Induction and targeting of the heat shock response in prostate cancer

Specific delivery of chemotherapeutic agents to cancerous tissues can potentially result in increased safety and decreased toxicity. For example, nanomedicines, including polymer-drug conjugates, can potentially accumulate in solid tumors via the "enhanced permeability and retention" (EPR) effect. Further increases in delivery can be achieved via active targeting strategies, wherein cancer-specific targeting moieties enhance cellular binding and internalization. This dissertation describes a strategy which attempts to increase the tumor accumulation and efficiency of active targeting using a combination of tumor hyperthermia and heat shock protein (HSP) targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates. Following exposure to hyperthermia, increases in cellular stress results in initiation of the heat shock response, which includes the synthesis and migration of certain heat shock proteins to the cell surface. It is hypothesized that the induced expression of these HSPs can serve as specific molecular targets for the delivery of anticancer macromolecular chemotherapeutics. HPMA copolymer-drug conjugates bearing peptides targeting cell surface expressed glucose regulated protein 78 kDa (GRP78), a member of the HSP70 family of proteins, were synthesized, characterized, and evaluated for activity in prostate cancer models. Following exposure to hyperthermia, the cell surface expression of GRP78 was also evaluated and correlated to increases in cellular delivery and cytotoxicity of GRP78 targeted HPMA copolymeriv drug conjugates. Combination index analyses indicated that a combination of hyperthermia and HSP targeted drug therapy resulted in combined synergistic effects. In vivo, gold nanorod-mediated plasmonic photothermal therapy was utilized to induce tumor hyperthermia in a human prostate cancer animal model to enhance the delivery and efficacy of GRP78 targeted HPMA copolymer-drug conjugates. Results demonstrate that a combination of tumor hyperthermia and HSP targeting can increase tumor accumulation and cellular delivery of macromolecular chemotherapeutics, enabling safer and more effective therapies.