Ultrasound-Triggered Piezocatalysis for Selectively Controlled NO Gas and Chemodrug Release to Enhance Drug Penetration in Pancreatic Cancer

作者：Yuan Wang, Qingshuang Tang, Ruiqi Wu, Suhui Sun, Jinxia Zhang, Jing Chen, Ming Gong, Chaoyi Chen, Xiaolong Liang · 发表于：ACS Nano · 年份：2023 · DOI：10.1021/acsnano.2c09948 · 被引用次数：114 · 研究领域：Nanoplatforms for cancer theranostics、Inhalation and Respiratory Drug Delivery、Cancer, Stress, Anesthesia, and Immune Response

Nitric oxide (NO) is drawing widespread attention in treating pancreatic ductal adenocarcinoma (PDAC) as a safe and therapeutically efficient technique through modulating the dense fibrotic stroma in the tumor microenvironment to enhance drug penetration. Considerable NO nanogenerators and NO releasing molecules have been developed to shield the systemic toxicity caused by free diffusion of NO gas. However, on-demand controlled release of NO and chemotherapy drugs at tumor sites remains a problem limited by the complex and dynamic tumor microenvironment. Herein, we present an ultrasound-responsive nanoprodrug of CPT-t-R-PEG 2000 @BaTiO 3 (CRB) which encapsulates piezoelectric nanomaterials barium titanate nanoparticle (BaTiO 3 ) with amphiphilic prodrug molecules that consisted of thioketal bond (t) linked chemotherapy drug camptothecin (CPT) and NO-donor l -arginine (R). Based on ultrasound-triggered piezocatalysis, BaTiO 3 can continuously generate ROS in the hypoxic tumor environment, which induces a cascade of reaction processes to break the thioketal bond to release CPT and oxidize R to release NO, simultaneously delivering CPT and NO to the tumor site. It is revealed that CRB shows a uniform size distribution, prolonged blood circulation time, and excellent tumor targeting ability. Moreover, controlled release of CPT and NO were observed both in vitro and in vivo under the stimulation of ultrasound, which is beneficial to the depletion of dense stroma and subsequently e...