(338b) Self-Assembled Polymeric Oral Delivery Platform for Therapeutic Proteins

In recent years, monoclonal antibodies have become one of the most relevant therapies to treat autoimmune diseases. These conditions are characterized by the failure of an organism to tolerate its own cells and tissues which can lead to inflammation and tissue dysfunction [1]. However, because monoclonal antibodies have a low bioavailability and are highly susceptible to degradation, their administration is limited to parenteral routes [2]. Injections have a higher manufacturing cost and risk of infection, in addition to restricting their accessibility to patients [3]. 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 [4]. 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, in the present work we developed pH-responsive self-assembled polymersomes based on block copolymers to deliver monoclonal antibodies orally.

Diblock copolymers were synthesized using reversible addition−fragmentation chain-transfer polymerization and carbodiimide-mediated coupling reactions. Poly(methacrylic acid) (PMAA) and poly(ethylene glycol) (PEG) were selected due to their pH-responsive properties and stealth abilities, respectively. Different degrees of polymerization were examined to study 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 PMAA and the successful addition of the PEG chain. Transmission electron microscopy confirmed the impact of the hydrophilic weight fraction on the micellar polymorphism as polymersomes and micelles were obtained. Since PMAA has a low pKa, strategies to improve the stability of the system at higher pH values have been implemented. The pKa of the system was increased by copolymerizing PMAA with hydrophobic comonomers, thus enhancing its suitability for oral delivery applications. In future studies, the loading and release capacity of the self-assembled systems 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 the nanocarriers with monoclonal antibodies to successfully deliver them 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,” Advanced Functional Materials, 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 in biotechnology, vol. 27, no. 11, pp. 628–635, Nov. 2009, doi: 10.1016/j.tibtech.2009.07.009.
[3] J.-P. Amorij et al., “Towards tailored vaccine delivery: needs, challenges and perspectives,” Journal of Controlled Release, vol. 161, no. 2, pp. 363–376, 2012.
[4] J. E. Vela Ramirez, L. A. Sharpe, and N. A. Peppas, “Current state and challenges in developing oral vaccines,” Advanced Drug Delivery Reviews, vol. 114, pp. 116–131, 2017, doi: 10.1016/j.addr.2017.04.008.