title: Quantitative study of focused ultrasound enhanced doxorubicin delivery to prostate tumor in vivo with MRI guidance.
abstract: OBJECTIVE
  The purpose of this study was to investigate the potential of MR-guided pulsed focused ultrasound (pFUS) for the enhancement of drug uptake in prostate tumors in vivo using doxorubicin (Dox).
  
  
  METHODS
  An antitumor drug Dox, an orthotopic animal prostate tumor model using human prostate cancer, LNCaP cell line, and a clinical FUS treatment system (InSightec ExAblate 2000) with a 1.5T GE MR scanner were used in this study. First, experiments on a tissue mimic phantom to determine the optimal acoustic power and exposure durations with a 10% duty cycle and a 1 Hz pulse rate were performed. The temperature variation was monitored using real-time MR thermometry. Second, tumor-bearing animals were treated with pFUS. There were three groups (n = 8/group): group 1 received pFUS + Dox (10 mg/kg i.v. injection immediately after pFUS exposure), group 2 received Dox only (10 mg/kg i.v. injection), and group 3 was a control. Animals were euthanized 2 h after the pFUS treatment. The Dox concentration in the treated tumors was measured by quantifying fluorescent tracers using a fluorometer. Third, the histological changes of tumors with and without pFUS treatments were evaluated. Finally, experiments were performed to study the spatial drug distribution in tumors after the pFUS treatment, in which two animals received pFUS + Dox, two animals received Dox only, and one animal was used as control. Two hours following the treatment, animals were euthanized and processed. The Dox distribution was determined using a fluorescence microscope.
  
  
  RESULTS
  Parametric measurements using a tissue phantom showed that the temperature increased with an increasing acoustic power (from 10 to 50 W) or sonication duration (from 10 to 60 s) with a given acoustic frequency of 1 MHz, duty cycle 10%, and pulse rate 1 Hz. A set of ultrasound parameters was identified with which the temperature elevation was less than 5 °C, which was used for nonthermal pFUS sonication. Increased Dox concentration (14.9 ± 2.5 μg/g) was measured in the pFUS-treated group compared to the Dox-only group (9.5 ± 1.6 μg/g), indicating an approximate 60% increase with p = 0.05. The results were consistent with the increased spatial drug distributions by fluorescence imaging. Histological analysis showed increased extravasation in pFUS-treated prostate tumors suggesting increased drug delivery with pFUS.
  
  
  CONCLUSIONS
  The results showed that pFUS-enhanced drug uptake in prostate tumors was significant. This increased uptake may be due to increased extravasation by pFUS. Optimal pFUS parameters may exist to maximize the drug uptake, and this study using Dox demonstrated a quantitative method for such systematic parametric studies. In addition, this study may provide useful data for the potential application of pFUS-mediated Dox delivery for prostate tumor therapy.
authors.affiliation: Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Chen
authors.forename: Dusica
authors.initials: D
authors.lastname: Cvetkovic
authors.forename: C-M
authors.initials: CM
authors.lastname: Ma
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D001692:Biological Transport; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D057086:High-Intensity Focused Ultrasound Ablation / Q000295:instrumentation / Q000379:methods*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin