title: Enhanced efficacy of combination heat shock targeted polymer therapeutics with high intensity focused ultrasound.
abstract: 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 78 kDa (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.
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT, USA; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Frazier
authors.affiliation: Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Payne
authors.affiliation: Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Dillon
authors.affiliation: Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
authors.forename: Nithya
authors.initials: N
authors.lastname: Subrahmanyam
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT, USA; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA. Electronic address: hamid.ghandehari@pharm.utah.edu.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000077143:Docetaxel; D016503:Drug Delivery Systems / Q000379:methods*; D000091342:Endoplasmic Reticulum Chaperone BiP; D057086:High-Intensity Focused Ultrasound Ablation / Q000379:methods*; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D008297:Male; D008819:Mice, Nude; D010455:Peptides / Q000737:chemistry; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D043823:Taxoids / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D010455:Peptides; D043823:Taxoids; D000077143:Docetaxel; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: Drug delivery; High intensity focused ultrasound; Hyperthermia; Magnetic resonance imaging; Prostate cancer