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By Abhirup Mandal and Ashim K. Mitra

Ocular delivery of biologics has been challenging. It has been a constant source of exasperation for ophthalmologists and formulation experts over the last few decades. High-molecular weight, short half-lives, structural complexity, and poor permeability render biologics as the most challenging molecules to formulate and deliver across ocular barriers. Since the advent of the anti-vascular endothelial growth factor aptamer Macugen in 2004 and monoclonal antibody Lucentis in 2006, the ophthalmology market has witnessed tremendous growth. Moreover, several biologics have received Food and Drug administration (FDA) approval recently. A majority of these biologics are delivered with intravitreal injections leading to high treatment cost for skilled professionals and serious side effects. The latest mind-boggling breakthroughs and discoveries in the field of self-assembling nanocomplexes have led scientists to think about whether biologics can be delivered via a convenient topical route.

The self-assembly of amphiphilic polymers and biologics including proteins and peptides into more organized nanovesicles has garnered tremendous interest recently for controlled drug delivery. A key aspect of self-assembly is the ubiquitous multiple cooperating or competing interactions or complexation to prepare hybrid nanocomplexes that are equally essential for biological processes. Nano-drug carriers with such self-assembly are, to a certain extent, similar to a virus-like architecture. For instance, viral proteins that constitute the capsids or outer shell of bacterial microcompartments self-assemble by design. Cataract formation and Parkinson disease are some of the conditions where pathology can be associated with the self-assembly of a condensed protein phase.

Self-assembled nanocomplexes or systems represent a significant advancement in the field of nanotechnology and holds potential for controlled and safe ocular drug delivery. Several groups have been extensively exploiting the biophysical properties of peptides and proteins as building blocks of self-assembled nanocarriers. However, controlling structural and functional features of biologics at molecular levels, unaccountable high-resolution crystallography, massive molecular weights (>MDa) for NMR, and fragmentary atomic-resolution data represent serious challenges impeding efficient rational design of protein and peptide-based self-assembling nanocomplexes. A research group from Utrecht University has made a serious effort in unraveling the supramolecular organization of a peptide-based nanocarrier with high molecular detailing (see figure).

Figure. Supramolecular organization of self-assembling nanocomplexes determined by integrating a multitude of experimental techniques: (A) Hollow, water-filled hemisphere of a nanovesicle formed by self-assembling peptides; (B) Slice through the hemisphere: peptides organized in antiparallel β-sheets in which the hydrophobic parts align, resulting in interdigitated peptide bilayers. Peptides with opposing C-termini are colored in orange and blue.

Studies in our laboratory have also demonstrated the immense potential of self-assembling nanocomplexes in delivering cyclosporine to the ocular tissues. One such patented nanomicellar formulation, Seciera (cyclosporine A, 0.09% ophthalmic solution), has demonstrated promising results in confirmatory phase 3 clinical trials for the treatment of dry eye syndrome and is currently undergoing evaluation by FDA for approval. Generations of self-assembling retina with embryonic stem cells (ESCs) and many other nanocomplexes mark an exciting advance and indicate the emergence of a self-assembling nancomplex-based market. We believe that with the advancement and better understanding of kinetics, intermediate pathways, molecular anisotropy, and greater use atomistic models, protein- and peptide-based self-assembling nanocomplexes will prevail the ophthalmology market in future.

Abhirup Mandal (Right) is currently in his fourth year of studies as a Ph.D. student in the Department of Pharmaceutical Sciences at University of Missouri-Kansas City, mentored by Curators’ Distinguished Professor of Pharmacy Ashim K. Mitra (Left).