Differential MRI imaging for brain tumor metastases diagnosis and treatment monitoring

 描述(申请人提供)：脑转移(BM)仍然是很难治疗的，是乳腺癌和肺癌致死的毁灭性原因。HER2/neu阳性和三阴性(TNBC；孕激素、雌激素和HER2受体阴性)常发生BM。我们关于用于有效的BM成像和治疗的新的纳米药物输送的建议符合FOA PAR-13-185《癌症和其他疾病的图像引导药物输送(IGDD)的创新研究》。脑部的磁共振成像(MRI)增强可能是由于原发或复发的脑肿瘤、放射性坏死、原发癌症(如肺癌、乳腺癌)的转移等。尽管采用了立体定向活组织检查技术，但在大脑的非口才部分进行活组织检查仍有1.2-8%的并发症风险。我们假设我们的新的纳米成像靶向纳米偶联物可以通过BBB/BTB并特异性识别脑瘤类型。通过共价连接的造影剂Gd-DOTA，当难以进行脑组织活检时，纳米结合物将区分脑MRI的增强，以区分脑部病变/肿瘤的类型。我们还假设，类似的纳米结合物可以治疗乳腺癌BMS。结合精确的诊断方法和抗肿瘤治疗，这两种方法都是针对肿瘤生物标志物的，可以帮助更有效地消除脑BMS。此外，针对脑肿瘤类型的纳米成像剂(NIA)还将用于EGFR、HER2或PDGFRA阳性(原发胶质瘤)脑瘤的治疗监测。我们将开发具有快速清除的NIA递送系统，以便在需要时为住院/出院患者进行几次诊断性注射，以进行准确的诊断和/或肿瘤治疗监测。目的1.合成并优化一种用于脑部病变验证的纳米造影剂。NIAS将被合成，以区分由于原发脑瘤和乳腺癌或肺癌的转移而引起的MRI增强。为了以最小的暴露时间和最小的毒性获得最高的增强效果，将使用几种不同版本的结合物来测试纳米MRI分辨率。将对纳米颗粒的稳定性、物理化学性质和合成重复性进行测试。将MRI与抗EGFR、抗HER2或抗PDGFRA单抗进行对比分析。目的2.体内应用纳米结合物治疗脑转移瘤。通过选择铅纳米制剂，研究体外和体内抑制BM的分子机制。通过EGFR或HER2有效抑制转移的纳米药物将被合成、表征并在BM小鼠模型中进行测试。目的3.用于脑BM显像、治疗和治疗监测的纳米结合物的毒性研究。以共价连接的环-Gd-DOTA或Star-Gd-DOTA作为MRI造影剂的纳米结合物将被制成用于成像，类似的版本将用于多种BM的治疗。将对铅成像和治疗纳米结合物进行药效学、药代动力学和毒性参数以及生物分布的测试。这些药物将带有与治疗相同的靶向单抗和肿瘤标志物抑制剂。

 DESCRIPTION (provided by applicant): Brain metastasis (BM) is still hard to treat and is a devastating cause of death from breast and lung cancer. HER2/neu positive and triple negative cancers (TNBC; progesterone, estrogen and HER2 receptors negative) often develop BM. Our proposal on new nano drug delivery for effective BM imaging and treatment fits FOA PAR-13-185, "The innovating research in image-guided drug delivery (IGDD) for cancer and other diseases". Magnetic Resonance Imaging (MRI) enhancement in the brain might result from a primary or recurrent brain tumor, radiation necrosis, metastasis from primary cancer (e.g., lung, breast), etc. Despite stereotactic biopsy techniques, biopsies in a non-eloquent part of the brain can still carry a 1.2-8% risk of complications. We hypothesize that our new nanoimaging targeted nanoconjugates can pass through BBB/BTB and specifically recognize brain tumor type. With covalently attached contrast agent Gd-DOTA, nanoconjugates would differentiate enhancements on brain MRI distinguishing types of brain lesions/tumors when it is difficult to perform brain tissue biopsy. We also hypothesize that similar nanoconjugates can treat breast cancer BMs. Combining precise diagnostic approach and antitumor therapy, which are both specific to tumor biomarkers, could help eliminate brain BMs more efficiently. The nanoimaging agents (NIA) specific to brain tumor type will be used in addition for treatment monitoring of EGFR-, HER2-, or PDGFRa-positive (primary gliomas) brain tumors. We are going to develop the NIA delivery system with fast clearance in order to perform several diagnostic injections when needed for in/out patients for precise diagnosis and/or tumor treatment monitoring. Aim 1. Synthesize and optimize a nanoscale contrast agent for brain lesion verification. NIAs will be synthesized to differentiate MRI enhancements due to primary brain tumors and metastases from breast or lung cancer. Nano-MRI resolution will be tested with several versions of conjugates in order to obtain the highest enhancement with minimum time of exposure and toxicity. Nanodrugs will be tested for stability, physico-chemical properties and synthesis reproducibility. Quantitative analysis of MRI contrast with anti- EGFR, anti-HER2 or anti-PDGFRa mAbs will be done. Aim 2. Treat metastatic brain tumors in vivo with nanoconjugates. Examine molecular mechanisms in vitro and in vivo for BM inhibition with selection of lead nanodrugs. Nanodrugs for effective metastasis inhibition through EGFR or HER2 will be synthesized, characterized, and tested in BM mouse models. Aim 3. Toxicity study of nanoconjugates for brain BM imaging, treatment and treatment monitoring. Nanoconjugates with covalently attached cyclic-Gd-DOTA or Star-Gd-DOTA as MRI contrast agents will be made for imaging, and similar versions for multiple treatment of BM. Lead imaging and treatment nanoconjugates will be tested for pharmacodynamic, pharmacokinetic, and toxicity parameters, as well as biodistribution. The drugs will bear the same targeting mAbs and tumor marker inhibitors as for treatment.