Preparation And Characterization Of Controlled Novel Microparticles For Drug Delivery Systems

Micro/Nano-particles, which serve as advanced drug delivery system with improved drug availability and reduced side effects, are widely applied in biomedicine aspects. Particularly, interest has grown in developing multi-functional carrier systems by combining treatment and diagnosis agents into a single vector, which received highly attention in the field of cancer therapy. Carrier properties such as composite, size, shape, surface morphology and ligand, etc. are main factors that influence its circulation behavior and drug release kinetics, however, limited delivery efficiency and real-time imaging remain to be the key challenge.This study focuses on the preparation and characterization of microparticles via electrospray. We aim to incorporate silicone oil, poly-caprolactone (PCL), and Fe3O4 nanoparticles (NPs) into an integrated platform as multi-functional microparticle system, tuning particle shape and microstructure by controlling parameters, and evaluating drug loading and controlled release capability of microparticles with diverse shape and morphology. Main contents of this study are listed as follows:(1) PCL microparticles with varied morphology were prepared using electrospraying technique in combination with various organic collection media. The five solutions used are non-solvent for PCL, which regulate the evaporation of residue solvents during the solidification process of electrosprayed droplets. In consequence, a series of distinct morphologies were gained when collected in methanol, ethanol, 1,2-propanediol, n-butanol and tetraethyl orthosilicate, including ellipsoidal, hemi-spherical, surface lamellar, Janus lotus-seedpods and spherical ones, respectively. The different microstructures rooted in the influences of varing phase separation degree by the introduced non-solvent with discrepant physical properties such as viscosity, surface tension, etc.(2) Based on the above experiment that porous PCL microparticles can be prepared by using tetraethyl orthosilicate as collection medium, we further the process for the fabrication of magnetic porous microparticles. Fe3O4 nanoparticles were mixed with PCL-dichlorometane (DCM) as precursor solution for electrospray to generate Fe3O4/doped PCL microparticles. Energy dispersive spectra analysis and infrared spectroscopy analysis confirmed the incorporation of Fe3O4 NPs within microspheres (～20μm in diameter). The microparticles showed good magnetic-responsive properties in vibrating sample magnetometer test, and the saturation magnetization can be enhanced by improving Fe3O4 NPs proportion. Drug loading and release behaviors from PCL microparticle with smooth surface morphology, porous morphology, and Fe3O4-doped porous microspheres, demonstrated high encapsulation efficiency of indomcthacin with a value of 98%,83% and 75%, respectively. X-ray diffraction results suggested that indomethacin existed in amorphous state after encapsulation.In vitro release studies indicated drug release rate from porous particles was obviously faster than solid particles with smooth morphology, and the release rate from magnetic porous microspheres can be promoted through external alternating magnetic fields (AMF,40 kHz). Based on mathematical fitting to both Higuchi and Korsmeyer-Peppas models, release mechanism followed Fickian diffusion.(3) Core-shell microparticles were produced through one-step coaxial electrospraying process, with silicone oil as the core and PCL-DCM as the shell fluid. Tunable particle diameter, shell thickness-to-radius ratio T/R, and shape are optimized by varing experimental parameters such as working distance, polymer concentration, voltage, flow rate and collection medium. MTT assay indicated no statistically significant reduction in cell viability over a 24 h period when co-culture mice fibroblast 3T3 cell lines with particles of various concentrations (from 10μg/mL to 10 mg/mL). Fluorescence microscopy further confirmed that cells can attach and grow normally in the petri-dish, no cytotoxicity was introduced by microparticles.(4) Dual functional drug carrier system with both therapeutic and imaging capability can be constructed by loading drug and Fe3O4 NPs within silicone oil-PCL core-shell particles. Follow-up studies will further assess the microparticle system in terms of imaging performance.In summary, this study systematically investigated the effect of various processing parameters on the resulted particle microstructure during electrospraying, which lays the foundation for further study of multi-functional drug delivery system.