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: 9187917
• 负责人: Xin Ming
• 金额: $ 28.37万
• 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/9187917
• 关键词: 3-Dimensional; ABCB1 gene; Address; Affect; Albumins; Animal Model; Apoptosis; Apoptotic; BCL2 gene; Cancer Model; Cancer Patient; Carrier Proteins; Cause of Death; Cell Culture Techniques; Cessation of life; Clinical; Combination Drug Therapy; Combined Modality Therapy; Complement; Custom; Diagnosis; Disseminated Malignant Neoplasm; Drug resistance; Endosomes; Family member; Genes; Goals; Grant; Hypoxia; Lasers; Ligands; Light; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Medicine; Membrane; Methods; MicroRNAs; Micrometastasis; Modality; Modeling; Neoplasm Metastasis; Nuclear; Oligonucleotides; Oncogenes; PUVA Photochemotherapy; Paclitaxel; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Photosensitization; Physicians; Procedures; RNA Splicing; Recurrence; Refractory; Residual state; Resistance; Singlet Oxygen; Site; Small Interfering RNA; System; Testing; Therapeutic; Toxic effect; Treatment Failure; Woman; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; cell killing; chemotherapy; cytotoxicity; design; efficacy study; fluorescence imaging; in vivo; irradiation; killings; nanoparticle; overexpression; permissiveness; public health relevance; receptor; resistance mechanism; response; synergism; targeted delivery; therapy resistant; 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 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 therapies 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 its own resistance mechanisms 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 triggers 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 an 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 OvCa-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. Test photochemical delivery of Bcl-x SSO in vivo. 4. Test photochemical delivery of MDR1 siRNA. 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(申请人提供)：在超过90%的转移性癌症患者中，耐药性导致治疗失败和死亡。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人死亡，通常在肿瘤转移和形成大量具有内在或获得性耐药的微转移时被诊断为晚期。我们的目标是利用纳米颗粒(NPs)将治疗性寡核苷酸(ONS)和光动力疗法(PDT)药物同步输送到OvCa，从而提供一种克服OvCa耐药的联合疗法。ONS和PDT可以为难治性OvCa提供机械上不同的治疗方法，但作为单一疗法使用时，两者都有局限性。ONS能够靶向任何导致耐药的特定基因；然而，由于非生产性内体捕获，它们的治疗活性受到细胞内作用部位难以获得的限制。PDT是一种临床批准的抗癌方法，但由于其自身的耐药机制和作用时间短，存在亚致死癌细胞的杀伤作用。我们假设，基于NP的联合交付使这两种模式能够互补，从而在两个层面上产生协同效应。首先，当激光激活的PDT一起输送到OvCa细胞的内体时，会触发ONS向其细胞内作用部位的内体逃逸。此后，ONS的功能传递可以靶向特定的基因，并以多种方式克服耐药性。因此，当使用促进凋亡的Bcl-x剪接开关寡核苷酸(SSO)时，它可以将PDT引导到一条凋亡途径。当使用mdr1 siRNA时，它可以使OvCa对治疗OvCa的一线化疗药物紫杉醇重新增敏。我们已经制备了携带ONS和PDT药物Ce6的超小OvCa靶向NPs。初步研究表明，激光激活Ce6可以实现ONS的功能性传递，并对OvCa细胞产生细胞毒作用。在这个方案中，我们设计了4个特定的目标来验证我们的假说并实现这个目标：1.阐明ONS和PDT协同作用的细胞机制，然后优化NPs以实现更大的协同作用。2.三维评价纳米粒子的治疗活性 OvCa模型概括了体内微环境的一些关键特征。3.体内光化学递送实验。4.检测mdr1 siRNA的光化学传递。因此，这项拨款中提出的研究将提供不同的方法来解决OvCa耐药的两个根本原因：OvCa细胞内在生存能力的提高和细胞内药物浓度的降低。