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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.

SUBMITTER: Tian L

PROVIDER: S-EPMC6804038 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Tian Li L Wang Lucas L Qiao Yang Y Lu Linfeng L Lee Patrick P Chang Ashley A Ravi Saisree S Rogers Thomas A TA Melancon Marites P MP

Molecules (Basel, Switzerland) 20191001 19

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 phar ...[more]

PMID: 31581445

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Project description:Human head and neck squamous cell carcinoma (HNSCC) is usually treated with chemoradiotherapy, but the therapeutic efficacy could be hampered by intrinsic radioresistance and early relapse. Repeated administrations of rhenium-188 (188Re)-conjugated radiopharmaceutical has been reported to escalate the radiation doses for better control of advanced human cancers. Here we found that high dosage of 188Re-liposome, the liposome-encapsulated 188Re nanoparticles exhibited significant killing effects on HNSCC FaDu cells and SAS cells but not on OECM-1 cells. To investigate the biological and pharmaceutical responses of high 188Re-liposomal dosage in vivo, repeated doses of 188Re-liposome was injected into the orthotopic tumor model. FaDu cells harboring luciferase reporter genes were implanted in the buccal positions of nude mice followed by intravenous injection of 188Re-liposome. The Cerenkov luminescence imaging (CLI) was performed to demonstrate an increased accumulation of 188Re-liposome in the tumor lesion of nude mice with repeated doses compared to a single dose. Repeated doses also enhanced tumor growth delay and elongated the survival of tumor-bearing mice. These observations were associated with significant loss of Ki-67 proliferative marker and epithelial-mesenchymal transition (EMT) markers in excised tumor cells. The body weights of mice were not significantly changed using different doses of 188Re-liposome, yet repeated doses led to lower blood counts than a single dose. Furthermore, the pharmacokinetic analysis showed that the internal circulation of repeated 188Re-liposomal therapy was elongated. The biodistribution analysis also demonstrated that accumulations of 188Re-liposome in tumor lesions and bone marrow were increased using repeated doses. The absorbed dose of repeated doses over a single dose was about twofold estimated for a 1?g tumor. Together, these data suggest that the radiopharmacotherapy of 188Re-liposome can enhance tumor suppression, survival extension, and internal circulation without acute toxicity using repeated administrations.

Dataset Information

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

Publications

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

Similar Datasets

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