A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction

Jinhui Gao; Keiran Logan; Heather Nesbitt; Bridgeen Callan; Thomas McKaig; Mark Taylor; Mark Love; Anthony P. McHale; D Griffith; J Callan

doi:10.1016/j.jconrel.2021.08.050

A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction

Jinhui Gao
, Keiran Logan
, Heather Nesbitt
, Bridgeen Callan
, Thomas McKaig
, Mark Taylor
, Mark Love
, Anthony P. McHale
, D Griffith
, J Callan

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

347 Downloads (Pure)

Abstract

FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant
improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment.

Original language	English
Pages (from-to)	358-366
Number of pages	9
Journal	Journal of Controlled Release
Volume	338
Early online date	1 Sept 2021
DOIs	https://doi.org/10.1016/j.jconrel.2021.08.050
Publication status	Published (in print/issue) - 10 Oct 2021

Bibliographical note

Funding Information:
JFC thanks Norbrook Laboratories Ltd. for an endowed chair and Mrs. Margaret McGowan for a charitable donation toward this research. DMG gratefully acknowledges funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under Grant Number 12/RC/2275_P2 . DMG thanks Dr. Diego Montagner (Maynooth University) for kindly running the 195 Pt NMR sample.

Funding Information:
JFC thanks Norbrook Laboratories Ltd. for an endowed chair and Mrs. Margaret McGowan for a charitable donation toward this research. DMG gratefully acknowledges funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under Grant Number 12/RC/2275_P2. DMG thanks Dr. Diego Montagner (Maynooth University) for kindly running the 195Pt NMR sample.

Publisher Copyright:
© 2021

Funding

Funding Information: JFC thanks Norbrook Laboratories Ltd. for an endowed chair and Mrs. Margaret McGowan for a charitable donation toward this research. DMG gratefully acknowledges funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under Grant Number 12/RC/2275_P2 . DMG thanks Dr. Diego Montagner (Maynooth University) for kindly running the 195 Pt NMR sample. Funding Information: JFC thanks Norbrook Laboratories Ltd. for an endowed chair and Mrs. Margaret McGowan for a charitable donation toward this research. DMG gratefully acknowledges funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under Grant Number 12/RC/2275_P2. DMG thanks Dr. Diego Montagner (Maynooth University) for kindly running the 195Pt NMR sample. Publisher Copyright: © 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

FOLFIRINOX
FOLFOXIRI
Microbubbles
ultrasound
pancreatic cancer
colorectal cancer
Pancreatic cancer
Colorectal cancer
Ultrasound
Humans
Antineoplastic Combined Chemotherapy Protocols
Treatment Outcome
Camptothecin/therapeutic use
Fluorouracil/therapeutic use
Irinotecan
Animals
Oxaliplatin
Uridine/analogs & derivatives
Mice
Pancreatic Neoplasms/drug therapy
Colonic Neoplasms/drug therapy
Leucovorin/therapeutic use

Access to Document

10.1016/j.jconrel.2021.08.050Licence: CC BY-NC-ND

DBP-5FUR manuscript R1 cleanAuthor Accepted Manuscript, 882 KBLicence: CC BY-NC-ND

Cite this

Gao, J., Logan, K., Nesbitt, H., Callan, B., McKaig, T., Taylor, M., Love, M., McHale, A. P., Griffith, D., & Callan, J. (2021). A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction. Journal of Controlled Release, 338, 358-366. https://doi.org/10.1016/j.jconrel.2021.08.050

@article{e4824dc143b946a9b7e17068dee7ad64,

title = "A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction",

abstract = "FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189\% and colorectal tumours 82\% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment. ",

keywords = "FOLFIRINOX, FOLFOXIRI, Microbubbles, ultrasound, pancreatic cancer, colorectal cancer, Pancreatic cancer, Colorectal cancer, Ultrasound, Humans, Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Camptothecin/therapeutic use, Fluorouracil/therapeutic use, Irinotecan, Animals, Oxaliplatin, Uridine/analogs \& derivatives, Mice, Pancreatic Neoplasms/drug therapy, Colonic Neoplasms/drug therapy, Leucovorin/therapeutic use",

author = "Jinhui Gao and Keiran Logan and Heather Nesbitt and Bridgeen Callan and Thomas McKaig and Mark Taylor and Mark Love and McHale, \{Anthony P.\} and D Griffith and J Callan",

note = "Funding Information: JFC thanks Norbrook Laboratories Ltd. for an endowed chair and Mrs. Margaret McGowan for a charitable donation toward this research. DMG gratefully acknowledges funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under Grant Number 12/RC/2275\_P2 . DMG thanks Dr. Diego Montagner (Maynooth University) for kindly running the 195 Pt NMR sample. Funding Information: JFC thanks Norbrook Laboratories Ltd. for an endowed chair and Mrs. Margaret McGowan for a charitable donation toward this research. DMG gratefully acknowledges funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under Grant Number 12/RC/2275\_P2. DMG thanks Dr. Diego Montagner (Maynooth University) for kindly running the 195Pt NMR sample. Publisher Copyright: {\textcopyright} 2021",

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month = oct,

day = "10",

doi = "10.1016/j.jconrel.2021.08.050",

language = "English",

volume = "338",

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journal = "Journal of Controlled Release",

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publisher = "Elsevier BV",

}

Gao, J, Logan, K, Nesbitt, H , Callan, B , McKaig, T, Taylor, M, Love, M, McHale, AP, Griffith, D & Callan, J 2021, 'A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction', Journal of Controlled Release, vol. 338, pp. 358-366. https://doi.org/10.1016/j.jconrel.2021.08.050

A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction. / Gao, Jinhui; Logan, Keiran; Nesbitt, Heather et al.
In: Journal of Controlled Release, Vol. 338, 10.10.2021, p. 358-366.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction

AU - Gao, Jinhui

AU - Logan, Keiran

AU - Nesbitt, Heather

AU - Callan, Bridgeen

AU - McKaig, Thomas

AU - Taylor, Mark

AU - Love, Mark

AU - McHale, Anthony P.

AU - Griffith, D

AU - Callan, J

N1 - Funding Information: JFC thanks Norbrook Laboratories Ltd. for an endowed chair and Mrs. Margaret McGowan for a charitable donation toward this research. DMG gratefully acknowledges funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under Grant Number 12/RC/2275_P2 . DMG thanks Dr. Diego Montagner (Maynooth University) for kindly running the 195 Pt NMR sample. Funding Information: JFC thanks Norbrook Laboratories Ltd. for an endowed chair and Mrs. Margaret McGowan for a charitable donation toward this research. DMG gratefully acknowledges funding received from the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund under Grant Number 12/RC/2275_P2. DMG thanks Dr. Diego Montagner (Maynooth University) for kindly running the 195Pt NMR sample. Publisher Copyright: © 2021

PY - 2021/10/10

Y1 - 2021/10/10

N2 - FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment.

AB - FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment.

KW - FOLFIRINOX

KW - FOLFOXIRI

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KW - ultrasound

KW - pancreatic cancer

KW - colorectal cancer

KW - Pancreatic cancer

KW - Colorectal cancer

KW - Ultrasound

KW - Humans

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Treatment Outcome

KW - Camptothecin/therapeutic use

KW - Fluorouracil/therapeutic use

KW - Irinotecan

KW - Animals

KW - Oxaliplatin

KW - Uridine/analogs & derivatives

KW - Mice

KW - Pancreatic Neoplasms/drug therapy

KW - Colonic Neoplasms/drug therapy

KW - Leucovorin/therapeutic use

UR - https://www.scopus.com/pages/publications/85114121937

U2 - 10.1016/j.jconrel.2021.08.050

DO - 10.1016/j.jconrel.2021.08.050

M3 - Article

C2 - 34481018

SN - 0168-3659

VL - 338

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JF - Journal of Controlled Release

ER -

Gao J, Logan K, Nesbitt H , Callan B , McKaig T, Taylor M et al. A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction. Journal of Controlled Release. 2021 Oct 10;338:358-366. Epub 2021 Sept 1. doi: 10.1016/j.jconrel.2021.08.050

A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Multifunctional microbubbles for ultrasound targeted treatment of solid tumours

Treatment of solid cancerous tumours using ultrasound-targeted microbubble destruction

Cite this

A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Student theses

Multifunctional microbubbles for ultrasound targeted treatment of solid tumours

Treatment of solid cancerous tumours using ultrasound-targeted microbubble destruction

Cite this