Prolonged delivery of HIV-1 vaccine nanoparticles from hydrogels.

Immunization is a straightforward concept but remains for some pathogens like HIV-1 a challenge. Thus, new approaches towards increasing the efficacy of vaccines are required to turn the tide. There is increasing evidence that antigen exposure over several days to weeks induces a much stronger and more sustained immune response compared to traditional bolus injection, which usually leads to antigen elimination from the body within a couple of days.

A shift of paradigm: From avoiding nanoparticular complement activation in the field of nanomedicines to its exploitation in the context of vaccine development.

The complement system plays a central role in our innate immunity to fight pathogenic microorganisms, foreign and altered cells, or any modified molecule. Consequences of complement activation include cell lysis, release of histamines, and opsonization of foreign structures in preparation for phagocytosis. Because nanoparticles interact with the immune system in various ways and can massively activate the complement system due to their virus-mimetic size and foreign texture, detrimental side effects have been described after administration like pro-inflammatory responses, inflammation, mild to severe anaphylactic crisis and potentially complement activated-related pseudoallergy (CARPA).

Immunogenicity of a silica nanoparticle-based SARS-CoV-2 vaccine in mice.

Safe and effective vaccines have been regarded early on as critical in combating the COVID-19 pandemic. Among the deployed vaccine platforms, subunit vaccines have a particularly good safety profile but may suffer from a lower immunogenicity compared to mRNA based or viral vector vaccines. In fact, this phenomenon has also been observed for SARS-CoV-2 subunit vaccines comprising the receptor-binding domain (RBD) of the spike (S) protein.

Encapsulation of Pioglitazone into Polymer-Nanoparticles for Potential Treatment of Atherosclerotic Diseases.

Atherosclerosis is one of the most urgent global health subjects, causes millions of deaths worldwide, and is associated with enormous healthcare costs. Macrophages are the root cause for inflammatory onset and progression of the disease but are not addressed by conventional therapy. Therefore, we used pioglitazone, which is a drug initially used for diabetes therapies, but at the same time has great potential regarding the mitigation of inflammation.

Injectable Anhydrous Poly(ethylene glycol) Polymer Liquids Form Protein Depot for Extended Controlled Release Applications Via Rapid In Situ Gelation.

Water-free preparation of protein delivery systems has the potential to overcome the limitations of hydrogel depot systems such as off-target reactions, functional group hydrolysis, and limited loading capacity. However, a major roadblock in the development and use of these systems is administration as implantation is often required. In this study, we developed a biodegradable and water-free injectable protein delivery system via inverse electron demand Diels-Alder reaction between norbornene- and tetrazine-functionalized four-armed poly(ethylene glycol) macromonomers.

Multivalent display of engineered HIV-1 envelope trimers on silica nanoparticles for targeting and in vitro activation of germline VRC01 B cells.

Selective targeting of germline B cells with specifically designed germline-targeting HIV-1 envelope immunogens (GT-Env) is considered a feasible vaccination strategy to elicit broadly neutralizing antibodies (bnAbs). BnAbs are extremely valuable because they neutralize genetically distant viral strains at the same time. To overcome its inherently low affinity to germline B cells, the aim of the study was to present GT-Env via different immobilization strategies densely arrayed on the surface of nanoparticles.

Angiopoietin-1 Mimetic Nanoparticles for Restoring the Function of Endothelial Cells as Potential Therapeutic for Glaucoma.

A root cause for the development and progression of primary open-angle glaucoma might be the loss of the Schlemm's canal (SC) cell function due to an impaired Angiopoietin-1 (Angpt-1)/Tie2 signaling. Current therapeutic options fail to restore the SC cell function. We propose Angpt-1 mimetic nanoparticles (NPs) that are intended to bind in a multivalent manner to the Tie2 receptor for successful receptor activation.

Augmenting the Immune Response against a Stabilized HIV-1 Clade C Envelope Trimer by Silica Nanoparticle Delivery.

The delivery of HIV-1 envelope (Env) trimer-based immunogens on the surface of nanoparticles holds promise to promote immunogenicity with the aim of inducing a potent, durable and broad neutralizing antibody (bnAb) response. Towards that goal, we examined the covalent conjugation of Env to 100 nm and 200 nm silica nanoparticles (SiNPs) to optimize conjugation density and attachment stability. Env was redesigned to enable site-specific cysteine-mediated covalent conjugation while maintaining its structural integrity and antigenicity.

Distribution of Gold Nanoparticles in the Anterior Chamber of the Eye after Intracameral Injection for Glaucoma Therapy.

In glaucoma therapy, nanoparticles (NPs) are a favorable tool for delivering drugs to the outflow tissues of the anterior chamber of the eye where disease development and progression take place. In this context, a prerequisite is an efficient enrichment of NPs in the trabecular meshwork with minimal accumulation in off-target tissues such as the cornea, lens, iris and ciliary body. We evaluated the optimal size for targeting the trabecular meshwork by using gold NPs of 5, 60, 80 and 120 nm with a bare surface (AuNPs) or coated with hyaluronic acid (HA-AuNPs).

Atherosclerosis: Conventional intake of cardiovascular drugs versus delivery using nanotechnology - A new chance for causative therapy?

Atherosclerosis is the leading cause of death in developed countries. The pathogenetic mechanism relies on a macrophage-based immune reaction to low density lipoprotein (LDL) deposition in blood vessels with dysfunctional endothelia. Thus, atherosclerosis is defined as a chronic inflammatory disease.

Silica particles incorporated into PLGA-based in situ-forming implants exploit the dual advantage of sustained release and particulate delivery.

Poly (lactic-co-glycolic acid) (PLGA) in situ-forming implants are well-established drug delivery systems for controlled drug release over weeks up to months. To prevent initial burst release, which is still a major issue associated with PLGA-based implants, drugs attached to particulate carriers have been encapsulated. Unfortunately, former studies only investigated the resulting release of the soluble drugs and hence missed the potential offered by particulate drug release.

Considerations for efficient surface functionalization of nanoparticles with a high molecular weight protein as targeting ligand.

Functionalization of nanoparticles with ligands is a powerful tool to achieve efficient targeting of receptors expressed on specific cell types. For optimal ligand-receptor interactions, the ligands should be attached on the nanoparticle surface in a predictable manner with specific orientations and density that preserve their bioactivity. While there are many publications on nanoparticles functionalized with small ligands that meet these requirements, achieving these conditions is particularly challenging for protein-based ligands of higher molecular weight.

Fasudil Loaded PLGA Microspheres as Potential Intravitreal Depot Formulation for Glaucoma Therapy.

Rho-associated protein kinase (ROCK) inhibitors allow for causative glaucoma therapy. Unfortunately, topically applied ROCK inhibitors suffer from high incidence of hyperemia and low intraocular bioavailability. Therefore, we propose the use of poly (lactide-co-glycolide) (PLGA) microspheres as a depot formulation for intravitreal injection to supply outflow tissues with the ROCK inhibitor fasudil over a prolonged time.

Critical design criteria for engineering a nanoparticulate HIV-1 vaccine.

Inducing a long-lasting as well as broad and potent immune response by generating broadly neutralizing antibodies is a major goal and at the same time the main challenge of preventive HIV-1 vaccine design. Immunization with soluble, stabilized and native-like envelope (Env) glycoprotein so far only led to low neutralization breadth and displayed low immunogenicity. A promising approach to generate a potent immune response is the presentation of Env on the surface of nanoparticles.

Presentation of HIV-1 Envelope Trimers on the Surface of Silica Nanoparticles.

Inducing immune responses protecting from HIV infection or at least controlling replication poses a huge challenge to modern vaccinology. An increasingly discussed strategy to elicit a potent and broad neutralizing antibody response is the immobilization of HIV's trimeric envelope (Env) surface receptor on a nanoparticulate carrier. As a conceptual proof, we attached an Env variant (BG505 SOSIP.

Causative glaucoma treatment: promising targets and delivery systems.

Glaucoma is one of the most common causes of blindness worldwide. Elevated intraocular pressure (IOP) is the major modifiable risk factor of the disease. Conventional therapy suffers from poor compliance, low bioavailability, and the lack of causative treatment options.

Layer-by-Layer Assembled Nanoparticles for siRNA Delivery.

Nanoparticles synthesized via layer-by-layer processes are promising candidates for successful drug and gene delivery. Widespread use of the layer-by-layer technique has resulted from its accessibility to every lab; to generate nanoscale structures, layer-by-layer processes require common lab equipment of only modest quality and do not involve the use of organic solvents. In addition, a wide range of different starting materials can be flexibly combined, enabling the production of a nearly unlimited number of different nanoparticles (NP) with various physicochemical properties.

Intracameral Delivery of Layer-by-Layer Coated siRNA Nanoparticles for Glaucoma Therapy.

Glaucoma is the second leading cause of blindness worldwide, often associated with elevated intraocular pressure. Connective tissue growth factor (CTGF) is a mediator of pathological effects in the trabecular meshwork (TM) and Schlemm's canal (SC). A novel, causative therapeutic concept which involves the intracameral delivery of small interfering RNA against CTGF is proposed.

Preventing Obstructions of Nanosized Drug Delivery Systems by the Extracellular Matrix.

Although nanosized drug delivery systems are promising tools for the treatment of severe diseases, the extracellular matrix (ECM) constitutes a major obstacle that endangers therapeutic success. Mobility of diffusing species is restricted not only by small pore size (down to as low as 3 nm) but also by electrostatic interactions with the network. This article evaluates commonly used in vitro models of ECM, analytical methods, and particle types with respect to their similarity to native conditions in the target tissue.

Hyaluronan as a promising excipient for ocular drug delivery.

Hyaluronan (HA) is a naturally occurring polysaccharide and well known for its exceptional properties such as high biocompatibility and biodegradability, along with a low immunogenicity. Besides its use for various biomedical applications it recently came into focus as a favorable excipient for the formulation of various ocular therapeutics. This review article summarizes the ocular distribution of HA and its most heavily investigated binding protein "cluster of differentiation 44" (CD44) which is the rationale for the clinical use of HA, primarily as an additive in ocular applications ranging from eye drops to contact lenses.

Influence of PEGylation on nanoparticle mobility in different models of the extracellular matrix.

Nanoparticle transport inside the extracellular matrix (ECM) is a crucial factor affecting the therapeutic success. In this work, two in vitro ECM models - a neutrally charged collagen I network with an effective pore size of 0.47μm and Matrigel, a basement membrane matrix with strong negative charge and effective pore size of 0.

Multivalent nanoparticles bind the retinal and choroidal vasculature.

The angiotensin II receptor type 1 (AT1R), which is expressed in blood vessels of the posterior eye, is of paramount significance in the pathogenesis of severe ocular diseases such as diabetic retinopathy and age-related macular degeneration. However, small molecule angiotensin receptor blockers (ARBs) have not proven to be a significant therapeutic success. We report here on a nanoparticle system consisting of ARB molecules presented in a multivalent fashion on the surface of quantum dots (Qdots).

Oligolayer-coated nanoparticles: impact of surface topography at the nanobio interface.

Layer-by-layer coating of nanoparticles with a layer number in the single-digit range has gained increasing attention in the field of nanomedicinal research. However, the impact of using various polyelectrolytes on oligolayer formation and, more importantly, their influence on the interaction with the biological system has not often been considered in the past. Hence, we investigated the polyelectrolyte deposition profiles and resulting surface topographies of up to three polyelectrolyte layers on a flat gold sensor surface using three different polycations, namely, poly(ethylene imine) (PEI), poly(allylamine hydrochloride) (PAH), and poly(diallylammonium chloride) (PD), each in combination with poly(styrenesulfonate) (PSS).

Nanoparticle multivalency counterbalances the ligand affinity loss upon PEGylation.

The conjugation of receptor ligands to shielded nanoparticles is a widely used strategy to precisely control nanoparticle-cell interactions. However, it is often overlooked that a ligand's affinity can be severely impaired by its attachment to the polyethylene glycol (PEG) chains that are frequently used to protect colloids from serum protein adsorption. Using the model ligand EXP3174, a small-molecule antagonist for the angiotensin II receptor type 1 (AT1R), we investigated the ligand's affinity before and after its PEGylation and when attached to PEGylated nanoparticles.

Monitoring the degradation of reduction-sensitive gene carriers with fluorescence spectroscopy and flow cytometry.

Polycations like poly(ethylene imine) (PEI) or poly(L-lysine) (pLL) form nanometer-sized complexes with nucleic acids (polyplexes) which can be used for gene delivery. It is known that the properties of these -carriers can be greatly improved by introducing disulfide bridges on the polymers, thus making them reduction sensitive. However, little is known about how such modified carriers behave intracellularly.