Naba Elsaid, Zeeneh Elsaid, Timothy L. Jackson, Jose Prieto, Aljawharah Alqathama, Kevin M.G. Taylor and Satyanarayana Somavarapu
School of Life and Medical Sciences, Department of Pharmacy, Pharmacology & Postgraduate Medicine University of Hertfordshire, College Lane Hatfield AL10 9AB, UK
Background and Purpose: The current issues facing drug delivery to the back of the eye, are repetitive intravitreal injections of therapeutic proteins like ranibizumab, which are associated with rare but sight-threatening complications, such as retinal detachment and endophthalmitis. Biodegradable polymers, such as PLGA, are delivery vehicles which can be used to treat posterior segment eye disease, but suffer from poor drug loading and release. This work describes a ‘system-within-system’, PLGA microparticles incorporating chitosan-based nanoparticles, for improved loading and sustained intravitreal delivery of ranibizumab.
Methods: Synthesis of chitosan-N-acetyl-L-cysteine (CNAC) was confirmed using FT-IR and 1H NMR. Chitosan/TPP, CNAC and CNAC/TPP nanoparticles containing ranibizumab were prepared and incorporated in PLGA microparticles and characterised for their size, zeta potential, morphology, solid-state properties, protein loading, stability, release, in vivo antiangiogenic activity and effects on cell viability.
Results: Chitosan-based ranibizumab-loaded nanoparticles measured 17 – 350 nm with a zeta potential of -1.4 to + 12 mV and PLGA microparticles with sizes of 3.0 – 6.6 μm and zeta potentials of -12 to + 9.7 mV. PLGA microparticles appeared mostly spherical; those prepared with chit/TPP, CNAC and CNAC/TPP had spherical nanoparticles on their surface.
Microparticle protein content ranged from 13 – 69%. All preparations showed burst release, with the exception of CNAC-containing microparticles, which had no initial burst release and showed the slowest protein release. Ranibizumab released from PLGA microparticles maintained structural integrity and in vitro activity. Microparticles showed no effect on cell viability up to a concentration of 12.5 mg/mL.
Conclusion: PLGA microparticles containing CNAC nanoparticles overcame the initial burst release typically associated with PLGA microparticles, significantly improved protein loading and provided sustained release of ranibizumab over 6 months. This drug delivery system may have potential for improved intravitreal delivery of therapeutic proteins, thereby reducing the frequency of burdensome intravitreal injections and associated costs.