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沸石咪唑酯骨架结构-8（ZIF-8）作为端粒酶抑制剂BIBR 1532运输与释放的药物递送载体。

Zeolitic Imidazolate Framework-8 (ZIF-8) as a Drug Delivery Vehicle for the Transport and Release of Telomerase Inhibitor BIBR 1532.

作者信息

Zhang Shunyu, Li Jinxia, Yan Liang, You Yue, Zhao Feng, Cheng Jixing, Yang Limin, Sun Yanqi, Chang Qingchao, Liu Ru, Li Yunhui

机构信息

Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing 210000, China.

CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.

出版信息

Nanomaterials (Basel). 2023 May 31;13(11):1779. doi: 10.3390/nano13111779.

DOI:10.3390/nano13111779
PMID:37299682
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10254680/
Abstract

Telomerase is constitutively overexpressed in the majority of human cancers and telomerase inhibition provides a promising broad-spectrum anticancer therapeutic strategy. BIBR 1532 is a well-known synthetic telomerase inhibitor that blocks the enzymatic activity of hTERT, the catalytic subunit of telomerase. However, water insolubility of BIBR 1532 leads to low cellular uptake and inadequate delivery and thus, limits its anti-tumor effects. Zeolitic imidazolate framework-8 (ZIF-8) is considered as an attractive drug delivery vehicle for improved transport, release and anti-tumor effects of BIBR 1532. Herein, ZIF-8 and BIBR 1532@ZIF-8 were synthesized, respectively, and the physicochemical characterizations confirmed the successful encapsulation of BIBR 1532 in ZIF-8 coupled with an improved stability of BIBR 1532. ZIF-8 could alter the permeability of lysosomal membrane probably by the imidazole ring-dependent protonation. Moreover, ZIF-8 encapsulation facilitated the cellular uptake and release of BIBR 1532 with more accumulation in the nucleus. BIBR 1532 encapsulation with ZIF-8 triggered a more obvious growth inhibition of cancer cells as compared with free BIBR 1532. A more potent inhibition on hTERT mRNA expression, aggravated G0/G1 arrest accompanied with an increased cellular senescence were detected in BIBR 1532@ZIF-8-treated cancer cells. Our work has provided preliminary information on improving the transport, release and efficacy of water-insoluble small molecule drugs by using ZIF-8 as a delivery vehicle.

摘要

端粒酶在大多数人类癌症中持续过度表达，抑制端粒酶提供了一种有前景的广谱抗癌治疗策略。BIBR 1532是一种著名的合成端粒酶抑制剂，可阻断端粒酶催化亚基hTERT的酶活性。然而，BIBR 1532的水不溶性导致细胞摄取率低和递送不足，因此限制了其抗肿瘤作用。沸石咪唑酯骨架-8（ZIF-8）被认为是一种有吸引力的药物递送载体，可改善BIBR 1532的运输、释放和抗肿瘤作用。在此，分别合成了ZIF-8和BIBR 1532@ZIF-8，物理化学表征证实BIBR 1532成功封装在ZIF-8中，同时BIBR 1532的稳定性得到提高。ZIF-8可能通过咪唑环依赖性质子化改变溶酶体膜的通透性。此外，ZIF-8封装促进了BIBR 1532的细胞摄取和释放，使其在细胞核中积累更多。与游离BIBR 1532相比，用ZIF-8封装BIBR 1532对癌细胞的生长抑制作用更明显。在BIBR 1532@ZIF-8处理的癌细胞中检测到对hTERT mRNA表达的更强抑制、G0/G1期阻滞加剧以及细胞衰老增加。我们的工作为利用ZIF-8作为递送载体改善水不溶性小分子药物的运输、释放和疗效提供了初步信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/2e325b48d941/nanomaterials-13-01779-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/3f8f225f1887/nanomaterials-13-01779-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/5473c9ea4c30/nanomaterials-13-01779-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/e0872ac53b1a/nanomaterials-13-01779-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/7c53041093c6/nanomaterials-13-01779-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/720b553be076/nanomaterials-13-01779-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/01aa213dccb5/nanomaterials-13-01779-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/5afd46226b2e/nanomaterials-13-01779-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/2e325b48d941/nanomaterials-13-01779-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/3f8f225f1887/nanomaterials-13-01779-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/5473c9ea4c30/nanomaterials-13-01779-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/e0872ac53b1a/nanomaterials-13-01779-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/7c53041093c6/nanomaterials-13-01779-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/720b553be076/nanomaterials-13-01779-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/01aa213dccb5/nanomaterials-13-01779-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/5afd46226b2e/nanomaterials-13-01779-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda5/10254680/2e325b48d941/nanomaterials-13-01779-g007.jpg

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