Abstract:

Photodynamic therapy （PDT） mainly uses light to stimulate photosensitizers to produce reactive oxygen species （such as singlet oxygen （¹O₂）， superoxide anion （·O^2-）， etc.） for killing tumor cells， which has excellent specificity and spatiotemporal selectivity. However， due to the short lifetime of ¹O₂ and the over-expressed reduced glutathione （GSH） in the tumor microenvironments， the therapeutic effect of PDT is limited. Therefore， the zeolite imidazole framework （ZIF-8）， which responds to the degradation of tumor microenvironment， was selected as the carrier in this work， and the photosensitizer indocyanine green （ICG）， the prodrug nicorandil （Nic） of nitrous oxide （NO）， and hyaluronic acid （HA） were packed on ZIF-8. An intelligent nanomedicine ZIF@IN@HA was successfully constructed. The drug can release NO in situ in response to over-expressed GSH in the tumor microenvironment to achieve gas therapy （GT）. Combined photothermal （PTT） and PDT can be achieved under irradiation with 808 nm near-infrared （NIR） light. At the same time， NO reacted with ¹O₂ to obtain more cytotoxic reactive nitrogen （RNS）， which further improved the therapeutic effect. The experimental results show that ZIF@IN@HA has excellent photothermal conversion performance， photodynamic treatment effect and GSH responsive NO release performance. Modification of HA enables ZIF@IN@HA to be specifically targeted and enriched in tumor cells. Under the irradiation of 808 nm laser， ZIF@IN@HA can not only produce ROS， but also show excellent photothermal conversion performance. In the weakly acidic condition of the tumor， ZIF@IN@HA gradually degrades， releases prodrug Nic in situ， and further responds to GSH in the tumor microenvironment to achieve controlled release of NO. The reaction of NO with ROS can also be converted to more cytotoxic RNS， further improving the therapeutic effect. In conclusion， ZIF@IN@HA can achieve safe and efficient tumor treatment through the synergistic effect of PDT/PTT/GT.

Key words: Tumor tissue microenvironment, Reactive oxygen species, Nitric oxide, Tumor therapy, Biodegradation