0000000000154163
AUTHOR
David Paßlick
Delivering all in one: Antigen-nanocapsule loaded with dual adjuvant yields superadditive effects by DC-directed T cell stimulation
Therapeutic vaccination is and remains a major challenge, particularly in cancer treatment. In this process, the effective activation of dendritic cells by a combination of distinctly acting adjuvants and an antigen is crucial for success. While most common vaccine formulations lack the efficiency to trigger sufficient T cell responses in a therapeutic tumor treatment, nanovaccines offer unique properties to tackle that challenge. Here, we report the stepwise development of a nanocapsule for vaccination approaches, comprising a shell consisting of antigen and loaded with a superadditive adjuvant combination. In a first initial step, we identified the combination of resiquimod (R848) and mur…
Fully degradable protein nanocarriers by orthogonal photoclick tetrazole-ene chemistry for the encapsulation and release
The encapsulation of sensitive drugs into nanocarriers retaining their bioactivity and achieving selective release is a challenging topic in current drug delivery design. Established protocols rely on metal-catalyzed or unspecific reactions to build the (mostly synthetic) vehicles which may inhibit the drug's function. Triggered by light, the mild tetrazole–ene cycloaddition enables us to prepare protein nanocarriers (PNCs) preserving at the same time the bioactivity of the sensitive antitumor and antiviral cargo Resiquimod (R848). This catalyst-free reaction was designed to take place at the interface of aqueous nanodroplets in miniemulsion to produce core–shell PNCs with over 90% encapsul…
Brush Conformation of Polyethylene Glycol Determines the Stealth Effect of Nanocarriers in the Low Protein Adsorption Regime
For nanocarriers with low protein affinity, we show that the interaction of nanocarriers with cells is mainly affected by the density, the molecular weight, and the conformation of polyethylene glycol (PEG) chains bound to the nanocarrier surface. We achieve a reduction of nonspecific uptake of ovalbumin nanocarriers by dendritic cells using densely packed PEG chains with a "brush" conformation instead of the collapsed "mushroom" conformation. We also control to a minor extent the dysopsonin adsorption by tailoring the conformation of attached PEG on the nanocarriers. The brush conformation of PEG leads to a stealth behavior of the nanocarriers with inhibited uptake by phagocytic cells, whi…
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 …