While vascular alterations in solid tumor malignancies are known to decrease therapeutic delivery, the effects of leukemia-induced bone marrow vasculature (BMV) alterations on therapeutic delivery are not well known. Additionally, functional quantitative measurements of the leukemic BMV during chemotherapy and radiotherapy are limited largely due to a lack of high-resolution imaging techniques available preclinically. This study develops a murine model using compartmental modeling for quantitative multiphoton microscopy (QMPM) to characterize the malignant BMV before and during treatment.
Using QMPM, live time-lapsed images of dextran leakage from the local BMV to the surrounding bone marrow of mice bearing acute lymphoblastic leukemia (ALL) were taken, and fit to a two-compartment model to measure the transfer rate (K), fractional extracellular extravascular space (ν), and vascular permeability parameters as well as functional single-vessel characteristics. In response to leukemia-induced BMV alterations, the effects of 2-4Gy low-dose radiotherapy (LDRT) on the BMV, drug delivery, and mouse survival were assessed post-treatment to determine if neo-adjuvant LDRT prior to chemotherapy improves treatment outcome.
Mice bearing ALL had significantly altered K, increased ν, and increased permeability compared to healthy mice. Angiogenesis, decreased single-vessel perfusion and decreased vessel diameter were observed. BMV alterations resulted in disease-dependent reductions in cellular uptake of Hoechst dye. LDRT to mice bearing ALL dilated BMV, increased single-vessel perfusion, and increased daunorubicin uptake by ALL cells. Consequently, LDRT administered to mice before receiving Nilotinib significantly increased survival compared to mice receiving LDRT after Nilotinib, demonstrating the importance of LDRT conditioning before therapeutic administration.
Developed QMPM enables single-platform assessments of the pharmacokinetics of fluorescent agents and characterization of the BMV. Initial results suggest BMV alterations after neo-adjuvant LDRT may contribute to enhanced drug delivery and increased treatment efficacy for ALL. Developed QMPM enables observations of the BMV for use in ALL treatment optimization.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.