Ultrasound-activated Agents Comprised of 5FU-bearing Nanoparticles Bonded to Microbubbles Inhibit Solid Tumor Growth and Improve Survival

Mol Ther. 2014 Feb;22(2):321-328. doi: 10.1038/mt.2013.259. Epub 2013 Oct 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Drug Delivery Systems / methods
  • Fluorouracil / administration & dosage*
  • Fluorouracil / chemistry
  • Mice
  • Microbubbles*
  • Nanoparticles* / chemistry
  • Neoplasms / drug therapy
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Rats
  • Tumor Burden / drug effects

Substances

  • Fluorouracil