Hypoxia-responsive nanocarriers for cancer imaging and therapy: recent approaches and future perspectives

Hypoxia, a condition in which the tissue is deprived of adequate oxygen supply, is a salient feature of various intractable diseases, including rheumatoid arthritis, ischemic stroke, and solid tumors. In particular, hypoxic regions in tumors are often associated with invasiveness, metastasis, and resistance to radiotherapy and chemotherapy. Given its unique role in tumor progression, hypoxia has been considered to be a primary target for the diagnosis and treatment of cancer. Owing to their sizes and tailorable physicochemical characteristics, nanocarriers are an emerging class of materials that are increasingly utilized in biomedical applications. Particularly, stimuli-responsive nanocarriers, which release their payloads specifically at the tumor-microenvironment, are materials of interest. Owing to the aberrant vascular properties of tumors, the transportation of anticancer drugs to hypoxic regions is challenging because they are distant from blood vessels. In addition, hypoxia upregulates various genes involved in drug resistance such as P-glycoprotein. To surmount the issues associated with hypoxia, nanocarriers that can release imaging agents or anticancer drugs in hypoxic regions must be developed. This review focuses on recently developed hypoxia-responsive conjugates or nanocarriers and their potential applications in cancer imaging and therapy. Low oxygen levels bring forth conformational changes in hypoxia-responsive nanocarriers through the cleavage or reduction of hypoxia-responsive functional groups. A greater understanding of these changes will help to design more efficient nanocarriers to address the challenges encountered with hypoxia in conventional chemotherapy.