分子影像监测SS-PEI介导shRNA-LDHA增加肺癌对紫杉醇敏感性的机制研究

The resistance of cancercells to paclitaxel is a serious problemin the clinical application. As is well known, how to improve the sensitivity of paclitaxel is a key issue to address. Previous study in our team has found thatLDHA plays an important role in paclitaxel resistance. Targeting LDHA is an effective way to restore the sensitivity of non-small cell lung carcinoma to paclitaxel via the AKT pathway. However, targeting LDHA is limited in the clinical application because he LDHA inhibitors are toxic and non-specific. So finding a way to targeting LDHA has become a major issue.The effectiveness of therapy may be different due to the tumor types, and whether molecular imaging could be used to predict the effectiveness of targeting LDHA is unclear. In this study we will use nanoparticle materials-PEI as novel vector to mediate the transmission of shRNA-LDHAto reveal the relationship between LDHA and tumor resistance both in vivo and in vitro. The purpose of this study is to predict the effectiveness of targeting LDHA of tumors and evaluate the role and mechanism of SS-PEI/pShRNA-LDHA re-sensitizing paclitaxel-resistant cancer cells to paclitaxel. Finally, we will establish a system to monitor metabolism viamolecular imaging, which can be used for analyzing drug responsive, predicting chemoresistance and evaluating prognosis. This study will provide rationale and tool for paclitaxel using in personalized diagnosis and treatment of lung carcinoma.

恢复肿瘤对紫杉醇等化疗药物敏感性并揭示其机制是当今医学研究的热点。本课题组前期研究发现LDHA与紫杉醇耐药关系密切，抑制LDHA的活性可以增加肿瘤对紫杉醇的药物敏感性，并且这与LDHA对AKT磷酸化的调控密切相关。然而推动LDHA靶向治疗走向临床还需要解决如何在活体中特异性地抑制LDHA基因的表达及如何预测LDHA靶向治疗的效果，其预测的分子机制又是什么等问题。本研究拟用新型的纳米材料SS-PEI作为LDHA转基因载体，通过体内和体外实验多角度揭示LDHA与肿瘤耐药的关系。重点研究通过分子影像预测、筛选对LDHA靶向治疗敏感的肿瘤及机制并监测新型纳米载体靶向LDHA进行肿瘤治疗的有效性。最终建立一套肿瘤代谢检测与显像的方法，系统评价肿瘤治疗反应、耐药预测、预后评估体系，为肿瘤个体化诊治提供重要的科学依据及监测手段。

紫杉醇是肺癌等肿瘤化疗常用药物，但在化疗过程中肿瘤会对紫杉醇产生耐药性，从而影响抗肿瘤疗效。恢复肿瘤对紫杉醇等化疗药物敏感性并揭示其机制是当今医学研究的热点。本课题组发现LDHA与紫杉醇耐药关系密切，抑制LDHA的活性可以增加肿瘤对紫杉醇的药物敏感性。由于缺乏高度特异性LDHA小分子抑制，使得在活体内靶向肿瘤LDHA恢复紫杉醇药物敏感性较为困难。为了进一步解决这个问题，在本课题研究中，我们使用了新型的纳米材料SS-PEI作为LDHA小干扰RNA转基因载体。我们的研究结果发现纳米载体SS-PEI具有很高的转染效率并且毒性很低。SS-PEI携带LDHA小干扰RNA通过荷瘤小鼠尾静脉注射后，对小鼠的毒性很低，没有引起明显毒性反应，同时SS-PEI/ShLDHA可以有效抑制荷瘤小鼠肿瘤组织内LDHA表达，从而抑制肿瘤生长并恢复肿瘤的紫杉醇药物敏感性。SS-PEI携带LDHA小干扰RNA靶向治疗肿瘤及恢复肿瘤紫杉醇药物敏感性为肿瘤治疗提供了一种的新的靶向治疗方案，也为肿瘤个体化诊治提供重要的科学依据。