Shnaikat Sewar G, Shakya Ashok K, Bardaweel Sanaa K
Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan.
School of Pharmacy, The University of Jordan, Amman, Jordan.
Saudi Pharm J. 2024 Jul;32(7):102099. doi: 10.1016/j.jsps.2024.102099. Epub 2024 May 18.
Colorectal cancer is one of the major causes of global cancer, with chemotherapy and radiation therapy being effective but limited due to low specificity. Regorafenib, a multikinase inhibitor, provides hope to patients with metastatic colorectal cancer and was approved by the FDA in 2012. However, due to resistance issues and adverse events, its efficacy is compromised, necessitating further refinement. Meanwhile, curcumin, a compound of turmeric, exhibits anticancer effects through antioxidant and anti-inflammatory actions, induction of the apoptosis, arrest of cell cycle, inhibition of angiogenesis, and modulation of signaling pathways. Unfortunately, its clinical utility is limited by its poor bioavailability, pointing towards innovative drug delivery strategies for enhanced efficacy in colorectal cancer treatment. Hyaluronic acid (HA)-decorated liposomes (LIPO) have been developed to target colorectal cells through an overexpressed CD44 receptor, increasing antitumor and antimetastasis efficacy. This study investigates the possibility of loading curcumin (CUR) or regorafenib (REGO) into a liposomal formulation for passive and HA-actively targeted treatment, evaluating its critical quality attributes (CQA) (size, zeta potential, polydispersity index) and cytotoxic activity in the HT29 colorectal cancer cell line. The average particle size of the plain liposomes and those decorated with HA was 144.00 ± 0.78 nm and 140.77 ± 1.64 nm, respectively. In contrast, curcumin-loaded plain liposomes and HA-decorated liposomes had 140 ± 2.46 nm and 164.53 ± 15.13 nm, respectively. The prepared liposomes had a spherical shape with a narrow size distribution and an acceptable zeta potential of less than -30 mV. The encapsulation efficiency was 99.2 % ± 0.3 and 99.9 ± 0.2 % for HA-decorated and bare regorafenib loaded. The % EE was 98.9 ± 0.2 % and 97.5 ± 0.2 % for bare liposomal nanoparticles loaded with curcumin and coated with curcumin. The IC of free REGO, CUR, REGO-LIPO, CUR-LIPO, REGO-LIPO-HA and CUR-LIPO-HA were 20.17 ± 0.78, 64.4 ± 0.33, 224.8 ± 0.06, 49.66 ± 0.22, 73.66 ± 0.6, and 27.86 ± 0.49 µM, respectively. The MTT assay in HT29 cells showed significant cytotoxic activity of the HA-decorated liposomal formulation compared to the base uncoated formulation, indicating that hyaluronic acid-targeted liposomes loaded with regorafenib or curcumin could be a promising targeted formulation against colorectal cancer cells.
结直肠癌是全球癌症的主要病因之一，化疗和放疗虽有效果，但由于特异性低，作用有限。瑞戈非尼是一种多激酶抑制剂，为转移性结直肠癌患者带来了希望，并于2012年获得美国食品药品监督管理局（FDA）批准。然而，由于耐药问题和不良事件，其疗效受到影响，需要进一步改进。同时，姜黄素是姜黄中的一种化合物，通过抗氧化和抗炎作用、诱导细胞凋亡、使细胞周期停滞、抑制血管生成以及调节信号通路发挥抗癌作用。不幸的是，其临床应用受到生物利用度差的限制，这表明需要创新的药物递送策略来提高结直肠癌治疗的疗效。已开发出用透明质酸（HA）修饰的脂质体（LIPO），通过过表达的CD44受体靶向结直肠细胞，提高抗肿瘤和抗转移疗效。本研究探讨将姜黄素（CUR）或瑞戈非尼（REGO）载入脂质体制剂进行被动和HA主动靶向治疗的可能性，评估其关键质量属性（CQA）（粒径、zeta电位、多分散指数）以及在HT29结直肠癌细胞系中的细胞毒性活性。普通脂质体和HA修饰脂质体的平均粒径分别为144.00±0.78nm和140.77±1.64nm。相比之下，载姜黄素的普通脂质体和HA修饰脂质体的粒径分别为140±2.46nm和164.53±15.13nm。所制备的脂质体呈球形，粒径分布窄，zeta电位小于-30mV，可接受。HA修饰的载瑞戈非尼脂质体和未修饰的载瑞戈非尼脂质体的包封率分别为99.2%±0.3和99.9%±0.2%。载姜黄素的普通脂质体纳米粒和载姜黄素的包衣脂质体纳米粒的包封率分别为98.9%±0.2%和97.5%±0.2%。游离REGO、CUR、REGO-LIPO、CUR-LIPO、REGO-LIPO-HA和CUR-LIPO-HA的半数抑制浓度（IC）分别为20.17±0.78、64.4±0.33、224.8±0.06、49.66±0.22、73.66±0.6和27.86±0.49μM。HT29细胞中的MTT试验表明，与未包衣的基础制剂相比，HA修饰的脂质体制剂具有显著的细胞毒性活性，这表明载瑞戈非尼或姜黄素的HA靶向脂质体可能是一种有前景的针对结直肠癌细胞的靶向制剂。
