Department of Interventional Radiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China.
Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, China.
Nano Lett. 2022 Sep 14;22(17):6877-6887. doi: 10.1021/acs.nanolett.2c01005. Epub 2022 Aug 29.
Intracellular transcytosis can enhance the penetration of nanomedicines to deep avascular tumor tissues, but strategies that can improve transcytosis are limited. In this study, we discovered that pyknomorphic extracellular matrix (ECM) is a shield that impairs endocytosis of nanoparticles and their movement between adjacent cells and thus limits their active transcytosis in tumors. We further showed that degradation of pivotal constituent of ECM (i.e., collagen) effectively enhances intracellular transcytosis of nanoparticles. Specifically, a collagenase conjugating transcytosis nanoparticle (Col-TNP) can dissociate into collagenase and cationized gold nanoparticles in response to tumor acidity, which enables their ECM tampering ability and active transcytosis in tumors. The breakage of ECM further enhances the active transcytosis of cationized nanoparticles into deep tumor tissues as well as radiosensitization efficacy of pancreatic adenocarcinoma. Our study opens up new paths to enhance the active transcytosis of nanomedicines for the treatment of cancers and other diseases.
细胞内转胞吞作用可以增强纳米药物向深部无血管肿瘤组织的渗透，但能够提高转胞吞作用的策略有限。在这项研究中，我们发现致密细胞外基质（ECM）是一种阻碍纳米颗粒内吞作用及其在相邻细胞间运动的屏障，从而限制了它们在肿瘤中的主动转胞吞作用。我们进一步表明，细胞外基质（即胶原）的关键成分的降解可有效增强纳米颗粒的细胞内转胞吞作用。具体而言，胶原酶偶联转胞吞纳米颗粒（Col-TNP）可在响应肿瘤酸度时分解为胶原酶和阳离子化金纳米颗粒，从而使它们具有 ECM 篡改能力和在肿瘤中的主动转胞吞作用。ECM 的破裂进一步增强了阳离子化纳米颗粒向深部肿瘤组织的主动转胞吞作用以及胰腺腺癌的放射增敏作用。我们的研究为增强纳米药物的主动转胞吞作用以治疗癌症和其他疾病开辟了新途径。
