Work

Nitroreductase-responsive gated mesoporous silica nanocarriers for hypoxia-targeted drug delivery

Year: 2025

Type: article

Abstract: A new hypoxia-responsive nanocarrier, consisting of mesoporous silica nanoparticles, loaded with doxorubicin, and capped with a nitroreductase-sensitive gatekeeper has been synthesized. In hypoxic conditions, the gatekeeper experiences a self-immolative process leading to delivery of the drug from inside the pores. The nitroreductase-responsive nanocarriers have been tested in vitro with A549 cells, highlighting their potential as nanocarriers for hypoxia-targeted cancer therapy. • Synthesis of gated mesoporous silica nanocarriers for hypoxia targeted drug delivery. • A self-immolative gatekeeper responsive to nitroreductase. • Doxorubicin controlled delivery in the presence of nitroreductase and NADH. • In vitro studies with A549 cells show doxorubicin delivery only in the absence of dicoumarol. Hypoxia, i.e ., low oxygen concentration at the tissue level, is a common feature of most solid tumors, and is responsible for their enhanced aggressiveness and resistance to chemotherapy, radiotherapy and photodynamic therapy. Hypoxic microenvironments are also characterized by the overexpression of various reductase enzymes such as nitroreductases. Herein, we report a hypoxia-responsive hybrid nanomaterial consisting of mesoporous silica nanoparticles, loaded with the chemotherapy drug doxorubicin, and functionalized on their surface with a self-immolative gatekeeper responsive to nitroreductases, for the controlled release of the cargo. Thus, under bioreductive conditions, elicited by the presence of nitroreductase and NADH, the reduction of the nitroaromatic containing molecular gate induces a self-immolative elimination leading to the disintegration of the gatekeeper and the delivery of the doxorubicin from inside the pores. The nitroreductase-responsive nanocarrier has been tested in vitro with A549 cells, that are known to express nitroreductase, to demonstrate its effectiveness as drug carrier for doxorubicin release, showing great potential for the treatment of hypoxic tumors.

Source: International Journal of Pharmaceutics

DOI: 10.1016/j.ijpharm.2025.125326