Antitumor Efficacy of Liposome-Encapsulated NVP-BEZ235 Combined with Irreversible Electroporation for Head and Neck Cancer.

ABSTRACT

Irreversible electroporation (IRE) kills tumor cells by the delivery of short pulses of strong electric fields. However, the field strength decreases with distance from the treatment center. When IRE cannot eradicate the entire tumor mass, the surviving tumor cells can regrow. NVP-BEZ235 is a dual PI3K/mTOR inhibitor that has been administered orally in clinical trials. However, its hydrophobicity and poor water solubility make NVP-BEZ235 difficult to deliver to target areas. To improve its pharmacokinetics and therapeutic efficacy, we have encapsulated NVP-BEZ235 in a liposome (termed as L-BEZ). Our current study focuses on the long-term antitumor efficacy of IRE and intratumoral injection of L-BEZ in HN5 head and neck cancer xenografts in nude mice. We compared in vitro efficacy, as well as the effect on tumor size and growth rate in vivo, between IRE alone, IRE + oral BEZ, and IRE + L-BEZ over the course of two months. All animals in the control group were sacrificed by day 36, due to excess tumor burden. Tumors treated with IRE alone grew faster and larger than those in the control group. IRE + oral BEZ suppressed tumor growth, but the growth rate increased to that of the controls toward the end of 21 days. Only IRE + L-BEZ eradicated the tumor masses, with no palpable or extractable tumor mass observed after two months. The combination of IRE and L-BEZ could effectively eradicate tumors and prevent recurrence.