Dual Stimuli-Responsive Polymer Prodrugs Quantitatively Loaded by Nanoparticles for Enhanced Cellular Internalization...

Area of Science:

• Biomaterials Science
• Polymer Chemistry
• Nanotechnology
• Drug Delivery

Background:

• Direct encapsulation of hydrophobic drugs into amphiphilic block copolymer micelles often results in poor drug loading efficiency (DLE), low loading content (DLC), reduced micellar stability, and uncontrolled drug release.
• Existing methods struggle to achieve efficient and stable delivery of hydrophobic therapeutics.

Purpose of the Study:

• To develop a novel polymer prodrug encapsulation strategy using amphiphilic block copolymer micelles for improved hydrophobic drug delivery.
• To enhance micellar stability, control drug release, and improve cellular internalization and tumor penetration capabilities.

Main Methods:

• Synthesized copolymer prodrugs (PPEMA-co-PCPTM) via reversible addition-fragmentation chain transfer (RAFT) polymerization.
• Encapsulated copolymer prodrugs into poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles.
• Evaluated nanoparticle stability, drug release kinetics, cellular uptake, cytotoxicity, and tumor spheroid penetration.

Main Results:

• The resulting polymer prodrug-loaded nanoparticles exhibited high stability in aqueous solutions and blood serum, even after lyophilization-dissolution.
• The nanoparticles demonstrated pH-triggered swelling and transition to a positively charged state at tumoral pH (∼6.8), eliminating burst drug release.
• Drug release was triggered by reductive agents and pH, with efficient cellular internalization observed at pH 6.8 due to the positively charged cores.
• Enhanced cytotoxicity and significant multicellular tumor spheroid (MCTs) penetration and growth suppression were achieved at pH 6.8.

Conclusions:

• The developed responsive polymer prodrug encapsulation strategy effectively overcomes limitations of traditional hydrophobic drug encapsulation methods.
• The strategy endows nanoparticles with responsive drug release, enhanced cellular internalization, and improved tumor penetration capabilities.
• This approach holds significant promise for advanced cancer nanomedicine.