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Ellipsoidal Polyaspartamide Polymersomes with Enhanced Cell-Targeting Ability.

ABSTRACT: Nano-sized polymersomes functionalized with peptides or proteins are being increasingly studied for targeted delivery of diagnostic and therapeutic molecules. Earlier computational studies have suggested that ellipsoidal nanoparticles, compared to spherical ones, display enhanced binding efficiency with target cells, but this has not yet been experimentally validated. We hypothesize that hydrophilic polymer chains coupled to vesicle-forming polymers would result in ellipsoidal polymersomes. In addition, ellipsoidal polymersomes modified with cell adhesion peptides bind with target cells more actively than spherical ones. We examine this hypothesis by substituting polyaspartamide with octadecyl chains and varying numbers of poly(ethylene glycol) (PEG) chains. Increasing the degree of substitution of PEG from 0.5 to 1.0 mol% drives the polymer to self-assemble into an ellipsoidal polymersome with an aspect ratio of 2.1. Further modification of these ellipsoidal polymersomes with peptides containing an Arg-Gly-Asp sequence (RGD peptides) lead to a significant increase in the rate of association and decrease in the rate of dissociation with a substrate coated with ?v?3 integrins. In addition, in a circulation-mimicking flow, the ellipsoidal polymersomes linked with RGD peptides adhere to target tissues more favorably than their spherical equivalents do. Overall, the results of this study will greatly serve to improve the efficiency of targeted delivery of a wide array of polymersomes loaded with various biomedical modalities.

SUBMITTER: Lai MH

PROVIDER: S-EPMC3749081 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Ellipsoidal Polyaspartamide Polymersomes with Enhanced Cell-Targeting Ability.

Lai Mei-Hsiu MH Jeong Jae Hyun JH Devolder Ross J RJ Brockman Christopher C Schroeder Charles C Kong Hyunjoon H

Advanced functional materials 20120801 15

Nano-sized polymersomes functionalized with peptides or proteins are being increasingly studied for targeted delivery of diagnostic and therapeutic molecules. Earlier computational studies have suggested that ellipsoidal nanoparticles, compared to spherical ones, display enhanced binding efficiency with target cells, but this has not yet been experimentally validated. We hypothesize that hydrophilic polymer chains coupled to vesicle-forming polymers would result in ellipsoidal polymersomes. In a ...[more]

PMID: 23976892

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Project description: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, we engineered the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)-b-poly(propylene sulfide) copolymers to selectively target and modulate DCs by transporting the anti-inflammatory agent 1, 25-Dihydroxyvitamin D3 (aVD) and ApoB-100 derived antigenic peptide P210. 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 enhanced the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro. Intravenous administration of the optimized polymersomes achieved selective targeting of DCs in atheroma and spleen compared to all other cell populations, including both immune and CD45- cells, and locally increased the presence of tolerogenic DCs and cytokines. aVD-loaded polymersomes significantly inhibited atherosclerotic lesion development in high fat diet-fed ApoE-/- mice following 8 weeks of administration. Incorporation of the P210 peptide generated the largest reductions in vascular lesion area (~33%, p<0.001), macrophage content (~55%, p<0.001), and vascular stiffness (4.8-fold). These results correlated with an ~6.5-fold increase in levels of Foxp3+ regulatory T cells within atherosclerotic lesions. Our 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.

Dataset Information

Ellipsoidal Polyaspartamide Polymersomes with Enhanced Cell-Targeting Ability.

Publications

Ellipsoidal Polyaspartamide Polymersomes with Enhanced Cell-Targeting Ability.

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