Biology subjects

Karabin, N. B.

Publications and source records attributed to Karabin, N. B..

3 recordsLinked to original sources

bioRxiv2021

Targeted Delivery of Chloroquine to Plasmacytoid Dendritic Cells Enhances Inhibition of the Type I Interferon Response

Systemic lupus erythematosus (SLE) causes damaging inflammation in multiple organs via the accumulation of immune complexes. These complexes activate plasmacytoid DCs (pDCs) via TLR7 and TLR9, contributing to disease pathogenesis by driving secretion of inflammatory type I IFNs. Antimalarial drugs, such as chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE. However, they require ~3 months of continuous use before achieving therapeutic efficacy and can accumulate in the retinal pigment epithelium with chronic use resulting in retinopathy. We hypothesized that poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) filamentous nanocarriers, filomicelles (FMs) could improve drug activity and reduce toxicity by directly delivering CQ to pDCs via passive, morphology-based targeting. Healthy human PBMCs were treated with soluble CQ or CQ-loaded FMs, stimulated with TLR agonists or SLE patient sera, and type I IFN secretion was quantified via multi-subtype IFN- ELISA and MX1 gene expression using real-time RT-qPCR. Our results showed that 50 {micro}g CQ/mg FM decreased MX1 expression and IFN- production after TLR activation with either synthetic nucleic acid agonists or immune complex rich sera from SLE patients. Cellular uptake and biodistribution studies showed that FMs preferentially accumulate in human pDCs in vitro and in tissues frequently damaged in SLE patients (i.e., liver and kidneys) while sparing the eye in vivo. These results showed that nanocarrier morphology enables drug delivery, and CQ-FMs may be equally effective and more targeted than soluble CQ at inhibiting SLE-relevant pathways.

bioengineering↗

bioRxiv2020

The Combination of Morphology and Surface Chemistry Defines the Biological Identity of Nanocarriers in Human Blood

Following intravenous administration, an adsorbed corona of blood proteins immediately forms on the surfaces of nanocarriers to confer a distinct biological identity that dictates interactions with the immune system. While the nanocarrier surface chemistry has long been the focus of protein corona formation, the influence of the nanocarrier structure has remained unclear despite well-documented influences on biodistribution, clearance and inflammation. Here, we present design rules for the combined engineering of both nanocarrier structure and surface chemistry derived from a comprehensive proteomic analysis of protein corona formation in human blood. A library of nine soft PEGylated nanocarriers that differ in their combination of morphology (spheres, vesicles, and cylinders) and surface chemistry (methoxy, hydroxyl, and phosphate) were synthesized to represent properties of commonly employed drug delivery vehicles. Using label-free proteomics and high-throughput techniques, we examined the relationship between physicochemical properties and the resulting nanocarrier biological identity, including dynamic changes in protein corona composition, differential immunostimulation and uptake by relevant immune cell populations. In human blood, non-polar spherical micelles developed a similar biological identity to polar vesicles, whereas the identities of polar spheres and cylinders resembled that of non-polar vesicles. The formed protein coronas were compositionally dynamic and morphology-dependent, and these time-dependent fingerprints altered nanocarrier complement activation as well as their uptake by human monocytes, macrophages, and dendritic cells. This comprehensive analysis provides mechanistic insights into rational design choices that impact nanocarrier fate in human blood. One Sentence SummaryWe demonstrate that not only the surface chemistry, but the combined chemical and structural properties of soft drug delivery vehicles impact the composition of blood proteins that adsorb to their surfaces, and these differences specify their interactions with and modulation of human immune cells.

bioengineering↗

bioRxiv2020

Surface chemistry-mediated modulation of adsorbed albumin folding state specifies nanocarrier clearance by distinct macrophage subsets

Controlling nanocarrier interactions with the immune system requires a thorough understanding of the surface properties that modulate protein adsorption in biological fluids, since the resulting protein corona redefines cellular interactions with nanocarrier surfaces. Albumin is initially the dominant protein to adsorb to nanobiomaterial surfaces, a process that is considered benign or beneficial by minimizing opsonization or inflammation. Here, we demonstrate the surface chemistry of a model self-assembled nanocarrier can be engineered to stabilize or denature the three-dimensional conformation of adsorbed albumin, which respectively promotes evasion or non-specific clearance in vivo. Interestingly, certain common chemistries that have long been considered to convey stealth properties were found to promote albumin recognition by macrophage class A1 scavenger receptors (SR-A1), providing a means for their eventual removal from systemic circulation. We establish that the surface chemistry of nanocarriers can be specified to modulate adsorbed albumin structure and thereby tune clearance by macrophage scavenger receptors.

bioengineering↗