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Site-targeted drug delivery systems enhance therapeutic efficacy while minimizing systemic toxicity and treatment costs. Unlike conventional methods, these systems ensure precise drug delivery, improving bioavailability and reducing side effects. Targeted drug delivery is classified into three levels. First-order targeting directs drugs to the capillary beds of specific organs or tissues. Second-order targets specific cell types, such as tumor cells, using receptor-mediated interactions.
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Multicheckpoint Cellular Targeting of siRNAs Using Antibody-Directed Lipid-Polymer Hybrid Nanoparticles.

Ritam Das1,2, Jewel Medeiros1,2, Jithu Krishna1,2

  • 1Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01003, United States.

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Researchers developed novel antibody-functionalized nanoparticles for targeted siRNA delivery to aggressive cancers like triple-negative breast cancer. This multicheckpoint strategy enhances safety and efficacy by targeting multiple receptors, improving nanomedicine selectivity.

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Area of Science:

  • Biomedical Engineering
  • Nanomedicine
  • Cancer Therapeutics

Background:

  • Current gene therapy struggles with tissue-specific targeting beyond major organs.
  • Passive targeting methods require extensive optimization.
  • Active targeting strategies like antibody-drug conjugates (ADCs) offer modularity and effectiveness.

Purpose of the Study:

  • To develop antibody-functionalized hybrid lipid-polymer nanoparticles for targeted siRNA delivery.
  • To target cancer-overexpressed receptors such as EGFR and TROP2, particularly in triple-negative breast cancer (TNBC).
  • To implement a multicheckpoint targeting strategy with multi-siRNA delivery for enhanced safety and efficacy.

Main Methods:

  • Fabrication of antibody-functionalized hybrid lipid-polymer nanoparticles.
  • Functionalization with antibodies targeting EGFR and TROP2.
  • Incorporation of multiple small interfering RNAs (siRNAs) for a multicheckpoint targeting approach.
  • In vitro testing using TNBC cell models.

Main Results:

  • Demonstrated successful nanoparticle functionalization for targeted delivery.
  • Validated targeting of EGFR and TROP2 receptors on TNBC cells.
  • Showcased the potential of a multicheckpoint strategy to improve target selectivity and reduce off-target effects.

Conclusions:

  • The developed nanoparticle platform shows promise for robust and safe siRNA delivery in cancer therapy.
  • A multicheckpoint targeting strategy is a viable approach to enhance selectivity in nanomedicine.
  • This work lays the foundation for advanced targeted cancer therapeutics, particularly for aggressive cancers like TNBC.