Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists

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This article presents 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. The proof-of-concept biological evaluation presented demonstrates the potential of T-SMPDCs for cancer immunomodulatory therapies.

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Debnath, Sashi; Hao, Guiyang; Guan, Bing; Thapa, Pawan; Hao, Justin; Hammers, Hans et al. June 28, 2022.

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  • Debnath, Sashi University of Texas Southwestern Medical Center
  • Hao, Guiyang University of Texas Southwestern Medical Center
  • Guan, Bing University of Texas Southwestern Medical Center
  • Thapa, Pawan University of Texas Southwestern Medical Center
  • Hao, Justin University of Texas Southwestern Medical Center; Texas Academy of Mathematics and Science, University of North Texas
  • Hammers, Hans University of Texas Southwestern Medical Center
  • Sun, Xiankai University of Texas Southwestern Medical Center

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This article presents 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. The proof-of-concept biological evaluation presented demonstrates the potential of T-SMPDCs for cancer immunomodulatory therapies.

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17 p.

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Abstract: 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.

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  • International Journal of Molecular Sciences, 23(13), MDPI, June 28, 2022, pp. 1-17

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  • Publication Title: International Journal of Molecular Sciences
  • Volume: 23
  • Issue: 13
  • Peer Reviewed: Yes

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  • June 28, 2022

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  • Aug. 26, 2022, 12:08 p.m.

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  • Dec. 5, 2023, 10:46 a.m.

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Debnath, Sashi; Hao, Guiyang; Guan, Bing; Thapa, Pawan; Hao, Justin; Hammers, Hans et al. Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists, article, June 28, 2022; [Basel, Switzerland]. (https://digital.library.unt.edu/ark:/67531/metadc1984194/: accessed January 15, 2025), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting Texas Academy of Mathematics and Science.

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