Stimuli-Responsive Polymeric Conjugates of Tacrolimus: A pH/Redox-Triggered Approach toward Precision Drug Delivery

Area of Science:

• Biomaterials Science
• Nanotechnology
• Drug Delivery

Background:

• Tacrolimus (TAC) is an immunosuppressant with limited oral bioavailability.
• Developing targeted drug delivery systems can improve TAC efficacy and reduce side effects.
• Responsive nanocarriers offer potential for controlled drug release at specific sites.

Purpose of the Study:

• To synthesize and characterize a dual pH- and redox-responsive macromolecular prodrug of tacrolimus.
• To evaluate the micellar nanostructures formed by the conjugate for drug loading and release properties.
• To investigate the cellular uptake mechanism and biocompatibility of the developed nanomicelles.

Main Methods:

• Stepwise conjugation of hyaluronic acid (HA) with cystamine, hydrazide functionalization, and coupling with succinate-modified tacrolimus (TAC).
• Characterization of the conjugate (HSNT) using 1H NMR.
• Analysis of micellar nanostructures using Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS).
• Determination of drug loading capacity.
• Cellular uptake studies using HCT-116 cells and CD44 receptor blocking.
• Hemolysis assay to assess biocompatibility.

Main Results:

• Successfully synthesized HA-cystamine-hydrazide-tacrolimus (HSNT) conjugate which formed stable micellar nanostructures (~200 nm).
• Achieved a high drug loading capacity of 10.24% for TAC.
• Confirmed CD44 receptor-mediated endocytosis of HSNT micelles in HCT-116 cells.
• Demonstrated nonhemolytic properties and good biocompatibility of the nanomicelles.

Conclusions:

• The developed dual responsive polymeric micelles (HSNT) are a promising nanocarrier for tacrolimus.
• The system exhibits efficient cellular uptake and favorable biocompatibility.
• Further translational studies are warranted for potential clinical applications.