Aptamer mediated targeting of Fanconi Anemia oral cancer initiating cells

适体介导的范可尼贫血口腔癌起始细胞的靶向

基本信息

批准号：
8896720
负责人：
Ananth V Annapragada
金额：
$ 38.36万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-25 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8896720
关键词：
Aftercare Antineoplastic Agents Behavior Binding Cancer Patient Cancer cell line Cell Fraction Cell Survival Cells Charge Checkpoint kinase 1 Clinic Clinical Cytosol Data Development Diagnosis Disease-Free Survival Distant E-Selectin Endosomes Evolution Exhibits Fanconi&apos s Anemia Gene Silencing Gene Targeting General Population Genes Goals Head and neck structure Hepatic Hepatocyte Hereditary Neoplastic Syndromes In Vitro Inherited Kupffer Cells Lead Libraries Ligands Link Lipids Liposomes Liver Maintenance Malignant Epithelial Cell Malignant Neoplasms Mediating Methodology Modality Modeling Mus Oral Outcome Patients Pharmaceutical Preparations Process Property Proteins Public Health Publishing RNA Interference Recurrence Recurrent disease Relapse Risk Role Site Small Interfering RNA Solutions Specificity Squamous cell carcinoma Syndrome System Techniques Testing Therapeutic Therapeutic Agents Time Toxic effect Translating Translations Treatment Efficacy Tumorigenicity Xenograft procedure aldehyde dehydrogenases aptamer base cancer cell cancer recurrence cancer stem cell cancer therapy cell type cellular engineering chemoradiation chemotherapy gemcitabine human stem cells imaging agent improved in vivo insight keratinocyte knock-down malignant mouth neoplasm mortality mouth squamous cell carcinoma nanoparticle neoplastic cell novel outcome forecast overexpression public health relevance response screening skills targeted delivery targeted sequencing therapy resistant tumor uptake

项目摘要

DESCRIPTION (provided by applicant): We seek to use a novel cell-internalization SELEX (Systemic Evolution of Ligands by Exponential enrichment) to isolate thioaptamer-conjugated liposomal nanoparticles (TA-NP) that internalize and deliver its siRNA into the cytosol of tumor initiating cells (TIC) of oral squamous cell carcinoma, minimizing off-target delivery. In vivo delivery and release of siRNA from the endosomes to cytosol remain the two biggest obstacles for translating anticancer siRNA drugs to the clinic. Oral squamous cell carcinoma commonly known as oral cancer (OC) is the most common malignancy of head and neck with high global public health impact. Fanconi anemia (FA) is a hereditary cancer syndrome that predisposes one to OC. Evidence points to TIC as the key driver of field cancerization, resistance to therapy and disease relapse. A therapeutic vehicle that selectively targets and delivers anticancer drugs to TIC offers great promise for OC treatment. Our data and published studies show: (1).TIC is more enriched in FA-OC than sporadic OC; (2) Chk1 and CD147 promote TIC survival and chemoresistance and its overexpression contribute to poor prognosis in OC. The main goal of this application is to use FA- OC-TIC as target cells to develop TA- NP for the cytosolic delivery of siRNA. We hypothesize that isolated TA-NP will facilitate targeted delivery of siRNA to OC-TIC cytosol, and silence CD-147/Chk1 in OC-TIC's, disrupting their niche and rendering them chemosensitive and susceptible to elimination by chemotherapy with gemcitabine. Aims:(1): Elucidate the effect of RNAi mediated silencing of CD147/Chk1 in FA-OC-TIC; (2A): Select a list of TA-Liposomal NP (TA-NP) specific for TIC fraction of FA-OC cells, while avoiding hepatocyte uptake, using a positive and negative cell-uptake based SELEX; (2B): Determine the selected TA-NP's targeting specificity and therapeutic efficacy in in vitro and in murine OC xenografts. We will isolate ALDH+ TIC in FA-OC cell lines and examine the effects of siRNA-mediated silencing of CD147 and Chk1. (2) We will use a modified conjugate SELEX with positive and negative selections to identify OC-TIC-specific internalizing TA-NP. (3) We will validate TIC-targeting specificity and silencing efficacy of isolated TA-NP-sRNA in vitro and in murine orthotopic FA-OC xenografts. RNAi mediated inhibition of CD147 and Chk1 in OC-TIC will yield valuable insight into their potential role in the tumor propagating and chemoresistant properties of OC-TIC. The proposed TA-NP will have important clinical potentials for in vivo delivery of therapeutic and imaging agents targeting the OC-TIC.

DESCRIPTION (provided by applicant): We seek to use a novel cell-internalization SELEX (Systemic Evolution of Ligands by Exponential enrichment) to isolate thioaptamer-conjugated liposomal nanoparticles (TA-NP) that internalize and deliver its siRNA into the cytosol of tumor initiating cells (TIC) of oral squamous cell carcinoma, minimizing off-target delivery.体内递送和siRNA从内体到细胞质的释放仍然是将抗癌siRNA药物转化为诊所的两个最大障碍。通常称为口腔癌（OC）的口腔鳞状细胞癌是头颈最常见的恶性肿瘤，全球公共卫生影响很大。 Fanconi贫血（FA）是一种遗传性癌症综合征，使OC易于使用。证据表明TIC是现场癌化，抗治疗和疾病复发的主要驱动力。一种有选择地靶向和靶向抗癌药物的治疗工具为TIC提供了巨大的OC治疗前景。我们的数据和已发表的研究表明：（1）.TIC在FA-OC中比零星的OC更富含FA-OC；（2）CHK1和CD147促进TIC的生存和化学耐药性及其过表达促进了OC的预后不良。该应用的主要目的是将fa-oc-tic用作靶细胞来开发siRNA胞质递送的ta-np。我们假设孤立的TA-NP将有助于将siRNA的靶向递送到OC-TIC细胞质中，并在OC-TIC中的CD-147/CHK1静音，破坏其利基市场，并使它们化学敏感，并容易通过gemcitabine化学疗法消除。目的：（1）：阐明了FA-OC-TIC中RNAi介导的CD147/CHK1沉默的影响；（2a）：选择针对FA-OC细胞的TIC分数的Ta-脂质体NP（TA-NP）的列表，同时避免使用基于细胞摄取的阳性和负细胞摄取的SELEX；（2b）：确定所选的TA-NP在体外和鼠OC异种移植物中的靶向特异性和治疗功效。我们将在FA-OC细胞系中分离ALDH+ TIC，并检查siRNA介导的CD147和CHK1沉默的影响。（2）我们将使用带有正和负选择的修改后的共轭SELEX来识别特定于OC-TIC的内部化TA-NP。（3）我们将验证分离的TA-NP-SRNA在体外和鼠的原始FA-OC异种移植物中的靶向特异性和沉默的功效。 RNAi介导的OC-TIC中CD147和CHK1的抑制作用将对其在OC-TIC的肿瘤传播和化学性特性中的潜在作用产生有价值的见解。拟议的TA-NP将具有重要的临床潜力，以在体内递送靶向OC-TIC的治疗剂和成像剂。