Alhudaithi Sulaiman S, Abul Kalam Mohd, Binobaid Lama, Ali Raisuddin, Almutairi Mohammed M, Qamar Wajhul, Bin Hithlayn Hessa, Almutairi Atheer, Alshememry Abdullah K
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Saudi Pharm J. 2024 May;32(5):102064. doi: 10.1016/j.jsps.2024.102064. Epub 2024 Apr 7.
Hepatocellular carcinoma (HCC) exhibits high mortality rates in the advanced stage (>90 %). Sorafenib (SORA) is a targeted therapy approved for the treatment of advanced HCC; however, the reported response rate to such a therapeutic is suboptimal (<3%). Piperine (PIP) is an alkaloid demonstrated to exert a direct tumoricidal activity in HCC and improve the pharmacokinetic profiles of anticancer drugs including SORA. In this study, we developed a strategy to improve efficacy outcomes in HCC using PIP as an add-on treatment to support the first-line therapy SORA using biodegradable Poly (D, L-Lactide-co-glycolide, PLGA) nanoparticles (NPs). SORA and PIP (both exhibit low aqueous solubility) were co-loaded into PLGA NPs (PNPs) and stabilized with various concentrations of polyvinyl alcohol (PVA). The SORA and PIP-loaded PNPs (SP-PNPs) were characterized using Fourier Transform Infrared (FTIR) Spectroscopy, X-ray Powder Diffraction (XRD), Dynamic Light Scattering (DLS), and Scanning Electron Microscopy (SEM), Release of these drugs from SP-PNPs was investigated at both physiological and acidic pH, and kinetic models were employed to assess the mechanism of drug release. The efficacy of SP-PNPs against HCC cells (HepG2) was also evaluated. FTIR and XRD analyses revealed that the drugs encapsulated in PNPs were in an amorphous state, with no observed chemical interactions among the drugs or excipients. Assessment of drug release at pH 5 and 7.4 showed that SORA and PIP loaded in PNPs with 0.5 % PVA were released in a sustained manner, unlike pure drugs, which exhibited relatively fast release. SP-PNPs with 0.5 % PVA were spherical, had an average size of 224 nm, and had a high encapsulation efficiency (SORA ∼ 82 %, PIP ∼ 79 %), as well as superior cytotoxicity compared to SORA monotherapy . These results suggest that combining PIP with SORA using PNPs may be an effective strategy for the treatment of HCC and may set the stage for a comprehensive study to evaluate the efficacy and safety of this novel formulation using a murine HCC model.
肝细胞癌（HCC）在晚期阶段的死亡率很高（>90%）。索拉非尼（SORA）是一种被批准用于治疗晚期HCC的靶向治疗药物；然而，报道的对这种治疗的反应率并不理想（<3%）。胡椒碱（PIP）是一种生物碱，已证明其在HCC中具有直接的杀肿瘤活性，并能改善包括SORA在内的抗癌药物的药代动力学特征。在本研究中，我们开发了一种策略，使用PIP作为一线治疗药物SORA的附加治疗，以提高HCC的疗效，PIP被负载于可生物降解的聚（D，L-丙交酯-共-乙交酯，PLGA）纳米颗粒（NPs）中。SORA和PIP（两者均表现出低水溶性）被共负载到PLGA NPs（PNPs）中，并用不同浓度的聚乙烯醇（PVA）进行稳定化处理。使用傅里叶变换红外（FTIR）光谱、X射线粉末衍射（XRD）、动态光散射（DLS）和扫描电子显微镜（SEM）对负载SORA和PIP的PNPs（SP-PNPs）进行表征。在生理和酸性pH条件下研究了这些药物从SP-PNPs中的释放情况，并采用动力学模型评估药物释放机制。还评估了SP-PNPs对HCC细胞（HepG2）的疗效。FTIR和XRD分析表明，包裹在PNPs中的药物呈无定形状态，未观察到药物或辅料之间的化学相互作用。在pH 5和7.4条件下的药物释放评估表明，负载于含0.5% PVA的PNPs中的SORA和PIP以持续方式释放，与表现出相对快速释放的纯药物不同。含0.5% PVA的SP-PNPs呈球形，平均粒径为224 nm，具有较高的包封率（SORA约为82%，PIP约为79%），与SORA单一疗法相比，具有更强的细胞毒性。这些结果表明，使用PNPs将PIP与SORA联合使用可能是治疗HCC的有效策略，并可能为使用小鼠HCC模型评估这种新型制剂的疗效和安全性的综合研究奠定基础。
