Supramolecular Nanoparticle-Based PET Probes for Pretargeted Tumor Imaging

描述(由申请人提供)：这项R21提案的长期目标是开发一种新的基于纳米颗粒(NP)的正电子发射断层扫描(PET)探测器，使高性能肿瘤成像成为可能。我们建议采用一种预靶向成像策略，将NP成分与其相应的放射性标记记者分离。首先，通过合理的分子设计，分别合成一对肿瘤靶向NP组分和具有所需PKs的放射性标记报告分子。然后，我们将调整其他实验变量之间的相互作用，如注射次数和剂量，以实现最佳的PET成像结果。成功的预靶向成像的先决条件是实现肿瘤靶向NP和体内连续注射放射性标记报告的选择性和不可逆偶联。因此，我们开发了一种基于一对反应基序的生物正交共轭化学的应用，即反式环辛烯(TCO)和四嗪(TZ)，它们具有快速的反应动力学和生物稳定性。PET成像的未来进展将涉及设计优先在肿瘤中积聚的分子成像探针。除了基于小分子和亲和配体的PET成像探针外，具有独特的增强渗透性和滞留(EPR)效应的NPs代表了一种能够被动靶向泄漏血管的新型PET探针--这是大多数实体肿瘤的普遍特征。虽然各种NP PET探针已经在临床前环境中进行了检查，但在进一步提高肿瘤摄取和减少其他器官的非特异性分布方面仍然存在挑战。在我们的分子设计中，TCO基序共价连接到超分子纳米颗粒(SNP)的聚合物构件上。分子构件的自组装导致TCO的包裹，从而产生TCO包裹的SNP(TCO？SNP)作为肿瘤靶向NP组分。此外，放射性标记报告由互补的TZ基序和18F-Tag组成。在拟议的PET成像研究中，TCO？SNP首先在动物身上进行。当TCO？SNPs接近其在肿瘤中的最佳积聚时，然后注射放射性标记的报告。体内的生物正交反应瞬间发生，产生高对比度的PET成像。我们的联合团队有一些初步数据支持这种新类别的NP PET成像探针的可行性。为了完成我们的研究工作，我们将实现以下两个具体目标：1)制备和选择具有最佳PKs的TCO？SNP和放射性标记记者；2)使用TCO？SNP和放射性标记记者对TCO？SNPs和放射性标记记者进行体内靶向PET成像演示。这项建议汇集了四个研究小组(PI和3名合作研究人员)的专业知识，涉及超分子化学、纳米粒子、放射化学、分子成像和癌症生物学等领域。我们预计，我们建议的研究的成功演示可能会改变目前肿瘤PET成像的模式，并为预靶向药物输送开辟新的机会。

DESCRIPTION (provided by applicant): The long-term objective of this R21 proposal is to develop a new class of nanoparticle (NP)-based positron emission tomography (PET) probes that enable high-performance tumor imaging. We propose to adopt a pretargeted imaging strategy to decouple the NP components from their corresponding radiolabeled reporters. First, a pair of tumor-targeting NP component and radiolabeled reporter with desired PKs will be synthesized separately via rational molecular designs. We will then modulate the interplay between other experimental variables such as injection times and dosage in order to achieve optimal PET imaging outcomes. A prerequisite to successful pretargeted imaging is to accomplish selective and irreversible coupling of the tumor- targeting NP and sequentially injected radiolabeled reporter in vivo. We thus exploit the use of a bioorthogonal conjugation chemistry based on a pair of reactive motifs, i.e., trans-cyclooctene (TCO) and tetrazine (Tz), which have fast reaction kinetics and biological stability. Future progress in PET imaging will involve designing molecular imaging probes that preferentially accumulate in tumors. Aside from small molecule and affinity ligand-based PET imaging probes, NPs exhibiting unique enhanced permeability and retention (EPR) effects represent a new category of PET probes capable of passively targeting leaky vasculature - a universal characteristic observed for most solid tumors. While a variety of NP PET probes have been examined in pre-clinical setting, challenges remain to further improve tumor uptake and reduce nonspecific distribution in other organs. In our molecular design, the TCO motif is covalently attached onto a polymer building block of supra-molecular nanoparticle (SNP). Self-assembly of the molecular building blocks leads to encapsulation of TCO to yield TCO-encapsulated SNP (TCO?SNP) as the tumor-targeting NP component. Further, the radiolabeled reporter is composed of the complementary Tz motif and 18F-tag. In the proposed PET imaging study, TCO?SNP is first administered to an animal. When the TCO?SNPs approach their optimal accumulation in tumor, the radiolabeled reporter is then injected. In vivo bio-orthogonal reaction occurs instantaneously, resulting in high-contras PET imaging. Our joint team has some preliminary data supporting the feasibility of this new class of NP PET imaging probes. We will implement the following two Specific Aims to accomplish our research endeavors, 1) Prepare and select TCO?SNPs and radiolabeled reporters with optimal PKs, and 2) In vivo demonstration of pretargeted PET imaging using pairs of TCO?SNPs and radiolabeled reporters. This proposal brings together the expertise of four research groups (PI and 3 co-investigators) covering the fields of supramolecular chemistry, nanoparticle, radiochemistry, molecular imaging and cancer biology. We envision that the successful demonstration of our proposed research could change current paradigm in oncologic PET imaging, and open up new opportunities for pretargeted drug delivery.