Supramolecular Nanoparticle-Based PET Probes for Pretargeted Tumor Imaging

用于预定位肿瘤成像的超分子纳米颗粒 PET 探针

• 批准号: 8596818
• 负责人: HSIAN-RONG TSENG
• 金额: $ 20.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596818
• 关键词: Adopted; Affect; Affinity; Animals; Biological; Cancer Biology; Categories; Characteristics; Chemistry; Collection; Coupling; Data; Diagnostic Imaging; Drug Delivery Systems; Drug Kinetics; Encapsulated; Exhibits; Future; Goals; Histology; Image; Injection of therapeutic agent; Joints; Kinetics; Label; Length; Ligands; Ligation; Liver; Molecular; Motivation; Organ; Outcome; Performance; Permeability; Polymers; Positron; Positron-Emission Tomography; Radiochemistry; Radioisotopes; Radiolabeled; Reaction; Reagent; Reporter; Research; Research Personnel; Solid Neoplasm; Surface Properties; Time; Xenograft procedure; base; controlled release; design; dosage; imaging probe; improved; in vivo; molecular assembly/self assembly; molecular imaging; mouse model; nanoparticle; novel strategies; pre-clinical; public health relevance; radiotracer; small molecule; tumor; uptake; vector

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.

描述（由申请人提供）：该R21提案的长期目标是开发一类新的基于纳米颗粒（NP）的正电子发射断层扫描（PET）探针，以实现高性能肿瘤成像。我们建议采用一种预先靶向的成像策略，将NP组分与其相应的放射性标记的报告分子分离。首先，通过合理的分子设计分别合成一对具有肿瘤靶向的NP组分和具有所需PK的放射性标记的报告物。然后，我们将调节其他实验变量（如注射时间和剂量）之间的相互作用，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在体内实现肿瘤靶向NP和顺序注射的放射性标记的报告物的选择性和不可逆偶联。因此，我们利用基于一对反应基序的生物正交缀合化学的使用，即，反式环辛烯（TCO）和四嗪（Tz），它们具有快速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累的分子成像探针。除了基于小分子和亲和配体的PET成像探针之外，表现出独特的增强渗透性和保留（EPR）效应的NP代表了能够被动靶向渗漏脉管系统的一类新的PET探针-这是在大多数实体瘤中观察到的普遍特征。虽然已经在临床前环境中检查了各种NP PET探针，但进一步改善肿瘤摄取和减少其他器官中的非特异性分布仍然存在挑战。 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）的聚合物构建块上。分子结构单元的自组装导致TCO的封装以产生TCO封装的SNP（TCO？SNP）作为肿瘤靶向NP组分。此外，放射性标记的报告基因由互补的Tz基序和18F-标签组成。在拟议的PET成像研究中，TCO？首先将SNP施用于动物。当TCO？SNP接近其在肿瘤中的最佳积累，然后注射放射性标记的报告基因。体内生物正交反应瞬间发生，导致高对比度PET成像。我们的联合团队有一些初步数据支持这种新型NP PET成像探头的可行性。我们将实现以下两个具体目标来完成我们的研究工作，1）准备和选择TCO？单核苷酸多态性和放射性标记的记者与最佳的PK，和2）在体内演示的预靶向PET成像使用对TCO？SNP和放射性标记的报告基因。 该提案汇集了四个研究小组（PI和3名共同研究者）的专业知识，涵盖超分子化学，纳米颗粒，放射化学，分子成像和癌症生物学领域。我们设想，我们所提出的研究的成功证明可以改变肿瘤PET成像的当前模式，并为预靶向药物递送开辟新的机会。

项目成果

A High-Throughput Platform for Formulating and Screening Multifunctional Nanoparticles Capable of Simultaneous Delivery of Genes and Transcription Factors.

• DOI: 10.1002/anie.201507546
• 发表时间: 2016-01-04
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Liu Y;Du J;Choi JS;Chen KJ;Hou S;Yan M;Lin WY;Chen KS;Ro T;Lipshutz GS;Wu L;Shi L;Lu Y;Tseng HR;Wang H
• 通讯作者: Wang H

Supramolecular nanosubstrate-mediated delivery system enables CRISPR-Cas9 knockin of hemoglobin beta gene for hemoglobinopathies.

• DOI: 10.1126/sciadv.abb7107
• 发表时间: 2020-10
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Yang P;Chou SJ;Li J;Hui W;Liu W;Sun N;Zhang RY;Zhu Y;Tsai ML;Lai HI;Smalley M;Zhang X;Chen J;Romero Z;Liu D;Ke Z;Zou C;Lee CF;Jonas SJ;Ban Q;Weiss PS;Kohn DB;Chen K;Chiou SH;Tseng HR
• 通讯作者: Tseng HR

Pretargeted Positron Emission Tomography Imaging That Employs Supramolecular Nanoparticles with in Vivo Bioorthogonal Chemistry.

• DOI: 10.1021/acsnano.5b06860
• 发表时间: 2016-01-26
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Hou S;Choi JS;Garcia MA;Xing Y;Chen KJ;Chen YM;Jiang ZK;Ro T;Wu L;Stout DB;Tomlinson JS;Wang H;Chen K;Tseng HR;Lin WY
• 通讯作者: Lin WY

Cross-Linked Fluorescent Supramolecular Nanoparticles as Finite Tattoo Pigments with Controllable Intradermal Retention Times.

• DOI: 10.1021/acsnano.6b06200
• 发表时间: 2017-01-24
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Choi JS;Zhu Y;Li H;Peyda P;Nguyen TT;Shen MY;Yang YM;Zhu J;Liu M;Lee MM;Sun SS;Yang Y;Yu HH;Chen K;Chuang GS;Tseng HR
• 通讯作者: Tseng HR