Tailoring polymeric nanocarriers for hypoxia-specific drug release: Insights into design and applications in clinics

Schematic representation of the various hypoxia-responsive drug carriers used in various cancers. [Display omitted] •Hypoxic conditions in TME could be used for controlled drug release.•Hypoxia active Prodrugs selectively target tumor cells minimizing systemic toxicity.•Azo, nitro, and N-oxide-modified polymers could serve as hypoxia-responsive carrier.•Hypoxia-responsive nanocarrier could co-deliver other chemotherapeutic drugs to TME. Hypoxic environment-responsive nanocarriers represent a promising future in targeted drug delivery to solid tumors since hypoxia has an important role in tumor proliferation, angiogenesis, and metastasis, offering a means to overcome resistance to cancer therapy. Exploiting hypoxic conditions for cancer treatment can be achieved through two distinct approaches. Firstly, by using hypoxia-activated prodrugs (HAP) and secondly by developing nanocarriers in response to hypoxia. HAPs, such as tirapazamine, metronidazole, etc can convert into anti-cancer drugs upon hypoxic conditions, reducing the chances of side effects by eliminating non-specific targeting due to the low oxygen content and the presence of numerous bioreductive enzymes like azo, nitro-reductase. However, HAPs were unsuccessful in clinical trials due to low extravascular transport which implies the necessity of nanocarriers for their effective delivery to tumor site. Thus, precise designing of the hypoxia-responsive nanocarriers that can deliver anticancer agents or HAPs is of utmost importance for tumor-specific delivery. The current review focuses on various nano vehicles, including liposomes, micelles, hydrogel, nanogel, and dendrimers synthesized by polymeric materials to render them hypoxia-responsive properties. Here, we explain the release of chemotherapeutic drugs from the nanocarriers in the tumor cells, due to the reduction of the hypoxia-responsive functional groups. Furthermore, the limitations and potential considerations of improving hypoxia-responsive drug administration are discussed.