Engineering the "Nanocarrier Chassis" for Targeted Drug Delivery: Controllable Multiscale Interactions for Immunomodulation and Glaucoma TherapyPublic
Nanocarriers are drug delivery vehicles that have at least one dimension at the nanoscale (10-9 m). Engineering the nanocarrier surface is a strategy for targeting drug delivery to specific cell types to enhance efficacy and minimize side effects. A useful analogy is to consider how the chassis of an automotive vehicle is optimized where the shape and materials employed have direct implications on the utility. Similarly, the “nanocarrier chassis” must be engineered to transport cargo, remain stable in vivo, interact with desired molecular targets, and degrade within specific biochemical environments. We investigated surface engineering principles for directing these interactions in the blood and in the eye using model nanocarriers self-assembled from poly(ethylene glycol)-b-poly(propylene sulfide) diblock copolymers. Features of the adsorbed protein corona are established as molecular determinants of nanocarrier fate in human and murine blood. It is found that the composition of the protein corona is sensitive to nanocarrier morphology/shape, surface chemistry, and charge. Adsorbed protein fingerprints dictate the preferential uptake of nanocarriers by immune cells, as well as anaphylactic and pro-inflammatory cytokine responses. Standard and novel biomimetic surface chemistries were investigated and linked to innate immune cell clearance via class A1 scavenger receptors. Latrunculin-transporting nanocarriers were engineered to target Schlemm’s canal endothelial cells using the lymphatic marker FLT4. This cell softening glaucoma nanotherapy was optimized using lipid-anchored peptide ligands that differed in their accessibility to biochemical processes on the surfaces of PEGylated nanocarriers. These nanocarriers lowered cell stiffness in culture and lowered intraocular pressure in mice. FLT4-targeted nanocarriers did not significantly participate in off-target interactions with donated human cornea tissue. Lastly, powder formulations were developed that permit nanocarrier self-assembly upon hydration and are compatible with diverse targeting strategies. The design rules and formulation strategies described herein can be used to meet diverse challenges in drug delivery.
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