Tumor hypoxia is a poor prognostic factor in a number of malignancies such as prostate cancer (PCa). Clinically relevant hypoxic levels are detected in 30-90% PCa with oxygen concentrations below that required for half-maximal radiosensitivity, thus making radiotherapy (RT) ineffective alone .
Recently our lab has created pharmaceutically acceptable bioreactive hybrid manganese dioxide nanoparticles (MDNPs) and demonstrated their ability to modulate tumor microenvironment (TME) by reacting with H2O2 and protons and producing O2 in hypoxic tumors, as well as to enhance radiation response of tumor.
Lipid encapsulated and polymer stabilizedMDNPs (LMD NPs) were prepared by dispersing MnO2 precursor particles in melted lipid and polymer and then characterized for the particle size and zeta potential. In-vitro oxygen generation of LMD NPs was examined by measuring oxygen saturation level (sO2) in the blood using photoacoustic (PA) imaging method with addition of LMD NPs and H2O2.
Biodistribution of LMD NPs in PCa tumor-bearing mice was evaluated by using a Xenogen IVIS Spectrum Imaging System following IV injection of ICG labeled NPs through the tail vein. Mice were monitored non-invasively for up to 24 hours.
To investigate the effect of combination of MDNPs and radiation therapy on tumor growth delay and survival, PCa tumor-bearing mice were treated intravenously with LMD NPs with saline as a control. Four hour post injection, 10 Gy radiation dose was given at the site of the tumor. Mice were monitored every 2 days by measuring tumor size using a caliper. Mice were sacrificed when the tumor size reached 500 mm3.
PA imaging demonstrated a controlled and prolonged generation of O2 in the blood with maximum oxygen saturation (90-95%) being reached within 60 min after incubation with LMD NPs and H2O2. The biodistribution and ex-vivo images of the resected organs showed that LMD NPs accumulated in the prostate tumor sites within 1 h post i.v. injection and remained in the tumor for at least 24 h. The ex vivo optical data of excised tissue showed a significant uptake of LMD nanoparticles by prostate tumor 24 hpost particle administration. The combination of LMD NPs treatment with single dose 10 Gy RT inhibited tumor growth by 24% at 5 days post treatment, whereas the tumor size increased about 47% in mice treated with RT alone. LMD NPs plus RT also improved survival rate of the cancerous mice for up to 53 days, which was about 3.3-fold enhancement in the mean survival rate compared to saline plus RT treatment (30 days).
The new bioreactive MnO2 NPs exhibited desirable oxygen- generating profile and high tumor accumulation and retention after systemic administration. This work has demonstrated, in a preclinical prostate tumor model, that the combination of LMD NPs with radiation therapy is a promising treatment approach for solid tumor..
Citation Format: Mohammad Ali Amini, Azhar Z. Abbasi, Claudia R. Gordijo1, Ping Cai, Andrew M. Rauth, Robert G. Bristow, Xiao Yu Wu. Hybrid bioactive nanoparticles for modulating prostate tumor microenvironment and enhancing radiation therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 745.