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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

基本信息

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
项目类别：
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&apos s Lymphoma Normal Cell Oncogenic Oncology Oncolytic Outcome PET/CT scan Paclitaxel Palate Kaposi&apos 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

项目摘要

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.

两种人类γ -疱疹病毒，eb病毒（EBV）和卡波西肉瘤相关