Development of an ultrasound-mediated nano-sized drug-delivery system for cancer treatment: from theory to experiment

Abstract

Aim: To establish a methodology for understanding how ultrasound (US) induces drug release from nano-sized drug-delivery systems (NSDDSs) and enhances drug penetration and uptake in tumors. This aims to advance cancer treatment strategies. Materials & methods: We developed a multi-physics mathematical model to elucidate and understand the intricate mechanisms governing drug release, transport and delivery. Unique in vitro models (monolayer, multilayer, spheroid) and a tailored US exposure setup were introduced to evaluate drug penetration and uptake. Results: The results highlight the potential advantages of US-mediated NSDDSs over conventional NSDDSs and chemotherapy, notably in enhancing drug release and inducing cell death. Conclusion: Our sophisticated numerical and experimental methods aid in determining and quantifying drug penetration and uptake into solid tumors.

Summary points

• Therapeutic ultrasound (TUS) permits targeted drug delivery by controlling the drug-release kinetics, thereby enhancing drug delivery and cell killing in tumors.

• Our study enabled a comprehensive understanding of the integration of TUS and nano-sized drug-delivery systems by combining experimental and theoretical analyses.

• We introduced a multi-scale and multi-physics mathematical and computational model for the penetration of TUS-triggered nano-sized drug-delivery systems into solid tumors.

• We examined three in vitro cancer cell culture methods – 2D monolayer, 3D spheroids and 3D multi-layer cells – to analyze initial cell toxicity, antiproliferative capacity and drug penetration.

• A customized experimental setup was developed that was suitable for TUS (i.e., LIPUS) and cell studies.

• The synergies between TUS, drug-release kinetics and transport characteristics were explored to increase the rate of cancer cell death.

• We proposed an optical sectioning technique for drug-penetration studies and utilized flow cytometry analysis for cell proliferation studies in a spheroid cancer cell model.

• Drug-release kinetics were determined with and without ultrasound exposure at 37°C.

Keywords: :

• cancer treatment
• controlled drug release
• drug-loaded nanocarriers
• drug penetration
• low-intensity pulsed ultrasound
• multi-physics and multi-scale computational modeling
• targeted chemotherapy
• therapeutic ultrasound
• ultrasound-activated nano-sized drug delivery

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2023-0259

Author contributions

Conceptualization: F Moradi Kashkooli, A Jakhmola, J Tavakkoli, and MC Kolios; idea development: F Moradi Kashkooli, J Tavakkoli and MC Kolios; methodology: F Moradi Kashkooli, A Jakhmola and GA Ferrier; investigation: F Moradi Kashkooli, A Jakhmola and GA Ferrier; software: F Moradi Kashkooli and GA Ferrier; Experimental setup design: F Moradi Kashkooli, GA Ferrier, J Tavakkoli, MC Koios; synthesis of nanoparticles: A Jakhmola; ultrasound measurements: F Moradi Kashkooli and GA Ferrier; resources, J Tavakkoli and MC Kolios; in vitro monolayer experiments: F Moradi Kashkooli and A Jakhmola; in vitro spheroid experiments: F Moradi Kashkooli, A Jakhmola and K Sathiyamoorthy; data gathering: F Moradi Kashkooli, GA Ferrier and A Jakhmola; data curation: F Moradi Kashkooli; postprocessing of data: F Moradi Kashkooli and A Jakhmola; visualization: F Moradi Kashkooli, A Jakhmola, GA Ferrier and K Sathiyamoorthy; writing – original draft preparation: F Moradi Kashkooli; writing – review and editing: A Jakhmola, GA Ferrier, K Sathiyamoorthy, J Tavakkoli and MC Kolios; supervision: J Tavakkoli and MC Kolios; project administration: F Moradi Kashkooli. All authors have read and agreed to the final version of the manuscript.

Financial disclosure

This research was funded by 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 MC Kolios (RGPIN-2022-04143). F Moradi Kashkooli is also supported by an NSERC Banting Postdoctoral Fellowship (funding reference no. 186566) administered by the Government of Canada. Additional funding support through a research contract from Toronto Poly Clinic Inc. is also acknowledged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Acknowledgments

The authors thank K Rod, the medical director of Toronto Poly Clinic and Kevin Liu from Toronto Metropolitan University, for their scientific input. Additionally, special thanks are extended to E Berndl, K Liu, and K Lee from Toronto Metropolitan University for their contributions to their technical help in setup design, as well as monolayer and multilayer cell culture experiments.

Additional information

Funding

This research was funded by 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 MC Kolios (RGPIN-2022-04143). F Moradi Kashkooli is also supported by an NSERC Banting Postdoctoral Fellowship (funding reference no. 186566) administered by the Government of Canada. Additional funding support through a research contract from Toronto Poly Clinic Inc. is also acknowledged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.