Modulating Hypoxia via Nanomaterials Chemistry for Efficient Treatment of Solid Tumors

The common existence of hypoxia in solid tumors has been heavily researched because it renders tumors more resistant to most standard therapeutic methods, such as radiotherapy (RT), chemotherapy, and photodynamic therapy (PDT), and is associated with a more malignant phenotype and poor survival in patients with tumors. The development of hypoxia modulation methods for advanced therapeutic activity is therefore of great interest but remains a considerable challenge. Since the significant development of nanotechnology and nanomedicine, functionalized nanomaterials can be exploited as adjuvant "drugs" for these oxygen-dependent standard therapies or as hypoxia initiators for advanced new therapies to solid tumors. In this Account, we summarize our recent studies on the design and synthesis of nanomaterials with a set of desired chemistry benefits achievable by modulating hypoxia, suggesting a valid therapeutic option for tumors. The investigated strategies can be categorized into three groups: The first strategy is based on countering hypoxia. Considering that O₂ deficiency is the major obstacle for the oxygen-dependent therapies, we initially developed methods to supply O₂ by taking advantage of the hypoxia-responsive properties of nano-MnO₂ or nanomaterials' photothermal effects for increased intratumoral blood flow. The second approach is to disregard hypoxia. Possible benefits of nanoagents include reducing/eliminating reliance on O₂ or making O₂ replacements as adjuvants to standard therapies. To this end, we investigated a nano-upconversion/scintillator with the capacity toup-/down-convert near-infrared light (NIR)/X-ray to luminescence in the ultraviolet/visible region fortype-I PDT with minimized oxygen-tension dependency or developed Fe-based nanomaterials for chemodynamic therapy (CDT) without external energy and oxygen participation for efficient free radical killing of deep tumors. The third strategy involves exploiting hypoxia. The unique biological characteristics of hypoxia are exploited to activate nanoagents for new therapies. To address the discrepancy between the nanoagents' demand and supply within the hypoxia region, a smart "molecule-nano" medicine that stays small-molecule-like in the bloodstream and turns into self-assembled nanovesicles after entry into the hypoxia region was constructed for hypoxia-adaptive photothermal therapy (PTT). In addition to traditional anti-angiogenesis therapy, we prepared Mg₂Si nanoparticles by a special self-propagating high-temperature synthesis approach. These nanoparticles can directly remove the intratumoral oxygen via the oxidation reactions of Mg₂Si and later efficiently block the rapid reoxygenation via tumor blood vessels by the resultant SiO₂ microsheets for cancer starvation therapy. Taken together, these findings indicate that nanomaterials will assume a valuable role for anticancer exploration based on either their properties to make up oxygen deficiency or the use of hypoxia for therapeutic applications.