Sequential Ultrasound-Triggered and Hypoxia-Sensitive Nanoprodrug for Cascade Amplification of Sonochemotherapy.

Abstract

Hypoxia, the typical and conspicuous characteristic of most solid tumors, worsens the tumor invasiveness and metastasis. Here, we engineered a sequential ultrasound (US)/hypoxia-sensitive sonochemotherapeutic nanoprodrug by initially synthesizing the hypoxia-activated azo bond-containing camptothecin (CPT) prodrug (CPT2-Azo) and then immobilizing it into the mesopores of sonosensitizer-integrated metal organic frameworks (MOF NPs). Upon entering the hypoxic tumor microenvironment (TME), the structure of CPT2-Azo immobilized MOFs (denoted as MCA) was ruptured and the loaded nontoxic CPT2-Azo prodrug was released from the MOF NPs. Under US actuation, this sonochemotherapeutic nanoprodrug not only promoted sonosensitizer-mediated sonodynamic therapy (SDT) via the conversion of oxygen into cytotoxic reactive oxygen species (ROS) but also aggravated hypoxia in the TME by elevating oxygen consumption. The exacerbated hypoxia in turn served as a positive amplifier to boost the activation of CPT2-Azo, and the controllable release of toxic chemotherapeutic drug (CPT), and compensated the insufficient treatment efficacy of SDT. In vitro and in vivo evaluations confirmed that sequential SDT and tumor hypoxia-activated sonochemotherapy promoted the utmost of tumor hypoxia and thereby contributed to the augmented antitumor efficacy, resulting in conspicuous apoptotic cell death and noteworthy tumor suppression in vivo. Our work provides a distinctive insight into the exploitation of the hypoxia-activated sonochemotherapeutic nanoprodrug that utilizes the hypoxic condition in TME, a side effect of SDT, to initiate chemotherapy, thus causing a significantly augmented treatment outcome compared to conventional SDT.

• Authors: Fan Zhuang, Qiong Ma, Caihong Dong, Huijing Xiang, Yujia Shen, Pei Sun, Cuixian Li, Yixin Chen, Beilei Lu, Yu Chen, Beijian Huang
• Journal: ACS nano (ACS Nano) Vol. 16 Issue 4 Pg. 5439-5453 (Apr 26 2022) ISSN: 1936-086X [Electronic] United States
• PMID: 35357810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Prodrugs
• Antineoplastic Agents
• Reactive Oxygen Species
• Camptothecin

Topics

• Humans
• Prodrugs (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Hypoxia (therapy)
• Reactive Oxygen Species (metabolism)
• Neoplasms (diagnostic imaging, drug therapy)
• Camptothecin (pharmacology, therapeutic use)
• Cell Line, Tumor
• Nanoparticles (chemistry)
• Ultrasonic Therapy
• Tumor Microenvironment