MMP-2响应金纳米棒，装有HSP-70 siRNA，用于增强光热肿瘤疗法
MMP-2 Responsive Gold Nanorods Loaded with HSP-70 siRNA for Enhanced Photothermal Tumor Therapy
影响因子:4.50000
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
摘要
金纳米棒（AU NRS）是用于肿瘤疗法的有价值的光热纳米材料。但是，当用AU NRS治疗用于光热治疗时，肿瘤中热休克蛋白的表达将增加，这将诱导肿瘤细胞中的耐热性并降低Au NRS的光热治疗作用。通过RNA干扰，将有效抑制热休克蛋白的表达，以提高肿瘤光热治疗的效率。然而，深层和无创的组织穿透仍然是成功应用siRNA的巨大障碍。因此，设计了纳米植物AGC/HSP-70 siRNA，可通过RNA干扰增强光热肿瘤治疗。在AGC/HSP-70 siRNA复合物中，Au-S键修改了金纳米棒表面上的基质金属蛋白酶-2（MMP-2）敏感肽GPLGLAG。此外，天然碱性多糖（壳聚糖）通过酰胺键与肽反应，用于传递热激蛋白70沉默siRNA（HSP-70 siRNA）。修改MMP-2敏感的接头可能会导致更多的Au NR在肿瘤中积聚以发挥光热作用，并促进HSP-70 siRNA和壳聚糖复合物在深肿瘤组织中的渗透。体外实验表明，用于AGC/HSP-70 siRNA的MMP-2敏感连接器的酶解会促进肿瘤细胞中HSP-70 siRNA的细胞摄取和核周分布，这可能是由于复合物的大小和阳性电力所致。所有这些结果确保了HSP-70 siRNA的有效基因沉默效应，以增强肿瘤组织中Au NR的光热治疗作用，如基因沉默和细胞凋亡实验所证明的那样。体内实验进一步证明了AGC/HSP-70 siRNA纳米植物有效改善了Au nrs的光热效应。总而言之，这项工作证明，AGC/HSP-70 siRNA是一种有希望的药物输送策略，可通过调节深肿瘤细胞的光热敏感性以及在肿瘤组织中保留更多的AU NR，并为肿瘤光疗疗法提供新的策略，从而增强肿瘤的光热治疗。
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.