(686a) Self-Assembled Polymer Carriers for the Oral Delivery of High Isoelectric Point, High Molecular Weight Protein Therapeutics

While protein therapeutics are a promising treatment option in many realms of disease, they are also limited by their fragility. Typically, these therapeutics must be delivered via intravenous or subcutaneous injection, both of which can be painful and lead to reduced patient compliance. An oral delivery mechanism would be preferable; however, the conditions of the human gastrointestinal tract are not amenable to naked protein delivery. Additionally, proteins that exhibit a high isoelectric point (pI > 7), and large molecular weight (e.g. Humira) are particularly difficult to deliver due to their cationic charge at intestinal pH. This causes electrostatic interaction with the anionic carriers previously investigated for oral protein delivery, and minimal drug release. Thus, this work focuses on the development of improved polymer delivery systems that can facilitate the oral delivery of high pI, high MW protein therapeutics.

Reversible addition-fragmentation chain transfer (RAFT) polymerization is used to synthesize block co-polymers of a pH responsive unit (e.g. Methacrylic acid, Propylacrylic acid), along with supporting monomers such as Poly(ethylene glycol) methacrylate and methyl methacrylate to allow pH responsive self-assembly and tuning of the responsive pH range. Varying mole ratios of the monomers are examined to determine their effects on final polymer properties. Particle size is determined by dynamic light scattering, while the polymer itself is characterized by FTIR, NMR, and GPC.

These polymers exhibit pH responsive behavior due to the presence of the carboxylic acid groups. Above a certain pH, the carboxyl groups are deprotonated and charged, leading to polymer solubility in water. However, below that pH the protonated carboxyl groups hydrogen bond with the oxygen present in the PEG, resulting in complexation and nanoparticle self-assembly. By tuning the pH where the polymer disassembles, the delivery system can be targeted to specific regions of the intestine where release is desired.

The block co-polymers synthesized appear to be viable candidates for the delivery of high pI, high MW protein therapeutics based on preliminary studies. The self-assembled nature of the particles should provide adequate protection for the drug in the stomach, while the higher pH of the intestine should lead to disassembly of the carrier and release of the therapeutics, mitigating the charge interaction between the protein and polymer.