Fluorinated PAMAM-Arginine Carrier Prodrugs for pH-Sensitive Sustained Ibuprofen Delivery

Objective The development of an efficient, multifunctional drug delivery system overcoming different obstacles generally associated with drug formulations, including the poor accumulation of the active principle in the target site and its sustained release for prolonged time. Methods Our study proposes the development of a fluorinated poly(amidoamine) (PAMAM) carrier prodrug combining drug release boosted in alkaline environments with a possible implementation in 19F MRI applications. In particular, we functionalized the terminal primary amines of PAMAM G2 and G4 through an ad hoc designed fluorinated ibuprofen-arginine Michael acceptor to obtain multifunctional ibuprofen-PAMAM-Arg conjugates. Results These carriers demonstrated pH-dependent and sustained ibuprofen release for more than 5 days. This advantage was observed in both weak alkaline and physiological buffer solutions, allowing to overcome the limits associated to the burst release from similar fluorinated Arg-PAMAM dendrimers with ibuprofen physically encapsulated. Conclusion These findings, coupled to the high biocompatibility of the system, suggest a potential synergistic biomedical application of our conjugates, serving as vehicles for drug delivery and as 19F magnetic resonance imaging contrast agents

Selectively Fluorinated PAMAM-Arginine Conjugates as Gene Delivery Vectors

: Polyamidoamine (PAMAM) dendrimers are among the most studied cationic polymers as non-viral gene delivery vectors. However, an "ideal" PAMAM-based gene delivery vector is still missing due to the high manufacturing costs and non-negligible cytotoxicity associated with the use of high-generation dendrimers, whereas low-generation dendrimers are far from displaying efficient gene transfection. In order to cover this gap in the literature, in this study, we propose the functionalization of the outer primary amines of PAMAM G2 and PAMAM G4 with building blocks bearing fluorinated moieties along with a guanidino functional group. We have designed and synthetized two fluorinated arginine (Arg)-based Michael acceptors which were straightforwardly "clicked" to PAMAM dendrimers without the need for coupling reagents and/or catalysts. The obtained conjugates, in particular, derivative 1 formed starting from the low-cost PAMAM G2 and a building block bearing two trifluoromethyl groups, were able to efficiently complex plasmid DNA, had negligible cytotoxicity, and showed improved gene transfection efficiency as compared to undecorated PAMAM dendrimers and a corresponding unfluorinated PAMAM-Arg derivative, with derivative 1 being two orders of magnitude more efficient than the gold standard branched polyethylenimine, bPEI, 25 kDa. These results highlight the importance of the presence of trifluoromethyl moieties for both gene transfection and a possible future application in 19F magnetic resonance imaging

Dual Antibiotic Approach: Synthesis and Antibacterial Activity of Antibiotic–Antimicrobial Peptide Conjugates

In recent years, bacterial resistance to conventional antibiotics has become a major concern in the medical field. The global misuse of antibiotics in clinics, personal use, and agriculture has accelerated this resistance, making infections increasingly difficult to treat and rendering new antibiotics ineffective more quickly. Finding new antibiotics is challenging due to the complexity of bacterial mechanisms, high costs and low financial incentives for the development of new molecular scaffolds, and stringent regulatory requirements. Additionally, innovation has slowed, with many new antibiotics being modifications of existing drugs rather than entirely new classes. Antimicrobial peptides (AMPs) are a valid alternative to small-molecule antibiotics offering several advantages, including broad-spectrum activity and a lower likelihood of inducing resistance due to their multifaceted mechanisms of action. However, AMPs face challenges such as stability issues in physiological conditions, potential toxicity to human cells, high production costs, and difficulties in large-scale manufacturing. A reliable strategy to overcome the drawbacks associated with the use of small-molecule antibiotics and AMPs is combination therapy, namely the simultaneous co-administration of two or more antibiotics or the synthesis of covalently linked conjugates. This review aims to provide a comprehensive overview of the literature on the development of antibiotic–AMP conjugates, with a particular emphasis on critically analyzing the design and synthetic strategies employed in their creation. In addition to the synthesis, the review will also explore the reported antibacterial activity of these conjugates and, where available, examine any data concerning their cytotoxicit

Synthesis of hexafluorovaline-containing di- and tripeptides

A new strategy for the synthesis of peptides incorporating racemic hexafluorovaline (hfVal) is presented. The synthetic pathway relies on the anti-Michael addition of benzyl amine derivatives to ad hoc prepared β-bis-trifluoromethyl-acryloyl-α-amino esters which proceeds in mild condition, high yields, even if with low stereocontrol. The following elaboration of the intermediates, namely deprotection of the benzyl moiety and coupling with α-amino esters allowed us to synthetize the targeted tripeptides in four overall synthetic steps, resulting in a synthetic pathway more favorable respect to those appeared in literature based on the synthesis and isolation of racemic Boc-hfVal-OH (eight synthetic steps)

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Surfactant-free and rinsing-resistant biodegradable nanoparticles with high adsorption on natural fibers for the long-lasting release of fragrances

Synthetic polymers are attracting growing attention as additives for laundry and personal care products. In particular, the high volatility of many common fragrances requires the development of polymeric particles for their encapsulation and controlled release. Unfortunately, the vast majority of these carriers is made from polymers that are not biodegradable. This poses severe concerns about the accumulation of nano- and microplastics. Hence, such particles are expected to be banned from the market in the coming years. Therefore, biodegradable particles enabling a long-lasting release of the fragrances are urgently needed. In this work, we produced biodegradable nanoparticles (NPs) that are structurally composed of lactones, i.e. well known perfumes that occur naturally and that are already considered safe by regulatory agencies. We polymerized these lactones via ring opening polymerization (ROP) using an ionizable tertiary amine as initiator to produce in a single step amphiphilic oligoesters able to directly self-assemble into NPs once nanoprecipitated in water. In this way, we can produce biodegradable NPs with a perfume loading up to 85 % w/w without the need for additional surfactants. Subsequently we show that the ionizable group is able to confer a positive charge to our nanoparticles and, in turn, a high adsorption capacity on natural fibers (i.e. hairs and cotton fabric). Finally, we demonstrate the nanoparticle resistance to rinsing and their ability to confer a long-lasting fragrance perception to treated hair swatches for at least 3 weeks

Global Analysis of Type Three Secretion System and Quorum Sensing Inhibition of <i>Pseudomonas savastanoi</i> by Polyphenols Extracts from Vegetable Residues

<div><p>Protection of plants against bacterial diseases still mainly relies on the use of chemical pesticides, which in Europe correspond essentially to copper-based compounds. However, recently plant diseases control is oriented towards a rational use of molecules and extracts, generally with natural origin, with lower intrinsic toxicity and a reduced negative environmental impact. In this work, polyphenolic extracts from vegetable no food/feed residues of typical Mediterranean crops, as <i>Olea europaea</i>, <i>Cynara scolymus</i>, and <i>Vitis vinifera</i> were obtained and their inhibitory activity on the Type Three Secretion System (TTSS) and the Quorum Sensing (QS) of the Gram-negative phytopathogenic bacterium <i>Pseudomonas savastanoi</i> pv. <i>nerii</i> strain <i>Psn23</i> was assessed. Extract from green tea (<i>Camellia sinensis</i>) was used as a positive control. Collectively, the data obtained through <i>gfp</i>-promoter fusion system and real-time PCR show that all the polyphenolic extracts here studied have a high inhibitory activity on both the TTSS and QS of <i>Psn23</i>, without any depressing effect on bacterial viability. Extracts from green tea and grape seeds were shown to be the most active. Such activity was confirmed <i>in planta</i> by a strong reduction in the ability of <i>Psn23</i> to develop hyperplastic galls on explants from adult oleander plants, as well as to elicit hypersensitive response on tobacco. By using a newly developed Congo red assay and an ELISA test, we demonstrated that the TTSS-targeted activity of these polyphenolic extracts also affects the TTSS pilus assembly. In consideration of the potential application of polyphenolic extracts in plant protection, the absence of any toxicity of these polyphenolic compounds was also assessed. A widely and evolutionary conserved molecular target such as Ca²⁺-ATPase, essential for the survival of any living organism, was used for the toxicity assessment.</p></div