Self-assembled nanosheets of biocompatible polymers as universal cell-membrane mimic to block viral infection.

Viruses cause severe damage to society due to seasonal and pandemic outbreaks; therefore, developing new antivirals is urgently needed. Multivalent virus inhibitors are promising broad-spectrum antivirals, as they can block the initial step of viral infection by mimicking the structure of the cell receptors on the host cell membrane. Biocompatible supramolecular architectures are particularly well-suited for virus inhibition due to the numerous weak non-covalent bindings, resulting in strong yet dynamic multivalent interactions.

Bioactive Polysulfate-Based Nano-Assemblies Against Virus Infection.

3D nanosystems equipped with polysulfates as binding sites are effective virus inhibitors due to their ability to dynamically deform while adhering to a virus. Here, a new supramolecular nanosystem assembled from a block copolymer consisting of sulfated linear polyglycerol and polytrimethylene carbonate is presented. It exhibits a unique morphology, 100 nm sized spheres with a distinct brush-like corona.

Multivalent 2D- and 3D-nanogels as carbohydrate-lectin binders.

The development of synthetic glycoarchitectures for targeted bacterial adhesion represents a promising strategy in anti-adhesion therapy. This study presents the synthesis and characterization of two distinct mannosylated nanogel architectures. First, a spherical 3D-nanogel was prepared nanoprecipitation and functionalized with α-D-mannose units.

Modular Synthesis of Dendritic Oligo-Glycerol Cationic Surfactants for Enhanced Antibacterial Efficacy.

Bacterial infections and antibiotic resistance present an ever-increasing threat to human health worldwide, and medicine urgently needs new alternatives for the successful treatment of bacterial infections. Cationic surfactants have proven to be effective antibacterial agents due to their ability to disrupt bacterial membranes, inhibit biofilm formation, and combat a broad spectrum of pathogens. We employed a orthogonal click chemistry strategy for the efficient modular synthesis of six novel cationic surfactants.

Three-Dimensional Polyglycerol-PEG-Based Hydrogels as a Universal High-Sensitivity Platform for SPR Analysis.

We developed a three-dimensional (3D) polyglycerol-poly(ethylene glycol)-based hydrogel as a new biosensing matrix for affinity analysis by surface plasmon resonance to enable a high loading of ligands for small molecule analysis while lacking a carbohydrate structure to reduce nonspecific binding. The hydrogel was synthesized by cross-linking a polyglycerol functionalized with carboxylate and maleimide groups with a dithiolated poly(ethylene glycol) by thiol-click chemistry. We demonstrated that the hydrogel coating enabled a high immobilization capacity of biomolecules and led to less nonspecific binding.

Synthesis of Dendritic Oligo-Glycerol Amphiphiles with Different Hydrophobic Segments to Improve their Performance as Nanocarriers.

A new class of non-ionic dendritic amphiphiles has been developed from biobased chemicals, in particular glycerol-based dendrons coupled to commercially available acids via the Steglich esterification process. These non-ionic amphiphiles are functionalized with different hydrophobic segments to investigate the contribution of the same towards their guest transport behaviour. Therefore, different alkyl chains i.

Sulfated Cellulose Nanofiber Hydrogel with Mucus-Like Activities for Virus Inhibition.

Mucus is the first defense barrier against viruses in the human immune system. Inspired by the mucus structure, we designed a highly sulfated hydrogel to bind viruses and prevent infection of the underlying cells. The hydrogel was formed by gelation of sulfated cellulose nanofiber (SCNF) with Ca.

Easy Synthetic Access to High-Melting Sulfurated Copolymers and their Self-Assembling Diblock Copolymers from Phenylisothiocyanate and Oxetane.

Although sulfurated polymers promise unique properties, their controlled synthesis, particularly when it comes to complex and functional architectures, remains challenging. Here, we show that the copolymerization of oxetane and phenyl isothiocyanate selectively yields polythioimidocarbonates as a new class of sulfur containing polymers, with narrow molecular weight distributions (M=5-80 kg/mol with Đ≤1.2; M=124 kg/mol) and high melting points of up to 181 °C.

Power of the Disulfide Bond: An Ideal Random Copolymerization of Biodegradable Redox-Responsive Hyperbranched Polyglycerols.

The development of copolymerization techniques that can randomly incorporate biodegradable moieties into the hyperbranched polyglycerol backbone is an option to prevent its bioaccumulation in vivo. In this study, redox-responsive and biocompatible hyperbranched polyglycerol copolymers of glycidol and 1,4,5-oxadithiepan-2-one were synthesized with an adjustable molecular weight and a defined disulfide bond content through anionic and coordination-insertion ring-opening polymerization. A truly random incorporation of the monomers was achieved under both copolymerization mechanisms.

Esterase-Responsive Polyglycerol-Based Nanogels for Intracellular Drug Delivery in Rare Gastrointestinal Stromal Tumors.

Rare gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and PDGFRA genes. Avapritinib (BLU-285) is a targeted selective inhibitor for mutated KIT and PDGFRA receptors that can be used to treat these tumors. However, there are subtypes of GISTs that exhibit resistance against BLU-285 and thus require other treatment strategies.

Dendritic Glycerol-Cholesterol Amphiphiles as Drug Delivery Systems: A Comparison between Monomeric and Polymeric Structures.

The application of micelles as drug delivery systems has gained a great deal of attention as a means to overcome the current several drawbacks present in conventional cancer treatments. In this work, we highlight the comparison of polymeric and monomeric amphiphilic systems with a similar hydrophilic-lipophilic balance (HLB) in terms of their biocompatibility, aggregation behavior in aqueous solution, and potential in solubilizing hydrophobic compounds. The polymeric system consists of non-ionic polymeric amphiphiles synthesized via sequential RAFT polymerization of polyglycerol first-generation [G1] dendron methacrylate and cholesterol methacrylate to obtain poly(G1-polyglycerol dendron methacrylate)-block-poly(cholesterol methacrylate) (pG1MA-b-pCMA).

Dendritic polyglycerolsulfate-SS-poly(ester amide) micelles for the systemic delivery of docetaxel: pushing the limits of stability through the insertion of π-π interactions.

Insufficient stability of micellar drug delivery systems is still the major limitation to their systematic application in chemotherapy. This work demonstrates novel π-electron stabilized polyelectrolyte block copolymer micelles based on dendritic polyglycerolsulfate-cystamine--poly(4-benzoyl-1,4-oxazepan-7-one)-pyrene (dPGS-SS-POxPPh-Py) presenting a very low critical micelle concentration (CMC) of 0.3 mg L (18 nM), 55-fold lower than that of conventional amphiphilic block copolymer micelles.

Chemical Approaches to Synthetic Drug Delivery Systems for Systemic Applications.

Poor water solubility and low bioavailability of active pharmaceutical ingredients (APIs) are major causes of friction in the pharmaceutical industry and represent a formidable hurdle for pharmaceutical drug development. Drug delivery remains the major challenge for the application of new small-molecule drugs as well as biopharmaceuticals. The three challenges for synthetic delivery systems are: (i) controlling drug distribution and clearance in the blood; (ii) solubilizing poorly water-soluble agents, and (iii) selectively targeting specific tissues.

Synthesis and functionalization of dendritic polyglycerol-based nanogels: application in T cell activation.

The concept of multivalency finds various applications in the fields of chemistry and biology, relying on the principle that multiple weak interactions can lead to strong adhesive forces. Polymeric carriers are promising tools to translate these properties into the field of biomedicine, especially upon functionalization by active biomolecules, such as antibodies. In this study we report on the synthesis of dendritic polyglycerol (dPG) and dPG-based nanogels (NGs) as platforms for the multivalent display of molecules and their potential application as carrier units.

Tunable Polyglycerol-Based Redox-Responsive Nanogels for Efficient Cytochrome C Delivery.

The sensitivity of therapeutic proteins is a challenge for their use in biomedical applications, as they are prone to degradation and opsonization, thus limiting their potential. This demands for the development of drug delivery systems shielding proteins and releasing them at the site of action. Here, we describe the synthesis of novel polyglycerol-based redox-responsive nanogels and report on their potential as nanocarrier systems for the delivery of cytochrome C (CC).

Toolbox of Biodegradable Dendritic (Poly glycerol sulfate)-SS-poly(ester) Micelles for Cancer Treatment: Stability, Drug Release, and Tumor Targeting.

In this paper, we present well-defined dPGS-SS-PCL/PLGA/PLA micellar systems demonstrating excellent capabilities as a drug delivery platform in light of high stability and precise and drug release combined with active targetability to tumors. These six amphiphilic block copolymers were each targeted in two different molecular weights (8 or 16 kDa) and characterized using H NMR, gel permeation chromatography (GPC), and elemental analysis. The block copolymer micelles showed monodispersed size distributions of 81-187 nm, strong negative charges between -52 and -41 mV, and low critical micelle concentrations (CMCs) of up to 1.

Gram Scale Synthesis of Dual-Responsive Dendritic Polyglycerol Sulfate as Drug Delivery System.

Biocompatible polymers with the ability to load and release a cargo at the site of action in a smart response to stimuli have attracted great attention in the field of drug delivery and cancer therapy. In this work, we synthesize a dual-responsive dendritic polyglycerol sulfate (DR-dPGS) drug delivery system by copolymerization of glycidol, ε-caprolactone and an epoxide monomer bearing a disulfide bond (SSG), followed by sulfation of terminal hydroxyl groups of the copolymer. The effect of different catalysts, including Lewis acids and organic bases, on the molecular weight, monomer content and polymer structure was investigated.

Polyglycerol for Half-Life Extension of Proteins-Alternative to PEGylation?

Since several decades, PEGylation is known to be the clinical standard to enhance pharmacokinetics of biotherapeutics. In this study, we introduce polyglycerol (PG) of different lengths and architectures (linear and hyperbranched) as an alternative polymer platform to poly(ethylene glycol) (PEG) for half-life extension (HLE). We designed site-selective N-terminally modified PG-protein conjugates of the therapeutic protein anakinra (IL-1ra, Kineret) and compared them systematically with PEG analogues of similar molecular weights.

Defined pH-sensitive nanogels as gene delivery platform for siRNA mediated in vitro gene silencing.

In the present study, a pH sensitive nanogel platform for gene delivery was developed. The cationic nanogels based on dendritic polyglycerol (dPG) and low molecular weight polyethylenimine units were able to encapsulate siRNA during the manufacturing process. The thiol-Michael nanoprecipitation method, which operates under mild conditions and did not require any catalyst or surfactant, was used to develop tailor-made nanogels in the sub-100 nm range.

Protein Corona Formation on Colloidal Polymeric Nanoparticles and Polymeric Nanogels: Impact on Cellular Uptake, Toxicity, Immunogenicity, and Drug Release Properties.

The adsorption of biomolecules to the surface of nanoparticles (NPs) following administration into biological environments is widely recognized. In particular, the "protein corona" is well understood in terms of formation kinetics and impact upon the biological interactions of NPs. Its presence is an essential consideration in the design of therapeutic NPs.

Synthesis and Validation of Functional Nanogels as pH-Sensors in the Hair Follicle.

In the present study, a pH responsive dendritic polyglycerol nanogel (dPG-NG) is developed to measure the pH values inside the hair follicle (HF) using an ex vivo porcine ear model. The macromolecular precursors are labeled with a pH sensitive indodicarbocyanine dye (pH-IDCC) and a control dye (indocarbocyanine dye: ICC) and crosslinked via a mild and surfactant-free Thiol-Michael reaction using an inverse nanoprecipitation method. With this method, it is possible to prepare tailor-made particles in the range of 100 nm to 1 µm with a narrow polydispersity.

Micelles with Sheddable Dendritic Polyglycerol Sulfate Shells Show Extraordinary Tumor Targetability and Chemotherapy in Vivo.

Cancer nanomedicines are typically stealthed by a poly(ethylene glycol) layer that is important to obtain extended blood circulation and elevated tumor accumulation. PEG stealth, however, also leads to poor tumor cell selectivity and uptake thereby reducing treatment efficacy. Here, we report that biodegradable micelles with sheddable dendritic polyglycerol sulfate (dPGS) shells show an unusual tumor targetability and chemotherapy in vivo.

Intradermal drug delivery by nanogel-peptide conjugates; specific and efficient transport of temoporfin.

Nanogels offer many unique features rendering them as very attractive candidates for drug delivery. However, for their applications the loading capacity and specific encapsulation, in particular for hydrophobic drugs, in a complex media are two critical factors. In this work, we report for the first time on the preparation of nanogel-peptide conjugates with the ability of specific encapsulation of temoporfin (m-THPC).

Synthesis of pH-Cleavable dPG-Amines for Gene Delivery Application.

The development of effective nonviral vectors for gene therapy is still a challenge in research, due to the high toxicity of many existing polycationic nanocarriers. In this paper, the development of two pH-cleavable polyglycerol-amine-based nanocarriers is described. The benz-acetal bond represents the pH-sensitive cleavage site between dendritic polyglycerol (dPG) and glycerol-based 1,2-diamines that can complex genetic material.