Enhanced Efficacy of Combination Heat Shock Targeted Polymer Therapeutics with High Intensity Focused Ultrasound.

Combination of polymer therapeutics and hyperthermia has been shown to enhance accumulation in selectively heated tumor tissue. The additional use of heat shock (HS)-targeting towards tumor tissues can further enhance accumulation and retention, and improve therapeutic outcomes. In this work, high intensity focused ultrasound (HIFU) was used to generate hyperthermia in prostate tumor tissue. Upregulation of the cell surface HS receptor glucose regulated protein 78kDa (GRP78) was observed after treatment with HIFU hyperthermia which was then targeted by specific HS-targeting peptides. We used the peptide sequence WDLAWMFRLPVG attached to the side chains of water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing docetaxel (DOC) conjugated via a lysosomally degradable linker. It was shown that HIFU-mediated HS-targeted copolymer-DOC conjugates improved treatment efficacy in a murine prostate tumor xenograft model. These results show that the use of HIFU hyperthermia in combination with HS-targeted polymer-drug conjugates has potential to improve therapeutic outcomes in prostate cancer treatment.

Nanomedicine : nanotechnology, biology, and medicine. 2016 Jan 29 [Epub ahead of print]

Nick Frazier, Allison Payne, Christopher Dillon, Nithya Subrahmanyam, Hamidreza Ghandehari

Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA., Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84112, USA., Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA., Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: .