Upconversion-Nanoparticle-Based Smart Drug-Delivery Platforms for Multimodal Imaging-Guided Cancer Therapies

Hypoxia-inducible factor-1α (HIF-1α)-dependent liver-metastasis-related factor expression mediates breast cancer liver invasion and metastasis, so downregulation of HIF-1α is of great significance for breast cancer treatment and liver metastasis prevention. Herein, UCNPs@mSiO2@Ce6&α-ketoglutarate&GOx@mMnO2@HA (UCAGMH), a smart drug-delivery nanoplatform of about 60 nm size, was prepared for both breast cancer treatment and liver metastasis prevention. The MnO2 was rapidly degraded by acidic pH to produce large amounts of Mn2+ and O2. Mn2+ acts as a contrast agent for magnetic resonance imaging (MRI) and an ideal Fenton-like agent, while O2 promotes photodynamic therapy (PDT) by alleviating hypoxia and promoting the oxidation of intratumoral glucose (Glu) by glucose oxidase (GOx) for starvation therapy (ST). Benefiting from the GOx-based glycolysis process, H2O2 and glucuronic acid were generated, which further amplifies the chemodynamic therapy (CDT) effect. Moreover, O2 and α-ketoglutarate could inhibit angiogenesis by promoting the production of proline hydroxylase (PHD), which accelerated the degradation of hypoxia-inducible factor-1α (HIF-1α), thus regulating angiogenesis-related factors and liver-metastasis-related factors. Angiogenesis inhibition and nutrient depletion at the tumor site can achieve ST, which is a promising strategy for cancer treatment, especially for suppressing the metastasis of tumor cells. The nanoparticles could achieve multimodal imaging (i.e., Ce6-endowed fluorescence imaging, UCNPs-provided computed tomography, and Mn2+-enabled MRI) to guide disease progression and therapeutic efficacy. This cascade bioreactor has the ability to modulate the tumor microenvironment, opening up opportunities to inhibit patterns of breast cancer invasion and metastasis through changes in the HIF-1α downregulated signaling pathways and synergies with multiple therapies.