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

Abstract

A pretargeted oncologic positron emission tomography (PET) imaging that leverages the power of supramolecular nanoparticles with in vivo bioorthogonal chemistry was demonstrated for the clinically relevant problem of tumor imaging. The advantages of this approach are that (i) the pharmacokinetics (PKs) of tumor-targeting and imaging agents can be independently altered via chemical alteration to achieve the desired in vivo performance and (ii) the interplay between the two PKs and other controllable variables confers a second layer of control toward improved PET imaging. In brief, we utilized supramolecular chemistry to synthesize tumor-targeting nanoparticles containing transcyclooctene (TCO, a bioorthogonal reactive motif), called TCO⊂SNPs. After the intravenous injection and subsequent concentration of the TCO⊂SNPs in the tumors of living mice, a small molecule containing both the complementary bioorthogonal motif (tetrazine, Tz) and a positron-emitting radioisotope (64Cu) was injected to react selectively and irreversibly to TCO. High-contrast PET imaging of the tumor mass was accomplished after the rapid clearance of the unreacted 64Cu-Tz probe. Our nanoparticle approach encompasses a wider gamut of tumor types due to the use of EPR effects, which is a universal phenomenon for most solid tumors.

New insights into the pretargeting approach to image and treat tumours

“…47 Recently, different nanoparticles have been proposed to replace tumour antigen specific mAbs as target specific component to target a broad range of different tumour entities. 48 Such nanoparticulate materials with in vivo hydrodynamic diameters above the glomerular filtration threshold and prolonged blood circulation passively accumulate in tumours through the EPR effect. 49 This process depends on their leaky vasculature and a poorly functional lymph system and results in increased permeability to nanomaterials.…”

“…Notwithstanding this impressive performance, also radioactivity levels in the liver were observed, most likely due to trapping of the nanoparticles by the mononuclear phagocyte system (MPS) or transchelation of 64 Cu from DOTA in vivo. 48 Although the EPR effect is a common phenomenon in rodent models using subcutaneous and orthotopic xenografts, its occurrence in human primary and metastatic lesions may be less widespread and less pronounced. As nanomaterials bypassing the renal filtration process will, however, inevitably end up in the organs of the MPS (spleen and liver), 49 also these organs will be exposed to radiation upon injection of the radiolabelled effector molecules as also observed by Lin and co-workers.…”

“…As nanomaterials bypassing the renal filtration process will, however, inevitably end up in the organs of the MPS (spleen and liver), 49 also these organs will be exposed to radiation upon injection of the radiolabelled effector molecules as also observed by Lin and co-workers. 48 This crucial aspect has to be kept in mind especially for therapeutic applications of this pretargeting system.…”

Multifunctional Shell–Core Nanoparticles for Treatment of Multidrug Resistance Hepatocellular Carcinoma

“…PET is an advanced modern biological medical technology, which can display the cellular metabolism, function, and proliferation status of the body and lesion tissue at molecular level . PET is also a favorable tool for tumor diagnosis and tumor biological characteristic evaluation.…”

Tetrazine Click Chemistry for the Modification of 1‐Hydroxy‐1,1‐methylenebisphosphonic Acids: Towards Bio‐orthogonal Functionalization of Gold Nanoparticles

“…[36,37] Thisr eaction, also stirringg reat interest recently, includes several important features such as fast kinetics, bio-orthogonality,t he fact that it is perfectly compatible with other click reactions and that suitable tetrazinesa re already readily availablew ith av ariety of chemicalf unctionalities (for example fluorophore linked tetrazine, non-natural tetrazine amino acids used for geneticencoding andt etrazine-derivatised chelators for radiometalated probes). [38][39][40][41][42][43][44][45][46] Moreover,t oo ur knowledge this reaction has only been described at the surfaceo fn anoparticles by Weissleder'sg roup [47][48][49] and was never evaluated on gold nanoparticles and neither was it described for the modification of HMBPs. So,i nthe presentw ork we evaluatedt he potency of iEDDA reactionf or the modification of an alkene functionalized HMBP and its applicability at the surface of gold nanoparticles bearing this molecule (Scheme1).…”