(16g) Prodrug Conjugates to Improve the Delivery Capacity of Nanoparticles for Protein Therapeutics

Hydrophilic peptides and protein macromolecules represent an important class of therapeutic compounds, although wide clinical application is hindered by low oral bioavailability, short circulation half-life, and in vivo instability due to enzymatic degradation. Polymeric nanoparticles are ideally suited to circumvent these limitations, as they can be made to extend circulation times in vivo and protect encapsulated molecules from degradation. Nonetheless, the capacity of polymeric particles to encapsulate hydrophilic compounds at sufficient concentrations is generally limited.

The approach developed in this work relies on the synthesis of prodrugs to modulate the supersaturation of hydrophilic macromolecules during the particle formation process. Prodrugs are prepared through chemical conjugation of the protein to hydrophobic anchor molecules via labile linkages. Depending on the properties of the anchor molecule and degree of protein modification, the prodrug solubility could be appropriately tuned. Using this strategy, polymer-stabilized protein particles were prepared via Flash NanoPrecipitation, a controlled precipitation process which utilizes amphiphilic block copolymers to direct particle self-assembly. Particles of nanometer size, narrow size distributions, and protein loadings in excess of 35wt% were prepared. Release of the prodrug from the particle is anticipated based on enzymatic degradation of the polymer, whereupon the prodrug is instantaneously cleaved into the active form. The prodrug conjugation strategy, coupled with Flash NanoPrecipitation technology, thus present an attractive system which permit the nanoparticle formulation of a wide range of active solutes irrespective of their intrinsic water solubilities.