Monophosphoryl lipid A coating of hydroxyethyl starch nanocapsules drastically increases uptake and maturation by dendritic cells while minimizing the adjuvant dosage.

Enhancing delivery of antigens to dendritic cells (DCs) is essential for the induction of vigorous antigen-specific cellular immune responses. Aim of the present study was to evaluate the properties of hydroxyethyl starch nanocapsules (HES-NCs) functionalized with anti-CD40, anti-DEC205, interferon-γ (IFNγ) and/or monophosphoryl lipid A (MPLA) with respect to the overall uptake, the released cytokine profile, and the influence on phenotypic maturation of human monocyte-derived DCs using flow cytometry, confocal microscopy and enzyme-linked immunosorbent assays. NC uptake by DCs was significantly enhanced by functionalizing NCs with anti-CD40 or MPLA. With respect to the cytokine profile and…

Novel strategies in vaccine design: can nanocapsules help prevent and treat hepatitis B?

Nanocapsules generated out of a polymeric dexamethasone shell suppress the inflammatory response of liver macrophages.

Abstract Dexamethasone (DXM) is a synthetic glucocorticoid with anti-inflammatory properties. Targeted delivery of dexamethasone to inflammatory cells, e.g. macrophages and Kupffer cells represents a promising approach to minimize side effects. The aim of the present study was to induce a targeted transport of novel DXM-based biodegradable nanocapsules to phagocytic cells. Nanocapsules (NCs) consisting of a hydroxyethylated glucose polymer (hydroxyethyl starch, HES) shell with encapsulated DXM and NCs synthesized exclusively in inverse miniemulsion out of DXM were investigated. Non-parenchymal murine liver cells served as target cells. HES-DXM NCs were predominantly incorporated by Kupffer …

Achieving dendritic cell subset-specific targeting in vivo by site-directed conjugation of targeting antibodies to nanocarriers

AbstractThe major challenge of nanocarrier-based anti-cancer vaccination approaches is the targeted delivery of antigens and immunostimulatory agents to cells of interest, such as specific subtypes of dendritic cells (DCs), in order to induce robust antigen-specific anti-tumor responses. An undirected cell and body distribution of nanocarriers can lead to unwanted delivery to other immune cell types like macrophages reducing the vaccine efficacy. An often-used approach to overcome this issue is the surface functionalization of nanocarriers with targeting moieties, such as antibodies, mediating cell type-specific interaction. Numerous studies could successfully prove the targeting efficiency…

Biodegradable Protein Nanocontainers

The application of synthetic polymers for drug delivery often requires tremendous efforts to ensure biocompatibility and -degradation. To use the body's own substances can help to overcome these problems. Herein, we present the first synthesis of nanocontainers entirely composed of albumin proteins. These protein nanocontainers (PNCs) were loaded with hydrophilic compounds and release of the payload is triggered through natural lysis in vitro in human monocyte-derived dendritic cells (moDCs). No aggregation of PNCs in human blood plasma was observed, indicating stability for blood circulation. As the PNCs were readily taken up by moDCs, they are considered as a promising delivery platform f…

Polymeric hepatitis C virus non-structural protein 5A nanocapsules induce intrahepatic antigen-specific immune responses

Targeting antigen combined with adjuvants to hepatic antigen-presenting cells (APCs) is essential for the induction of intrahepatic T cellular immunity controlling and resolving viral infections of the liver. Intravenous injection of antigen-loaded nanoparticles is a promising approach for the delivery of antigens to liver APCs. Accordingly, polymeric nanocapsules (NCs) synthesized exclusively of hepatitis C virus non-structural protein 5A (NS5A) and the adjuvant monophosphoryl lipid A (MPLA) adsorbed to the nanocapsule surface were developed. Aim of the present study was the evaluation of the in vitro and in vivo behavior of MPLA-functionalized NS5A-NCs regarding the interaction with liver…

Encapsulation of polyprodrugs enables an efficient and controlled release of dexamethasone

Water-soluble low molecular weight drugs, such as the synthetic glucocorticoid dexamethasone (DXM), can easily leak out of nanocarriers after encapsulation due to their hydrophilic nature and small size. This can lead to a reduced therapeutic efficacy and therefore to unwanted adverse effects on healthy tissue. Targeting DXM to inflammatory cells of the liver like Kupffer cells or macrophages is a promising approach to minimize typical side effects. Therefore, a controlled transport to the cells of interest and selective on-site release is crucial. Aim of this study was the development of a DXM-phosphate-based polyprodrug and the encapsulation in silica nanocontainers (SiO2 NCs) for the red…

MPLA-coated hepatitis B virus surface antigen (HBsAg) nanocapsules induce vigorous T cell responses in cord blood derived human T cells.

Chronic hepatitis B virus (HBV) infection is the most prevalent serious liver infection in the world. A frequent route of infection represents mother-to-child transmission. Efficient control of HBV replication depends on antigen-specific cellular immune response mediated by dendritic cells (DCs). Aim of the present study was to evaluate optimized adjuvant combinations, efficiently maturing monocyte-derived neonatal and adult dendritic cells (moDCs). In addition, the potential of polymeric HBsAg-nanocapsules (HBsAg-NCs) was investigated regarding up-take by moDCs and the subsequent induction of specific T cell responses in a human co-culture model. Simultaneous stimulation of moDCs with MPLA…

Density of conjugated antibody determines the extent of Fc receptor dependent capture of nanoparticles by liver sinusoidal endothelial cells

Despite considerable progress in the design of multifunctionalized nanoparticles (NPs) that selectively target specific cell types, their systemic application often results in unwanted liver accumulation. The exact mechanisms for this general observation are still unclear. Here we asked whether the number of cell-targeting antibodies per NP determines the extent of NP liver accumulation and also addressed the mechanisms by which antibody-coated NPs are retained in the liver. We used polysarcosine-based peptobrushes (PBs), which in an unmodified form remain in the circulation for >24 h due to the absence of a protein corona formation and low unspecific cell binding, and conjugated them with …

Enhanced in vivo targeting of murine nonparenchymal liver cells with monophosphoryl lipid A functionalized microcapsules.

A broad spectrum of infectious liver diseases emphasizes the need of microparticles for targeted delivery of immunomodulatory substances to the liver. Microcapsules (MCs) are particularly attractive for innovative drug and vaccine formulations, enabling the combination of antigen, drugs, and adjuvants. The present study aimed to develop microcapsules characterized by an enhanced liver deposition and accelerated uptake by nonparenchymal liver cells (NPCs). Initially, two formulations of biodegradable microcapsules were synthesized from either hydroxyethyl starch (HES) or mannose. Notably, HES-MCs accumulated primarily in the liver, while mannose particles displayed a lung preference. Functio…

Controlling protein interactions in blood for effective liver immunosuppressive therapy by silica nanocapsules

Immunosuppression with glucocorticoids is a common treatment for autoimmune liver diseases and after liver transplant, which is however associated with severe side-effects. Targeted delivery of glucocorticoids to inflammatory cells, e.g. liver macrophages and Kupffer cells, is a promising approach for minimizing side effects. Herein, we prepare core–shell silica nanocapsules (SiO2 NCs) via a sol–gel process confined in nanodroplets for targeted delivery of dexamethasone (DXM) for liver immunosuppressive therapy. DXM with concentrations up to 100 mg mL−1 in olive oil are encapsulated while encapsulation efficiency remains over 95% after 15 days. Internalization of NCs by non-parenchymal muri…

Heparin-Based Nanocapsules as Potential Drug Delivery Systems

Herein, the synthesis and characterization of heparin-based nanocapsules (NCs) as potential drug delivery systems is described. For the synthesis of the heparin-based NCs, the versatile method of miniemulsion polymerization at the droplets interface was achieved resulting in narrowly distributed NCs with 180 nm in diameter. Scanning and transmission electron microscopy images showed clearly NC morphology. A highly negative charge density for the heparin-based NCs was determined by measuring the electro-kinetic potential. Measuring the activated clotting time demonstrated the biological intactness of the polymeric shell. The ability of heparin-based NCs to bind to antithrombin (AT III) was i…

Unraveling the In Vivo Protein Corona

Understanding the behavior of nanoparticles upon contact with a physiological environment is of urgent need in order to improve their properties for a successful therapeutic application. Most commonly, the interaction of nanoparticles with plasma proteins are studied under in vitro conditions. However, this has been shown to not reflect the complex situation after in vivo administration. Therefore, here we focused on the investigation of magnetic nanoparticles with blood proteins under in vivo conditions. Importantly, we observed a radically different proteome in vivo in comparison to the in vitro situation underlining the significance of in vivo protein corona studies. Next to this, we fou…