Drug Delivery and Translational Research ( IF 5.7 ) Pub Date : 2022-06-09 , DOI: 10.1007/s13346-022-01142-5 Lekshmi Gopakumar 1 , Maya Sreeranganathan 1 , Shalin Chappan 1 , Sneha James 1 , Genekehal Siddaramana Gowd 1 , Maneesh Manohar 1 , Arya Sukumaran 1 , Ayalur Kodakara Kochugovindan Unni 2 , Shantikumar Vasudevan Nair 1 , Manzoor Koyakutty 1
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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 \(\pm\) 2%, and drug-loading efficiency of 48 \(\pm\) 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.
Graphical abstract
中文翻译：
增强索拉非尼在核壳蛋白纳米颗粒中的口服生物利用度和抗肿瘤疗效
口服分子靶向小分子药物在将癌症作为一种慢性疾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差，需要大剂量给药，导致剂量限制性毒性，尤其是在长时间每天给药时。在这里，我们报告了一种用于小分子多激酶抑制剂甲苯磺酸索拉非尼的口服纳米制剂，与目前的临床制剂相比，口服生物利用度提高了近两倍，治疗效果增强，安全性更好。使用涉及高压均质化的可扩展过程，将索拉非尼以约 50 w/w% 的浓度加载到白蛋白纳米载体中。克级批次的重复制备 ( n = 7) 显示平均粒径为 180 ± 9 nm，包封效率为 95 \(\pm\) 2%，载药效率为 48 \(\pm\) 0.7%。此外，在纳米颗粒上具有粘膜粘附层的表面工程（称为 ABSORF）导致最终尺寸为 299 ± 38 nm，表面电荷为 -54 ± 8 mV。单剂量和多剂量药代动力学研究表明，与目前临床使用的片剂相比，索拉非尼的血浆浓度提高了两倍。在原位大鼠肝肿瘤模型中进行的抗肿瘤疗效研究显示肿瘤显着消退（p值 = 0.0037) 即使是 ABSORF 与临床对照（相当于 400 毫克）相比的一半剂量（相当于 200 毫克人体等效剂量）。来自 ABSORF 的索拉非尼在肝脏中的生物分布更高；然而，肝肾功能测试参数与2×剂量的临床对照相当。在 ABSORF 治疗动物的组织病理学分析中未见异常和毒性迹象。总之，我们展示了一种可扩展的小分子载药纳米制剂制剂，其口服生物利用度提高了大约两倍，抗肿瘤疗效提高，毒性可接受。
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