Design of Hybrid MnO₂‐Polymer‐Lipid Nanoparticles with Tunable Oxygen Generation Rates and Tumor Accumulation for Cancer Treatment

Abstract

Manganese dioxide (MnO2) nanoparticles (NPs) were discovered in previous work to be effective in improving tumor oxygenation (hypoxia) and reducing H2O2 and acidity in the tumor microenvironment (TME) via local injection. To develop MnO2 formulations useful for clinical application, hybrid NPs are designed with tailored hydrophobicity and structure suitable for intravenous injection, with good blood circulation, biocompatibility, high tumor accumulation, and programmable oxygen generation rate. Two different hybrid NPs are constructed by embedding polyelectrolyte‐MnO2 (PMD) in hydrophilic terpolymer/protein‐MnO2 (TMD) or hydrophobic polymer/lipid‐MnO2 (LMD) matrices. The in vitro reactivity of the MnO2 toward H2O2 is controlled by matrix material and NP structure and dependent on pH with up to two‐fold higher O2 generation rate at acidic (tumor) pH than at systemic pH. The hybrid NPs are found to be safe to cells in vitro and organs in vivo and effectively decrease tumor hypoxia and hypoxia‐inducible‐factor‐1alpha through local or systemic administration. Fast acting TMD reduces tumor hypoxia by 70% in 0.5 h by local injection. Slow acting LMD exhibits superior tumor accumulation and retention through the systemic administration and decreased hypoxia by 45%. These findings encourage a broader use of hybrid MD NPs to overcome TME factors for cancer treatment.

Manganese Dioxide Coated WS2@Fe3O4/sSiO2 Nanocomposites for pH‐Responsive MR Imaging and Oxygen‐Elevated Synergetic Therapy

“…Interestingly, cells treated with WS 2 ‐IO/S@MO‐PEG showed further reduced viable cell colonies post RT compared to the enhanced RT with WS 2 ‐IO/S‐PEG, indicating that the MnO 2 component could further promote RT‐induced cell killing possibly by increasing the intracellular oxygen level through decomposing endogenous H 2 O 2 produced by tumor cells. [2d,16a,17] Next, γ‐H2AX immunoflourescence staining assay was further employed to study the RT‐induced DNA damage to cells. As shown in Figure e, very low levels of γ‐H2AX fluorescent spots were observed in phosphate buffered saline (PBS) incubated cells regardless of X‐ray radiation, as well as cells treated with WS 2 ‐IO/S‐PEG or WS 2 ‐IO/S@MO‐PEG in absence of X‐ray irradiation.…”

In‐Situ Oxygen‐Evolving Photoactive Nanococktail: The Future of Hypoxic Tumour Photodynamic Therapy

“…To overcome hypoxia‐related therapeutic resistance, they coloaded a near‐infrared light‐absorbing aza‐BODIPY photosensitizer and an anticancer drug, doxorubicin (DOX) onto hydrangea‐structured MnO 2 nanoparticles to generate an in‐situ oxygen‐self‐generating nanocomposite (Scheme ). MnO 2 NPs were used for their well‐known ability to produce O 2 and thus to increase the O 2 concentration within the hypoxic environment in tumours . Dong and co‐workers improved the bioavailability of the nanocomposite by encapsulating it within an amphiphilic polymer polyvinylpyrrolidone (PVP) and achieved a degradable nanoplatform that was responsive to the tumour microenvironment (MDSP NP).…”

Tumor Microenvironment Adaptable Nanoplatform for O2 Self‐Sufficient Chemo/Photodynamic Combination Therapy

“…As we know, MnO 2 could catalyze H 2 O 2 into O 2 for enhanced PDT against hypoxic tumor 41–43. By using dissolve oxygen meter, the generation of O 2 in PMDH solution was quantified after adding H 2 O 2 .…”