Drug Delivery and Device Development, MedImmune LLC, Gaithersburg, Maryland 20878.
Formulation Sciences, MedImmune LLC, Gaithersburg, Maryland 20878.
J Pharm Sci. 2017 Aug;106(8):2037-2045. doi: 10.1016/j.xphs.2017.04.041. Epub 2017 Apr 27.
Toll-like receptor (TLR) agonists TLR 7/8, MEDI9197, is a imidazoquinoline analogue that can be used for cancer immunotherapy based on its efficacy toward a variety of tumors. Systemic administration of TLR agonists results in stimulation of the immune system throughout the entire body causing undesirable side effects. To minimize these adverse events, local administration of TLR agonists including intratumoral (IT) delivery has been introduced. Here, a poloxamer 407 thermogel formulation for IT delivery of a TLR 7/8 dual agonist, MEDI9197, is described in which the combination of the aqueous thermogel and the ethanolic TLR 7/8 dual agonist, MEDI9197, solution leads to precipitated drug particles within the gel. The in vitro release profile showed an initial burst followed by sustained release. A B16-OVA mouse tumor model was used to assess the in vivo pharmacokinetics, efficacy, and systemic cytokine and chemokine (cytokine) production of the poloxamer 407-based thermogel formulation. The pharmacokinetic evaluation showed that the agonist level within the tumor was reduced by ∼70% over 14 days while serum agonist levels indicated an initial burst at the 6-h time point followed by a drop in serum drug levels over the 14 days of the experiment. The tumor growth inhibition, survival, and serum cytokines for post-IT injection of the poloxamer 407 formulation showed that it slowly released TLR 7/8 agonist, MEDI9197, resulting in more efficacious tumor growth inhibition compared with control groups. In addition, the cytokine levels in circulation indicated that a dose increase led to a decrease in the serum inflammatory and interferon-inducible cytokines levels. This observation could be due to a reduction of drug diffusion and escape from the tumor site due to the precipitation of the drug inside the tumor leading to sustained release. IT delivery of TLR 7/8 dual agonist, MEDI9197, via a thermosensitive gel-based formulation was efficacious and could offer an alternate method of local drug delivery.
Toll 样受体 (TLR) 激动剂 TLR7/8、MEDI9197 是一种咪唑并喹啉类似物，可通过其对多种肿瘤的疗效用于癌症免疫治疗。TLR 激动剂的全身给药会导致整个免疫系统受到刺激，从而产生不良副作用。为了最小化这些不良反应，已经引入了 TLR 激动剂的局部给药，包括肿瘤内 (IT) 给药。本文描述了一种用于 TLR7/8 双重激动剂 MEDI9197 的 IT 给药的泊洛沙姆 407 温敏凝胶制剂，其中水性温敏凝胶与乙醇 TLR7/8 双重激动剂 MEDI9197 溶液的组合导致凝胶内沉淀药物颗粒。体外释放曲线显示初始突释后持续释放。使用 B16-OVA 小鼠肿瘤模型评估泊洛沙姆 407 基温敏凝胶制剂的体内药代动力学、疗效以及系统细胞因子和趋化因子 (细胞因子) 产生。药代动力学评估显示，在 14 天内，肿瘤内激动剂水平降低了约 70%，而血清激动剂水平在 6 小时时间点显示初始突释，随后在 14 天实验过程中血清药物水平下降。IT 注射后泊洛沙姆 407 制剂的肿瘤生长抑制、存活和血清细胞因子表明，它缓慢释放 TLR7/8 激动剂 MEDI9197，与对照组相比，肿瘤生长抑制更有效。此外，循环中的细胞因子水平表明，剂量增加会导致血清炎症和干扰素诱导的细胞因子水平降低。这种观察结果可能是由于药物扩散减少和由于药物在肿瘤内沉淀导致药物从肿瘤部位逃逸，从而导致持续释放。TLR7/8 双重激动剂 MEDI9197 通过热敏凝胶制剂的 IT 给药是有效的，可为局部药物递送提供替代方法。
