用于增强实体瘤深度渗透及同时进行磁热致敏免疫疗法以对抗肿瘤增殖和转移的磁性纳米液滴

Magnetic Nanodroplets for Enhanced Deep Penetration of Solid Tumors and Simultaneous Magnetothermal-Sensitized Immunotherapy against Tumor Proliferation and Metastasis.

作者信息

Wang Junrui, Zhang Wenli, Xie Zhuoyan, Wang Xingyue, Luo Ying, Jiang Weixi, Liu Yun, Wang Zhigang, Ran Haitao, Song Weixiang, Guo Dajing

机构信息

Department of Radiology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P. R. China.

Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P. R. China.

出版信息

Adv Healthc Mater. 2022 Dec;11(23):e2201399. doi: 10.1002/adhm.202201399. Epub 2022 Oct 3.

Abstract

The central cells of solid tumors are more proliferative and metastatic than the marginal cells. Therefore, more intelligent strategies for targeting cells with deep spatial distributions in solid tumors remain to be explored. In this work, a biocompatible nanotheranostic agent with a lipid membrane-coated, Fe O and perfluoropentane (PFP)-loaded, cRGD peptide (specifically targeting the integrin αvβ3 receptor)-grafted, magnetic nanodroplets (MNDs) is developed. The MNDs exhibit excellent magnetothermal conversion and controllable magnetic hyperthermia (MHT) through alternating magnetic field regulation. Furthermore, MHT-mediated magnetic droplet vaporization (MDV) induces the expansion of the MNDs to transform them into ultrasonic microbubbles, increasing the permeability of tissue and the cell membrane via the ultrasound-targeted microbubble destruction (UTMD) technique and thereby promoting the deep penetration of MNDs in solid tumors. More importantly, MHT not only causes apoptotic damage by downregulating the expression of the HSP70, cyclin D1, and Bcl-2 proteins in tumor cells but also improves the response rate to T-cell-related immunotherapy by upregulating PD-L1 expression in tumor cells, thus inhibiting the growth of both primary and metastatic tumors. Overall, this work introduces a distinct application of nanoultrasonic biomedicine in cancer therapy and provides an attractive immunotherapy strategy for preventing the proliferation and metastasis of deeply distributed cells in solid tumors.

摘要

实体瘤的中心细胞比边缘细胞具有更强的增殖和转移能力。因此,针对实体瘤中具有深层空间分布的细胞的更智能策略仍有待探索。在这项工作中,开发了一种生物相容性纳米诊疗剂,其为脂质膜包裹、负载Fe₃O₄和全氟戊烷(PFP)、接枝cRGD肽(特异性靶向整合素αvβ3受体)的磁性纳米液滴(MNDs)。MNDs通过交变磁场调节表现出优异的磁热转换和可控的磁热疗(MHT)。此外,MHT介导的磁滴汽化(MDV)诱导MNDs膨胀,将其转化为超声微泡,通过超声靶向微泡破坏(UTMD)技术增加组织和细胞膜的通透性,从而促进MNDs在实体瘤中的深度渗透。更重要的是,MHT不仅通过下调肿瘤细胞中HSP70、细胞周期蛋白D1和Bcl-2蛋白的表达引起凋亡损伤,还通过上调肿瘤细胞中PD-L1的表达提高对T细胞相关免疫疗法的反应率,从而抑制原发性和转移性肿瘤的生长。总体而言,这项工作介绍了纳米超声生物医学在癌症治疗中的独特应用,并为预防实体瘤中深层分布细胞的增殖和转移提供了一种有吸引力的免疫治疗策略。

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