Development of bacteria inspired polymers for improved pulmonary drug delivery
Creators: name: Ruben, Christopher
Publisher: name: University of Iowa
Year: 2026
Subjects: Cell Uptake
pMPC
Polymer Brushes
Protein Adsorption
Targeted Drug Delivery
Zwitterionic
public abstract

description: Target drug delivery shows great potential to increase therapeutic effectiveness while decreasing off-target side effects by localizing therapeutics to specific regions in the body. However, the body has many defense mechanisms that drug-delivery technologies need to overcome. When drug carriers enter the body, their first interactions are with protein-rich fluids like mucus, phlegm, blood, or interstitial fluids. The proteins in these fluids can adsorb to the carrier surfaces forming a protein corona and that can reduce transport through the body, limit cellular interaction, and lower cell uptake of the carrier. Additionally, certain proteins in the corona can flag the drug carrier for early removal via the immune system and macrophage uptake. Current strategies including zwitterionic polymer coatings are well known for their ability to resist protein adsorption and macrophage uptake.
description: Pathogens have developed methods to avoid the body’s natural defenses and increase their retention time in the body. Ligands on the surface of certain bacterial species enable the bacteria to anchor or internalize into human cells and tissues. In some cases, the exact chemical entity that enables specific cell interactions is known. For example, the zwitterionic chemical moiety phosphorylcholine (ChoP) has been identified as a key chemistry in the progression of bacteria, including Streptococcus pneumonia and non-typeable Hemophilus influenza, in the lungs. The bacteria use ChoP to bind to the platelet-activating factor receptor (PAFR) to aid in bacterial internalization. This thesis is focused on creating bio-inspired zwitterionic ChoP-containing polymer coatings to simultaneously decrease protein adsorption and increase cellular uptake through specific polymer-receptor interactions.
description: ChoP-based polymers were synthesized using reversible addition–fragmentation chain transfer (RAFT) polymerization using 2-methacryloyloxyethyl phosphorylcholine (MPC) as the vi monomer. MPC polymers (pMPC) with molecular weights ranging from 10 to 30 kDa were synthesized and coated onto gold surfaces via thiol-gold bonds with coatings thickness of 1-3 nm and average grafting densities of 0.15 to 0.05 chains/nm2 . Ethanol-based coatings resulted in thicker coatings and higher grafting densities when compared to water-based coatings. However, in both solvents, the polymer coatings have grafting densities near or above the required density to form brush-like coatings which is ideal for protein resistances. When challenged with albumin or human serum the coatings decreased non-specific protein adsorption significantly more than bare gold surfaces. High MW pMPC coatings formed the most effective barrier and decreased adsorption by over 80% in both albumin and human serum. Solvent choice did not affect the protein adsorption indicating either solvent can be used to form effective pMPC coatings. These results show how MW and solvent affect the grafting density and protein resistance of pMPC coatings. Because pMPC coatings are effective at reducing non-specific protein adsorption, they are promising candidates for reducing protein corona formation on drug delivery vehicles.
description: The pMPC polymer coatings were then applied to 100 nm gold nanoparticles and their resistance to protein adsorption and cellular interactions were determined. The pMPC-coated nanoparticles showed a more neutral zeta-potential and hydrodynamic size as the pMPC MW increased. The polymer-coated nanoparticles were still stable in solution despite the more neutral zeta potential. After incubation with albumin or 10% FBS, the smaller MW coatings showed smaller shifts in the LSPR peak and hydrodynamic size when compared to bare gold indicating that the lower MW polymer coatings form smaller protein coronas when compared to the bare gold nanoparticles. The bare gold nanoparticles aggregated when challenged with cell media containing 10% FBS, but the polymer-coated nanoparticles showed minimal signs of aggregation. Because cell uptake is size-dependent, avoiding aggregation is critical to developing vii effective drug carriers. The 15 and 20 kDa pMPC coatings increased uptake and PAFR interactions when compared to bare gold nanoparticles. All pMPC coatings shifted nanoparticle uptake in lung cells to energy-dependent pathways thus altering the fate of the gold nanoparticles and removing some off-target pathways. Together this data illustrates the effectiveness of pMPC coatings to minimize protein adsorption, increase cell uptake, and interact with PAFR. Because of these findings, the pMPC coatings are valuable tools for targeting drug carriers to locations with increased PAFR expression like lung cancer, chronic obstructive pulmonary disease, or respiratory infections.
description: To further investigate the PAFR-ChoP interactions molecular dynamic simulations were conducted. Using a modified crystal structure of PAFR, PAF and pMPC polymers were docked with PAFR followed by MD- and steered MD-simulation using the docking poses as the starting poses. PAF showed similar docking poses to those seen in the literature validating the model parameters. The pMPC polymers accessed the binding pocket of PAFR through the same interhelix channel as PAF implying similar interactions with PAFR. The MD-simulation showed the polymers were very stable in the binding pocket and that the polymer averaged between 2 and 6 hydrogen bonds with PAFR showing the docking poses were realistic in a dynamic environment. The PMF values from the steered MD-simulation showed no correlation between MW and binding energy, but a correlation was observed between the distances of the phosphorus and nitrogen atoms of pMPC and PAF, and the corresponding pMPC PMF value. Thus, the distance between the phosphorous and nitrogen atoms of PAF and pMPC is a valid metric for estimating the strength of the binding energy. Random co-polymers of methyl methacrylate and MPC were created to space out the MPC units to decrease steric hindrances. Slight increases in binding energy phosphorus and choline atoms were recorded indicating higher binding energies. viii This work illustrates the utility of MD-simulations to quickly iterate and optimize the polymer chemistry for receptor interactions and sets the foundation for future optimization of pMPC PAFR interactions for more effective drug carriers.
description: Overall, this work focused on understanding the interactions pMPC has with biological fluids and cells using multiple platforms. The ability of pMPC to resist protein adsorption and target PAFR makes this system useful for drug delivery applications. With PAFR being overexpressed in diseases such as lung cancer, respiratory infections, and chronic obstructive pulmonary disease, pMPC-coated drug carriers are a viable option for targeting these disease states and localizing therapeutics to increase efficacy. Beyond pMPC, using bacteria-inspired design is a promising avenue for future drug delivery design to generate treatments for other diseases.