Abstract 5051: Comparison of microbeam versus conventional broadbeam radiation therapy on tumor delivery enhancement of PEGylated liposomal doxorubicin in a triple negative breast cancer mouse model
Authors: Chang Sha X. , Rivera Judith N. , Herity Leah B. , Price Lauren S. , Madden Andrew J. , Roques Jose R. , Santos Charlene , Darr David , Zamboni William C. 
Published: July 2017

Background: Recent meta-analyses have reported that the tumor delivery of nanoparticles (NPs) is lower than expected and inefficient. Thus, there is a strong need to develop new methods to enhance the tumor delivery of NPs without increasing toxicity. Microbeam radiation therapy (MRT) is an experimental therapy utilizing an array of parallel microplaner X-ray beams to deliver periodically oscillating high and low dose regions in the treatment volume. MRT has been shown to eradicate tumors and causes significantly less toxicity compared to equivalent radiation doses delivered by conventional broadbeam radiation therapy (BRT). Our prior studies reported that MRT significantly altered tumor microvasculature and enhanced the tumor delivery of PEGylated liposomal doxorubicin (PLD) compared to PLD alone in mice (Chang et al. AACR 2015). In this study we compared MRT and the clinically widely used BRT in their ability to enhance the tumor delivery of PLD in a preclinical murine tumor model.

Methods: Plasma and tumor PK studies of PLD were performed in a genetically engineered mouse model of claudin-low triple-negative breast cancer (T11) in 4 treatment regimens: 1) PLD alone, 2) BRT 28 Gy + PLD, 3) MRT 28 Gy + PLD, 4) MRT 100 Gy + PLD. Mice received a single radiation treatment 24 h prior to administration of PLD at 6 mg/kg IVP x 1 via a tail vein. Following administration of PLD, mice were harvested at 5 min and 24 h. Encapsulated and released doxorubicin concentrations (conc) in plasma and sum total (encapsulated + released) doxorubicin conc in tumor were measured by HPLC with fluorescence.

Results: The mean ± SD conc of sum total doxorubicin in tumor at 24 h after administration of PLD alone, BRT 28 Gy + PLD, MRT 28 Gy + PLD, and MRT 100 Gy + PLD were 2,575 ± 459, 8,601 ± 1,552*, 7,579 ± 4,428, and 12,911 ± 3,445* ng/mL, respectively (*P&lt;0.05 vs PLD alone). In addition, the ratio of tumor sum total conc to plasma encapsulated conc at 24 h for PLD alone, BRT 28 Gy + PLD, MRT 28 Gy + PLD, and MRT 100 Gy + PLD were 0.21 ± 0.04, 0.51 ± 0.17*, 0.39 ± 0.22, and 1.45 ± 0.70*, respectively (*P&lt;0.05 vs PLD alone). The exposures of sum total doxorubicin in tumor at 5 min were similar in all groups. The plasma PK of PLD was also similar in all groups.

Conclusions: MRT and BRT administered 24 h prior to PLD increased the tumor exposure of sum total doxorubicin compared to PLD alone with 100Gy MRT having the greatest increase in tumor delivery of PLD. In addition, MRT exhibits significantly lower toxicity to normal tissues in comparison to BRT allowing for enhanced PLD tumor delivery with low toxicity. Studies are ongoing to evaluate the mechanism(s) for the enhanced tumor uptake of PLD induced by MRT. Future studies include investigating dose dependence of MRT-induced tumor delivery enhancement and effects on other NP agents and tumor models.

Citation Format: Sha X. Chang, Judith N. Rivera, Leah B. Herity, Lauren S. Price, Andrew J. Madden, Jose R. Roques, Charlene Santos, David Darr, William C. Zamboni. Comparison of microbeam versus conventional broadbeam radiation therapy on tumor delivery enhancement of PEGylated liposomal doxorubicin in a triple negative breast cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5051. doi:10.1158/1538-7445.AM2017-5051