Theranostic nanoparticles for the treatment of RAI refractory thyroid cancer

描述（由申请人提供）：药物的位点特异性递送同时最小化不想要的分布一直是癌症治疗中追求的目标之一。在这项奋进中，我们开发了基于聚合物的药物递送载体，其在体内的分布也可以通过MRI定量成像，从而实现全身、药物分布的实时映射以及药代动力学、药效学和毒性特征的测量。该方案的两个创新点是：1）高分子药物载体具有优异的稳定性， 药物的容量，以及与各种癌症药物和靶向配体组装的多功能性，以及2）用于定量测量体内顺磁性造影剂的新型MRI技术。这些方面满足了药物递送载体是“治疗诊断学”的要求。我们最近发现一种称为细胞间粘附分子（ICAM）-1的分子高度表达与甲状腺癌的恶性程度相关，因此我们建议开发负载紫杉醇的治疗诊断药物载体作为甲状腺癌的新治疗方式。本提案中将实现的两个具体目标是：1）开发用于治疗诊断纳米颗粒的生产和验证以及用于药物功效和成像技术的体外评价的综合方案; 2）确定药物载体的时空分布以及治疗功效和毒性特征，以定量评估肿瘤-药物相互作用。总的来说，我们的药物载体的治疗诊断能力将在小鼠中的人甲状腺癌的异位和原位异种移植物中得到证明，该研究旨在验证开发的药物载体，用于未来治疗侵袭性、转移性和放射性碘难治性甲状腺癌。

DESCRIPTION (provided by applicant): Site-specific delivery of drugs while minimizing unwanted distribution has been one of the pursued goals in cancer therapy. In this endeavor, we have developed polymer-based drug delivery carriers, whose distribution in vivo can also be quantitatively imaged by MRI, enabling whole body, real-time mapping of drug distribution, and measurements of pharmacokinetic, pharmacodynamic, and toxicity profiles. Two innovative aspects in this proposal are 1) polymeric drug carriers with exceptional stability, large retention capacity of drugs, and versatility in assembly with diverse cancer drugs and targeting ligands and 2) novel MRI techniques for quantitative measurement of paramagnetic contrast agents in the body. These aspects fulfill the requirement for drug delivery carriers to be 'theranostic'. Motivated by our recent findings that a molecule called the intercellular adhesion molecule (ICAM)-1 is highly expressed in correlation with the malignancy of thyroid cancer, we propose to develop the theranostic drug carriers loaded with Paclitaxel as a new treatment modality of thyroid cancer. Two specific aims that will be achieved in this proposal are: 1) Develop comprehensive protocols for production and validation of theranostic nanoparticles, and for in vitro evaluation of drug efficacy and imaging techniques; 2) Determine spatiotemporal distribution of drug carriers, and therapeutic efficacy and toxicity profiles to quantitatively assss tumor-drug interactions. Overall, theranostic capability of our drug carriers will be demonstrated in ectopic and orthotopic xenografts of human thyroid carcinomas in mice, a study designed to validate developed drug carriers for future use to treat aggressive, metastatic, and radioactive iodine refractory thyroid cancer.