Star polymers for PET/MRI: a passive pretargeting approach

Objectives: The pretargeting approach, in which a targeting ligand is allowed to accumulate at the target site before a small effector molecule is injected, has successfully been applied to enhance specificity and reduce off-target radiation dose in positron emission tomography (PET) imaging and radioimmunotherapy. To enable accumulation at the target site without the need to rely on receptor availability, passive targeting may be preferred. Nanoparticles may utilize the enhanced permeability and retention (EPR) effect that is often associated with solid tumors. Not only will such nanoparticles exploit the advantages of pretargeting, they also profit from the increased availability of binding sites for the radiolabeled effector, as well as allow for multimodality imaging, combining PET with magnetic resonance imaging (MRI).

Methods: Via RAFT polymerization, a star-shaped copolymer was synthesized, consisting of oligoethylene glycol methyl ether acrylate (OEGA) units, 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) units modified with [Gd³⁺]1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid)-10-(aminoethylacetamide) ([Gd³⁺]DO3A) and aminoethyl acrylate (AEA) units modified with either deferoxamine (DFO) or trans-cyclooctene (TCO). The DFO-conjugated star polymer was radiolabeled with ⁸⁹Zr, whereas the TCO-conjugated star polymer was used for pretargeting with [¹⁸F]F-tetrazine-poly(ethylene glycol)₁₁-1,4,7-triazacyclononane-1,4-diacetic acid ([¹⁸F]F-Tz-PEG₁₁-NODA).¹ Biodistribution and bioorthogonal ligation will be assessed in athymic nude mice carrying subcutaneous BxPC3 xenografts. ¹H longitudinal relaxivities were determined over a continuum of magnetic field strengths ranging from 0.24 mT - 0.94 T at 37 °C (nuclear magnetic relaxation dispersion (NMRD) profile). RESULTS: The star polymer (84 kDa, PDI = 1.16, D_h = 11 nm) consisted of 7 to 8 cross-linked polymer arms, each containing approximately 19×OEGA repeat units, 5×VDM-[Gd³⁺]DO3A units and 4×AEA-DFO or AEA-TCO units. Radiolabeling of the star polymer with ⁸⁹Zr was achieved with high radiochemical yield (>99%) and purity (>99%) and high molar activity (>290 GBq µmol^-1). Accumulation of the star polymers in BxPC3 xenografts and bioorthogonal click efficiency will be discussed. The NMRD profile was typical of a paramagnetic nanoparticle, with maximal relaxivity (16.9 mM^-1s^-1) at ~30 MHz. CONCLUSIONS: Star-shaped nanoparticles were developed in which passive pretargeting PET imaging is combined with MRI. Such nanoparticles minimize the radiation dose to healthy tissues, while offering increased sensitivity and specificity as well as improved tissue contrast.