Longer heating duration increases localized doxorubicin deposition and therapeutic index in Vx2 tumors using MR-HIFU mild hyperthermia and thermosensitive liposomal doxorubicin

Chenchen Bing, Pratik Patel, Robert M. Staruch, Sumbul Shaikh, Joris Nofiele, Michelle Wodzak Staruch, Debra Szczepanski, Noelle S. Williams, Theodore W Laetsch, Rajiv Chopra

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Thermosensitive liposomal doxorubicin (LTSL-Dox) combined with mild hyperthermia enhances the localized delivery of doxorubicin (Dox) within a heated region. The optimal heating duration and the impact of extended heating on systemic drug distribution are unknown. Here we evaluated local and systemic Dox delivery with two different mild hyperthermia durations (42 °C for 10 or 40 minutes) in a Vx2 rabbit tumor model. We hypothesized that longer duration of hyperthermia would increase Dox concentration in heated tumors without increasing systemic exposure. Temporally and spatially accurate controlled hyperthermia was achieved using a clinical MR-HIFU system for the prescribed heating durations. Forty-minutes of heating resulted in a nearly 6-fold increase in doxorubicin concentration in heated vs unheated tumors in the same animals. Therapeutic ratio, defined as the ratio of Dox delivered into the heated tumor vs the heart, increased from 1.9-fold with 10 minutes heating to 4.4-fold with 40 minutes heating. MR-HIFU can be used to guide, deliver and monitor mild hyperthermia of a Vx2 tumor model in a rabbit model, and an increased duration of heating leads to higher Dox deposition from LTSL-Dox in a target tumor without a concomitant increase in systemic exposure. Results from this preclinical study can be used to help establish clinical treatment protocols for hyperthermia mediated drug delivery.

Original languageEnglish (US)
Pages (from-to)196-203
Number of pages8
JournalInternational Journal of Hyperthermia
Volume36
Issue number1
DOIs
StatePublished - Jan 1 2019

Keywords

  • MR-guided high intensity focused ultrasound
  • Targeted drug delivery
  • mild hyperthermia
  • therapeutic ratio
  • thermosensitive liposomal doxorubicin

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cancer Research

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