Longitudinal preclinical imaging characterization of drug delivery potential after radiotherapy in the healthy and leukemic bone marrow vascular microenvironment

Abstract

AbstractObjectivesRadiotherapy improves blood perfusion and cellular chemotherapy uptake in mice with acute lymphoblastic leukemia (ALL). However, its ability to influence drug delivery and permeation through the bone marrow vasculature (BMV) is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton (L-QMPM) imaging and used it to characterize drug delivery potential and the BMV before and after radiotherapy in mice bearing leukemia.MethodsWe developed a longitudinal window implant for L-QMPM imaging of the calvarium BMV before, 2 days after, and 5 days after radiotherapy. Live time-lapsed images of a fluorescent drug surrogate were used to obtain measurements including tissue wash-in slope (WIStissue) to measure drug delivery potential. We performed L-QMPM imaging using 2 Gy and 10 Gy total body irradiation (TBI) on C57/B6 (WT) mice, mice bearing ALL, and acute myeloid leukemia (AML).ResultsImplants had no effects on calvarium dose, and parameters for WT untreated mice were stable during imaging. We observed increased angiogenesis, decreased single-vessel blood flow, and decreased WIStissuewith the onset of AML and ALL. 2Gy and 10Gy TBI increased WIStissue2 days after radiotherapy in all 3 groups of mice and increased single-vessel blood flow in mice bearing ALL and AML. Significant increases in WIStissuewere observed 2 days after 2Gy TBI compared to 5 days. Morphological and functional alterations in the BMV were sustained for a significantly longer time period after 10Gy TBI (5 days post-treatment) compared to 2Gy TBI (2 days post-treatment).ConclusionL-QMPM provides stable functional assessments of the BMV. TBI increases the drug delivery potential of the leukemic BMV 2-5 days post-treatment, likely through improved blood perfusion and drug exchange from the BMV to the extravascular tissue. Our data show that neo-adjuvant 2Gy and 10Gy TBI condition the BMV for increased drug delivery.