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 10 mg/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.

Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

“…By itself, thermal therapy can also kill cancer cells4748. Prostate cancer xenograft tumour sizes were about 60% of control group on day 30 after mice were heated at 42–43 °C for 10 min using gold nanorod49. Comparing with local hyperthermia, whole body thermal therapy is a systemic treatment, and whole-body fever-range thermal therapy can safely treat cancer cells wherever they are throughout the entire body5051.…”

Anisotropic Gold-based Nanoparticles: Preparation, Properties, and Applications

“…These results show that there is potential for tumor hyperthermia to enhance the delivery of targeted macromolecular chemotherapeutics. 114 In recent years, the combination of chemotherapeutics and phototherapy has become more interesting because of their ability to carry an anticancer drug. However, hydrophobicity is an obstacle that restricts the use of many anticancer drugs.…”

Prostate cancer relevant antigens and enzymes for targeted drug delivery

“…215 HSP-targeted drug delivery is also an exciting and useful area to explore. A few HSP-70 specific peptide sequences, such as WIFPWIQL 216 and WDLAWMFRLPVG, 216, 217 were also identified and used for targeted delivery of cytotoxic agents to cells overexpressing HSPs, including prostate cancer cells. 217-219216 These peptides were successfully employed as ligand for HPMA copolymer–drug conjugate and efficiently delivered to prostate tumor cells.…”

“…217-219216 These peptides were successfully employed as ligand for HPMA copolymer–drug conjugate and efficiently delivered to prostate tumor cells. 217-219 …”