Tumor Microenvironment Responsive “Head-to-Foot” Self-Assembly Nanoplatform for Positron Emission Tomography Imaging in Living Subjects

Abstract

Sensitivity and specificity of molecular probes are two important factors in determining the accuracy of cancer diagnosis or the efficacy of cancer treatment. However, the development of probes with high sensitivity and strong specificity still poses many challenges. Herein, we report an 18F-labeled smart tracer ([18F]1) targeting cancer-associated biotin receptor (BR) and self-assembling into nanoparticles in response to intracellular glutathione. The tracer [18F]1 selectively targeted BR-positive cancer cells A549 and Hela and formed nanoparticles through self-assembly with an average diameter of 138.2 ± 16.3 nm. The character of self-assembly into nanoparticles enhanced the uptake and extended the retention of probe [18F]1 in the target tissue and hence improved the quality of positron emission tomography (PET) images. Thus, [18F]1 is a promising PET tracer for accurately detecting BR-positive cancers. Moreover, the tumor microenvironment responsive “head-to-foot” self-assembly nanoplatform is particularly attractive for development of other smart molecular probes.

Optimized molecular design of PET probe for the visualization of γ-glutamyltranspeptidase activity in tumors

“…This may be attributed to the fact that the dimer formation was much easier and more spontaneous compared to competition with endogenous free cysteine. 33 These in vitro results indicated that the probe [ 18 F]JM-10 could respond quickly to GGT and be reduced by GSH, resulting in an intermolecular condensation reaction to yield the dimer [ 18 F]JM-D in GGT-overexpressed cells (Fig. 3c).…”

Stimuli-Responsive Macrocyclization Scaffold Allows In Situ Self-Assembly of Radioactive Tracers for Positron Emission Tomography Imaging of Enzyme Activity

“…To date, many bioorthogonal reactions have been developed to design small molecules with the propensity for controlled self-assembly in living cells. − One of the pioneering works was reported by Rao and others, in which a biocompatible condensation reaction occurred between 2-cyano-benzothiazole (CBT) and free cysteine (Cys) for specific labeling of terminal cysteine residues in medicinal chemistry. − This reaction can proceed smoothly under physiological conditions, with a second-order rate constant of 9.19 M –1 S –1 . Creating a compound bearing both CBT and Cys groups could allow it to condense in cell, forming cyclic dimers/oligomers and subsequently self-assembling into nano/microstructures through hydrophobic and π–π interactions. − With the introduction of bio-responsive caging groups on the amino and/or thiol groups, such as enzyme-cleavable bonds and/or disulfide bonds, such a bioorthogonal reaction could be successfully applied to create a target-enabled in situ self-assembly system, − which has shown promise for developing various protease-triggered nanoaggregation probes. − In our laboratory, this method has also been used to design and synthesize enzyme-responsive small-molecule positron emission tomography (PET) tracers for tumor imaging. − …”

Tailoring a Near‐Infrared Macrocyclization Scaffold Allows the Control of In Situ Self‐Assembly for Photoacoustic/PET Bimodal Imaging

“…We then synthesized the radioactive tracer [ 18 F]-IR780-1 through a well-established 18 F-exchange reaction between 18 F À and the AMBF 3 group in IR780-1 (Figure 5a). [23] After purification, [ 18 F]-IR780-1 was obtained with a radiochemical purity of ca. 95 % and a specific activity of ca.…”