Multifunctional Albumin–MnO₂ Nanoparticles Modulate Solid Tumor Microenvironment by Attenuating Hypoxia, Acidosis, Vascular Endothelial Growth Factor and Enhance Radiation Response

Abstract

Insufficient oxygenation (hypoxia), acidic pH (acidosis), and elevated levels of reactive oxygen species (ROS), such as H2O2, are characteristic abnormalities of the tumor microenvironment (TME). These abnormalities promote tumor aggressiveness, metastasis, and resistance to therapies. To date, there is no treatment available for comprehensive modulation of the TME. Approaches so far have been limited to regulating hypoxia, acidosis, or ROS individually, without accounting for their interdependent effects on tumor progression and response to treatments. Hence we have engineered multifunctional and colloidally stable bioinorganic nanoparticles composed of polyelectrolyte-albumin complex and MnO2 nanoparticles (A-MnO2 NPs) and utilized the reactivity of MnO2 toward peroxides for regulation of the TME with simultaneous oxygen generation and pH increase. In vitro studies showed that these NPs can generate oxygen by reacting with H2O2 produced by cancer cells under hypoxic conditions. A-MnO2 NPs simultaneously increased tumor oxygenation by 45% while increasing tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor in a murine breast tumor model. Intratumoral treatment with NPs also led to the downregulation of two major regulators in tumor progression and aggressiveness, that is, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to radiation therapy alone. These results suggest great potential of A-MnO2 NPs for modulation of the TME and enhancement of radiation response in the treatment of cancer.

Manganese dioxide nanosheets-based redox/pH-responsive drug delivery system for cancer theranostic application

“…Previous research showed that MnO 2 material was capable of enhancing the effect of radiation treatment, which involved in mediation of tumor progression-related factors, such as hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the tumor. 43 These findings may explain partly for the observed inhibition action of MnO 2 /HA in this study. Interestingly, compared to the CDDP group, MnO 2 /HA/CDDP nanosheets exhibited an obviously strengthened antitumor efficiency (P,0.05) because the relative tumor volume was only 1.72±0.25, indicating that this is a successful application in which MnO 2 nanosheet was used as a theranostic system.…”

“…The improved antitumor effect for MnO 2 /HA/CDDP could be explained from the following two aspects: 1) the tumor-targeting property and extended circulation time of CDDP with the help of HA led to the accumulation in tumor and 2) the efficient cellular internalization by tumor cells would result in enhanced cell growth inhibition because of the combination of the inherent role of CDDP and the downregulation of tumor progressionrelated factors derived from MnO 2 nanosheets. 43 A major drawback of CDDP is its side effects in normal cells and tissues, prominently toxicity in the kidneys. 44 International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 34.215.51.103 on 13-May-2018 For personal use only.…”

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

“…Using systemic buffers may increase the activity of certain drugs that are normally inactive in such acidic environments [216,219]. Recently, nanoparticles that target both hypoxia and acidosis of the tumor microenvironment have been developed [226]. These bioinorganic nanoparticles are composed of polyelectrolyte-albumin complex and MnO 2 that rescue the oxygen depleted environment by the reactivity of MnO 2 with ROS, such as H 2 O 2 , and increasing the tumor pH from 6.7 to 7.2.…”

“…These bioinorganic nanoparticles are composed of polyelectrolyte-albumin complex and MnO 2 that rescue the oxygen depleted environment by the reactivity of MnO 2 with ROS, such as H 2 O 2 , and increasing the tumor pH from 6.7 to 7.2. This therapy has been shown to reduce tumor growth, down-regulate HIF-1, VEGF, and increase cancer cell death when combined with radiation therapy in a mouse model [226]. Exciting new cancer therapies such as these are on the horizon in the direct targeting of the tumor microenvironment.…”

Copper-Free Click Chemistry Modification of Nanovectors for Integrin-Targeted Cancer Therapy

“…The bilayer structure affords liposome to load both hydrophilic and hydrophobic drugs. Other amphiphilic nanoparticulate systems have also been investigated for cancer drug delivery, such as polymeric nanostructures (e.g., polymersomes, micelles, and dendrimers) [17,18], and inorganic nanomaterials, including gold, single-/multi-wall carbon nanotubes, mesoporous silica, quantum dots, magnetic, and porous silicon (PSi) nanomaterials [19][20][21][22][23].…”