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.

Tumor‐Targeting W18O49 Nanoparticles for Dual‐Modality Imaging and Guided Heat‐Shock‐Response‐Inhibited Photothermal Therapy in Gastric Cancer

“…The subsequent heat shock response could directly lead to stressful overexpression of heat shock proteins (HSPs) including HSP110, HSP90, and HSP70 . Due to the obvious contribution to tumor survival and growth of HSPs, some HSP inhibitors were developed to cut down the thermoresistance and improve the curative effect . The Hsp90 inhibitors, 17‐allylamino‐17‐demethoxygeldanamycin (17AAG), can specifically bind to the HSP90 ATP pocket reversibly, thus destroying its thermal‐protected function potently and further leading to the death of cancer cells .…”

Histotripsy: The Next Generation of High‐Intensity Focused Ultrasound for Focal Prostate Cancer Therapy

“…Chiang compared radical prostatectomy, high‐dose brachytherapy, cryoablation, and HIFU for localized prostate carcinoma and concluded that whereas oncologic outcomes were similar, the HIFU group had better urinary function, better sexual function, and an improved quality of life. High‐intensity focused US–induced hyperthermia has also been investigated in preclinical studies to trigger the release of chemotherapeutic drugs from temperature‐sensitive liposomes . In general, various forms of focal therapy are all very similar in efficacy.…”

GRP78‐Targeted HPMA Copolymer‐Photosensitizer Conjugate for Hyperthermia‐Induced Enhanced Uptake and Cytotoxicity in MCF‐7 Breast Cancer Cells

“…Greater cell uptake and binding of HSP‐targeted polymer after hyperthermia induction was found . Also, in vivo studies showed that the hyperthermia induced GRP78 expression in a prostate xenograft model measured by immunohistochemical analysis was found to be high at 8 h . Therefore, we can use one of these approaches for hyperthermia induction in conjunction with the use of the present copolymer conjugate for future in vivo studies.…”

“…Previous studies have shown that biocompatible macromolecules like HPMA‐based carrier systems are able to extend blood circulation time and increase accumulation in solid tumors tissue by the EPR effect . Furthermore, we have previously demonstrated that HIFU and plasmonic photothermal therapy (PPTT) generate mild hyperthermia that can enhance heat shock protein expression in cells and accumulation of polymer‐drug conjugates in a tumor model . For example, in previous reports, higher expression of GRP78 through hyperthermia in human prostate cancer cells was measured using flow cytometry.…”

“…In addition to augmenting the EPR effect, mild hyperthermia can be used to induce the expression of heat shock receptor proteins on cancer cells, which can serve as a target. Previous work has shown that the combination of localized hyperthermia and heat shock peptide‐conjugated copolymers results in increased accumulation in solid tumors and improved treatment efficacy . Hyperthermia can be induced via a variety of methods including laser exposure following administration of metallic nanoparticles such as gold nanoparticles or via high intensity focused ultrasound (HIFU).…”