(265c) Design of a Self-Assembled Polymeric Oral Delivery Platform for Therapeutic Proteins

Autoimmune diseases are characterized by the failure of an organism to tolerate its own cells and tissues which can lead to inflammation and tissue dysfunction [1]. One of the most relevant therapies to treat these diseases is by using protein biologics such as monoclonal antibodies. However, because of their high molecular weight, low bioavailability, and susceptibility to degradation, their administration is limited to parenteral routes [2]. Out of the numerous alternative administration routes that have been proposed, oral delivery offers the most advantages regarding costs, accessibility, and reduced discomfort, which increases patient compliance [2]. Nevertheless, the oral route has significant biological and physicochemical challenges such as the presence of proteolytic enzymes, drastic changes in pH, as well as the mucus and the epithelial cell layer [3]. All these challenges have to be overcome to successfully deliver monoclonal antibodies across the intestinal epithelium into the bloodstream. One approach to protect them from these barriers is to use polymeric nanocarriers based on block copolymers. Thus, the goal of this project is to develop pH-responsive self-assembled polymersomes based on block copolymers to deliver high isoelectric point and high molecular weight monoclonal antibodies to treat autoimmune diseases.

In the present work, di- and triblock copolymers were synthesized using reversible addition−fragmentation chain-transfer polymerization and carbodiimide-mediated coupling reactions. The monomers methacrylic acid and ethylene glycol were used due to their pH-responsive properties and stealth abilities, respectively. Different degrees of polymerization and number of blocks were examined to see the effect of the hydrophilic weight fraction on the micellar polymorphism. Analysis by Fourier-transform infrared spectroscopy and ¹H nuclear magnetic resonance spectroscopy confirmed the polymerization of methacrylic acid and the successful addition of the poly(ethylene glycol) chain. Dynamic light scattering studies confirmed hydrodynamic diameters ranging from 201 nm to 591 nm. Transmission electron microscopy confirmed the effect of the hydrophilic weight fraction on the micellar polymorphism. Inverse micelle, polymersomes, and micelles were obtained. In future studies, strategies to increase the pKa of methacrylic acid will be implemented. The loading and release capacity of the polymersomes will be studied as well as their cytocompatibility with Caco-2 cells. The potential to cross the mucus and the epithelial cell barrier will be analyzed using Caco-2 and HT-29/MTX co-culture. The development of these nanocarriers will help us achieve the oral delivery of monoclonal antibodies for the treatment of autoimmune diseases. By combining the material design of self-assembled nanocarriers with monoclonal antibodies and their successful delivery through the oral route, the proposed work has the potential to impact the scientific community and the lives of many patients.

This work was supported by the NIH (R01-EB022025), the Cockrell Family Chair Foundation, the Office of the Dean of the Cockrell School of Engineering at the University of Texas at Austin (UT) for the Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, and the UT-Portugal Collaborative Research Program. FAC-V acknowledges support from the CONACYT/ConTex Fellowship (Mexico).

References

[1] A. B. Shodeinde, A. C. Murphy, H. F. Oldenkamp, A. S. Potdar, C. M. Ludolph, and N. A. Peppas, “Recent Advances in Smart Biomaterials for the Detection and Treatment of Autoimmune Diseases,” Adv. Funct. Mater., vol. 30, no. 37, p. 1909556, Sep. 2020, doi: https://doi.org/10.1002/adfm.201909556.
[2] Z. Antosova, M. Mackova, V. Kral, and T. Macek, “Therapeutic application of peptides and proteins: parenteral forever?,” Trends Biotechnol., vol. 27, no. 11, pp. 628–635, Nov. 2009, doi: 10.1016/j.tibtech.2009.07.009.
[3] J. E. Vela Ramirez, L. A. Sharpe, and N. A. Peppas, “Current state and challenges in developing oral vaccines,” Adv. Drug Deliv. Rev., vol. 114, pp. 116–131, 2017, doi: 10.1016/j.addr.2017.04.008.