title: Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy.
abstract: BACKGROUND
  Drug delivery in polymeric micelles combined with tumor irradiation by ultrasound results in effective drug targeting, but this technique requires prior tumor imaging. A technology that combined ultrasound imaging with ultrasound-mediated nanoparticle-based targeted chemotherapy could therefore have important applications in cancer treatment.
  
  
  METHODS
  Mixtures of drug-loaded polymeric micelles and perfluoropentane (PFP) nano/microbubbles stabilized by the same biodegradable block copolymer were prepared. Size distribution of nanoparticles was measured by dynamic light scattering. Cavitation activity (oscillation, growth, and collapse of microbubbles) under ultrasound was assessed based on the changes in micelle/microbubble volume ratios. The effect of the nano/microbubbles on the ultrasound-mediated cellular uptake of doxorubicin (Dox) in MDA MB231 breast tumors in vitro and in vivo (in mice bearing xenograft tumors) was determined by flow cytometry. Statistical tests were two-sided.
  
  
  RESULTS
  Phase state and nanoparticle sizes were sensitive to the copolymer/perfluorocarbon volume ratio. At physiologic temperatures, nanodroplets converted into nano/microbubbles. Doxorubicin was localized in the microbubble walls formed by the block copolymer. Upon intravenous injection into mice, Dox-loaded micelles and nanobubbles extravasated selectively into the tumor interstitium, where the nanobubbles coalesced to produce microbubbles with a strong, durable ultrasound contrast. Doxorubicin was strongly retained in the microbubbles but released in response to therapeutic ultrasound. Microbubbles cavitated under the action of tumor-directed ultrasound, which enhanced intracellular Dox uptake by tumor cells in vitro to a statistically significant extent relative to that observed with unsonicated microbubbles (drug uptake ratio = 4.60; 95% confidence interval [CI] = 1.70 to 12.47; P = .017) and unsonicated micelles (drug uptake ratio = 7.97; 95% CI = 3.72 to 17.08; P = .0032) and resulted in tumor regression in the mouse model.
  
  
  CONCLUSIONS
  Multifunctional nanoparticles that are tumor-targeted drug carriers, long-lasting ultrasound contrast agents, and enhancers of ultrasound-mediated drug delivery have been developed and deserve further exploration as cancer therapeutics.
authors.affiliation: Department of Bioengineering, University of Utah, 20 S. 2030 E. Rm 108, Salt Lake City, UT 84112, USA. natasha.rapoport@m.cc.utah.edu
authors.forename: Natalya
authors.initials: N
authors.lastname: Rapoport
authors.forename: Zhonggao
authors.initials: Z
authors.lastname: Gao
authors.forename: Anne
authors.initials: A
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003287:Contrast Media / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005466:Fluorocarbons / Q000737:chemistry; D006801:Humans; D007773:Lactates / Q000737:chemistry; D051379:Mice; D008815:Mice, Inbred Strains; D008823:Micelles; D045423:Microbubbles; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D013696:Temperature; D014463:Ultrasonography; D023041:Xenograft Model Antitumor Assays; D010420:Pentanes
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D004317:Doxorubicin; D004337:Drug Carriers; D005466:Fluorocarbons; D007773:Lactates; D008823:Micelles; D011092:Polyethylene Glycols; C088513:poly(lactic acid-ethylene glycol); C008806:perfluoropentane; D010420:Pentanes