Nano-Therapeutic Approaches for Oncogenic Herpesvirus-Mediated Malignancies

疱疹病毒介导的致癌性恶性肿瘤的纳米治疗方法

• 批准号: 10203875
• 负责人: Yoshihiro Izumiya
• 金额: $ 53.74万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-06 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203875
• 关键词: Affinity; Antineoplastic Agents; B-Cell Lymphomas; Biochemical; Biological; Bortezomib; Breast; Cells; Communication; Comprehensive Cancer Center; Core Facility; Development; Disease; Dose; Doxorubicin; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Effectiveness; Elderly; Encapsulated; Etiology; Evaluation; FDA approved; Fluorescence; Fluorescence Resonance Energy Transfer; Formulation; Future; Glioblastoma; Goals; HIV Infections; Herpesviridae; Herpesviridae Infections; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Imaging Techniques; Immune; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Interleukin-10; Interleukin-6; Kaposi Sarcoma; Knowledge; Ligands; Link; Liver Dysfunction; Lymphoma; Lymphoma cell; Lymphoproliferative Disorders; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Mediating; Methods; Modeling; Molecular; Multicentric Angiofollicular Lymphoid Hyperplasia; Multimodal Imaging; Mus; Myocardial dysfunction; Nanotechnology; Nasopharynx Carcinoma; Natural Killer Cells; Nature; Neoplasm Metastasis; Non-Hodgkin' s Lymphoma; Normal Cell; Oncogenic; Oncology; Oncolytic; Outcome; PET/CT scan; Paclitaxel; Palate Kaposi' s Sarcoma; Patients; Pharmaceutical Preparations; Physicians; Porphyrins; Primary Neoplasm; Production; Prostate; Publishing; Rattus; Research; Series; Site; Synthesis Chemistry; Therapeutic; Tissues; Toxic effect; Translating; Treatment Efficacy; Treatment-related toxicity; Vincristine; Virus; Virus Latency; Virus Replication; Xenograft Model; body cavity; cancer cell; cancer type; cell killing; chemotherapeutic agent; chemotherapy; clinical practice; comorbidity; dosage; drug efficacy; fluorescence imaging; gammaherpesvirus; human old age (65+); improved; in vivo; inhibitor/antagonist; innovation; invention; kidney dysfunction; lytic gene expression; malignant breast neoplasm; mouse model; nano; nanocapsule; nanocarrier; nanoformulation; nanomedicine; nanoparticle; nanotheranostics; nanotherapeutic; neoplastic; neoplastic cell; novel; novel therapeutic intervention; optical imaging; post-transplant; primary effusion lymphoma; prototype; side effect; small molecule; systemic toxicity; targeted treatment; tumor; tumor growth; tumor microenvironment; tumor progression; tumor xenograft; virology

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.

两种类型的人类γ-疱疹病毒，EB病毒（EBV）和卡波西肉瘤相关的 疱疹病毒（KSHV）与多种淋巴增生性和肿瘤性疾病有关。已知KSHV感染 与卡波西肉瘤（KS）、口腔KS、原发性渗出性淋巴瘤（PEL;或体腔B淋巴瘤）相关， 以及多中心Castleman病的一个亚型。EB病毒在病因学上与伯基特淋巴瘤有关， 鼻咽癌、霍奇金淋巴瘤和非霍奇金淋巴瘤、T/NK细胞淋巴瘤和淋巴瘤后转移。 移植淋巴组织增生性疾病PEL是非霍奇金淋巴瘤最具侵袭性的形式之一。 不幸的是，目前的化疗方法导致了令人沮丧的结果，中位生存期短， 超过10个月。尽管其发病率相对罕见，但我们认为新治疗方法的开发 仍然很重要。此外，为PEL开发的成功治疗方法应适用于其他 致癌疱疹病毒介导的癌症类型。 目前的化学治疗剂可以有效地根除癌细胞，但功效受到"脱靶"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， 有效性受到包括肾、肝或心脏功能障碍的共病状况的限制。如果我们能操纵 从而药物主要在肿瘤中积累而同时降低"脱靶效应"， 我们可以增加药物的有效性，减少副作用;这将最终提高疗效。 在这种应用中，我们正在开发新的治疗方法与纳米胶囊通过利用FDA- 批准卟啉作为材料。通过将抗癌药物封装在我们的纳米颗粒中， 在小鼠研究中，化疗药物的适用剂量为3至8倍，在大鼠研究中甚至为20倍。这是非常 重要的原因有很多;（1）我们可能能够恢复非常有效但有毒的抗癌药物， 此前由于脱靶效应未能获得FDA批准。(2)我们也可以增加剂量水平 目前使用的抗癌药物不会增加副作用。(3)最重要的是，我们的发明 医生治疗由于合并症而无法选择化疗的患者。最后通过 运用我们在疱疹病毒学方面的知识，我们从自然感染的病毒中， 癌细胞与抗癌药物的组合。通过这样做，感染的病毒开始在癌症中复制 并最终杀死肿瘤细胞。癌细胞而不是健康的正常细胞被病毒感染，因此我们 可以通过使用已经感染的疱疹病毒来选择性地杀死癌细胞。通过仔细选择抗癌药物，我们 抑制病毒复制的完成，使其感染邻近的正常细胞。通过组合使用 纳米技术与溶瘤策略，我们将建立新的治疗方法，更具体地说， 致癌疱疹病毒介导的恶性肿瘤。