Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA-Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

Sukumar Uday Kumar; Arsenii V. Telichko; Huaijun Wang; Dongwoon Hyun; Eric G. Johnson; Michael S. Kent; Robert B Rebhun; Jeremy J. Dahl; William T.N. Culp; Ramasamy Paulmurugan

doi:10.1002/adtp.202000120

Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA-Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

Sukumar Uday Kumar, Arsenii V. Telichko, Huaijun Wang, Dongwoon Hyun, Eric G. Johnson, Michael S. Kent, Robert B Rebhun, Jeremy J. Dahl, William T.N. Culp, Ramasamy Paulmurugan

School of Veterinary Medicine

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

Abstract

Spatially localized microbubble cavitation by ultrasound offers an effective means of altering the permeability of natural barriers (i.e., blood vessels and cell membranes) in favor of nanomaterial accumulation in target sites. In this study, a clinically relevant, minimally invasive ultrasound guided therapeutic approach is investigated for the targeted delivery of anticancer microRNA loaded PLGA-b-PEG nanoparticles to spontaneous hepatocellular neoplasia in a canine model. Quantitative assessment of the delivered microRNAs reveals a prominent and consistent increase in microRNAs levels (1.5- to 2.3-fold increase [p < 0.001]) in ultrasound treated tumor regions compared to untreated control regions. The immunohistology of ultrasound treated tumor tissue presents clear evidence for a higher amount of nanoparticle extravasation from the blood vessels. A distinct pattern of cytokine expression supporting a CD8+ T cells mediated “cold-to-hot” tumor transition is evident in all patients. This proposed platform can enhance delivery of microRNA-loaded nanoparticles to deeply located visceral tumors in large animals to enhance chemotherapy.

Original language	English (US)
Article number	2000120
Journal	Advanced Therapeutics
Volume	3
Issue number	12
DOIs	https://doi.org/10.1002/adtp.202000120
State	Published - Dec 2020

Keywords

dog model
focused ultrasound
microbubbles
microRNA
nanoparticles
targeted delivery

ASJC Scopus subject areas

Medicine (miscellaneous)
Biochemistry, medical
Pharmacology (medical)
Genetics(clinical)
Pharmaceutical Science
Pharmacology

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Kumar, S. U., Telichko, A. V., Wang, H., Hyun, D., Johnson, E. G., Kent, M. S., Rebhun, R. B., Dahl, J. J., Culp, W. T. N., & Paulmurugan, R. (2020). Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA-Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines. Advanced Therapeutics, 3(12), [2000120]. https://doi.org/10.1002/adtp.202000120

Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA-Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines. / Kumar, Sukumar Uday; Telichko, Arsenii V.; Wang, Huaijun; Hyun, Dongwoon; Johnson, Eric G.; Kent, Michael S.; Rebhun, Robert B; Dahl, Jeremy J.; Culp, William T.N.; Paulmurugan, Ramasamy.

In: Advanced Therapeutics, Vol. 3, No. 12, 2000120, 12.2020.

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

Kumar, Sukumar Uday ; Telichko, Arsenii V. ; Wang, Huaijun ; Hyun, Dongwoon ; Johnson, Eric G. ; Kent, Michael S. ; Rebhun, Robert B ; Dahl, Jeremy J. ; Culp, William T.N. ; Paulmurugan, Ramasamy. / Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA-Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines. In: Advanced Therapeutics. 2020 ; Vol. 3, No. 12.

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title = "Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA-Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines",

abstract = "Spatially localized microbubble cavitation by ultrasound offers an effective means of altering the permeability of natural barriers (i.e., blood vessels and cell membranes) in favor of nanomaterial accumulation in target sites. In this study, a clinically relevant, minimally invasive ultrasound guided therapeutic approach is investigated for the targeted delivery of anticancer microRNA loaded PLGA-b-PEG nanoparticles to spontaneous hepatocellular neoplasia in a canine model. Quantitative assessment of the delivered microRNAs reveals a prominent and consistent increase in microRNAs levels (1.5- to 2.3-fold increase [p < 0.001]) in ultrasound treated tumor regions compared to untreated control regions. The immunohistology of ultrasound treated tumor tissue presents clear evidence for a higher amount of nanoparticle extravasation from the blood vessels. A distinct pattern of cytokine expression supporting a CD8+ T cells mediated “cold-to-hot” tumor transition is evident in all patients. This proposed platform can enhance delivery of microRNA-loaded nanoparticles to deeply located visceral tumors in large animals to enhance chemotherapy.",

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author = "Kumar, {Sukumar Uday} and Telichko, {Arsenii V.} and Huaijun Wang and Dongwoon Hyun and Johnson, {Eric G.} and Kent, {Michael S.} and Rebhun, {Robert B} and Dahl, {Jeremy J.} and Culp, {William T.N.} and Ramasamy Paulmurugan",

note = "Funding Information: The authors would like to thank Canary Center at Stanford, Department of Radiology for providing the facility and resources for executing this work. The authors also thank support staff at Department of Surgical and Radiological Sciences at University of California at Davis for their kind assistance in treatment procedures. The authors would also like to thank Stanford Animal Histology Services (AHS) for preparation of histology. The authors acknowledge Dr. Jos? G. Vilches-Moure, Veterinary pathologist, Animal Histology Services, for his advice regarding histological analysis of animal tissues. This work was supported by the Focused Ultrasound Foundation and the National Institutes of Health (Grants Numbers R01CA209888, R21EB022298). The authors would like to thank NIH for the funding support for the purchase of Celigo S Imaging Cytometer (200-BFFL-S) used in this study under NIH Small Instrumentation Grant (Award No: S10 OD023518-01A1 to R.P.). Publisher Copyright: {\textcopyright} 2020 Wiley-VCH GmbH",

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AU - Hyun, Dongwoon

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AU - Rebhun, Robert B

AU - Dahl, Jeremy J.

AU - Culp, William T.N.

AU - Paulmurugan, Ramasamy

N1 - Funding Information: The authors would like to thank Canary Center at Stanford, Department of Radiology for providing the facility and resources for executing this work. The authors also thank support staff at Department of Surgical and Radiological Sciences at University of California at Davis for their kind assistance in treatment procedures. The authors would also like to thank Stanford Animal Histology Services (AHS) for preparation of histology. The authors acknowledge Dr. Jos? G. Vilches-Moure, Veterinary pathologist, Animal Histology Services, for his advice regarding histological analysis of animal tissues. This work was supported by the Focused Ultrasound Foundation and the National Institutes of Health (Grants Numbers R01CA209888, R21EB022298). The authors would like to thank NIH for the funding support for the purchase of Celigo S Imaging Cytometer (200-BFFL-S) used in this study under NIH Small Instrumentation Grant (Award No: S10 OD023518-01A1 to R.P.). Publisher Copyright: © 2020 Wiley-VCH GmbH

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Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA-Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

Abstract

Keywords

ASJC Scopus subject areas

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