Ionizing radiation increases systemic nanoparticle tumor accumulation

Abstract

Nanoparticle-based therapies are currently being explored for both the imaging and treatment of primary and metastatic cancers. Effective nanoparticle cancer therapy requires significant accumulations of nanoparticles within the tumor environment. Various techniques have been used to improve tumor nanoparticle uptake and biodistribution. Most notable of these techniques is the use of tumor-specific peptide-conjugated nanoparticles and chemical modification of the nanoparticles with immune-evading polymers. Another strategy for improving the tumor uptake of the nanoparticles is modification of the tumor microenvironment with a goal of intensifying the enhanced permeability and retention effect inherent to solid tumors. We demonstrate a twofold increase in the tumor accumulation of systemically delivered iron oxide nanoparticles following a single 15-Gy radiation dose in a syngeneic mouse breast tumor model. This increase in nanoparticle tumor accumulation correlates with a radiation-induced decrease in tumor interstitial pressure and a subsequent increase in vascular permeability.

Figure 1

Top:A single 15 Gy fraction of 6 MeV electron radiation significantly decreases interstitial tumor pressure as compared to non-irradiated controls. Bottom: Three days following irradiation vascular permeability is correspondingly increased (Evans blue spectrophotometry assessment). * = p < 0.05 and ** = p < 0.01. Error bars show standard deviations.

Figure 2

This boxplot of ICP-MS-based tumor iron quantification demonstrates that PEG coating increases nanoparticle accumulation in irradiated tumors. Nanoparticle size was irrelevant with respect to tumor accumulation when PEG-coated. When not PEG coated, smaller nanoparticles (SPIO) accumulated in tumors more than larger nanoparticles (BNF). The numbers in the figure legends (i.e. n=7) refers to number of animals in each group; each animal had anirradiated (Rad) and non-treated (control) tumor.The top of each box is the 75^th percentile, the middle line the median and the bottom of the box the 25^th percentile for each group. The errors bars show the range of data in each group and the filled diamonds show outliers. The 95% confidence interval for each group is the range between the two triangles overlaying each box. * = p < 0.05 and ** = p < 0.01.

Figure 3

Bilateral flank tumors were excised from the same mouse three days after systemic administration of BNF PEG200 nanoparticles. Gross and histological analyses demonstrate an increased level of mNPs (brown in topand bottom, blue in middle) in irradiated tumors. IHC-stained endothelial cells (anti-CD31) demonstrate the close spatial relationship of tumor vessels (light brown, arrows) and nanoparticles (dark brown).