Engineering shape-defined PLGA microPlates for the sustained release of anti-inflammatory molecules

Over the years, nanoparticles, microparticles, implants of poly(D,L-lactide-co-glycolide) (PLGA) have been demonstrated for diverse biomedical applications. Yet, initial burst release and optimal modulation of the release profiles limit their clinical use. Here, shape-defined PLGA microPlates (mu PLs) were realized for the sustained release of two anti-inflammatory molecules, the natural polyphenol curcumin (CURC) and the corticosteroid dexamethasone (DEX). Under the electron microscope, mu PLs appeared as square prisms with an edge length of 20 mu m. The top-down fabrication process allowed the authors to vary, readily and systematically, the mu PL height from 5 to 10 mu m and the PLGA mass from 1 to 5, 10 and 20 mg. 'Taller' particles realized with higher PLGA concentrations encapsulated more drug reaching on average values of about 150 pg/mu PL, for both CURC and DEX. The mu PL height and PLGA concentration had major effects on drug release, too. Under sink conditions, DEX release from tall mu PLs at 1 h reduced from 50% to 10% and 2% for the 5, 10 and 20 mg PLGA configurations, respectively. Also, DEX was released more slowly from taller as compared to short mu PLs. The opposite trend was observed for CURC, possibly for its lower hydrophobicity and molecular weight as compared to DEX. This was also confirmed by quantifying the free energy of translocation for the two drugs via molecular dynamics simulations. Finally, the anti-inflammatory activity of mu PLs was tested in vitro on LPS-stimulated rat monocytes and in vivo on a murine model of UVB-induced skin burns. Both in vitro and in vivo, the expression of proinflammatory cytokines (IL-6, IL-1 beta, and TNF-alpha) was significantly reduced by the application of mu PLs as compared to the free compounds. In vivo, one single topical deposition of CURC-mu PLs outperformed multiple, free CURC applications. This work demonstrates that geometry and polymer density can be effectively used to modulate the pharmacological performance of microparticles and mitigate the initial burst release.