Shaikh Rehan, Bhattacharya Sankha, Saoji Suprit D
Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra, 425405, India.
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Nagpur, Mahatma Jyotiba Fuley Shaikshanik Parisar, University Campus, Amravati Road, Nagpur, 440033, Maharashtra, India.
Heliyon. 2024 Oct 22;10(21):e39632. doi: 10.1016/j.heliyon.2024.e39632. eCollection 2024 Nov 15.
The efficacy of dasatinib (DAS) in treating hepatocellular carcinoma (HCC) is hindered by its poor bioavailability, limiting its clinical potential. In this study, we explored the use of TPGS-Soluplus micelles as an innovative drug delivery platform to enhance DAS solubility, stability, and therapeutic impact. A series of TPGS-Soluplus copolymers were synthesized, varying the D-α-tocopheryl polyethylene glycol succinate (TPGS) forms (1000, 2000, and 3500) and adjusting the TPGS to Soluplus weight ratios (1:1, 1:2, and 1:3). Our goal was to identify the optimal formulation with the highest entrapment efficiency, smallest particle size, and enhanced drug loading. The TPGS1000-Soluplus copolymer, with a DAS-to-polymer ratio of 1:30 and a TPGS ratio of 1:2, demonstrated superior performance, achieving an entrapment efficiency of 64.479 ± 1.45 % and drug loading of 5.05 ± 1.01 %. The DAS-loaded micelles (DAS-PMs) exhibited a notably small particle size of 64.479 ± 1.45 nm and demonstrated controlled release kinetics, with 85.60 ± 5.4 % of the drug released over 72 h. Cellular uptake studies using Hep G2 cells revealed significantly enhanced absorption of DAS-PMs compared to free DAS, reflected in lower IC50 values in MTT assays at 24 and 48 h. Pharmacokinetic analysis further highlighted the benefits of the DAS-PMs, with an AUC0-∞ 2.16 times higher and mean residual time (MRT) 1.3 times longer than free DAS, a statistically significant improvement (p < 0.01). These findings suggest that TPGS-Soluplus micelles offer a promising strategy for improving the bioavailability and efficacy of DAS in HCC treatment, presenting a potential new therapeutic avenue for patients with limited options. This innovative formulation could significantly enhance DAS delivery, potentially leading to improved clinical outcomes in liver cancer therapy.
达沙替尼（DAS）治疗肝细胞癌（HCC）的疗效因其生物利用度差而受到阻碍，限制了其临床应用潜力。在本研究中，我们探索了使用TPGS-固体分散体胶束作为一种创新的药物递送平台，以提高达沙替尼的溶解度、稳定性和治疗效果。合成了一系列TPGS-固体分散体共聚物，改变了D-α-生育酚聚乙二醇琥珀酸酯（TPGS）的形式（1000、2000和3500），并调整了TPGS与固体分散体的重量比（1:1、1:2和1:3）。我们的目标是确定具有最高包封率、最小粒径和增强载药量的最佳制剂。TPGS1000-固体分散体共聚物，达沙替尼与聚合物的比例为1:30，TPGS比例为1:2，表现出优异的性能，包封率达到64.479±1.45%，载药量为5.05±1.01%。载有达沙替尼的胶束（DAS-PMs）粒径显著小，为64.479±1.45nm，并表现出控释动力学，72小时内85.60±5.4%的药物被释放。使用Hep G2细胞的细胞摄取研究显示，与游离达沙替尼相比，DAS-PMs的吸收显著增强，这在24小时和48小时的MTT试验中表现为较低的IC50值。药代动力学分析进一步突出了DAS-PMs的优势，其AUC0-∞ 比游离达沙替尼高2.16倍，平均残留时间（MRT）长1.3倍，具有统计学显著改善（p<0.01）。这些发现表明，TPGS-固体分散体胶束为提高达沙替尼在HCC治疗中的生物利用度和疗效提供了一种有前景的策略，为选择有限的患者提供了一条潜在的新治疗途径。这种创新制剂可显著增强达沙替尼的递送，可能导致肝癌治疗临床结果的改善。
