The Effect of Surface Modification of PLGA Drug Carriers on Vascular Wall Adhesion and Plasma Protein Corona for Improved Vascular Targeting
Creators: name: Lopez, Genesis
Publisher: name: My University
Year: 2022
Subjects: subject: surface modification
subject: PLGA
subject: chitosan
subject: albumin
subject: vascular targeted drug delivery
subject: Chemical Engineering
subject: FOS: Chemical engineering
subject: Engineering

description: Vascular-targeted drug delivery requires the successful localization and adhesion of drug carriers to diseased sites via biomarkers, such as inflammation. Poly (lactic-co-glycolic acid) (PLGA), a negatively charged copolymer, is one of the most appealing biodegradable materials because of its biocompatibility and FDA approval. Unfortunately, the adhesion of targeted PLGA to an inflamed endothelium is reduced in the presence of plasma proteins acquired in human blood. Hydrophobic and strongly charged surfaces typically adsorb more protein than hydrophilic or neutrally charged surfaces. The addition of polyethylene glycol (PEG) chains to particle surfaces is a commonly used approach to mitigate protein adsorption. However, past work also saw a reduction in adhesion for PEGylated PLGA in human plasma conditions creating a need for alternative coatings. In this dissertation, we explored coating PLGA with chitosan (CS), glycol chitosan (GC), human serum albumin (HSA), and CS plus HSA to evaluate their effect on vascular targeting. PLGA microparticles (MPs) were mainly used since they have shown enhanced binding over nanoparticles (NPs). Sialyl Lewis A (sLeA) and anti-ICAM antibodies were conjugated onto particles to target E-selectin and ICAM-1 expressed by inflamed endothelial cells (ECs), serving as a model system for vascular adhesion. Adhesion of targeted particles to inflamed ECs was evaluated in vitro using a parallel plate flow chamber assay. The binding of particles in red blood cells (RBC) in plasma was normalized to their binding RBC-in-flow buffer depicted as adhesion efficiency. Additionally, the adhesion of PLGA NPs modified with optimized coatings, HSA and HSA-CS, was evaluated to determine the impact of size. The adhesion efficiency of bare PLGA was consistently below 20%, while coated PLGA produced different levels of adhesion in plasma. The adhesion efficiency of targeted CSPLGA MPs showed no improvement over PLGA MPs. Conversely, sLeA GCPLGA MPs maintained an adhesion efficiency of 80% independent of shear rate. Additionally, sLeA HSA-PLGA and HSA-CSPLGA MPs showed significant improvement in adhesion in plasma conditions. sLeA HSA-CSPLGA had a max adhesion efficiency of 80%, which was dependent on ligand density and shear rate. Lastly, we discovered that sLeA HSA-PLGA NPs also saw an adhesion efficiency of 40%. Interestingly, sLeA HSA-CSPLGA NPs did not show improved adhesion, which suggests that changes in size affect adhesion of coated PLGA . To better understand the impact of different coatings, we characterized association to ECs and protein corona composition. GCPLGA MPs had increased association to ECs and changes in protein corona composition, mainly a decrease in large molecular weight proteins, potentially driving its enhanced adhesion. HSA-PLGA MPs did not associate with ECs in plasma, while HSA-CSPLGA showed an increase in EC association likely due to the higher amount HSA. Protein corona characterization of HSA coated MPs showed increases in 75 and 150 kDa proteins, which could correlate to histidine-rich glycoprotein (HRG) and immunoglobulin G. The enhanced adhesion of HSA coated MPs is likely driven by multiple interactions with HSA-specific receptors and HRG receptor found on ECs. Interestingly, the use of different anticoagulants led to differences in protein adsorption and impacted particle adhesion efficiencies. This work suggests that coating PLGA with favorable proteins enhances adhesion over non-fouling coatings. Overall, we found that surface modification via HSA, HSA plus CS, and GC onto PLGA MPs positively influenced particle binding and emphasized the importance of understanding protein-particle interactions.