Surface Engineered Polymersomes for Enhanced Modulation of Dendritic Cells During Cardiovascular Immunotherapy

Abstract

The principle cause of cardiovascular disease (CVD) is atherosclerosis, a chronic inflammatory condition characterized by immunologically complex fatty lesions within the intima of arterial vessel walls. Dendritic cells (DCs) are key regulators of atherosclerotic inflammation, with mature DCs generating pro-inflammatory signals within vascular lesions and tolerogenic DCs eliciting atheroprotective cytokine profiles and regulatory T-cell (Treg) activation. Here, the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)-bpoly(propylene sulfide) copolymers to enhance the targeted modulation of DCs by transporting the anti-inflammatory agent 1,25-dihydroxyvitamin D3-(aVD) and ApoB-100-derived antigenic peptide P210 are engineered. Polymersomes decorated with an optimized surface display and density for a lipid construct of the P-D2 peptide, which binds CD11c on the DC surface, significantly enhance the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro. Weekly lowdose intravenous administration of DC-targeted, aVD-loaded polymersomes significantly inhibit atherosclerotic lesion development in high-fat-diet-fed ApoE −/− mice. The results validate the key role of DC immunomodulation during aVD-dependent inhibition of atherosclerosis and demonstrate the therapeutic enhancement and dosage lowering capability of cell-targeted nanotherapy in the treatment of CVD.

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

“…These results are consistent with our previous findings that neither Latrun culin A loading nor incorporation of targeting peptide via lipid anchoring alter the size or structure of micelles. [8,11] tLatAMC demonstrated significantly greater uptake by SC cells and cell softening compared to nontargeted micelles in vitro. To evaluate the targeting efficacy of the FLT4 binding pep tide, we examined the uptake of micelles.…”

“…Nanomaterials have been shown to be advantageous drug delivery platforms that are wellsuited for targeting specific cells and tissues. [8,9] Enhanced targeting and cell specificity allows for less offtarget drug delivery and a lower potential for side effects. [10] Targeted nanomaterials have been shown to lower the therapeutic threshold concentration for cer tain drugs after encapsulation as well as reduce cytotoxicity and other unwanted effects in many cell types including SC cells.…”

“…[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. Here, we report on the design and development of a PEG-b-PPS controlled delivery system to deliver latrunculin A to SC cells.…”

Co-administration of macropinocytosis inhibitory nanoparticles (MiNP) for enhanced nanoparticle circulation time and target tissue accumulation following subcutaneous injection

“…The resulting FA-PEG-PA construct was incorporated into micelles by shaking overnight in phosphate buffered saline, allowing the palmitoleic acid anchor to partition into the hydrophobic PPS core of the micelle. We have previously demonstrated that such lipid anchored constructs could be stably retained within self-assembled PEG-b-PPS nanoparticles for controlled surface display of targeting moieties, such as peptides [32] . The formation of folate displaying micelles (E-MC(FA)) at controllable molar ratios of PEG-b-PPS polymer to FA-PEG-PA construct was confirmed using UV-Vis spectroscopy ( Figure S2).…”

High Density Display of an Anti-Angiogenic Peptide on Micelle Surfaces Enhances Their Inhibition of αvβ3 Integrin-Mediated Neovascularization In Vitro

“…Recently, Stack et al employed PEG-b-PPS micelles for targeted intracellular delivery of latrunculin A as a treatment for glaucoma [45]. Furthermore, Yi et al demonstrated that lipidated peptides could be stably incorporated into PEG-b-PPS nanocarriers for in vivo applications and that the surface density of these peptides could be optimized using in vitro cell culture systems for enhanced binding to specific cell membrane receptors [46]. In this study, we present PEG-b-PPS micelles decorated with anti-angiogenic peptide (aANG-peptide) lipid constructs to modulate and study inhibition of α v β 3 mediated neovascularization on endothelial cells.…”