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.

Public Health Relevance

The goal of this proposal is to develop a new approach for pretargeted oncologic PET imaging that leverages the power of in vivo bioorthogonal chemistry and a supramolecular nanoparticle (SNP) vector pioneered by our research group. Such a pretargeted imaging approach is based on in vivo bioorthogonal ligation of a pair of tumor-targeting SNP component and radiolabeled reporter. By modulating the interplay between experimental variables for example injection times and dosage, optimal imaging performance of the proposed SNP PET probes can be achieved.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Liu, Christina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Choi, Jin-Sil; Zhu, Yazhen; Li, Hongsheng et al. (2017) Cross-Linked Fluorescent Supramolecular Nanoparticles as Finite Tattoo Pigments with Controllable Intradermal Retention Times. ACS Nano 11:153-162
Hou, Shuang; Choi, Jin-Sil; Garcia, Mitch Andre et al. (2016) Pretargeted Positron Emission Tomography Imaging That Employs Supramolecular Nanoparticles with in Vivo Bioorthogonal Chemistry. ACS Nano 10:1417-24
Liu, Yang; Du, Juanjuan; Choi, Jin-sil et al. (2016) A High-Throughput Platform for Formulating and Screening Multifunctional Nanoparticles Capable of Simultaneous Delivery of Genes and Transcription Factors. Angew Chem Int Ed Engl 55:169-73
Hou, Shuang; Choi, Jin-sil; Chen, Kuan-Ju et al. (2015) Supramolecular nanosubstrate-mediated delivery for reprogramming and transdifferentiation of mammalian cells. Small 11:2499-504
Peng, Jinliang; Garcia, Mitch André; Choi, Jin-sil et al. (2014) Molecular recognition enables nanosubstrate-mediated delivery of gene-encapsulated nanoparticles with high efficiency. ACS Nano 8:4621-9
Lee, Jae-Hyun; Chen, Kuan-Ju; Noh, Seung-Hyun et al. (2013) On-demand drug release system for in vivo cancer treatment through self-assembled magnetic nanoparticles. Angew Chem Int Ed Engl 52:4384-4388