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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
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PSMA-targeted SMART molecules outfitted with SN38.

Emily A Savoy1, Feyisola P Olatunji1, Nooshin Mesbahi1

  • 1Washington State University, Department of Chemistry, Pullman, WA 99164-4630, United States.

Bioorganic & Medicinal Chemistry Letters
|February 15, 2024
PubMed
Summary

We developed a prostate-specific membrane antigen (PSMA)-targeted drug conjugate delivering SN38 chemotherapy. The conjugate shows pH-dependent payload release, enhancing efficacy in PSMA-positive prostate cancer cells.

Keywords:
Acid-labile linkerPSMASMDCSN38Smart-moleculeStimuli-responsive

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Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Drug Delivery

Background:

  • Prostate cancer remains a significant health concern.
  • Targeted drug delivery systems aim to improve therapeutic efficacy and reduce side effects.
  • Small molecule drug conjugates (SMDCs) offer a promising approach for targeted cancer therapy.

Purpose of the Study:

  • To synthesize and evaluate a novel PSMA-targeted SMDC.
  • To assess the payload release kinetics of SN38 from the SMDC under different pH conditions.
  • To confirm the selective efficacy of the SMDC against PSMA-positive prostate cancer cells.

Main Methods:

  • Modular synthesis of a PSMA-targeted SMDC.
  • Evaluation of SN38 payload release at physiological (pH 7.4) and endosomal (pH ~5.0) pH.
  • Assessment of chemotherapeutic efficacy in PSMA-positive and PSMA-negative prostate cancer cell lines.

Main Results:

  • The SMDC demonstrated stability at physiological pH with minimal SN38 release.
  • Rapid SN38 release was observed at acidic pH, mimicking endosomal conditions.
  • Selective killing of PSMA-positive prostate cancer cells was confirmed, with minimal impact on PSMA-negative cells.

Conclusions:

  • The developed SMDC platform enables targeted delivery of SN38.
  • The pH-sensitive release mechanism ensures payload delivery within cancer cells.
  • This approach overcomes solubility limitations of chemotherapeutic agents and enhances targeted efficacy.