响应MMP-2的金纳米棒载HSP-70 siRNA以增强光热肿瘤治疗

MMP-2 Responsive Gold Nanorods Loaded with HSP-70 siRNA for Enhanced Photothermal Tumor Therapy

MOLECULAR PHARMACEUTICS

影响因子:4.5

分区:医学2区 / 药学2区医学：研究与实验3区

发表日期:2024 Nov 04

作者: Ran Sun, Yaoqi Wang, Qi Sun, Yan Su, Jie Zhang, Danni Liu, Ran Huo, Yang Tian, Myagmarsuren Baldan, Shuang Zhang, Chunying Cui

DOI: 10.1021/acs.molpharmaceut.4c00188

摘要

金纳米棒（Au NRs）是一种具有重要价值的光热纳米材料，广泛用于肿瘤治疗。然而，在采用Au NRs进行光热治疗时，肿瘤中的热休克蛋白表达会升高，这会诱导肿瘤细胞产生耐热性，降低Au NRs的光热治疗效果。通过RNA干扰技术，能够有效抑制热休克蛋白的表达，从而提高肿瘤光热治疗的疗效。然而，深层且非侵入性的组织穿透仍是成功应用siRNA的重大障碍。因此，设计了AGC/HSP-70 siRNA纳米平台，以通过RNA干扰增强光热肿瘤治疗。在AGC/HSP-70 siRNA复合物中，Au-S键修饰了金纳米棒表面的基质金属蛋白酶-2（MMP-2）敏感肽GPLGLAG。此外，自然碱性多糖壳聚糖通过酰胺键与肽反应，用于输送热休克蛋白70沉默siRNA（HSP-70 siRNA）。修饰MMP-2敏感连接子可以促使更多Au NRs在肿瘤中积聚，以发挥光热作用，并促进HSP-70 siRNA和壳聚糖复合物穿透深层肿瘤组织。体外实验表明，MMP-2敏感连接子的酶解可以促进HSP-70 siRNA在肿瘤细胞中的细胞摄取和核周分布，这可能归因于复合物体积较小且带正电。所有这些结果确保了HSP-70 siRNA的高效基因沉默作用，从而增强Au NRs在肿瘤组织中的光热治疗效果，基因沉默和细胞凋亡实验均证实了这一点。体内实验进一步证明，AGC/HSP-70 siRNA纳米平台有效改善了Au NRs的光热效果。总之，本研究证明，AGC/HSP-70 siRNA是一种有前景的药物递送策略，能够通过调节深层肿瘤细胞的光热敏感性，增强肿瘤的光热治疗效果，同时保持更多的Au NRs在肿瘤组织中，为肿瘤光热治疗提供了新的策略。

Abstract

Gold nanorods (Au NRs) are a valuable photothermal nanomaterial for tumor therapy. However, when treated with Au NRs for photothermal therapy, the expression of heat shock proteins in tumors will increase, which will induce heat resistance in tumor cells and reduce the photothermal therapeutic effect of Au NRs. By RNA interference, the expression of heat shock proteins would be effectively inhibited to improve the efficasy of tumor photothermal therapy. However, deep and noninvasive tissue penetration remains a great obstacle to applying siRNA successfully. Thus, the nanoplatform AGC/HSP-70 siRNA was designed for enhanced photothermal tumor therapy by RNA interference. In the AGC/HSP-70 siRNA complex, the Au-S bond modified the matrix metalloproteinase-2 (MMP-2)-sensitive peptide GPLGLAG on the surface of gold nanorods. Moreover, the natural basic polysaccharide (chitosan) was reacted with the peptide by an amide bond for delivering heat shock protein 70 silencing siRNA (HSP-70 siRNA). Modifying the MMP-2-sensitive linker could cause more Au NRs to accumulate in tumors to exert a photothermal effect and promote the penetration of HSP-70 siRNA and chitosan complexes into deep tumor tissues. In vitro experiments indicated that the enzymolysis of the MMP-2-sensitive linker for AGC/HSP-70 siRNA could promote the cellular uptake and perinuclear distribution of HSP-70 siRNA in tumor cells, which may be due to the smaller size and positive electricity of the complexes. All of these results ensured the efficient gene silencing effect of HSP-70 siRNA to enhance the photothermal therapeutic effect of Au NRs in tumor tissues, as demonstrated by the gene silencing and cellular apoptotic experiments. In vivo experiments further proved that the AGC/HSP-70 siRNA nanoplatform efficiently improved the photothermal effect of Au NRs. In summary, this work proved that AGC/HSP-70 siRNA is a promising drug delivery strategy for enhancing the photothermal therapy of tumors by regulating the photothermal sensitivity of deep tumor cells as well as retaining more Au NRs in tumor tissues, and also provides a novel strategy for tumor photothermal therapy.