Nano-Therapeutic Approaches for Oncogenic Herpesvirus-Mediated Malignancies

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Two types of human gamma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are linked to variety of lymphoproliferative and neoplastic disorders. KSHV infection is known to associate with Kaposi’s sarcoma (KS), oral-KS, primary effusion lymphoma (PEL; or body-cavity B-lymphoma), as well as a subset of multicentric Castleman’s disease. EBV is etiologically associated with Burkett’s lymphoma, nasopharyngeal carcinoma, both Hodgkin's and non-Hodgkin's lymphomas, T/NK cell lymphoma, and post- transplant lymphoproliferative disorder. PEL is one of the most aggressive forms of non-Hodgkin’s lymphoma. Current chemotherapeutic approaches, unfortunately, result in dismal outcomes with a short median survival of less than 10 months. Although its incidence is relatively rare, we think development of new therapeutic approaches is still important. Furthermore, successful therapeutic approaches developed for PEL should be applicable to other oncogenic herpesvirus-mediated cancer types. Current chemotherapeutic agents can effectively eradicate cancer cells but efficacy is limited by “off-target effects” leading to considerable toxicity. In addition, the majority of patients with lymphoma are elderly and effectiveness is limited by co-morbid conditions that include renal, liver or cardiac dysfunction. If we could manipulate the drugs so that the drugs primarily accumulate in the tumors while simultaneously decreasing the “off-target effects”, we can increase the effectiveness of the drugs and decrease side-effects; this will ultimately improve efficacy. In this application, we are developing new therapeutic approaches with Nano capsules by utilizing FDA- approved porphyrin as a material. By encapsulating cancer drugs in our nanoparticles, we could increase the applicable dose of chemotherapy drugs from 3 to 8-fold in mouse and even 20-fold in rat studies. This is very important for a number of reasons; (1) we may be able to revive very effective but toxic anti-cancer drugs that previously failed to obtain FDA approval due to off-target effects. (2) We may also increase the dose level of currently used anti-cancer drugs without increasing side effects. (3) Most importantly, our invention may enable physicians to treat patients who did not have an option for chemotherapy due to co-morbid conditions. Finally, by applying our knowledge in herpesvirology, we robustly reactivate latently infected virus from naturally-infected cancer cells with a combination of cancer drugs. By doing this, the infected virus starts to replicate in the cancer cells and eventually kills the tumor cells. Cancer cells but not healthy normal cells are infected by the virus, thus we can selectively kill cancer cells by using already infected herpesvirus. By careful selection of the cancer drugs, we inhibit the completion of viral replication thereof infection to neighboring normal cells. By using the combination of nanotechnology with oncolytic strategy, we will establish new therapeutic approaches for more specific to oncogenic herpesvirus mediated malignancies.