Polymeric Materials For Improving Biological Drug Stability And Delivery

Abstract

Biological-based therapies are becoming an important way to treat diseases that were previously untreatable and/or with higher success rates compared to small molecule drugs. Two of these therapies include proteins, typically antibodies, and antisense oligonucleotides. However, they both struggle with different issues making these therapies difficult to translate into human patients; antibodies struggle with instability due to aggregation and antisense oligonucleotides with cellular delivery. In this thesis, I studied the use of polymeric materials to alleviate these downfalls and what structure-performance relationships were involved in the performance of these polymers. First, we saw that polymeric surfactants with mid tail lengths (14 carbons) were able to stabilize antibodies effectively through competing with the antibody on the surface (where the antibody typically aggregates). Next, we used cationic micelles, made from cationic-hydrophobic diblock polymers, to deliver antisense oligonucleotides. We observed that less bulky cations could deliver antisense oligonucleotides better than more bulky cations. This was hypothesized to be due to smaller cations having less steric hindrance to bind to the antisense oligonucleotide. We also developed a method to increase throughput of new delivery formulation testing through blending multiple diblocks together into one micelle or mixing two micelles together. We observed that we could improve delivery through blending or mixing if the micelle was going through a proton sponge-based endosomal escape method. Overall, this thesis focuses on understanding structure-performance relationships to rationally design polymers and developing methods to increase throughput of formulation testing for biological applications.