Design, Development, In Silico, and In Vitro Characterization of Camptothecin-Loaded Mixed Micelles: In Vitro Testing of Verapamil and Ranolazine for Repurposing as Coadjuvant Therapy in Cancer

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of Pharmaceutical Innovation Pub Date : 2022-10-06 DOI:10.1007/s12247-022-09688-0

Kiran S. Patil, Ashok A. Hajare, Arehalli S. Manjappa, Harinath N. More, John I. Disouza

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引用次数: 2

Abstract

Purpose

Camptothecin has poor solubility, high systemic toxicity, and intrinsic structural instability. To deal with these challenges, present research aimed to develop camptothecin-loaded mixed micelles (CPT MMs) using TPGS and Pluronic^® F108 copolymers. Furthermore, our research aimed to test in vitro anticancer activities of non-micellar verapamil and ranolazine for repurposing as coadjuvant therapy with CPT MMs in cancer.

Methods

CPT MMs were fabricated by solvent evaporation method and optimized using 3² full factorial design. CPT MMs were characterized for % entrapment efficiency (%EE), mean particle size (MPS), zeta potential, surface morphology, % drug loading capacity (%DLC), in vitro drug release, and in vitro cytotoxicity and cell cycle arresting behaviors.

Result

The in silico studies revealed decent camptothecin interaction with a cavity of mixed micelles (MMs). CPT MMs composition (H5) is considered optimum based on %EE (94.92 ± 2.46%), MPS (136.9 ± 1.71 nm), zeta potential (− 22.9 ± 0.87 mV), and %DLC (1.810 ± 0.02%). TEM image shows self-assembled micelles with spherical shape. CPT MMs showed sustained release profile. The drug-excipient compatibility study revealed no primary incompatibilities. The CPT MMs showed moderately higher IC₅₀ values than camptothecin against A549 and B16F10 cells. The non-micellar verapamil and ranolazine when combined with CPT MMs at lower concentrations have resulted in substantially higher cytotoxicity. Whereas, the CPT MMs + ranolazine combination has shown higher cell cycle arresting behavior than CPT MMs + verapamil combination.

Conclusion

Elaborative and molecular mechanism–based studies are further needed to validate the repurposing potential of non-micellar verapamil and ranolazine as coadjuvant with CPT MMs in cancer.

Graphical Abstract

Abstract Image

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喜树碱负载混合胶束的设计、开发、计算机和体外表征:维拉帕米和雷诺嗪作为癌症辅助治疗的体外测试

摘要目的喜树碱具有溶解性差、全身毒性大和内在结构不稳定等特点。为应对这些挑战，本研究旨在利用 TPGS 和 Pluronic® F108 共聚物开发喜树碱负载混合胶束（CPT MMs）。此外，我们的研究还旨在测试非胶束维拉帕米和雷诺拉嗪的体外抗癌活性，以便将其与 CPT MMs 重新用作癌症的辅助治疗。对 CPT MMs 进行了表征，包括夹带率（%EE）、平均粒径（MPS）、ZETA 电位、表面形态、载药率（%DLC）、体外药物释放、体外细胞毒性和细胞周期阻滞行为。根据%EE（94.92 ± 2.46%）、MPS（136.9 ± 1.71 nm）、zeta 电位（- 22.9 ± 0.87 mV）和%DLC（1.810 ± 0.02%），CPT MMs 的组成（H5）被认为是最佳的。TEM 图像显示自组装胶束呈球形。CPT MMs 具有持续释放特性。药物与辅料的相容性研究表明没有主要的不相容性。CPT MMs 对 A549 和 B16F10 细胞的 IC50 值略高于喜树碱。非乳糜泻维拉帕米和雷诺拉嗪与较低浓度的 CPT MMs 合用时，细胞毒性大大增加。结论需要进一步开展基于实验和分子机理的研究，以验证非微粒维拉帕米和雷诺拉嗪与 CPT MMs 共同辅助治疗癌症的再利用潜力。

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来源期刊

Journal of Pharmaceutical Innovation PHARMACOLOGY & PHARMACY-

CiteScore

3.70

自引率

3.80%

发文量

审稿时长

>12 weeks

期刊介绍： The Journal of Pharmaceutical Innovation (JPI), is an international, multidisciplinary peer-reviewed scientific journal dedicated to publishing high quality papers emphasizing innovative research and applied technologies within the pharmaceutical and biotechnology industries. JPI''s goal is to be the premier communication vehicle for the critical body of knowledge that is needed for scientific evolution and technical innovation, from R&D to market. Topics will fall under the following categories: Materials science, Product design, Process design, optimization, automation and control, Facilities; Information management, Regulatory policy and strategy, Supply chain developments , Education and professional development, Journal of Pharmaceutical Innovation publishes four issues a year.