Microfluidic synthesis of alginate 6-methoxyenthylamino numonafide (MEAN)– eluting microspheres for catheter-directed delivery to liver tumors

Abstract

Purpose Amonafide has demonstrated potent efficacy to treat a broad range of solid tumors including HCC but clinical application has been limited due to severe toxicities. These toxicities have been mitigated with a new metabolically stable drug, 6-methoxyenthylamino numonafide (MEAN). Local transcatheter delivery to liver tumors using drug-eluting beads could also reduce toxicity of this drug. We aimed to test the hypothesis that microfluidic techniques can be used to synthesize MEAN-eluting alginate microspheres. Materials and Methods Microspheres were produced via custom-made microfluidic set-up, consisting of microfluidic chip, syringe pumps and optical microscope. Continuous synthesis of MEAN loaded magnetic alginate microspheres was performed by controlling the flow rate of oil (Qo) phase (N’-hexadecane and span 80) and aqueous (Qa) phase (alginate, magnetic clusters, and MEAN) constituents. Fluorescence measurements (λex=445 nm and λem=550 nm) were used to quantify MEAN elution rates from these alginate spheres into release media in triplicate tests. Imaging of these magnetic microspheres was performed using a 7T MR scanner (Bruker). Results Microfluidic methods effectively produced hydrophilic, deformable, and non-aggregated biodegradable alginate microspheres with a mono size range of 30~70 um (size dependent upon channel size and flow rates). Encapsulation of MEAN and magnetic clusters in the alginate microspheres was confirmed with fluorescent microscopy. The magnetic clusters embedded into the alginate matrix controlled drug release rates and prevented initial burst drug release. Strong T2-weighted image contrast was achieved due to the magnetic clusters within these microsphere drug carriers. Conclusion Microfluidic methods effectively produced MEAN-eluting magnetic alginate microspheres. These microspheres offer the benefits of controlled drug release and visibility with MR imaging. Future animal studies should verify efficacy of selective transcatheter delivery to liver tumors.