local heating has been shown to improve anticancer drug delivery in both animal models and human patients. The lyso-lipid temperature sensitive liposomes (LTSL) consisting of DPPC, MSPC and DSPE-PEG(2000) is currently under evaluation in clinical trials. We hypothesized that Brij surfactants resembling the chemical structures of MSPC and DSPE-PEG(2000) could be utilized for generating a thermosensitive formulation with DPPC. Here, we report using a robust in vitro system to efficiently screen a series of liposomal candidates composed of DPPC and a Brij surfactant for thermosensitive delivery of doxorubicin. The data indicated that the optimal acyl chain length of the surfactant was between C(16) and C(18) with a saturated carbon chain, a PEG repeating unit ranging between 10 and 100 and a molecule weight above 600Da. The linking chemistry between the acyl chain and the PEG chain did not influence thermosensitivity. In the panel of surfactants tested, Brij78 was optimal and could be incorporated into the liposomes by the thin film hydration or the post-insertion method with an optimal range of 1 to 8mol%. Doxorubicin was incorporated into the formulation by pH gradient with >95% loading efficiency at drug/lipid of 1/20 (w/w). The transition temperature of the Brij78-liposomes was slightly lower than that of LTSL (41 v.s. 41.5°C), leading to enhanced drug release at the low end of the hyperthermic temperatures (40°C) with similar stability at 37°C, which was confirmed by cell based assays. Finally, the Brij78-liposomes and LTSL displayed comparable blood compatibility with mild hemolytic activity. This in vitro system allowed for efficient screening and optimization to produce an optimal formulation.
热敏脂质体与局部加热相结合已被证明可提高动物模型和人类患者中抗癌药物的递送效果。由 DPPC、MSPC 和 DSPE-PEG（2000）组成的溶脂质体热敏脂质体（LTSL）目前正在临床试验中进行评估。我们假设，与 MSPC 和 DSPE-PEG（2000）的化学结构相似的 Brij 表面活性剂可用于生成具有 DPPC 的热敏制剂。在这里，我们报告了使用强大的体外系统来有效地筛选一系列由 DPPC 和 Brij 表面活性剂组成的脂质体候选物，以热敏方式递送达柔比星。数据表明，表面活性剂的最佳酰链长度为 C（16）和 C（18）之间，具有饱和碳链、PEG 重复单元在 10 到 100 之间和分子量高于 600Da。酰链和 PEG 链之间的连接化学不影响热敏性。在所测试的表面活性剂中，Brij78 是最佳的，可通过薄膜水化或后插入法以 1 至 8mol%的最佳范围掺入脂质体中。阿霉素通过 pH 梯度掺入制剂中，药物/脂质比为 1/20（w/w）时载药效率>95%。Brij78 脂质体的相变温度略低于 LTSL（41 对 41.5°C），导致在低热疗温度（40°C）下药物释放增强，在 37°C 下具有相似的稳定性，这通过细胞基测定得到了证实。最后，Brij78 脂质体和 LTSL 具有相似的血液相容性，溶血活性轻微。该体外系统允许进行高效筛选和优化，以产生最佳制剂。
