A spatiotemporal computational model of focused ultrasound heat-induced nano-sized drug delivery system in solid tumors

Abstract

Focused Ultrasound (FUS)-triggered nano-sized drug delivery, as a smart stimuli-responsive system for treating solid tumors, is computationally investigated to enhance localized delivery of drug and treatment efficacy. Integration of thermosensitive liposome (TSL), as a doxorubicin (DOX)-loaded nanocarrier, and FUS, provides a promising drug delivery system. A fully coupled partial differential system of equations, including the Helmholtz equation for FUS propagation, bio-heat transfer, interstitial fluid flow, drug transport in tissue and cellular spaces, and a pharmacodynamic model is first presented for this treatment approach. Equations are then solved by finite element methods to calculate intracellular drug concentration and treatment efficacy. The main objective of this study is to present a multi-physics and multi-scale model to simulate drug release, transport, and delivery to solid tumors, followed by an analysis of how FUS exposure time and drug release rate affect these processes. Our findings not only show the capability of model to replicate this therapeutic approach, but also confirm the benefits of this treatment with an improvement of drug aggregation in tumor and reduction of drug delivery in healthy tissue. For instance, the survival fraction of tumor cells after this treatment dropped to 62.4%, because of a large amount of delivered drugs to cancer cells. Next, a combination of three release rates (ultrafast, fast, and slow) and FUS exposure times (10, 30, and 60 min) was examined. Area under curve (AUC) results show that the combination of 30 min FUS exposure and rapid drug release leads to a practical and effective therapeutic response.

Keywords:

• Focused ultrasound
• ultrasound-triggered nano-sized drug delivery system
• solid tumor treatment
• spatiotemporal modeling
• bio-heat transfer
• mass transport
• stimuli-responsive drug-loaded nanocarriers
• hyperthermia
• thermo-sensitive liposome
• drug release kinetics

Acknowledgements

This research was funded by Toronto Poly Clinic Inc., Ontario Research Fund - Research Excellence (ORF-RE #RE02-032), the Natural Sciences and Engineering Research Council of Canada (NSERC) Alliance grant (ALLRP 556270-20), and NSERC Discovery grants that were awarded to J. Tavakkoli (RGPIN-2022-03799) and M.C. Kolios (RGPIN-2022-04143). F.M. Kashkooli is also supported by an NSERC Banting Postdoctoral Fellowship, administered by the Government of Canada.

Authors’ contributions

Farshad Moradi Kashkooli: Conceptualization, Investigation, Methodology, Formal analysis, Software, Visualization, Validation, Discussion, Writing-original draft, Project administration _ Mohammad Souri: Methodology, Formal analysis, Software, Visualization, Validation, Discussion,Writing—review & editing _ Jahangir(Jahan) Tavakkoli: Investigation, Methodology, Resources, Discussion, Writing—review & editing, Supervision _ Michael C. Kolios: Investigation, Methodology, Resources, Discussion, Writing—review & editing, Supervision, Funding acquisition.

Data availability statement

The data supporting this work are accessible upon reasonable request from the corresponding author.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval statement

NA.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.