Enhancement of radiotherapy efficacy by docetaxel-loaded gelatinase-stimuli PEG-Pep-PCL nanoparticles in gastric cancer.

ABSTRACT

Docetaxel (DOC) is widely used as radiosensitizer in various tumors, including gastric cancer (GC), but its therapeutic effect remains to be improved. In this study, using docetaxel-loaded nanoparticles (DOC-NPs) based on gelatinase-stimuli strategy, we compared their radioenhancement efficacy with docetaxel in GC. Compared with DOC, radiosensitization of DOC-NPs was improved significantly (sensitization enhancement ratio increased 1.09-fold to 1.24-fold, P<0.01) in all three gelatinase overexpressing GC cells, while increased slightly (1.02-fold, P=0.38) in gelatinase deficient normal gastric mucosa cells. The improved radiosensitization efficacy was associated with enhanced G2/M arrest, increased reactive oxygen species (ROS), more effective DSBs and promoted apoptosis. More importantly, the radiosensitization efficacy of DOC-NPs (estimated as ''very active'') was more prominent than DOC (estimated as ''moderately active'') by intravenous injection in xenograft. In conclusion, DOC-NPs are highly selective radiosensitizers in gelatinase over-expressing tumors, and more effective than DOC. By manipulating the common microenvironment difference between tumor and normal tissue, gelatinase-mediated nanoscale delivery system serves as a potential strategy possessing both universality and selectivity for radiosensitizers.