title: Ultrasound-activated agents comprised of 5FU-bearing nanoparticles bonded to microbubbles inhibit solid tumor growth and improve survival.
abstract: Nanoparticle (NP) drug delivery vehicles may eventually offer improved tumor treatments; however, NP delivery from the bloodstream to tumors can be hindered by poor convective and/or diffusive transport. We tested whether poly(lactic-co-glycolic acid) NP delivery can be improved by covalently linking them to ultrasound (US)-activated microbubbles in a "composite-agent" formulation and whether drug 5-fluorouracil (5FU)-loaded NPs delivered in this fashion inhibit the growth of tumors that are typically not responsive to intravenously administered 5FU. After intravenous composite-agent injection, C6 gliomas implanted on Rag-1(-/-) mice were exposed to pulsed 1 MHz US, resulting in the delivery of 16% of the initial NP dose per gram tissue. This represented a five- to 57-fold increase in NP delivery when compared to multiple control groups. 5FU-bearing NP delivery from the composite-agent formulation resulted in a 67% reduction in tumor volume at 7 days after treatment, and animal survival increased significantly when compared to intravenous soluble 5FU administration. We conclude that NP delivery from US-activated composite agents may improve tumor treatment by offering a combination of better targeting, enhanced payload delivery, and controlled local drug release.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
authors.forename: Caitlin W
authors.initials: CW
authors.lastname: Burke
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
authors.forename: Eben
authors.initials: E
authors.lastname: Alexander
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
authors.forename: Kelsie
authors.initials: K
authors.lastname: Timbie
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA; The Cardiovascular Division, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Kilbanov
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA; Department of Radiology, University of Virginia, Charlottesville, Virginia, USA; Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia, USA. Electronic address: rprice@virginia.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Price
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D045423:Microbubbles; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D005472:Fluorouracil