Surface modification of biodegradable poly(lactide-co-glycolide) microparticles for targeted and controlled drug delivery

Surface modification is often desirable for controlled and targeted drug delivery with biodegradable polymers to attach targeting ligands, inhibit protein adsorption, or condense polynucleic acids. However, because both common surface modification reactions or copolymerizations with monomers possessing surface functional groups typically (1) render the biomaterial a new chemical entity not previously FDA approved, (2) affect the bulk properties of the polymer, and/or (3) are labor-intensive and expensive, physical mixing may be a logistical alternative. In this study, we developed a novel approach to surface-modify PLGA by incorporating surface-active agents possessing functional groups (which we call FUN emulsifiers) during microsphere preparation by the emulsion-solvent evaporation method. Two model FUN emulsifiers, polylysine (as a model polypeptide) and heparin (as a model polysaccharide), were selected for surface modification by the physical mixing procedure.; Modification of polylysine surface activity was accomplished by adjustment of ionization and secondary structure. Polylysine with ≥68% dissociation and ≥50% alpha helix content stabilized the PLGA oil-in-water emulsion and promoted surface-entrapment of the polypeptide, likely because hydrophobic and helical structures under such conditions tend to adsorb onto the oil-water interface.; The emulsifying activity of heparin was adjusted by exchanging its counter ions. Heparin with univalent and amino acid counter ions (Na+, K+, NH₄+) was found to exhibit emulsifying activity from poor to excellent, with further improvement with a hardening buffer of high pH (≥7.4). This was tentatively explained by the extent of the counterion binding and chain conformations of heparin. After desorption, ∼0.2 mg/m2 heparin coverage was obtained on the microspheres prepared from potassium heparin after 1-day incubation at 37°C, with 50% retained after 2 weeks.; The application of PLGA microspheres surface-modified with polylysine was explored in vaccine delivery. Either surface-conjugation to, or encapsulation in, PLGA microspheres was found to enhance the immunogenicity of a synthetic peptide antigen, C-TT2-CTP35.; In conclusion, the surface of PLGA microspheres can be rapidly modified by FUN macromolecules following adjustment of ionization and counter ions. This novel methodology eliminates the need for expensive chemical synthesis and minimizes regulatory hurdles associated with a new synthetic polymer.