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

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 (t_1/2) 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.