Biophysical Characterization of the Leukemic Bone Marrow Vasculature Reveals Benefits of Neoadjuvant Low-Dose Radiation Therapy

Jamison Brooks, Bijender Kumar, Darren M. Zuro, Jonathan D. Raybuck, Srideshikan Sargur Madabushi, Paresh Vishwasrao, Liliana Echavarria Parra, Marcin Kortylewski, Brian Armstrong, Jerry Froelich, Susanta K. Hui

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Although 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 radiation therapy 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. Methods and Materials: 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 2-compartment model to measure the transfer rate (Ktrans), fractional extracellular extravascular space (νec), and vascular permeability parameters, as well as functional single-vessel characteristics. In response to leukemia-induced BMV alterations, the effects of 2 to 4 Gy low-dose radiation therapy (LDRT) on the BMV, drug delivery, and mouse survival were assessed post-treatment to determine whether neoadjuvant LDRT before chemotherapy improves treatment outcome. Results: Mice bearing ALL had significantly altered Ktrans, increased νec, and increased permeability compared with 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 with mice receiving LDRT after nilotinib, demonstrating the importance of LDRT conditioning before therapeutic administration. Conclusion: The developed QMPM enables single-platform assessments of the pharmacokinetics of fluorescent agents and characterization of the BMV. Initial results suggest BMV alterations after neoadjuvant LDRT may contribute to enhanced drug delivery and increased treatment efficacy for ALL. The developed QMPM enables observations of the BMV for use in ALL treatment optimization.

Original languageEnglish (US)
Pages (from-to)60-72
Number of pages13
JournalInternational Journal of Radiation Oncology Biology Physics
Volume109
Issue number1
DOIs
StatePublished - Jan 1 2021

Bibliographical note

Funding Information:
Research reported in this publication is supported by the National Cancer Institute of the National Institutes of Health under (R01CA154491) (S.H.), partly supported by National Institutes of Health grant (P30CA033572) (City of Hope), and supported by ONCOTEST (Ghent, Belgium) (S.H.).

Funding Information:
Disclosures: S.H. reports grants from the National Institutes of Health and Oncotest during the conduct of the study and receives honoraria from and consults for Janssen Research & Development, LLC. J.F. reports personal fees from Merle and Fern Loken Professor in Radiologic Sciences outside the submitted work. All other authors report no conflict of interest.

Publisher Copyright:
© 2020 The Author(s)

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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