title: Disposition of ultrasound sensitive polymeric drug carrier in a rat hepatocellular carcinoma model.
abstract: OBJECTIVE
  A doxorubicin-loaded microbubble has been developed that can be destroyed with focused ultrasound resulting in fragments, or "nanoshards" capable of escaping through the leaky tumor vasculature, promoting accumulation within the interstitium. This study uses a rat liver cancer model to examine the biodistribution and tumoral delivery of this microbubble platform compared with de novo drug-loaded polymer nanoparticles and free doxorubicin.
  
  
  METHODS
  Microbubbles (1.8 μm) and 217-nm nanoparticles were prepared containing 14-C labeled doxorubicin. Microbubbles, nanoparticles, a combination of the two, or free doxorubicin were administered intravenously in rats bearing hepatomas, concomitant with tumor insonation. Doxorubicin levels in plasma, organs, and tumors were quantified after 4 hours and 7 and 14 days. Tumors were measured on sacrifice and evaluated with autoradiography and histology.
  
  
  RESULTS
  Animals treated with microbubbles had significantly lower plasma doxorubicin concentrations (0.466 ± 0.068%/mL) compared with free doxorubicin (3.033 ± 0.612%/mL, P = .0019). Drug levels in the myocardium were significantly lower in animals treated with microbubbles compared to free doxorubicin (0.168%/g tissue vs. 0.320%/g, P = .0088). Tumors treated with microbubbles showed significantly higher drug levels than tumors treated with free doxorubicin (2.491 ± 0.501 %/g vs. 0.373 ± 0.087 %/g, P = .0472). These tumors showed significantly less growth than tumors treated with free doxorubicin (P = .0390).
  
  
  CONCLUSIONS
  Doxorubicin loaded microbubbles triggered with ultrasound provided enhanced, sustained drug delivery to tumors, reduced plasma and myocardium doxorubicin levels, and arresting tumor growth. The results suggest that in situ generation of nano particles provides a superior treatment over injection of free drug and also de novo synthesized nanoparticles.
authors.affiliation: School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Cochran
authors.forename: John R
authors.initials: JR
authors.lastname: Eisenbrey
authors.forename: Michael C
authors.initials: MC
authors.lastname: Soulen
authors.forename: Susan M
authors.initials: SM
authors.lastname: Schultz
authors.forename: Richard O
authors.initials: RO
authors.lastname: Ouma
authors.forename: Sarah B
authors.initials: SB
authors.lastname: White
authors.forename: Emma E
authors.initials: EE
authors.lastname: Furth
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Wheatley
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001345:Autoradiography; D002250:Carbon Radioisotopes; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004337:Drug Carriers; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D045423:Microbubbles; D053758:Nanoparticles; D011108:Polymers; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D002250:Carbon Radioisotopes; D004337:Drug Carriers; D011108:Polymers; D004317:Doxorubicin