Heat-activated drug delivery increases tumor accumulation of synergistic chemotherapies

Doxorubicin is a clinically important anthracycline chemotherapeutic agent that is used to treat many cancers. Nanomedicine formulations including Doxil (R) and ThermoDox (R) have been developed to mitigate doxorubicin cardiotoxicity. Doxil is used clinically to treat ovarian cancer, AIDS-related Kaposi's sarcoma, and multiple myeloma, but there is evidence that therapeutic efficacy is hampered by lack of drug release. ThermoDox is a lipid-based heat-activated formulation of doxorubicin that relies on externally applied energy to increase tissue temperatures and efficiently trigger drug release, thereby affording therapeutic advantages compared to Doxil. However, elevating tissue temperatures is a complex treatment process requiring significant time, cost, and expertise compared to standard intravenous chemotherapy. This work endeavors to develop a companion therapeutic to ThermoDox that also relies on heat-triggered release in order to increase the therapeutic index of doxorubicin. To this end, a thermosensitive liposome formulation of the heat shock protein 90 inhibitor alvespimycin has been developed and characterized. This research demonstrates that both doxorubicin and alvespimycin are potent anti-cancer agents and that heat amplifies their cytotoxic effects. Furthermore, the two drugs are proven to act synergistically when cancer cells are treated with the drugs in combination. The formulation of alvespimycin was rationally designed to exhibit similar pharmacokinetics and drug release kinetics compared to ThermoDox, enabling the two drugs to be delivered to heated tumors at similar efficiencies resulting in control of a particular synergistic ratio of drugs. In vivo measurements demonstrated effective heatmediated triggering of doxorubicin and alvespimycin release from thermosensitive liposomes within tumor vasculature. This treatment strategy resulted in a similar to 10-fold increase in drug concentration within tumors compared to free drug administered without tumor heating.