Interpolyelectrolyte Complexes as an Emerging Technology for Pharmaceutical Delivery of Polypeptides

Polyelectrolyte complexes and the derivatives thereof comprise some of the most promising vehicles for the encapsulation and delivery of macromolecular therapeutics. In particular, protein therapeutics, which present a host of special considerations, can often be effectively packaged and delivered using interpolyelectrolyte complexes. While the technologies are still in the developmental phase, there are numerous examples of complexes where control is exerted over spacial and temporal delivery of a model protein cargo or candidate protein therapeutic agent. Here we provide a historical and practical background to promote a deeper understanding of interpolyelectrolyte complexes and the derivative technologies. Additionally, we review the physical principles underlying the association of polyelectrolyte complexes and the application of those principles to novel strategies and technologies driving interpolyelectrolyte complexation. Then, the application of polyelectrolyte complex technology to protein therapeutics is discussed in detail including discussions of several types of protein cargo with a special emphasis on Brain-Derived Neurotrophic Factor. Finally, we focus on the use of stealth polymers in block ionomer complexes, specifically PEG; its benefits, flaws, and possible alternatives. Comprehensive understanding of the field may promote the continued development of derivative technologies for the delivery of particularly intransigent protein therapeutics, much as has been accomplished for small molecule drugs. We also aim to link current advances to the historical developments which inaugurated the field. With consideration to the field, industrial and academic researchers can utilize the discussed technologies and continue to elucidate novel modalities for a myriad of therapeutic and commercial applications.