(483d) Self-Assembled pH-Responsive Nanoparticles for the Oral Delivery of Protein Therapeutics

Protein therapeutics are a popular and relevant therapy to treat autoimmune diseases. However, presently their administration is limited to parenteral routes because of their high molecular weight, low bioavailability, and susceptibility to degradation [1]. Injections have a higher manufacturing cost and risk of infection, in addition to restricting their accessibility to patients [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 [1]. 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 protein therapeutics, such as monoclonal antibodies, across the intestinal epithelium and into the bloodstream. One approach to protect them from these barriers is to use polymeric nanocarriers. 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. The pKa of the system was increased by copolymerizing PMAA with hydrophobic comonomers, thus enhancing its suitability for oral delivery applications. The loading and release capacity of the self-assembled systems has been studied using Alexa Fluor 488-tagged Bovine Serum Albumin at different pH values to mimic the gastrointestinal environment. The cytocompatibility of the systems was evaluated with Caco-2 cells. The development of these nanocarriers will help us achieve the oral delivery of monoclonal antibodies for the treatment of autoimmune diseases. By applying the material design of self-assembled nanocarriers to deliver therapeutic antibodies through the oral route, the proposed work has the potential to revolutionize treatment strategies for autoimmune diseases.

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

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