title: Synergistic enhancement of cancer therapy using a combination of heat shock protein targeted HPMA copolymer-drug conjugates and gold nanorod induced hyperthermia.
abstract: In the field of nanomedicine, selective delivery to cancer cells is a common goal, where active targeting strategies are often employed to increase tumor accumulation. In this study, tumor hyperthermia was utilized as a means to increase the active delivery of heat shock protein (HSP) targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates. Following hyperthermia, induced expression of cell surface heat shock protein (HSP) glucose regulated protein 78 kDa (GRP78) was utilized for targeted drug therapy. Conjugates bearing the anticancer agents aminohexylgeldanamycin (AHGDM), docetaxel (DOC), or cisplatin and the GRP78 targeting peptide WDLAWMFRLPVG were synthesized and characterized. Binding to cell surface expressed heat shock protein GRP78 on the surface of human prostate cancer DU145 cells was evaluated. HSP targeted AHGDM and DOC conjugates demonstrated active binding comparable to native targeting peptide. They were then assessed in vitro for the ability to synergistically induce cytotoxicity in combination with moderate hyperthermia (43 °C, 30 min). HSP targeted DOC conjugates exhibited high potency against DU145 cells with an IC₅₀ of 2.4 nM. HSP targeted AHGDM and DOC conjugates demonstrated synergistic effects in combination with hyperthermia with combination index values of 0.65 and 0.45 respectively. Based on these results, HSP targeted DOC conjugates were selected for in vivo evaluation. In DU145 tumor bearing mice, a single treatment of tumor hyperthermia, induced via gold nanorod mediated plasmonic photothermal therapy, and intravenous administration of HSP targeted HPMA copolymer-docetaxel at 10mg/kg resulted in maintained tumor regression for a period of 30 days. These results demonstrate the potential for tumor hyperthermia to increase the delivery of HSP targeted macromolecular chemotherapeutics.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, Salt Lake City 84112, USA.
authors.forename: Nate
authors.initials: N
authors.lastname: Larson
authors.forename: Adam
authors.initials: A
authors.lastname: Gormley
authors.forename: Nick
authors.initials: N
authors.lastname: Frazier
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D016227:Benzoquinones / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry; D003131:Combined Modality Therapy; D000077143:Docetaxel; D000091342:Endoplasmic Reticulum Chaperone BiP; D006046:Gold / Q000737:chemistry; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D006979:Hyperthermia, Induced; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000737:chemistry; D008689:Methacrylates / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D043942:Nanotubes / Q000737:chemistry; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D009842:Oligopeptides / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D047029:Lactams, Macrocyclic; D008689:Methacrylates; D009842:Oligopeptides; D043823:Taxoids; D000077143:Docetaxel; D006046:Gold; D002945:Cisplatin; C032802:hydroxypropyl methacrylate; C001277:geldanamycin