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Self-Immolative Polymer Nanoparticles with Precise and Controllable pH-Dependent Degradation.

Samuel A Smith1, Bruna Rossi Herling2, Changhe Zhang1

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New self-immolative polymer nanoparticles offer tunable pH-triggered drug release. The 4:1 PGAm nanoparticles show promise for intracellular delivery, demonstrating efficient endosomal escape and controlled degradation.

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Area of Science:

  • Materials Science
  • Nanotechnology
  • Biomedical Engineering

Background:

  • Polymer nanoparticles are extensively researched for therapeutic cargo delivery.
  • Self-immolative polymers (SIPs) enable controlled disintegration and cargo release.
  • pH-responsive materials are crucial for targeted intracellular drug delivery.

Purpose of the Study:

  • To develop pH-responsive self-immolative polymer nanoparticles for drug delivery.
  • To tune the disassembly pH of nanoparticles by altering polymer composition.
  • To evaluate the cargo loading, degradation, and endosomal escape efficiency of the developed nanoparticles.

Main Methods:

  • Synthesis of nanoparticles using poly(ethylene glycol)-b-(2-diisopropyl)amino ethyl methacrylate) and a self-immolative polymer P(DPAEGAm-r-DBAEGAm).
  • Varied the ratio of diisopropylamino to dibutylamino substituents in P(DPAEGAm-r-DBAEGAm) to create four types of PGAm particles (4:1, 2:1, 2:3, 0:1).
  • Assessed particle disassembly pH, polymer depolymerization rates at different pH values, peptide cargo loading, and endosomal escape efficiency.

Main Results:

  • Disassembly pH was tunable from 7.0 to 5.0 by adjusting the amine substituent ratio.
  • P(DPAEGAm-r-DBAEGAm) polymers showed significant depolymerization (60-80%) below disassembly pH within 2 hours, with minimal degradation (<10%) at pH 7.4.
  • 4:1 PGAm nanoparticles exhibited higher endosomal escape efficiency (∼4%) compared to other formulations (<1%), while all loaded peptide cargo.

Conclusions:

  • The developed PGAm nanoparticles offer tunable, pH-triggered degradation for controlled cargo release.
  • The 4:1 PGAm nanoparticle formulation demonstrates potential as an effective intracellular drug delivery system.
  • Further optimization of 4:1 PGAm nanoparticles is warranted for advanced therapeutic applications.