Hierarchical Microplates as Drug Depots with Controlled Geometry, Rigidity, and Therapeutic Efficacy

A variety of microparticles have been proposed for the sustained and localized delivery of drugs with the objective of increasing therapeutic indexes by circumventing filtering organs and biological barriers. Yet, the geometrical, mechanical, and therapeutic properties of such microparticles cannot be simultaneously and independently tailored during the fabrication process to optimize their performance. In this work, a top-down approach is employed to realize micron-sized polymeric particles, called microplates (mu PLs), for the sustained release of therapeutic agents. mu PLs are square hydrogel particles, with an edge length of 20 mu m and a height of 5 mu m, made out of poly(lactic-co-glycolic acid) (PLGA). During the synthesis process, the mu PL Young's modulus can be varied from 0.6 to 5 MPa by changing the PLGA amounts from 1 to 7.5 mg, without affecting the mu PL geometry while matching the properties of the surrounding tissue. Within the porous mu PL matrix, different classes of therapeutic payloads can be incorporated including molecular agents, such as anti-inflammatory dexamethasone (DEX), and nanoparticles containing imaging and therapeutic molecules themselves, thus originating a truly hierarchical platform. As a proof of principle, mu PLs are loaded with free DEX and 200 nm spherical polymeric nanoparticles, carrying DEX molecules (DEX-SPNs). Electron and fluorescent confocal microscopy analyses document the uniform distribution and stability of molecular and nanoagents within the mu PL matrix. This multiscale, hierarchical micropartide releases DEX for at least 10 days. The inclusion of DEX-SPNs serves to minimize the initial burst release and modulate the diffusion of DEX molecules out of the mu PL matrix. The biopharmacological and therapeutic properties together with the fine tuning of geometry and mechanical stiffness make mu PLs a unique polymeric depot for the potential treatment of cancer, cardiovascular, and chronic, inflammatory diseases.