Laboratory synthesis and preparation of thermo-responsive polymeric micelle and hydrogel for resveratrol delivery and release

Background: Resveratrol (RSV) exhibits anti-inflammatory, antioxidative, antiaging, and cardioprotective properties. However, due to its hydrophobic nature, it is prone to instability and oxidation, which significantly limit its biomedical applications.

Objectives: The aims of this study were: 1) To prepare and characterize hydrogels and micelles by mixing the synthesized PNIPAM-b-PEO-b-PNIPAM copolymer and RSV in an aqueous environment; 2) To investigate the molecular interactions between the polymer and RSV; 3) To evaluate various properties of the polymeric micelles and hydrogels; 4) To determine the efficiency of RSV release from the polymeric micelles.

Material and methods: A well-defined PNIPAM-b-PEO-b-PNIPAM block copolymer was synthesized and purified. Gel permeation chromatography and 1H NMR were used to characterize the chemical composition and molecular weight of each copolymer. The encapsulation of RSV and its interaction with PNIPAM-b-PEO-b-PNIPAM were confirmed using 2D nuclear Overhauser effect spectroscopy (NOESY). The lower critical solution temperature (LCST), critical micelle concentration (CMC) and structure of the polymeric micelle were characterized using surface tension measurements, a viscometer, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The rheological behavior of the RSV-loaded hydrogels was also investigated.

Results: The results showed that the RSV-loaded micelles were successfully prepared. The LCST and CMC of PNIPAM-b-PEO-b-PNIPAM polymeric micelles were determined to be 35°C and 0.005 g/L, respectively. The micelles have a spherical profile with a particle size of 100 nm and a narrow size distribution.

Conclusions: Resveratrol can be encapsulated within polymeric micelles formed by PNIPAM-b-PEO-b-PNIPAM block copolymer below the LCST. Its molecules are incorporated into the hydrophobic domains of poly(N-isopropyl acrylamide) (PNIPAM), forming a molecular complex. The point of molecular interaction is primarily at the phenolic region of RSV. Below LCST, PNIPAM-b-PEO-b-PNIPAM behaves as a polymeric surfactant at low concentrations and as an associating polymer at high concentrations. At high polymer concentrations, PNIPAM-b-PEO-b-PNIPAM formed a hydrogel. Above LCST, it was released from the polymeric micelles.