Development of hybrid manganese dioxide-organic nanoparticles for diabetes and cancer treatment

Manganese dioxide (MnO2) is one of the strongest oxidants naturally found in the environment and has a wide range of industrial applications. As an old inorganic material, MnO2 has been widely applied in dry cell batteries. Due to its selectivity toward hydrogen peroxide (H2O2), MnO2 has also been explored in the field of sensors, but rarely employed in the biomedical field. Recently Professor Wu’s laboratory at the University of Toronto, Canada, has created hybrid MnO2 nanoparticles and discovered their new applications for diabetes and cancer treatment. The researchers have utilized the triple effects of reactivity of MnO2: decomposition of H2O2, generation of O2, and concurrent increase of pH by consumption of protons required for the reaction between MnO2 and H2O2 (reaction 1). In the present comment, recent developments in exploring these properties of MnO2 by Wu’s group in the areas of diabetes and cancer treatment are presented.

  1. MnO2 + H2O2 + 2H+ --> O2 + Mn2+ + 2H2O

Insulin therapy is an essential treatment for millions of people with diabetes for controlling blood sugar (glucose) levels; however associated with side effects. To provide “smart” insulin delivery, various glucose-responsive insulin delivery systems have been devised through integration of pH-responsive materials with the enzyme glucose oxidase (GOX).  In these systems, glucose is converted to gluconic acid catalyzed by GOX to trigger morphological changes in the pH-responsive material allowing for glucose controlled insulin release. Nevertheless, GOX deactivation by H2O2 (an enzyme by-product) and limited O2 supply (required for glucose oxidation) have compromised the in vivo application of GOX/glucose systems. Even when catalase (CAT) is used in combination with GOX to convert H2O2 to O2, there is still a limitation of O2 supply as only a half of O2 molecule is regenerated by CAT. Wu’s group has developed a strategy to overcome these limitations by introducing MnO2 NPs to composite membranes that contain embedded pH-responsive hydrogel NPs and the enzymes GOX and CAT[1] (Fig. 1). Integration of MnO2 NPs with GOX/CAT/Glucose in one system enhanced the decomposition of generated H2O2 and extended the functional life of the enzymes while recovering O2 fully for glucose oxidation. Wu’s group also took advantage of the pH increase caused by the MnO2 reaction to fine tune the pH change in the microenvironment around the hydrogel nanoparticles in response to small changes in glucose concentration relevant to physiological conditions. Overall, MnO2 was demonstrated to be a vital component in the GOX/CAT-based insulin delivery system, allowing for prolonged efficacy and fast response in vivo in a diabetic rat model[2]. This was the first time that MnO2 was used as a bioreactive component in therapeutic applications.

Figure 1. (Left) SEM image of the surface of a glucose-responsive composite membrane containing MnO2 nanoparticles. The large contrast of electron density between the MnO2 nanoparticles and the biopolymer matrix enables the visualization of the distribution of MnO2 clusters in the membrane. (Right) Cross-sectional ESEM image of the composite membrane. The color coded back-scattering image shows the base matrix in green and MnO2 NPs in red and yellow.
Figure 1. (Left) SEM image of the surface of a glucose-responsive composite membrane containing MnO2 nanoparticles. The large contrast of electron density between the MnO2 nanoparticles and the biopolymer matrix enables the visualization of the distribution of MnO2 clusters in the membrane. (Right) Cross-sectional ESEM image of the composite membrane. The color coded back-scattering image shows the base matrix in green and MnO2 NPs in red and yellow.

Wu’s group has also pioneered the application of the MnO2 chemistry for normalization of the abnormal tumor microenvironment (TME). Differently from normal tissue, the TME is often lack of oxygen (hypoxia), acidic (acidosis) and contains high levels of reactive oxygen species (ROS), such as H2O2. Together, these factors promote tumor growth, spread, and resistance to cancer therapies, leading to treatment failures. Strategies to normalize the TME have previously focused on targeting single factors or proteins in the tumor associated with the abnormal TME. Wu’s group has discovered that MnO2 nanoparticles delivered to tumors could modulate multiple factors simultaneously and tackle the major problems of TME at their roots. The MnO2 nanoparticles were shown to exert multiple effects within the tumor: 1) reacting with H2O2 produced by cancer cells (ROS attenuation), 2) quenching H+ and thus elevating the tumor pH (acidosis attenuation), and 3) producing O2 sustainably within the tumor tissue (hypoxia attenuation)[3] (Fig.2). 

To make MnO2 suitable for clinical application, the Wu lab has designed a library of hybrid MnO2 nanoparticles with a variety of organic materials, e.g. proteins, polymers and lipids alone or in combinations[4]. By controlling the size, shape, surface charge, structure, and chemistry of the nanoparticles, the researchers obtained hybrid MnO2 nanoparticles that are non-toxic, colloidally stable under physiological conditions, and excellent in blood circulation and tumor accumulation. A unique feature of the hybrid MnO2 nanoparticles is that the kinetics of O2 generation can be tailored by changing the hydrophobicity and structure of the nanoparticles[4].  In addition, a higher reaction rate of MnO2 nanoparticles in the acidic condition enables their selective effect on tumors. In the studies with tumor-bearing mice, the hybrid MnO2 nanoparticles were able to simultaneously generate oxygen within tumors by consuming hydrogen peroxide produced by cancer cells while increasing tumor pH. These reactions generated biological effects on the tumor tissue by decreasing the levels of harmful proteins responsible for tumor aggressiveness and angiogenesis such as hypoxia inducible factor 1-alpha and vascular endothelial growth factor[3]. The increased tumor oxygenation by the action of MnO2 also made cancer cells more sensitive to radiation treatment[3]. The pioneer work of Wu and co-workers encourage a broad range of biomedical applications of MnO2, which are exemplified in their work for diabetes and cancer treatment.

Figure 2. Schematic illustration of the abnormal tumor microenvironment resulting in resistance to therapy and the novel approach discovered by Wu’s group to modulating tumor microenvironment with hybrid MnO2 nanoparticles. Hybrid nanoparticles are composed of a biocompatible carrier (polymers, protein, solid lipids and their combinations) loaded with bioreactive MnO2 and with a PEG-like brush on the surface. The hybrid MnO2 nanoparticles can react with endogenous levels of H2O2 (ROS attenuation) and quench H+ (acidosis attenuation) and produce O2 sustainably within the tumor (hypoxia attenuation). The triple effect of the hybrid MnO2 nanoparticles also reduced levels of tumor-promoting proteins and enhanced treatment efficacy.
Figure 2. Schematic illustration of the abnormal tumor microenvironment resulting in resistance to therapy and the novel approach discovered by Wu’s group to modulating tumor microenvironment with hybrid MnO2 nanoparticles. Hybrid nanoparticles are composed of a biocompatible carrier (polymers, protein, solid lipids and their combinations) loaded with bioreactive MnO2 and with a PEG-like brush on the surface. The hybrid MnO2 nanoparticles can react with endogenous levels of H2O2 (ROS attenuation) and quench H+ (acidosis attenuation) and produce O2 sustainably within the tumor (hypoxia attenuation). The triple effect of the hybrid MnO2 nanoparticles also reduced levels of tumor-promoting proteins and enhanced treatment efficacy.

Authors:

Dr. Claudia R. Gordijo is Research Associate at the Leslie L. Dan Faculty of Pharmacy, the University of Toronto and Projects Officer at Sunnybrook Research Institute in Toronto, Ontario, Canada. Dr. Xiao Yu (Shirley) Wu is Professor and Director of Advanced Pharmaceutics & Drug Delivery Laboratory at the Leslie L. Dan Faculty of Pharmacy, the University of Toronto.

*Corresponding author Prof. Xiao Yu (Shirley) Wu: xywu@phm.utoronto.ca

Further Reading:

  1. C. R. Gordijo, A. J. Shuhendler, X. Y. Wu, Glucose-Responsive Bioinorganic Nanohybrid Membrane for Self-Regulated Insulin Release, Adv. Funct. Mater. 2010, 20, 1404.
  2. C. R. Gordijo, K. Koulajian, A. J. Shuhendler, L. D. Bonifacio, H. Y. Huang, S. Chiang, G. A. Ozin, A. Giacca , X. Y. Wu, Nanotechnology-Enabled Closed Loop Insulin Delivery Device: In Vitro and In Vivo Evaluation of Glucose-Regulated Insulin Release for Diabetes Control, Adv. Funct. Mater. 2011, 21, 73.
  3. P. Prasad, C. R. Gordijo, A. Z. Abbasi, A. Ip, A. Maeda, A. M. Rauth, R. S. DaCosta, X. Y. Wu, Multifunctional Albumin-MnO2 Nanoparticles Modulate Solid Tumor Microenvironment by Attenuating Hypoxia, Acidosis, Vascular Endothelial Growth Factor and Enhance Radiation Response, ACS Nano. 2014, 8, 3202.
  4. C. R. Gordijo, A. Z. Abbasi, M. A. Amini, H. Lip, A. Maeda, P. Cai,  P. J. O’Brien, R. S. DaCosta, A. M. Rauth, X. Y. Wu, Design of Hybrid MnO2-Polymer-Lipid Nanoparticles with Tunable Oxygen Generation Rates and Tumor Accumulation for Cancer Treatment, Adv. Funct. Mater. 2015, DOI: 10.1002/adfm.201404511.