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

PDF Version Also Available for Download.

Description

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.

Physical Description

17 p.

Creation Information

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

Context

This article is part of the collection entitled: UNT Scholarly Works and was provided by the Texas Academy of Mathematics and Science to the UNT Digital Library, a digital repository hosted by the UNT Libraries. It has been viewed 16 times. More information about this article can be viewed below.

Who

People and organizations associated with either the creation of this article or its content.

Authors

  • 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

Editor

Publisher

Provided By

Texas Academy of Mathematics and Science

The Texas Academy of Mathematics and Science (TAMS) is a unique residential program for high school-aged Texas students who are high achievers and interested in mathematics and science.

Contact Us

What

Descriptive information to help identify this article. Follow the links below to find similar items on the Digital Library.

Degree Information

Description

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.

Physical Description

17 p.

Notes

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.

Source

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

Language

Item Type

Identifier

Unique identifying numbers for this article in the Digital Library or other systems.

Publication Information

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

Collections

This article is part of the following collection of related materials.

UNT Scholarly Works

Materials from the UNT community's research, creative, and scholarly activities and UNT's Open Access Repository. Access to some items in this collection may be restricted.

What responsibilities do I have when using this article?

When

Dates and time periods associated with this article.

Creation Date

  • June 28, 2022

Added to The UNT Digital Library

  • Aug. 26, 2022, 12:08 p.m.

Description Last Updated

  • Dec. 5, 2023, 10:46 a.m.

Usage Statistics

When was this article last used?

Yesterday: 0
Past 30 days: 0
Total Uses: 16

Interact With This Article

Here are some suggestions for what to do next.

Start Reading

PDF Version Also Available for Download.

International Image Interoperability Framework

IIF Logo

We support the IIIF Presentation API

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 March 4, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting Texas Academy of Mathematics and Science.

Back to Top of Screen