In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.
Three new low-band-gap copolymers were synthesized by fusing dipyrromethene difluoroborane (BODIPY) as the acceptor (A) and thiophene-capped 5,5-bis(hexyloxymethyl)-5,6-dihydro-4H-cyclopenta[c]-thiophene (CPT) as the donor (D). The BODIPY unit was copolymerized through the ̀α′ positions (1 and 7 positions) in P1 and through the ̀β′ positions (2 and 6 positions) in P2 and P3. The additional acetylene unit between D and A in P3 enhanced the conjugation by minimizing the possible steric hindrance compared to that in P2, whereas P1 exhibited a more red-shifted absorption than P2 and P3 because of the more effective conjugaion through the ̀α′ positions of BODIPY. Importantly, the optical band gaps (E g opt) obtained from the onset of the absorption spectra are 1.28, 1.71, and 1.57 eV for P1, P2, and P3, respectively. P1 has the lowest band gap for any CPT-containing polymer. In the best transistor devices, a mobility improvement by 4 orders of magnitude from 3.22 × 10–6 cm2 V–1 s–1 for P2 to 0.01 cm2 V–1 s–1 for P1 was achieved. DFT calculations alongside measured charge-transport properties indicated that appreciable alterations in the optoelectronic properties of the polymers were achieved through minor changes in their structural features. The polymers were further characterized by thin-film X-ray diffraction, atomic force microscopy, and spectroelectrochemistry to investigate their material and electrochemical properties.
The synthesis of new conjugated building blocks, diselenolodiselenole (C4Se4) derivatives, is described for the first time. The structural and optoelectronic properties of C4Se4-derivatives are tuned by varying end-capping aromatic substituents. In cyclic voltammetry, all C4Se4-derivatives show two reversible oxidation peaks.
We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody–drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA− PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.
A single-step intramolecular radical cascade reaction of diynes and thioacetic acid in the presence of a catalytic amount of azobis(isobutyronitrile) as a radical initiator has been developed to synthesize thiophenes. This method allows easy and effective construction of a thiophene scaffold having 3,4-fused-ring substitution and unsubstituted 2,5-positions for further functionalization and polymerization. Using this method, derivatives of cyclopenta[ c]thiophene, 3,4-ethylenedioxythiophene, and thiophene-containing spirocyclic compound have been synthesized.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.