Differential MRI imaging for brain tumor metastases diagnosis and treatment monitoring

 描述（由申请人提供）：脑转移（BM）仍然很难治疗，是乳腺癌和肺癌死亡的毁灭性原因。HER2/neu阳性和三阴性癌症（TNBC;孕酮、雌激素和HER2受体阴性）通常发展为BM。我们关于有效BM成像和治疗的新型纳米药物递送的建议符合FOA PAR-13 - 185，“癌症和其他疾病的图像引导药物递送（IGDD）的创新研究”。脑中的磁共振成像（MRI）增强可能由原发性或复发性脑肿瘤、放射性坏死、原发性癌症的转移（例如，尽管采用了立体定向活检技术，但在大脑的非功能区进行活检仍有1.2 - 8%的并发症风险。我们假设我们的新纳米成像靶向纳米缀合物可以通过BBB/BTB并特异性识别脑肿瘤类型。通过共价连接的造影剂Gd-DOTA，当难以进行脑组织活检时，纳米缀合物将区分脑MRI上的增强，区分脑病变/肿瘤的类型。我们还假设类似的纳米缀合物可以治疗乳腺癌BM。结合精确的诊断方法和抗肿瘤治疗，这两者都是特异性的肿瘤生物标志物，可以帮助更有效地消除脑BM。此外，脑肿瘤类型特异性纳米显像剂（NIA）将用于EGFR、HER2或PDGFRa阳性（原发性神经胶质瘤）脑肿瘤的治疗监测。我们将开发具有快速清除的NIA给药系统，以便在需要时为住院/门诊患者进行多次诊断注射，以进行精确诊断和/或肿瘤治疗监测。目标1。合成和优化用于脑损伤验证的纳米级造影剂。将合成NIA以区分由于原发性脑肿瘤和乳腺癌或肺癌转移引起的MRI增强。将使用几种版本的结合物测试Nano-MRI分辨率，以获得最高的增强效果和最短的暴露时间和毒性。将测试纳米药物的稳定性、物理化学性质和合成再现性。将使用抗EGFR、抗HER2或抗PDGFRa mAb进行MRI造影定量分析。目标2.用纳米缀合物治疗体内转移性脑肿瘤。通过选择先导纳米药物，检查体外和体内BM抑制的分子机制。通过EGFR或HER2有效抑制转移的纳米药物将在BM小鼠模型中合成、表征和测试。目标3。用于脑BM成像、治疗和治疗监测的纳米缀合物的毒性研究。将制备具有共价连接的环状-Gd-DOTA或星形-Gd-DOTA作为MRI造影剂的纳米缀合物用于成像，以及用于BM的多种治疗的类似形式。将测试铅成像和治疗纳米缀合物的药效学、药代动力学和毒性参数以及生物分布。这些药物将携带与治疗相同的靶向mAb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.