An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis

Abstract

Chronic unresolved vascular inflammation is a critical factor in the development of atherosclerosis. Cardiovascular immunotherapy has therefore become a recent focus for treatment, with the objective to develop approaches that can suppress excessive inflammatory responses by modulating specific immune cell populations. A benefit of such immunomodulatory strategies is that low dosage stimulation of key immune cell populations, like antigen presenting cells, can subsequently propagate strong proliferation and therapeutic responses from effector cells. We have previously demonstrated that intravenous injections of anti-inflammatory nanocarriers provided atheroprotection that was mediated by regulatory T cells (Tregs) upregulated in lymphoid organs and atherosclerotic lesions. Here, we demonstrate an injectable filamentous hydrogel depot (FM-depot) engineered for low dosage, sustained delivery of anti-inflammatory nanocarriers. The bioactive form of vitamin D (aVD; 1, 25-Dihydroxyvitamin D3), which inhibits pro-inflammatory transcription factor NF-κB via the intracellular nuclear hormone receptor vitamin D receptor (VDR), was stably loaded into poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) filomicelles. These aVD-loaded filaments underwent morphological transitions to release monodisperse drug-loaded micelles upon oxidation. This cylinder-to-micelle transition was characterized in vitro by cryogenic transmission electron microscopy (CryoTEM) and small angle X-ray scattering (SAXS). Following crosslinking with multi-arm PEG for in situ gelation, aVD-loaded FM-depots maintained high levels of Foxp3 + Tregs in both lymphoid organs and atherosclerotic lesions for weeks following a single subcutaneous injection into ApoE −/− mice. FM-depots therefore present a customizable delivery platform to both develop and test nanomedicine-based approaches for anti-inflammatory cardiovascular immunotherapy.

Nanocarrier-enhanced intracellular delivery of benznidazole for treatment of Trypanosoma cruzi infection

“…The size distribution and zeta potential of PS and BNZ-PS (1 mg/mL) were characterized by Zetasizer Nano-ZS using a 4 mW He-Ne 633 laser (Malvern Instruments). The morphology of PS and BNZ-PS was determined by cryo–transmission electron microscopy as described previously ( 55 ). In brief, 200 mesh Cu grids with a lacey carbon membrane (catalog LC200-CU-100, EMS) were glow discharged in a Pelco easiGlow glow discharger (Ted Pella Inc.) using an atmosphere plasma generated at 15 mA for 15 seconds with a pressure of 0.24 mbar.…”

Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma

“…Selfassembled poly (ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) block copolymers have been used as versatile nanocarriers in a wide range of applications. [12,[17][18][19][20][21][22][23] Depending on the morphology employed, PEG-b-PPS nanocarriers can retain both hydrophobic and hydrophilic payloads, respectively, in their cores or aqueous interior compartments [20,21,[24][25][26] and are highly customizable through control of charge, size, and targeting moieties on their surfaces. [8,27] Nanomaterials provide a wide range of options for sustained drug and gene delivery, [19,22,28] and the development of SC targeted nanocarriers will thus provide versatile options for the long term delivery of glaucoma therapeutics following a single intracameral injection.…”

Inflammation-responsive delivery systems for the treatment of chronic inflammatory diseases

“…It was demonstrated that such nanomedicine could effectively accumulate in the inflamed joints and subsequently alleviate major RA-related symptoms including synovial inflammation, bone erosion, and cartilage degradation. Analogously, Scott group explored anti-inflammatory potentials of PPS-based nanovehicles with distinct morphologies (i.e., spherical micelles; filamentous worm-like micelles, filomicelles; polymeric vesicles, polymersomes) against atherosclerosis [ 57 – 60 ]. Notably, morphology-dependent organ and cellular level biodistributions of nanocarriers assembled from PEG- b -PPS BCPs with identical surface chemistries were disclosed [ 57 ].…”