Nano-Therapeutic Approaches for Oncogenic Herpesvirus-Mediated Malignancies

两种人类伽玛-疱疹病毒：EB病毒和卡波西肉瘤相关病毒 疱疹病毒(KSHV)与多种淋巴增生性和肿瘤性疾病有关。KSHV感染已知 与Kaposi肉瘤(KS)、口腔KS、原发性渗出性淋巴瘤(PEL；或体腔B淋巴瘤)有关， 以及多中心性卡斯特尔曼病的一个子集。EB病毒在病因上与伯克特淋巴瘤有关， 鼻咽癌，霍奇金淋巴瘤和非霍奇金淋巴瘤，T/NK细胞淋巴瘤，以及非霍奇金淋巴瘤 移植物淋巴增生性疾病。PEL是最具侵袭性的非霍奇金淋巴瘤之一。 不幸的是，目前的化疗方法结果令人沮丧，中位生存期短。 比10个月还多。虽然它的发生率相对较低，但我们认为新的治疗方法的发展是 仍然很重要。此外，为PEL开发的成功的治疗方法应该适用于其他 致癌性疱疹病毒介导的癌症类型。 目前的化疗药物可以有效地清除癌细胞，但其疗效受到非靶点的限制 效果“导致相当大的毒性。此外，大多数淋巴瘤患者是老年人和 有效性受到包括肾、肝或心脏功能障碍在内的共病条件的限制。如果我们能操纵 药物使得药物主要积聚在肿瘤中，同时减少“靶外效应”， 我们可以提高药物的有效性，减少副作用；这最终将提高疗效。 在这项应用中，我们正在利用FDA开发纳米胶囊的新治疗方法- 批准以卟啉为原料。通过将抗癌药物包裹在我们的纳米粒子中，我们可以增加 化疗药物的适用剂量在小鼠中从3倍到8倍不等，在大鼠研究中甚至是20倍。这是非常重要的 重要的原因有几个；(1)我们可能能够复兴非常有效但有毒的抗癌药物， 此前由于偏离目标的影响，未能获得FDA的批准。(2)我们也可能增加 目前使用的抗癌药物没有增加副作用。最重要的是，我们的发明可以使 医生治疗因合并症而无法选择化疗的患者。最后，通过 应用我们在疱疹病毒学方面的知识，我们可以将潜伏感染的病毒从自然感染的病毒中恢复过来。 癌症细胞与抗癌药物的组合。通过这样做，被感染的病毒开始在癌症中复制 并最终杀死肿瘤细胞。被病毒感染的是癌细胞而不是健康的正常细胞，因此我们 可以通过使用已经感染的疱疹病毒选择性地杀死癌细胞。通过仔细挑选抗癌药物，我们 抑制病毒复制完成，从而感染到邻近的正常细胞。通过组合使用 随着纳米技术与溶瘤策略的结合，我们将建立新的治疗方法，以更具体地 致癌性疱疹病毒介导的恶性肿瘤。

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.