Convection-Enhanced Delivery of Antiangiogenic Drugs and Liposomal Cytotoxic Drugs to Heterogeneous Brain Tumor for Combination Therapy

Ajay Bhandari*, Kartikey Jaiswal, Anup Singh, Wenbo Zhan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
2 Downloads (Pure)

Abstract

Although convection-enhanced delivery can successfully bypass the blood-brain barrier, its clinical performance remains disappointing. This is primarily attributed to the heterogeneous intratumoral environment, particularly the tumor microvasculature. This study investigates the combined convection-enhanced delivery of antiangiogenic drugs and liposomal cytotoxic drugs in a heterogeneous brain tumor environment using a transport-based mathematical model. The patient-specific 3D brain tumor geometry and the tumor’s heterogeneous tissue properties, including microvascular density, porosity and cell density, are extracted from dynamic contrast-enhanced magnetic resonance imaging data. Results show that antiangiogenic drugs can effectively reduce the tumor microvascular density. This change in tissue structure would inhibit the fluid loss from the blood to prevent drug concentration from dilution, and also reduce the drug loss by blood drainage. The comparisons between different dosing regimens demonstrate that the co-infusion of liposomal cytotoxic drugs and antiangiogenic drugs has the advantages of homogenizing drug distribution, increasing drug accumulation, and enlarging the volume where tumor cells can be effectively killed. The delivery outcomes are susceptible to the location of the infusion site. This combination treatment can be improved by infusing drugs at higher microvascular density sites. In contrast, infusion at a site with high cell density would lower the treatment effectiveness of the whole brain tumor. Results obtained from this study can deepen the understanding of this combination therapy and provide a reference for treatment design and optimization that can further improve survival and patient quality of life.
Original languageEnglish
Article number4177
Number of pages32
JournalCancers
Volume14
Issue number17
DOIs
Publication statusPublished - 29 Aug 2022

Bibliographical note

Acknowledgments
The authors thank RK Gupta for providing the clinical DCE-MRI data of human brain tumors.
Funding
Ajay Bhandari would like to acknowledge the support received by a grant from the Science and Engineering Research Board (Grant Number: SRG/2021/000053) and the Indian Institute of Technology (Indian School of Mines), Dhanbad (Grant Number: FRS (147)/2020-2021/MECH). Wenbo Zhan would like to acknowledge the support received from the Children with Cancer UK under the project Children’s Brain Tumor Drug Delivery Consortium (Grant Number:16-224). Both authors would like to acknowledge the support received from the Royal Society (Grant Number: IES\R1\221015).

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Keywords

  • antiangiogenesis
  • combination therapy
  • convection-enhanced delivery
  • DCE-MR imaging
  • heterogeneous tumor
  • mathematical model

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