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The development of numerous drugs is often arrested at clinical testing stages, due to their unfavorable biopharmaceutical characteristics. It is the case of fenretinide (4-HPR), a second-generation retinoid, that demonstrated promising in vitro cytotoxic activity against several cancer cell lines. Unfortunately, response rates in early clinical trials with 4-HPR did not confirm the in vitro findings, mainly due to the low bioavailability of the oral capsular formulation that was initially developed. Capsular 4-HPR provided variable and insufficient drug plasma levels attributable to the high hepatic first-pass effect and poor drug water solubility. To improve 4-HPR bioavailability, several approaches have been put forward and tested in preclinical and early-phase clinical trials, demonstrating generally improved plasma levels and minimal systemic toxicities, but also modest antitumor efficacy. The challenge is thus currently still far from being met. To redirect the diminished interest of pharmaceutical companies toward 4-HPR and promote its further clinical development, this manuscript reviewed the attempts made so far by researchers to enhance 4-HPR bioavailability. A comparison of the available data was performed, and future directions were proposed.

Since they are difficult and sometimes impossible to treat, infections sustained by multidrug-resistant (MDR) pathogens, emerging especially in nosocomial environments, are an increasing global public health concern, translating into high mortality and healthcare costs. In addition to having acquired intrinsic abilities to resist available antibiotic treatments, MDR bacteria can transmit genetic material encoding for resistance to non-mutated bacteria, thus strongly decreasing the number of available effective antibiotics. Moreover, several pathogens develop resistance by forming biofilms (BFs), a safe and antibiotic-resistant home for microorganisms. BFs are made of well-organized bacterial communities, encased and protected in a self-produced extracellular polymeric matrix, which impedes antibiotics’ ability to reach bacteria, thus causing them to lose efficacy. By adhering to living or abiotic surfaces in healthcare settings, especially in intensive care units where immunocompromised older patients with several comorbidities are hospitalized BFs cause the onset of difficult-to-eradicate infections. In this context, recent studies have demonstrated that quaternary ammonium compounds (QACs), acting as membrane disruptors and initially with a low tendency to develop resistance, have demonstrated anti-BF potentialities. However, a paucity of innovation in this space has driven the emergence of QAC resistance. More recently, quaternary phosphonium salts (QPSs), including tri-phenyl alkyl phosphonium derivatives, achievable by easy one-step reactions and well known as intermediates of the Wittig reaction, have shown promising anti-BF effects in vitro. Here, after an overview of pathogen resistance, BFs, and QACs, we have reviewed the QPSs developed and assayed to this end, so far. Finally, the synthetic strategies used to prepare QPSs have also been provided and discussed to spur the synthesis of novel compounds of this class. We think that the extension of the knowledge about these materials by this review could be a successful approach to finding effective weapons for treating chronic infections and device-associated diseases sustained by BF-producing MDR bacteria.

Aiming at developing a dermal formulation against melanoma, the synthesized imidazo-pyrazoles 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (3-methoxy-4-phenoxy-benzylidene)-hydrazide (4G) and 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (4-benzyloxy-3-methoxy-benzylidene)-hydrazide (4I) were screened on patient-isolated melanoma cells (MEOV NT) and on Vemurafenib (PLX4032)-resistant (MEOV PLX-R) ones. Since 4I on MEOV PLX-R cells was 1.4-fold more effective than PLX, a hydrogel formulation containing 4I (R4HG-4I) was prepared in parallel with an empty R4-based hydrogel (R4HG) using a synthesized antibacterial resin (R4) as gelling agent. Thanks to its high hydrophilicity, porosity (85%), and excellent swelling capability (552%), R4 allowed to achieve R4HG and R4HG-4I with high equilibrium degree of swelling (EDS) and equilibrium water content (EWC). Chemometric-assisted ATR-FTIR analyses confirmed the chemical structure of swollen and fully dried (R4HG-D and R4HG-4I-D) hydrogels. The morphology of R4HG-D and R4HG-4I-D was examined by optical microscopy and SEM, while UV–vis analyses were carried out to obtain the drug loading (DL%) and the encapsulation efficiency (EE%) of R4HG-4I. Potentiometric titrations were performed to determine the equivalents of NH3+ in both R4HG and R4HG-4I. The swelling and water release profiles of both materials and related kinetics were assessed by equilibrium swelling rate and water loss studies, respectively, while their biodegradability over time was assessed by in vitro degradation experiments determining their mass loss. Rheological experiments established that both R4HG and R4HG-4I are shear-thinning Bingham pseudoplastic fluids with low yield stress, thus assuring easy spreadability in a future topical application. Release studies evidenced a sustained and quantitative release of 4I governed mainly by diffusion. Upon favorable results from further experiments in a more realistic 3D model of melanoma, R4HG-4I could represent a starting point to develop new topical therapeutic options to adjuvate the treatments of melanoma cells also when resistant to currently available drugs.

Due to the rapid emergence of multi drug resistant (MDR) pathogens against which current antibiotics are no longer functioning, severe infections are becoming practically untreatable. Consequently, the discovery of new classes of effective antimicrobial agents with novel mechanism of action is becoming increasingly urgent. The bioactivity of Cannabis sativa, an herbaceous plant used for millennia for medicinal and recreational purposes, is mainly due to its content in phytocannabinoids (PCs). Among the 180 PCs detected, cannabidiol (CBD), Δ8 and Δ9-tetrahydrocannabinols (Δ8-THC and Δ9-THC), cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN) and some of their acidic precursors have demonstrated from moderate to potent antibacterial effects against Gram-positive bacteria (MICs 0.5–8 µg/mL), including methicillin-resistant Staphylococcus aureus (MRSA), epidemic MRSA (EMRSA), as well as fluoroquinolone and tetracycline-resistant strains. Particularly, the non-psychotropic CBG was also capable to inhibit MRSA biofilm formation, to eradicate even mature biofilms, and to rapidly eliminate MRSA persiter cells. In this scenario, CBG, as well as other minor non-psychotropic PCs, such as CBD, and CBC could represent promising compounds for developing novel antibiotics with high therapeutic potential. Anyway, further studies are necessary, needing abundant quantities of such PCs, scarcely provided naturally by Cannabis plants. Here, after an extensive overture on cannabinoids including their reported antimicrobial effects, aiming at easing the synthetic production of the necessary amounts of CBG, CBC and CBD for further studies, we have, for the first time, systematically reviewed the synthetic pathways utilized for their synthesis, reporting both reaction schemes and experimental details.

Here, a new two-component hydrogel (CP1OP2-Hgel) was developed, simply by dispersing in water two cationic bactericidal polymers (CP1 and OP2) effective against several multidrug-resistant (MDR) clinical isolates of the most relevant Gram-positive and Gram-negative species. Interestingly, while OP2 acts only as an antibacterial ingredient when in gel, CP1 works as both an antibacterial and a gelling agent. To verify whether it would be worthwhile to use CP1 and OP2 as bioactive ingredients of a new hydrogel supposed for a future treatment of skin infections, dose-dependent cytotoxicity studies with CP1 and OP2 were performed on human fibroblasts for 24 h, before preparing the formulation. Although a significant cytotoxicity at concentrations > 2 µM was evidenced for both polymers, selectivity indices (SIs) over 12 (CP1) and up to six (OP2) were determined, due to the powerful antibacterial properties of the two polymers, thus supporting the rationale for their formulation as a hydrogel. The chemical structure and morphology of CP1OP2-Hgel were investigated by PCA-assisted attenuated total reflectance (ATR) Fourier-transform infrared (FTIR) analysis and scanning electron microscopy (SEM), while its rheological properties were assessed by determining its dynamic viscosity. The cumulative weight loss and swelling percentage curves, the porosity, and the maximum swelling capability of CP1OP2-Hgel were also determined and reported. Overall, due to the potent bactericidal effects of CP1 and OP2 and their favorable selectivity indices against several MDR pathogens, good rheological properties, high porosity, and strong swelling capability, CP1OP2-Hgel may, in the future, become a new weapon for treating severe nosocomial skin infections or infected chronic wounds. Further investigations in this sense are currently being carried out.

Multidrug resistance (MDR) among pathogens and the associated infections represent an escalating global public health problem that translates into raised mortality and healthcare costs. MDR bacteria, with both intrinsic abilities to resist antibiotics treatments and capabilities to transmit genetic material coding for further resistance to other bacteria, dramatically decrease the number of available effective antibiotics, especially in nosocomial environments. Moreover, the capability of several bacterial species to form biofilms (BFs) is an added alarming mechanism through which resistance develops. BF, made of bacterial communities organized and incorporated into an extracellular polymeric matrix, self-produced by bacteria, provides protection from the antibiotics’ action, resulting in the antibiotic being ineffective. By adhering to living or abiotic surfaces present both in the environment and in the healthcare setting, BF causes the onset of difficult-to-eradicate infections, since it is difficult to prevent its formation and even more difficult to promote its disintegration. Inspired by natural antimicrobial peptides (NAMPs) acting as membrane disruptors, with a low tendency to develop resistance and demonstrated antibiofilm potentialities, cationic polymers and dendrimers, with similar or even higher potency than NAMPs and with low toxicity, have been developed, some of which have shown in vitro antibiofilm activity. Here, aiming to incite further development of new antibacterial agents capable of inhibiting BF formation and dispersing mature BF, we review all dendrimers developed to this end in the last fifteen years. The extension of the knowledge about these still little-explored materials could be a successful approach to find effective weapons for treating chronic infections and biomaterial-associated infections (BAIs) sustained by BF-producing MDR bacteria.

The pyrazole ring represents a widely applied chemical scaffold in medicinal chemistry research and we have observed that the physicochemical and biological features of highly substituted pyrazoles can be successfully improved by their encapsulation in dendrimer nanoparticles (NPs). For the future development of new optimized antibacterial delivery systems, we report the synthesis and biological evaluation of 5-amino functionalized pyrazole library (compounds 2–7). In detail, new derivatives 2–7 were differently decorated in C3, C4 and C5 positions. An in silico study predicted pyrazoles 2–7 to exert good drug-like and pharmacokinetic properties. Compounds 3c and 4b were endowed with moderate, but nanotechnologically improvable activity against multidrug-resistant (MDR) clinical isolates of Gram-positive species, especially of the Staphylococcus genus (MICs = 32–64 µg/mL). In addition, derivatives 3c and 4a showed moderate activities against Mycobacterium tuberculosis and 4a evidenced activity also against MDR strains. Overall, the collected evidence supported that, upon nano-formulation with proper polymer matrices, the new synthesized compounds could provide new pyrazole-based drug delivery systems with an enhanced and enlarged-spectrum of antibacterial activity.

Ursolic acid (UA), a pentacyclic triterpenoid acid found in many medicinal plants and aromas, is known for its antibacterial effects against multi-drug-resistant (MDR) Gram-positive bacteria, which seriously threaten human health. Unfortunately, UA water-insolubility, low bioavailability, and systemic toxicity limit the possibilities of its application in vivo. Consequently, the beneficial activities of UA observed in vitro lose their potential clinical relevance unless water-soluble, not cytotoxic UA formulations are developed. With a nano-technologic approach, we have recently prepared water-soluble UA-loaded dendrimer nanoparticles (UA-G4K NPs) non-cytotoxic on HeLa cells, with promising physicochemical properties for their clinical applications. In this work, with the aim of developing a new antibacterial agent based on UA, UA-G4K has been tested on different strains of the Enterococcus genus, including marine isolates, toward which UA-G4K has shown minimum inhibitory concentrations (MICs) very low (0.5–4.3 µM), regardless of their resistance to antibiotics. Time-kill experiments, in addition to confirming the previously reported bactericidal activity of UA against E. faecium, also established it for UA-G4K. Furthermore, cytotoxicity experiments on human keratinocytes revealed that nanomanipulation of UA significantly reduced the cytotoxicity of UA, providing UA-G4K NPs with very high LD50 (96.4 µM) and selectivity indices, which were in the range 22.4–192.8, depending on the enterococcal strain tested. Due to its physicochemical and biological properties, UA-G4K could be seriously evaluated as a novel oral-administrable therapeutic option for tackling difficult-to-treat enterococcal infections.

Difficult-to-treat bacterial infections caused by resistant human and plant pathogens severely afflict hospitals, and concern the agri-food sectors. Bacteria from the Pseudomonadaceae family, such as P. aeruginosa, P. putida, P. fluorescens, and P. straminea, can be responsible for severe nosocomial infections in humans. P. fragi is the major cause of dairy and meat spoilage, while P. syringae can infect a wide range of economically important plant species, including tobacco, kiwi, and tomato. Therefore, a cationic water-soluble lysine dendrimer (G5-PDK) was tested on several species of Pseudomonas genus. Interestingly, G5-PDK demonstrated variable minimum inhibitory concentrations (MICs), depending on their pigment production, on Pseudomonas aeruginosa (1.6-> 6.4 µM), MICs = 3.2–6.4 µM on P. putida clinical isolates producing pyoverdine, and very low MICs (0.2–1.6 µM) on strains that produced non-pigmented colonies. Time-kill experiments established the rapid bactericidal activity of G5-PDK. In the cytotoxicity experiments on human keratinocytes, after 4 h of treatment with G5-PDK at concentrations 16–500 × MIC, more than 80% of viable cells were observed, and after 24 h, the selectivity indices were maintained above the maximum value reported as acceptable. Due to its proven bactericidal potency and low cytotoxicity, G5-PDK should be seriously considered to counteract clinically and environmentally relevant Pseudomonas isolates.

Atherosclerosis is a chronic progressive disease involving inflammatory events, such as the overexpression of adhesion molecules including the endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1). VCAM-1 is rapidly overexpressed in the first stages of atherosclerosis, thus representing a promising target for early atheroma detection. Two novel Positron Emission Tomography (PET) radiopharmaceuticals (MacroP and NAMP), based on the VCAM-1-binding peptide having sequence VHPKQHRGGSKGC, were synthesized and characterized. MacroP is derived from the direct conjugation of a DOTA derivative with the peptide, while NAMP is a biotin derivative conceived to be employed in a three-step pretargeting system, involving the use of a double-chelating derivative of DOTA. The identity of the newly synthesized radiopharmaceuticals was confirmed by mass spectrometry and, after radiolabeling with 68Ga, both showed high radiochemical purity; in vitro tests on human umbilical vein endothelial cells evidenced their VCAM-1 binding ability, with higher radioactive uptake in the case of NAMP. Moreover, NAMP might also be employed in a theranostic approach in association with functionalized biotinylated nanoparticles.

Children affected by chronic liver disease exhibit impaired neurocognitive development and growth due to the low absorption and digestion of nutrients. Furthermore, malnutrition is an adverse prognostic factor in liver transplantation as it is associated with an increase in morbidity and mortality. D-α-tocopheryl-polyethylene-glycol-succinate (TPGS) is currently administered per os as a vitamin E source to improve children’s survival and well-being; however, TPGS alone does not reverse spinocerebellar degeneration and lipid peroxidation. To potentiate the effects of TPGS, we loaded micelles with resveratrol (RES), a natural polyphenol, with antioxidant and antiinflammatory activities, which has demonstrated protective action in the liver. Firstly, we investigated the suitability of TPGS to encapsulate RES in micelles by means of a phase-solubility study, then RES-TPGS formulations were prepared via solvent casting and solvent diffusion evaporation methods. RES-TPGS colloidal dispersions showed small mean diameters (12 nm), low polydispersity, and quite neutral Zeta potentials. The formulations showed a sustained drug release and a good drug loading capacity, further confirmed by infrared spectroscopy and differential scanning calorimetry. RES-TPGSs exhibited unaltered antioxidant activity compared to pristine RES via the DPPH assay and a significant reduction in toxicity compared to empty TPGS on HaCaT cells. Thus, RES-TPGS micelles may overcome the challenges of current liver disease therapy by providing more protective effects thanks to the antioxidant activity of RES and by reducing the surfactant toxicity on normal cells.