Centre for Nanosciences and Molecular Medicine, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India.
Central Lab Animal Facility, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Ponekkara PO, Edappally, Kochi, 41, Kerala, India.
Drug Deliv Transl Res. 2022 Nov;12(11):2824-2837. doi: 10.1007/s13346-022-01142-5. Epub 2022 Jun 9.
Orally delivered molecularly targeted small-molecule drugs play a significant role in managing cancer as a chronic disease. However, due to the poor oral bioavailability of some of these molecules, high-dose administration is required leading to dose-limiting toxicity especially when delivered daily for a long duration. Here, we report an oral nanoformulation for small-molecule multi-kinase inhibitor, sorafenib tosylate, showing nearly two fold enhancement in the oral bioavailability and enhanced therapeutic efficacy with a better safety profile compared to the current clinical formulation. Using a scalable process involving high-pressure homogenization, sorafenib was loaded into an albumin nanocarrier at ~ 50 w/w%. Repeated preparation of gram-scale batches (n = 7) showed an average particle size of 180 ± 9 nm, encapsulation efficiency of 95 [Formula: see text] 2%, and drug-loading efficiency of 48 [Formula: see text] 0.7%. Further, surface engineering with a mucoadhesive layer on nanoparticles (referred to as ABSORF) resulted in the final size of 299 ± 38 nm and surface charge of -54 ± 8 mV. Single-dose and multidose pharmacokinetic studies showed two fold enhancement in the plasma concentration of sorafenib compared to current clinically used tablets. Antitumor efficacy studies in the orthotopic rat liver tumor model showed significant tumor regression (p value = 0.0037) even at half dose (eqv. to 200 mg of human equivalent dose) of ABSORF compared to clinical control (eqv. to 400 mg). The biodistribution of sorafenib from ABSORF was higher in the liver; however, liver and kidney function test parameters were comparable with that of the 2 × dose of clinical control. No abnormalities and signs of toxicity were seen in the histopathological analysis for ABSORF-treated animals. In summary, we demonstrate a scalable preparation of small-molecule drug-loaded nanoformulation with approximately two fold enhancement in oral bioavailability, improved antitumor efficacy, and acceptable toxicity profile.
口服递呈的分子靶向小分子药物在将癌症作为慢性病进行管理方面发挥着重要作用。然而，由于其中一些分子的口服生物利用度较差，因此需要高剂量给药，从而导致剂量限制毒性，尤其是当这些药物需要长期每日给药时。在这里，我们报告了一种小分子多激酶抑制剂索拉非尼甲苯磺酸盐的口服纳米制剂，与目前的临床制剂相比，该制剂的口服生物利用度提高了近两倍，治疗效果增强，且安全性更好。通过涉及高压匀质的可扩展工艺，将索拉非尼负载到白蛋白纳米载体中，载药比例约为 50 w/w%。重复制备克级批次（n=7）显示平均粒径为 180±9nm，包封效率为 95[Formula: see text]2%，载药量为 48[Formula: see text]0.7%。此外，通过在纳米颗粒表面进行粘弹性层工程处理（称为 ABSORF），最终粒径为 299±38nm，表面电荷为-54±8mV。单次和多次药代动力学研究表明，与目前临床使用的片剂相比，索拉非尼在血浆中的浓度提高了两倍。在原位大鼠肝肿瘤模型中的抗肿瘤功效研究表明，与临床对照（相当于 400mg 人体等效剂量）相比，即使使用 ABSORF 的半剂量（相当于 200mg 人体等效剂量），也能显著抑制肿瘤生长（p 值=0.0037）。ABSORF 中的索拉非尼的生物分布在肝脏中更高；然而，肝功能和肾功能测试参数与临床对照的 2 倍剂量相当。在接受 ABSORF 治疗的动物的组织病理学分析中未观察到异常和毒性迹象。总之，我们展示了一种可扩展的小分子药物载药纳米制剂的制备方法，该方法可使口服生物利用度提高约两倍，抗肿瘤疗效提高，且毒性谱可接受。
