TUMOR SPECIFIC DELIVERY OF VERTICILLIN A OVERCOMES EPIGENETIC SILENCING RESPONSIBLE FOR DRUG RESISTANCE
TUMOR SPECIFIC DELIVERY OF VERTICILLIN A OVERCOMES EPIGENETIC SILENCING RESPONSIBLE FOR DRUG RESISTANCE
批准号:
9889919
负责人:
Yolonda L Colson
金额:
$52.61万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-04-01 至 2023-03-31
关键词:
3-DimensionalAddressAffinityAlkaloidsAntibodiesApoptosisArchitectureBiochemistryBiological AssayCancer PatientCardiotoxicityCell LineCellsCisplatinClinicalClinical TrialsCollaborationsCombined Modality TherapyDNA MethylationDataDecitabineDevelopmentDiagnosisDiseaseDrug Delivery SystemsDrug ExposureDrug ModelingsDrug resistanceEmulsionsEncapsulatedEnsureEnvironmentEpigenetic ProcessExperimental DesignsFDA approvedFamilyFormulationHealthcareHepatotoxicityHistone Deacetylase InhibitorHistonesHospitalsHumanHydrophobicityInternationalKidneyLiverMalignant neoplasm of ovaryMeasuresMesotheliomaMetabolismMitochondriaMusNatural ProductsNatural Products ChemistryOutcomeOvarian CarcinomaOvaryPaclitaxelPathologyPatient CarePatientsPb clearancePemetrexedPenetrationPeritonealPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacognosyPleural effusion disorderPolymer ChemistryPredispositionPropertyQuality of lifeResearchResistanceRouteSpecificitySpleenStimulusSurgical OncologySurvival RateSwellingTestingThe science of MycologyTimeToxic effectTreatment FailureTumor Suppressor GenesUp-RegulationVorinostatWomanXenograft ModelXenograft procedureanalogbasechemotherapeutic agentcytotoxiccytotoxicityexperimental studyextracellularhistone methyltransferasehydrophilicityimprovedin vitro Assayin vitro Modelin vivoin vivo Modelinnovationintraperitonealmembermetabolic ratemortalitymouse modelnanometernanoparticleneoplastic cellnovelparticleperitoneal cancerpharmacokinetics and pharmacodynamicsprogramssmall moleculesuccesstargeted deliverytumorverticillin A
中文摘要
摘要
该提案描述了针对间皮瘤治疗失败主要原因的创新解决方案:药物
阻力。解决方案是新型表观遗传修饰剂的受控和靶向递送——
轮枝菌素 A 或其类似物之一 – 重新建立化疗药物的敏感性
通过表观遗传沉默的肿瘤抑制基因的重新表达来抵抗肿瘤。与其他小
分子表观遗传制剂,包括 FDA 批准的药物,即全局 DNA 甲基化和组蛋白
脱乙酰酶抑制剂 Verticillin A 选择性靶向 H3K9me2/3。刺激响应颗粒药物输送
系统采用独特的基于材料的靶向策略,以确保轮枝菌素和
化疗药物定位并集中于腹膜肿瘤。这种 pH 响应性药物递送
系统利用肿瘤的基本病理生理学特性(例如弱酸性细胞外
环境和高代谢率)以诱导成分和结构变化(例如颗粒膨胀
从0.1到1微米)导致肿瘤特异性积累。这种基于材料的靶向方法
克服了传统策略的局限性(例如,通过增强的渗透性和被动靶向性
保留效应,以及通过基于抗体的亲和力的主动靶向),同时提供一个平台来实现这两种效果
分别通过单乳剂和双乳剂制备疏水性药物和亲水性药物。拟议的
实验将检验以下假设:将轮枝菌素药物与化疗药物一起递送
(作为单一药物或与胶囊或游离药物的联合制剂的联合治疗)
与递送药物相比,间皮瘤肿瘤将克服耐药性并延长生存期
轮枝菌素或单独化疗。重要的是,关键的初步数据支持拟议的
研究、良好表征的材料和严格的实验设计已经建立,并且必要的交叉
学科合作和专业知识已经到位来解决这一假设。这五项具体目标
今年的提案是: 目标 1. 评估轮枝菌素 A 及其五种类似物在人类中的表观遗传活性
间皮瘤细胞 (MSTO-211H) 和从患者胸腔积液中收集的肿瘤细胞以及
通过肝毒性、心脏毒性和线粒体毒性的体外测定进行毒性分析。目标 2. 优化
将两种轮枝菌素药物与紫杉醇、顺铂或培美曲塞联合配制以达到最大效果
对耐药间皮瘤细胞系和从患者胸膜收集的肿瘤细胞的细胞毒性作用
积液。目标 3. 评估健康小鼠的毒性以及优化制剂在体内的 PK 和 PD/功效
耐药间皮瘤的患者来源异种移植(PDX)小鼠模型。
英文摘要
ABSTRACT
This proposal describes an innovative solution to a primary cause of treatment failure in mesothelioma: drug
resistance. The solution is the controlled and targeted delivery of a novel epigenetic modifying agent –
verticillin A or one of its analogs – which re-establishes chemotherapeutic susceptibility in chemotherapeutic
resistant tumors via re-expression of epigenetically silenced tumor suppressor genes. Unlike other small
molecule epigenetic agents, including FDA-approved drugs, which are global DNA methylation and histone
deacetylase inhibitors, Verticillin A selectively targets H3K9me2/3. A stimuli-responsive particle drug delivery
system employing a unique materials-based targeting strategy is used in order to ensure that the verticillin and
chemotherapeutic agents localize and concentrate in peritoneal tumors. This pH-responsive drug delivery
system leverages fundamental pathophysiological properties of tumors (e.g., mildly acidic extracellular
environment and high metabolic rate) to induce compositional and architectural changes (e.g., particle swelling
from 0.1 to 1 micron) resulting in tumor-specific accumulation. This materials-based targeting approach
overcomes limitations of traditional strategies (e.g., passive targeting via the enhanced permeability and
retention effect, and active targeting via antibody-based affinity) while providing a platform to deliver both
hydrophobic and hydrophilic drugs via single- and double-emulsions, respectively. The proposed
experiments will test the hypothesis that delivery of a verticillin agent with a chemotherapeutic
(combination therapy either as single agents or co-formulation with encapsulated or free drug) to
mesothelioma tumors will overcome drug resistance and extend survival compared to the delivery of
verticillin or the chemotherapeutic alone. Importantly, key preliminary data are in support of the proposed
studies, well-characterized materials and rigorous experimental designs are established, and essential cross-
disciplinary collaborations and expertise are in place to address this hypothesis. The specific aims of this five-
year proposal are: Aim 1. Evaluate the epigenetic activity of verticillin A and five of its analogs in human
mesothelioma cells (MSTO-211H) and tumor cells collected from patient pleural effusions as well as the
toxicity profile via in vitro assays for hepatotoxicity, cardiotoxicity, and mitochondrial toxicity. Aim 2. Optimize
the co-formulation of the two verticillin agents with paclitaxel, cisplatin, or pemetrexed to achieve the maximum
cytotoxic effect in drug resistant mesothelioma cell lines and tumor cells collected from patient pleural
effusions. Aim 3. Assess toxicity in healthy mice and PK and PD / efficacy of the optimized formulation in
patient-derived xenograft (PDX) murine models of drug resistant mesothelioma.
期刊论文(0)
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