Targeted Platinates/siRNA Combination Therapy for Resistant Lung Cancer

靶向铂酸盐/siRNA 联合治疗耐药肺癌

基本信息

批准号：
8688558
负责人：
Mansoor M Amiji
金额：
$ 16.91万
依托单位：
NORTHEASTERN UNIVERSITY
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：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688558
关键词：
A549 Accounting Acute Amino Acids Animal Model Antineoplastic Agents Applications Grants Azides Aziridines Biocompatible Biological Assay Blood Cell Count Body Weight CD44 gene Cancer Etiology Cancer Model Cancer Patient Carbon Carboplatin Cause of Death Cells Cessation of life Charge Chemicals Cisplatin Clinic Combined Modality Therapy Cytotoxic Chemotherapy Development Diagnosis Dose-Limiting Drug Formulations Drug resistance Dyes Encapsulated Enzymes Epidermal Growth Factor Receptor Ethylene Glycols Evaluation Fatty Acids Formazans Forms Controls Future Gene Silencing Genes Histopathology Human Hyaluronic Acid In Vitro Individual Length Ligation Lipids Liver Malignant Neoplasms Malignant neoplasm of lung Mus Non-Small-Cell Lung Carcinoma Patients Peptides Pharmaceutical Preparations Phase Platinum Play Pump RNA Interference Refractory Refractory Disease Resistance Role Safety Series Small Interfering RNA Solutions Stem cells Sulfhydryl Compounds Surface System Tail Therapeutic Therapeutic Effect Tissues Toxic effect Transgenic Animals Transgenic Organisms United States Variant Woman Work Xenograft Model base cancer cell cancer therapy cancer type cell killing chemotherapy combination gene therapy combinatorial design effective therapy ethylene glycol improved in vivo knock-down men nano nanoparticle nanosystems neoplastic cell public health relevance receptor subcutaneous survivin targeted delivery therapeutic development therapy resistant tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Lung cancer accounts for more deaths than any other types of cancer in both men and women, with an estimated 226,160 new cases and 160,770 deaths in 2012, in the United States. Although platinum drugs have played a very important role in the chemotherapy of lung cancer, their major limitations are systemic toxicity and the rapid acquisition of resistance. As such, there is an urgent need to develop alternative strategies to effectively treat refractory lung cancer in a clinically-meaningful way without the associated toxicity burden. RNA interference therapy can be a powerful approach to down-regulate specific genes involved in platinum resistance and, therefore, can work synergistically with cytotoxic chemotherapy in refractory lung cancer patients. The main objective of this R21 proposal is to evaluate the therapeutic potential for combination lung cancer therapy using lipophilic (lipid-tailed) platinate derivatives and small interfering RNAs (siRNAs) delivered in CD44- and epidermal growth factor receptor (EGFR)-targeted biocompatible hyaluronic acid (HA) based self-assembling nano-systems. As part of the preliminary studies, we have developed a series of modified HA derivatives, using "click" chemical conjugation that allow for combinatorial- designed formulation development approach for encapsulation of hydrophobic (e.g., lipid-tailed platinates) and hydrophilic/charged (e.g., siRNA) molecules. Additionally, the modular nano-platform allows for incorporation of additional functionalities, including EGFR specific peptide, for dual targeting in lung cancer. The specific aims of the proposal are as follows: (1) synthesis and characterization of "lipid tailed" platinate derivatives and encapsulation, along with siRNA duplexes, in HA-based self-assembling nano- systems, (2) evaluation of in vitro gene silencing and cell-kill efficacy using single (lipid-tailed platinate alone) and combination (siRNA+platinate therapy in sensitive A549 and cisplatin-resistant A549DDP human non-small cell lung cancer cells, and (3) establish A549 and A549DDP tumor xenografts in athymic (nu/nu) mice and in vivo evaluation of anti-tumor efficacy and safety of single and combination siRNA/platinate therapy using dual targeting HA-based self-assembled nano-systems. This study is highly significant in evaluating gene silencing strategy in vivo for overcoming tumor drug resistance using a safe and effective delivery system. Following successful completion, future studies in the R01 phase will focus on evaluation of multiple gene silencing and combination therapy delivered with dual targeted HA nanoparticles in a transgenic human lung cancer model.

描述（由申请人提供）：肺癌的死亡人数比男性和女性的任何其他类型的癌症都要多，估计在2012年，2012年的226,160例新病例和160,770例死亡。尽管铂药在肺癌的化学疗法中起着非常重要的作用，但它们的主要局限性是全身毒性和抗药性的快速获取。因此，迫切需要制定替代策略，以临床上敏锐的方式有效治疗难治性的肺癌，而没有相关的毒性负担。 RNA干扰疗法可以是一种强大的方法，可下调参与铂耐药性的特定基因，因此可以协同作用在难治性肺癌患者中与细胞毒性化学疗法协同作用。该R21提案的主要目的是使用亲脂性（脂质尾巴）铂衍生物和小型干扰RNA（SIRNA）评估肺癌治疗的治疗潜力。作为初步研究的一部分，我们使用“单击”化学缀合开发了一系列改良的HA衍生物，从而允许组合设计的配方开发方法用于封装疏水性（例如脂质尾铂）和氢化/充电（例如，脂肪/sirna）分子。此外，模块化纳米平台允许在肺癌中纳入包括EGFR特异性肽在内的其他功能。该提案的具体目的如下：（1）合成 and characterization of "lipid tailed" platinate derivatives and encapsulation, along with siRNA duplexes, in HA-based self-assembling nano- systems, (2) evaluation of in vitro gene silencing and cell-kill efficacy using single (lipid-tailed platinate alone) and combination (siRNA+platinate therapy in sensitive A549 and cisplatin-resistant A549DDP human non-small细胞肺癌细胞，（3）在无胸腺（NU/NU）小鼠中建立A549和A549DDP肿瘤异种移植物，并在体内评估单一和组合siRNA/Platinate治疗的抗肿瘤疗效和安全性使用双靶向HA基于HA的自我组合的nano-for for nano-formenty progripty them serrecrive inve inve inve。使用安全有效的递送系统的耐药性。