Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 3100016, China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Biomater Sci. 2023 Nov 21;11(23):7556-7567. doi: 10.1039/d3bm00002h.
Normal prostate tissues generally exhibit a higher level of zinc to maintain their special "citrate-producing" metabolism, while its level dramatically decreases during prostate tumorigenesis. Despite the significant antitumor effects, the intracellular accumulation of zinc in prostate cancer cells also promotes the expression of ZNT1, which in turn results in the efflux of zinc and attenuated cytotoxicity against cancer cells. To solve the dilemma, we developed a 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA)-decorated zeolitic imidazolate framework-8 (ZIF8), which is able to load plasmid DNA encoding the Cas9 editor and single-guide RNA to form Cas9@ZIF8-DUPA nanocomplexes. The intracellular delivery of Cas9@ZIF8-DUPA simultaneously increases the level of zinc and inhibits the ZNT-1 function by disrupting the gene to prevent the efflux of zinc in prostate cancer cells. Due to the high affinity between DUPA and the prostate-specific membrane antigen, Cas9@ZIF8-DUPA nanocomplexes exhibit excellent prostate tumor-targeting ability. The internalization and degradation of Cas9@ZIF8-DUPA not only release free zinc and Cas9 editors, but also reduce zinc efflux through Cas9-mediated genome editing that disables the function of ZNT1. As a result, Cas9@ZIF8-DUPA nanocomplexes exhibit significant antitumor activity and extended survival in the mouse model bearing prostate tumors. The current platform offers an alternative therapeutic strategy and holds tremendous translational potential as an anticancer nanomedicine for prostate cancer treatment.
正常前列腺组织通常表现出更高水平的锌以维持其特殊的“柠檬酸盐产生”代谢，而在前列腺肿瘤发生过程中其水平显著下降。尽管具有显著的抗肿瘤作用，但锌在前列腺癌细胞中的细胞内积累也促进了 ZNT1 的表达，进而导致锌的外排和对癌细胞的细胞毒性减弱。为了解决这一困境，我们开发了一种 2-[3-(1,3-二羧基丙基)脲基]戊二酸（DUPA）修饰的沸石咪唑酯骨架-8（ZIF8），它能够负载编码 Cas9 编辑器和单链向导 RNA 的质粒 DNA 形成 Cas9@ZIF8-DUPA 纳米复合物。Cas9@ZIF8-DUPA 的细胞内递送同时增加了锌的水平，并通过破坏基因抑制 ZNT-1 的功能，以防止前列腺癌细胞中锌的外排。由于 DUPA 与前列腺特异性膜抗原之间的高亲和力，Cas9@ZIF8-DUPA 纳米复合物表现出优异的前列腺肿瘤靶向能力。Cas9@ZIF8-DUPA 的内化和降解不仅释放游离锌和 Cas9 编辑器，而且通过 Cas9 介导的基因组编辑减少锌外排，从而使 ZNT1 失活。结果，Cas9@ZIF8-DUPA 纳米复合物在携带前列腺肿瘤的小鼠模型中表现出显著的抗肿瘤活性和延长的生存时间。该平台提供了一种替代的治疗策略，并作为一种用于前列腺癌治疗的抗癌纳米医学具有巨大的转化潜力。
