Improved Antitumor Efficiency of N⁴ -Tetradecyloxycarbonyl Gemcitabine-Loaded Liposomes for Pancreatic Cancer Chemotherapy.

IF 6.6 2区医学 Q1 NANOSCIENCE & NANOTECHNOLOGY International Journal of Nanomedicine Pub Date : 2024-12-11 eCollection Date: 2024-01-01 DOI:10.2147/IJN.S485861

Dan Wang, Xiaobo Wang, Yan Li, Xiaowei Wang, Xuelei Wang, Jiayi Su, Apeng Wang, Kai Lv, Mingliang Liu, Guimin Xia

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Abstract

Background: Gemcitabine (Gem) is one of the first-line chemotherapy drugs for pancreatic cancer treatment. However, its short half-life in plasma and adverse effects limited its broader application.

Methods: A novel Gem derivative (N⁴ -tetradecyloxycarbonyl gemcitabine, tcGem) was synthesized and encapsulated into liposomes (LipotcGem) to overcome the above shortcomings.

Results: LipotcGem has been successfully formulated, with the average size of 115 nm, zeta potential values of -36 mV, encapsulation efficiency of up to 98%, and drug loading capacity of 8.1%. Compared to Gem, LipotcGem improved in vitro antitumor activity significantly, as evidenced by the lower IC₅₀, the higher percentage of apoptotic cells, the stronger ability to inhibit cell migration and invasion due to the higher cellular accumulation (100 times). Additionally, the endocytosis of LipotcGem was mainly mediated by caveolae, and was then processed in the lysosome, where tcGem was released and hydrolyzed into Gem. LipotcGem inhibited tumor growth by 70% in subcutaneous xenograft model and 90% in orthotopic xenograft model, respectively. LipotcGem suppressed tumor metastasis and prolonged survival without perceptible systemic toxicity, which may be caused by the longer t_1/2 in vivo (3.5 times, 5.23 vs 1.46 h) and more enrichment in tumor tissue (750 times).

Conclusion: LipotcGem significantly increased the anti-tumor efficiency and decreased the toxicity for chemotherapy of pancreatic cancer.

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N4 -十四烷氧基羰基吉西他滨负载脂质体用于胰腺癌化疗的抗肿瘤效率得到提高

背景：吉西他滨（Gem吉西他滨（Gem）是治疗胰腺癌的一线化疗药物之一。然而，吉西他滨在血浆中的半衰期短以及不良反应限制了它的广泛应用：方法：合成了一种新型的吉西他滨衍生物（N4-十四烷氧基羰基吉西他滨，tcGem），并将其封装到脂质体（LipotcGem）中，以克服上述缺点：LipotcGem 的平均粒径为 115 nm，zeta 电位为 -36 mV，包封效率高达 98%，载药量为 8.1%。与 Gem 相比，LipotcGem 显著提高了体外抗肿瘤活性，具体表现在 IC50 更低、凋亡细胞比例更高、细胞蓄积量更高（100 倍）导致抑制细胞迁移和侵袭的能力更强。此外，LipotcGem 的内吞主要由洞穴孔介导，然后在溶酶体中进行处理，tcGem 在溶酶体中被释放并水解为 Gem。在皮下异种移植模型中，LipotcGem 对肿瘤生长的抑制率为 70%；在正位异种移植模型中，LipotcGem 对肿瘤生长的抑制率为 90%。LipotcGem 可抑制肿瘤转移并延长生存期，且无明显的全身毒性，这可能是由于它在体内的 t1/2 时间更长（3.5 倍，5.23 小时对 1.46 小时），在肿瘤组织中的富集度更高（750 倍）：结论：脂质凝胶能明显提高胰腺癌化疗的抗肿瘤效率并降低毒性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Nanomedicine NANOSCIENCE & NANOTECHNOLOGY-PHARMACOLOGY & PHARMACY

CiteScore

14.40

自引率

3.80%

发文量

511

审稿时长

1.4 months

期刊介绍： The International Journal of Nanomedicine is a globally recognized journal that focuses on the applications of nanotechnology in the biomedical field. It is a peer-reviewed and open-access publication that covers diverse aspects of this rapidly evolving research area. With its strong emphasis on the clinical potential of nanoparticles in disease diagnostics, prevention, and treatment, the journal aims to showcase cutting-edge research and development in the field. Starting from now, the International Journal of Nanomedicine will not accept meta-analyses for publication.