Designing Mesoporous Prussian Blue@zinc Phosphate Nanoparticles with Hierarchical Pores for Varisized Guest Delivery and Photothermally-Augmented Chemo-Starvation Therapy.

Background: With the rapid development of nanotechnology, constructing a multifunctional nanoplatform that can deliver various therapeutic agents in different departments and respond to endogenous/exogenous stimuli for multimodal synergistic cancer therapy remains a major challenge to address the inherent limitations of chemotherapy. Methods: Herein, we synthesized hollow mesoporous Prussian Blue@zinc phosphate nanoparticles to load glucose oxidase (GOx) and DOX (designed as HMPB-GOx@ZnP-DOX NPs) in the non-identical pore structures of their HMPB core and ZnP shell, respectively, for photothermally augmented chemo-starvation therapy. Results: The ZnP shell coated on the HMPB core, in addition to providing space to load DOX for chemotherapy, could also serve as a gatekeeper to protect GOx from premature leakage and inactivation before reaching the tumor site because of its degradation characteristics under mild acidic conditions. Moreover, the loaded GOx can initiate starvation therapy by catalyzing glucose oxidation while causing an upgradation of acidity and H2O2 levels, which can also be used as forceful endogenous stimuli to trigger smart delivery systems for therapeutic applications. The decrease in pH can improve the pH-sensitivity of drug release, and O2 can be supplied by decomposing H2O2 through the catalase-like activity of HMPBs, which is beneficial for relieving the adverse conditions of anti-tumor activity. In addition, the inner HMPB also acts as a photothermal agent for photothermal therapy and the generated hyperthermia upon laser irradiation can serve as an external stimulus to further promote drug release and enzymatic activities of GOx, thereby enabling a synergetic photothermally enhanced chemo-starvation therapy effect. Importantly, these results indicate that HMPB-GOx@ZnP-DOX NPs can effectively inhibit tumor growth by 80.31% and exhibit no obvious systemic toxicity in mice. Conclusion: HMPB-GOx@ZnP-DOX NPs can be employed as potential theranostic agents that incorporate multiple therapeutic modes to efficiently inhibit tumors.

Designed synthesis of prussian blue@Cu-doped zinc phosphate nanocomposites for chemo/chemodynamic/photothermal combined cancer therapy.

Designing a multifunctional nanoplatform that combines multiple treatments has emerged as an innovative cancer treatment strategy. A simple and clear route is put forward to develop Cu2+-doped zinc phosphate coated prussian blue nanoparticles (designated as PB@Cu2+/ZnP NPs) integrating tri-modal therapy (chemo, chemodynamic and photothermal therapy) for maximizing anti-tumor efficacy. The obtained PB@Cu2+/ZnP NPs possess drug loading capacity due to the mesoporous structure present in the Cu2+-doped ZnP shell. In addition, the Cu2+-doped ZnP shell can gradually degrade in response to the mildly acidic tumor microenvironment to release DOX and Cu2+, where the released drug plays the role of chemotherapy agent and the Cu2+ can react with intracellular glutathione to achieve a Cu-mediated Fenton-like reaction for chemodynamic therapy. Moreover, under laser irradiation, the heat garnered by the photothermal conversion of PB can be applied for photothermal therapy and enhance the generation of toxic ˙OH as well as the amount of DOX released, further boosting chemo- and chemodynamic therapy to realize a combined therapy. Importantly, the PB@Cu2+/ZnP NPs effectively limit the growth of tumors via the coordinated action of chemo/chemodynamic/photothermal therapy and no noticeable systematic toxicity can be found in mice. Taken together, the PB@Cu2+/ZnP NPs can act as a prospective therapeutic nanoplatform for multi-modal therapy of tumors.