Abstract 4516: The effects of microbeam radiation therapy on the pharmacokinetics of PEGylated liposomal doxorubicin in a triple negative breast cancer GEM model
Authors: Chang Xiao S. , Madden Andrew Jacob , Rivera Judith , Santos Charlene , Darr David , Hunter Lucas , Zamboni William C. 
Published: August 2015

Background: Carrier-mediated agents (CMAs), such as nanoparticle and liposomes, can achieve greater exposure in tumors compared with small molecule drugs; however, the overall percent of CMAs that distribute from the plasma to tumor is relatively low (e.g. &lt;10-20%). Thus, there is a need to discover methods of improving the overall delivery of CMAs to tumors. Microbeam radiation therapy (MRT) is a novel radiation therapy treatment that has been shown to eradicate tumor without damaging the function of normal tissues exposed to the same high dose radiation in animal studies. MRT utilizes an array of parallel microplaner beams delivering periodically oscillating high and low dose regions in the treatment volume. Our preliminary results suggest that MRT alters tumor microvasculature differently than normal tissue microvasculature. We hypothesize that the changes in microvasculature induced by MRT can be used to enhance drug delivery to tumors. Thus, we evaluated the effects of MRT on the pharmacokinetics (PK) of PEGylated liposomal doxorubicin (PLD) in preclinical tumor models.

Methods: Studies were performed in mice bearing p53 null syngeneic orthotopic tumor transplants. This model, named “T11”, has been characterized by gene expression array to reflect the claudin-low subtype of triple-negative breast cancer. Prior to administration of PLD, mice received a single treatment of 28Gy or 34Gy (peak dose at skin entrance) MRT to the tumor site (treatment area is ∼1cm x 1cm), or no radiation treatment. All groups were then administered PLD at 6 mg/kg IV x 1 at 16 h after MRT. Mice (n = 3) were sacrificed at 5 min, 6 h, and 24 h after PLD. Mice treated with 34 Gy MRT were only sacrificed at 24 h after PLD. The PK of PLD in plasma and tumor was evaluated.

Results: Mice treated with 28 Gy MRT prior to PLD administration and PLD alone had a total doxorubicin tumor AUC of 206,040.0 ng/mL•h and 55,506.5 ng/mL•h, respectively. After treatment with 28 Gy and 34 Gy MRT the concentration of total doxorubicin in tumor at 24 h after administration of PLD were 10,665.8 ng/ml and 20,779.0 ng/ml, respectively. The plasma PK of PLD was similar in all groups.

Conclusions: MRT treatment prior to PLD administration significantly improves the delivery of PLD to tumors without altering the plasma PK. In addition, higher doses of MRT resulted in a greater increase in the delivery of PLD to tumors. The improved delivery of PLD to tumors may be due to MRT's acute effects on tumor microvasculature; however, the exact mechanism needs to be further evaluated. Future studies include evaluation of the effect of duration and dose of MRT on drug uptake in tumor, effects of MRT on other CMAs, and the mechanisms of enhanced tumor delivery.

Citation Format: Xiao S. Chang, Andrew Jacob Madden, Judith Rivera, Charlene Santos, David Darr, Lucas Hunter, William C. Zamboni. The effects of microbeam radiation therapy on the pharmacokinetics of PEGylated liposomal doxorubicin in a triple negative breast cancer GEM model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4516. doi:10.1158/1538-7445.AM2015-4516