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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.

Multidrug resistance (MDR) is a main cause of chemotherapy failure in cancer treatment. It is associated with complex cellular and molecular mechanisms including overexpression of drug efflux transporters, increased membrane rigidity, and impaired apoptosis. Numerous efforts have been made to overcome efflux transporter-mediated MDR using nanotechnology-based approaches. However, these approaches fail to surmount plasma membrane rigidity that attenuates drug penetration and nanoparticle endocytosis. Here, a “one-two punch” nanoparticle approach is proposed to coordinate intracellular biointeraction and bioreaction of a nanocarrier material docosahexaenoic acid (DHA) and an anticancer prodrug mitomycin C (MMC) to enhance mitochondrion-targeted toxicity. Incorporation of DHA in solid polymer-lipid nanoparticles first reduces the membrane rigidity in live cancer cells thereby increasing nanoparticle cellular uptake and MMC accumulation. Subsequent intracellular MMC bioreduction produces free radicals that in turn react with adjacent DHA inducing significantly elevated mitochondrial lipid peroxidation, leading to irreversible damage to mitochondria. Preferential tumor accumulation of the nanoparticles and the synergistic anticancer cytotoxicity remarkably inhibit tumor growth and prolonged host survival without any systemic toxicity in an orthotopic MDR breast tumor model. This work suggests that combinatorial use of biophysical and biochemical properties of nanocarrier materials with bioreactive prodrugs is a powerful approach to overcoming multifactorial MDR in cancer.