A review of thermosensitive polysaccharide-based composite hydrogels for therapeutic applications.

In recent years, polysaccharide-based thermosensitive hydrogels have been widely used in therapeutic applications ranging from controlled drug release to wound healing and cell culture. One type of thermosensitive hydrogel is a solution below its transition temperature and a gel above this temperature. In addition to being biocompatible and biodegradable, these hydrogels are easily injectable, making them ideal for local injections at desired sites.

Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogens.

Antibiotic resistance is a major threat to human health and new drugs are urgently needed. Ideally, these drugs should have several cellular targets in pathogens, decreasing the risk of resistance development. We show here that two natural ribosomally synthesized lasso peptides (LPs), sviceucin and siamycin I, (1) abolish bacterial virulence of pathogenic enterococci, (2) restore vancomycin clinical susceptibility of vancomycin-resistant (VR) enterococci and in a surrogate animal model, and (3) re-sensitize VR .

Evidence from a mouse model supports repurposing an anti-asthmatic drug, bambuterol, against Alzheimer's disease by administration through an intranasal route.

Bambuterol is a long-acting anti-asthmatic prodrug which releases terbutaline. Terbutaline is an agonist of the β-adrenergic receptors which is formed by decarbamoylation of bambuterol by butyrylcholinesterase. Inhibition of the latter, as well as activation of β-AR, are of interest for the treatment of Alzheimer's disease (AD).

Glucuronidation of orally administered drugs and the value of nanocarriers in strategies for its overcome.

The gastrointestinal tract (GIT) plays a pivotal role in the absorption of orally administered drugs, with the small intestine serving as the primary site due to its extensive surface area and specialized cell types, including enterocytes and M cells. After oral administration, drugs are generally transported via the portal vein to the liver, where they undergo first-pass metabolism. This process involves various enzymatic reactions, including glucuronidation, facilitated by uridine diphosphate-glucuronosyltransferase (UGT), a major phase 2 reaction in mammalian metabolism.

Injectable polyoxazoline grafted hyaluronic acid thermoresponsive hydrogels for biomedical applications.

Injectable thermosensitive hydrogels based on hyaluronic acid (HA) grafted with lower critical solution temperature (LCST) polyoxazoline (copolymers of poly(isopropyl--butyl oxazoline)) or P(iPrOx--BuOx) have been elaborated with tunable solution/gel temperature transitions and gel state elastic modulus. A suitable HA--P(iPrOx--BuOx-67/33)-0.10 sample with an iPrOx/BuOx ratio of 67/33, a polymerization degree (DP) of 25, a substitution degree (DS) of 10%, and displaying thermally induced gelling character with elastic (') and viscous ('') moduli crossover points at 25 °C and a ' at 37 °C around 80 Pa has been chosen for medical application.

In vitro evaluation of NA1-115-7-loaded nanoemulsions, an MCL-1-specific inhibitor of natural origin, intended to treat B-cell lymphoproliferative disorders after oral administration.

MCL-1, an anti-apoptotic member of the BCL-2 protein family, is overexpressed in many types of cancer and contributes to chemotherapy resistance. The drimane derivative NA1-115-7 is a natural compound isolated from Zygogynum pancheri that can be considered as a very promising lead for treating MCL-1-dependent hematological malignancies. As this drug suffers from low stability in acidic conditions and poor aqueous solubility, we evaluated the potential oral use of NA1-115-7 by encapsulating it in lipid nanoemulsions (NA-NEs) prepared by spontaneous emulsification.

NA1-115-7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes.

The overexpression of antiapoptotic members (BCL-2, BCL-xL, MCL-1, etc.) of the BCL-2 family contributes to tumor development and resistance to chemotherapy or radiotherapy. Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax).

How nano-engineered delivery systems can help marketed and repurposed drugs in Alzheimer's disease treatment?

Given the continual increase in the number of patients and the lack of curative treatment, the development of new therapies to treat Alzheimer's disease (AD) is becoming ever more urgent. In this review, we summarize the most promising preclinical studies in, and the significant benefits offered by, nanocarriers to realize the full potential of marketed drugs and identify repurposed drugs. No clinical trials have yet been conducted on nanocarriers for drug repurposing in AD.

Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer's Disease Treatment.

Background And Purpose: The activation of 5-HT receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer's disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood-brain barrier shuttle peptide.

Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL-1.

Drimane sesquiterpenoid dialdehydes are natural compounds with antiproliferative properties. Nevertheless, their mode of action has not yet been discovered. Herein, we demonstrate that various drimanes are potent inhibitors of MCL-1 and BCL-xL, two proteins of the BCL-2 family that are overexpressed in various cancers, including lymphoid malignancies.

Design of Non-Haemolytic Nanoemulsions for Intravenous Administration of Hydrophobic APIs.

Among advanced formulation strategies, nanoemulsions are considered useful drug-delivery systems allowing to improve the solubility and the bioavailability of lipophilic drugs. To select safe excipients for nanoemulsion formulation and to discard any haemolytic potential, an in vitro miniaturized test was performed on human whole blood. From haemolysis results obtained on eighteen of the most commonly used excipients, a medium chain triglyceride, a surfactant, and a solubilizer were selected for formulation assays.

Relevant Physicochemical Methods to Functionalize, Purify, and Characterize Surface-Decorated Lipid-Based Nanocarriers.

Surface functionalization of lipid-based nanocarriers (LBNCs) with targeting ligands has attracted huge interest in the field of nanomedicines for their ability to overcome some physiological barriers and their potential to deliver an active molecule to a specific target without causing damage to healthy tissues. The principal objective of this review is to summarize the present knowledge on LBNC decoration used for biomedical applications, with an emphasis on the ligands used, the functionalization approaches, and the purification methods after ligand corona formation. The most potent experimental techniques for the LBNC surface characterization are described.

Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer's Disease Treatment.

Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer's disease.

A comparison of different strategies for antimicrobial peptides incorporation onto/into lipid nanocapsules.

Over the last decade, antimicrobial peptides (AMPs) have emerged as a promising alternative for the treatment of various infections. The aim of this work is to explore the potential of lipid nanocapsules for the delivery of AMPs. Three approaches were compared in terms of encapsulation efficiency, peptide activity and protection against proteases: peptide encapsulation, surface adsorption or covalent attachment of three selected AMPs.

Reverse micelle-lipid nanocapsules: a novel strategy for drug delivery of the plectasin derivate AP138 antimicrobial peptide.

Introduction: Resistance to traditional antibiotics is an increasingly serious problem. Antimicrobial peptides (AMPs) have emerged as a new therapeutic class with great potential against infectious diseases, as they are less prone to induce resistance. Nanotechnology-based delivery strategies can improve the efficiency and stability of AMPs, particularly against proteolytic degradation.

Understanding the adsorption of salmon calcitonin, antimicrobial peptide AP114 and polymyxin B onto lipid nanocapsules.

The adsorption of therapeutic molecules, e.g., peptides, onto nanocarriers is influenced by the properties of the carrier, adsorbed molecule and continuous phase.

Lipid-based nanoformulations for peptide delivery.

Nanoformulations have attracted a lot of attention because of their size-dependent properties. Among the array of nanoformulations, lipid nanoformulations (LNFs) have evoked increasing interest because of the advantages of their high degree of biocompatibility and versatility. The performance of lipid nanoformulations is greatly influenced by their composition and structure.

Mucus models to evaluate nanomedicines for diffusion.

In the fast-growing field of nanomedicine, mucus is often the first barrier encountered by drug products in the body, and can be the only barrier if it is not overcome by the drug delivery system. Thus, there is a need to design new nanomedicines that are able to diffuse easily across mucus to reach their pharmacological targets. In this design process, mucus diffusion studies are mandatory and have an important role in the selection of the best drug candidates.

Development of 2D and 3D mucus models and their interactions with mucus-penetrating paclitaxel-loaded lipid nanocapsules.

Purpose: To study, diffusion through mucus (3D model) of different formulations of paclitaxel loaded lipid nanocapsules (Ptx-LNCs), to interpret the results in the light of LNC behavior at air-mucus interface (2D model).

Methods: LNC surface properties were modified with chitosan or poly(ethylene glycol) (PEG) coatings of different size (PEG 2,000 to 5,000 Da) and surface charges. LNC diffusion through 446 μm pig intestinal mucus layer was studied using Transwell(®).

Fate of paclitaxel lipid nanocapsules in intestinal mucus in view of their oral delivery.

The bioavailability of paclitaxel (Ptx) has previously been improved via its encapsulation in lipid nanocapsules (LNCs). In this work, the interactions between LNCs and intestinal mucus are studied because they are viewed as an important barrier to successful oral delivery. The rheological properties of different batches of pig intestinal mucus were studied under different conditions (the effect of hydration and the presence of LNCs).