Lee Jihoon, Kim Jung Mo, Baek Yeon-Ju, Kang Hyojeung, Choi Min-Koo, Song Im-Sook
BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea.
Pharmaceutics. 2025 Aug 11;17(8):1042. doi: 10.3390/pharmaceutics17081042.
: Paclitaxel (PTX) faces clinical limitations in melanoma treatment due to poor solubility, P-glycoprotein (P-gp)-mediated efflux, and systemic toxicity. This study aimed to develop PTX-loaded mesoporous silica nanoparticles (PS), which would be co-administered with curcumin (CUR) and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) to enhance intracellular accumulation and improve anti-tumor activity. CUR and TPGS were integrated with PS to inhibit P-gp-mediated PTX-efflux, to enhance the intracellular accumulation of PTX, and to improve anti-tumor activity in B16F10 cells. The physicochemical properties of PS were analyzed using standard characterization methods. The antitumor activity of PS co-administered with CUR and TPGS was evaluated using two-dimensional (2D) culture and three-dimensional (3D) spheroid assays, and also assessed in B16F10 tumor-bearing mice. The therapeutic mechanism of the PS combination was compared using apoptosis and microtubule disruption through flow cytometry and confocal microscopy. The pharmacokinetics and biodistribution of the PS combination were compared in B16F10 tumor-bearing mice. PS formulations exhibited amorphous transformation with an approximate particle size of 200 nm. PS co-administered with CUR and TPGS reduced the IC to 178.7 nM compared with 283.3 nM for free PTX in B16F10 melanoma cells and achieved significant tumor growth inhibition in B16F10 melanoma spheroid culture. The intracellular accumulation of PTX correlated with its therapeutic efficacy. Flow cytometry revealed a significant induction of both early and late apoptosis in cells treated with the PS + CUR + TPGS combination, while confocal imaging confirmed enhanced microtubule disruption. In B16F10 tumor-bearing mice, PS co-administered with CUR and TPGS demonstrated higher and selective distribution of PTX into tumor tissue without affecting systemic exposure of PTX in B16F10-xenografted mice. PS + CUR + TPGS combination enhanced PTX delivery by improving solubility and enhancing distribution to tumor tissue through P-gp inhibition, thereby increasing its therapeutic potential. The combination of CUR and TPGS offers synergistic apoptosis induction and microtubule disruption. Thus, the PS + CUR + TPGS combination represents a promising approach for treating drug-resistant melanomas.
紫杉醇（PTX）在黑色素瘤治疗中面临临床局限性，原因在于其溶解度差、P-糖蛋白（P-gp）介导的外排以及全身毒性。本研究旨在开发负载PTX的介孔二氧化硅纳米颗粒（PS），将其与姜黄素（CUR）和聚乙二醇1000维生素E琥珀酸酯（TPGS）联合使用，以增强细胞内蓄积并提高抗肿瘤活性。将CUR和TPGS与PS整合，以抑制P-gp介导的PTX外排，增强PTX的细胞内蓄积，并提高对B16F10细胞的抗肿瘤活性。使用标准表征方法分析PS的理化性质。使用二维（2D）培养和三维（3D）球体试验评估与CUR和TPGS联合使用的PS的抗肿瘤活性，并在荷B16F10肿瘤小鼠中进行评估。通过流式细胞术和共聚焦显微镜，利用细胞凋亡和微管破坏比较PS组合的治疗机制。在荷B16F10肿瘤小鼠中比较PS组合的药代动力学和生物分布。PS制剂呈现非晶态转变，粒径约为200nm。与B16F10黑色素瘤细胞中游离PTX的283.3nM相比，与CUR和TPGS联合使用的PS将IC降低至178.7nM，并在B16F10黑色素瘤球体培养中实现了显著的肿瘤生长抑制。PTX的细胞内蓄积与其治疗效果相关。流式细胞术显示，用PS + CUR + TPGS组合处理的细胞中早期和晚期凋亡均有显著诱导，而共聚焦成像证实微管破坏增强。在荷B16F10肿瘤小鼠中，与CUR和TPGS联合使用的PS在不影响B16F10异种移植小鼠中PTX全身暴露的情况下，显示出PTX在肿瘤组织中的更高且选择性分布。PS + CUR + TPGS组合通过改善溶解度和通过抑制P-gp增强向肿瘤组织的分布来增强PTX递送，从而增加其治疗潜力。CUR和TPGS的组合提供协同的凋亡诱导和微管破坏。因此，PS + CUR + TPGS组合代表了一种治疗耐药黑色素瘤的有前景的方法。
