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Silicon-Based Linkers for Tunable Acid-Sensitive Drug Release from Polymeric Nanoparticles.

Matt Timmers1,2, Marco Kong2, Peter Schuckman3

  • 1Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, The Netherlands.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|December 11, 2024
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Summary

Researchers developed tunable silyl-based linkers for core-crosslinked polymeric micelles (CCPMs). These linkers control the release rate of active pharmaceutical ingredients (APIs), like gemcitabine, offering potential for targeted drug delivery.

Keywords:
Drug releasePolymeric nanoparticleSilyl linkerTunable linker

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Area of Science:

  • Polymer chemistry
  • Drug delivery systems
  • Nanotechnology

Background:

  • Active Pharmaceutical Ingredients (APIs) often require carriers to enhance pharmacokinetic and pharmacodynamic properties.
  • Core-crosslinked polymeric micelles (CCPMs) are effective carriers for hydrophobic small molecule APIs.
  • APIs are typically covalently attached to CCPM cores via linkers, allowing for controlled release modulation.

Purpose of the Study:

  • To synthesize and investigate silyl-based linkers for controlled API release from CCPMs.
  • To explore the tunability of drug release rates by modifying linker substituents.
  • To assess the potential of acid-triggered release for targeted drug delivery.

Main Methods:

  • Synthesis of silyl-based linkers with varying substituents.
  • Covalent attachment of linkers to gemcitabine via an Si ether bond.
  • Evaluation of gemcitabine release kinetics at different pH values (5.0 and 7.4) and temperatures (37°C).

Main Results:

  • Varying substituents on the silyl atom significantly altered gemcitabine release half-life (t1/2) from <1 to >96 hours at pH 5.0.
  • Release half-lives at pH 7.4 ranged from 24 to 240 hours.
  • Increased steric hindrance from larger substituents correlated with slower drug release at acidic pH.

Conclusions:

  • Silyl-based linkers offer tunable control over API release kinetics from CCPMs.
  • Steric hindrance is a key factor in modulating release rates, particularly in acidic environments.
  • This approach is adaptable for various APIs and carrier systems, enhancing targeted drug delivery possibilities.