Combination Therapy of OvCA with Oligonucleotides and Photodynamic Therapy

OvCA 与寡核苷酸和光动力疗法的联合治疗

• 批准号: 9323752
• 负责人: Xin Ming
• 金额: $ 19.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323752
• 关键词: 3-Dimensional; ABCB1 gene; Address; Affect; Albumins; Animal Model; Animals; Apoptosis; Apoptotic; BCL2 gene; Cancer Model; Cancer Patient; Carrier Proteins; Cause of Death; Cell Culture Techniques; Cells; Cessation of life; Combined Modality Therapy; Diagnosis; Disseminated Malignant Neoplasm; Drug resistance; Endosomes; Extracellular Matrix; Family member; Flow Cytometry; Fluorescence; Gene Family; Genes; Goals; Grant; Health; Heterogeneity; Hypoxia; Integrins; Lasers; Lead; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Medicine; Membrane; MicroRNAs; Micrometastasis; Modality; Modeling; Neoplasm Metastasis; Nuclear; Oligonucleotides; Oncogenes; PUVA Photochemotherapy; Paclitaxel; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Physicians; Procedures; Process; RNA Splicing; Recurrence; Refractory; Reporter Genes; Residual state; Resistance; Resistance development; Singlet Oxygen; Site; Small Interfering RNA; Staging; System; Testing; Therapeutic; Treatment Failure; Tumor Tissue; Woman; Xenograft Model; Xenograft procedure; anticancer activity; base; cancer cell; cancer therapy; cell killing; chemotherapy; cytotoxicity; design; in vivo; killings; nanoparticle; overexpression; receptor; response; synergism; systemic toxicity; targeted delivery; therapy resistant; tool; treatment response; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): Drug resistance causes treatment failure and death in more than 90% of patients with metastatic cancer. Ovarian cancer (OvCa) is a leading cause of death from cancer in women with a projected 14,270 deaths in US in 2014, and it is generally diagnosed in advanced stages when the tumor has metastasized and numerous micrometastases with intrinsic or acquired resistance have formed. We aim to synchronize delivery of therapeutic oligonucleotides (ONs) and photodynamic therapy (PDT) agents to OvCa using nanoparticles (NPs), and thus to provide a combination therapy to overcome drug resistance in OvCa. ONs and PDT can provide mechanistically distinct therapy for resistant OvCa but both have limitations when used as monotherapy. ONs are capable of targeting any specific gene that causes drug resistance; however, their therapeutic activity had been constrained by the poor access to their intracellular sites of action because of non-productive endosomal trapping. PDT is a clinically approved anticancer procedure; however, it suffers from sub-lethal cancer cell killing due to a prosurvival autophagic mechanism and a short duration of action. We hypothesize that NP-based co- delivery enables complementation of these two modalities, leading to synergism at two levels. Firstly, when delivered together to endosomes in OvCa cells, laser-activated PDT effects trigger endosomal escape of ONs to their intracellular action sites. Thereafter, the functional delivery of the ONs can target specific genes and overcome drug resistance in multiple modes. Thus, when apoptosis-promoting Bcl-x splice-switching oligonucleotide (SSO) is used, it can guide PDT to a pro-death apoptotic pathway. When MDR1 siRNA is used, it can resensitize OvCa to paclitaxel, the first line chemotherapy drug to OvCa. We have prepared ultra-small integrin-targeted NPs carrying ONs and the PDT drug Ce6. Preliminary studies indicated that laser activation of Ce6 enables functional delivery of the ONs and causes cytotoxicity to OvCa cells. In this proposal, 4 specific aims are designed to test our hypothesis and realize the goal: 1. Elucidate cellular mechanisms for synergism of ONs and PDT and then optimize the NPs for greater synergistic action. 2. Evaluate therapeutic activity of the NPs in 3-D OvCa models that recapitulate some key features of in vivo microenvironment. 3. Evaluate anticancer activity of the NPs carrying Bcl-x SSO and Ce6 in vivo. 4. Test therapeutic activity of the NPs carrying MDR1 siRNA and Ce6. Studies proposed in this grant will thus provide distinct approaches to address the two underlying causes of drug resistance in OvCa: increased intrinsic survival ability and reduced intracellular drug concentration of OvCa cells.

 描述（由申请人提供）：耐药性导致超过90%的转移性癌症患者治疗失败和死亡。卵巢癌（OvCa）是女性癌症死亡的主要原因，2014年美国预计有14，270例死亡，并且通常在肿瘤转移和许多具有内在或获得性抗性的微转移形成时被诊断为晚期。我们的目标是使用纳米颗粒（NPs）将治疗性寡核苷酸（ON）和光动力治疗（PDT）剂同步递送至OvCa，从而提供克服OvCa中的耐药性的组合疗法。ON和PDT可以为耐药OvCa提供机制上不同的治疗，但作为单一疗法使用时都有局限性。ON能够靶向引起耐药性的任何特定基因;然而，由于非生产性内体捕获，它们的治疗活性受到难以进入其细胞内作用位点的限制。PDT是临床批准的抗癌程序;然而，由于促存活自噬机制和作用持续时间短，它遭受亚致死癌细胞杀伤。我们假设基于NP的共同递送能够实现这两种模式的互补，从而在两个水平上产生协同作用。首先，当一起递送到OvCa细胞中的内体时，激光激活的PDT效应触发ON的内体逃逸到其细胞内作用位点。此后，ON的功能性递送可以以多种模式靶向特定基因并克服耐药性。因此，当使用促凋亡Bcl-x剪接转换寡核苷酸（SSO）时，它可以将PDT引导至促死亡凋亡途径。当使用MDR 1 siRNA时，它可以使OvCa对OvCa的一线化疗药物紫杉醇重新敏感。我们已经制备了携带ON和PDT药物Ce 6的超小整合素靶向NP。初步研究表明，Ce 6的激光活化使得ON的功能性递送成为可能，并导致对OvCa细胞的细胞毒性。在本研究中，我们设计了四个具体的目标来验证我们的假设并实现目标：1。阐明ONs和PDT协同作用的细胞机制，然后优化NP以获得更大的协同作用。2.评价NP在3-D OvCa模型中的治疗活性，该模型概括了体内微环境的一些关键特征。3.评价携带Bcl-x SSO和Ce 6的NP的体内抗癌活性。4.测试携带MDR 1 siRNA和Ce 6的NP的治疗活性。因此，这项资助中提出的研究将提供不同的方法来解决OvCa耐药性的两个根本原因：OvCa细胞内在存活能力增加和细胞内药物浓度降低。