title: Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound.
abstract: BACKGROUND
  Oncolytic viruses are among the most powerful and selective cancer therapeutics under development and are showing robust activity in clinical trials, particularly when administered directly into tumor nodules. However, their intravenous administration to treat metastatic disease has been stymied by unfavorable pharmacokinetics and inefficient accumulation in and penetration through tumors.
  
  
  METHODS
  Adenovirus (Ad) was "stealthed" with a new N-(2-hydroxypropyl)methacrylamide polymer, and circulation kinetics were characterized in Balb/C SCID mice (n = 8 per group) bearing human ZR-75-1 xenograft tumors. Then, to noninvasively increase extravasation of the circulating polymer-coated Ad into the tumor, it was coinjected with gas microbubbles and the tumor was exposed to 0.5 MHz focused ultrasound at peak rarefactional pressure of 1.2 MPa. These ultrasound exposure conditions were designed to trigger inertial cavitation, an acoustic phenomenon that produces shock waves and can be remotely monitored in real-time. Groups were compared with Student t test or one-way analysis of variance with Tukey correction where groups were greater than two. All statistical tests were two-sided.
  
  
  RESULTS
  Polymer-coating of Ad reduced hepatic sequestration, infection (>8000-fold; P < .001), and toxicity and improved circulation half-life (>50-fold; P = .001). Combination of polymer-coated Ad, gas bubbles, and focused ultrasound enhanced tumor infection >30-fold; (4 × 10(6) photons/sec/cm(2); standard deviation = 3 × 10(6) with ultrasound vs 1.3 × 10(5); standard deviation = 1 × 10(5) without ultrasound; P = .03) and penetration, enabling kill of cells more than 100 microns from the nearest blood vessel. This led to substantial and statistically significant retardation of tumor growth and increased survival.
  
  
  CONCLUSIONS
  Combining drug stealthing and ultrasound-induced cavitation may ultimately enhance the efficacy of a range of powerful therapeutics, thereby improving the treatment of metastatic cancer.
authors.affiliation: Affiliations of authors: Institute of Biomedical Engineering, Department of Engineering Science(RC, JC, C-CC) and Department of Oncology (RL, LWS), University of Oxford, Oxford, UK; Institut d'Investigacio Biomedica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain (MB-P); Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic (VS, LK, KU).
authors.forename: Robert
authors.initials: R
authors.lastname: Carlisle
authors.forename: James
authors.initials: J
authors.lastname: Choi
authors.forename: Miriam
authors.initials: M
authors.lastname: Bazan-Peregrino
authors.forename: Richard
authors.initials: R
authors.lastname: Laga
authors.forename: Vladimir
authors.initials: V
authors.lastname: Subr
authors.forename: Libor
authors.initials: L
authors.lastname: Kostka
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.forename: Constantin-C
authors.initials: CC
authors.lastname: Coussios
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Seymour
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage*; D000256:Adenoviridae; D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D045423:Microbubbles; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage*; D014464:Ultrasonic Therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000277:Adjuvants, Pharmaceutic; D014677:Pharmaceutical Vehicles; C032976:N-(2-hydroxypropyl)methacrylamide