Novel liposomal formulations for protection and delivery of levodopa: Structure-properties correlation.

Liposomes are promising drug carriers for a wide range of central nervous system disorders, such as Parkinson's disease (PD), since they can protect active substances from degradation and could be administered intranasally, ensuring a direct access to the brain. Levodopa (LD), the drug commonly used to treat PD, spontaneously oxidizes in aqueous solutions and thus needs to be stabilized. Our investigation focuses on the preparation and the physico-chemical characterization of mixed liposomes to vehiculate LD and two natural substances (L-ascorbic acid and quercetin) that can prevent its oxidation and contribute to the treatment of Parkinson's disease. These co-loaded vesicles were prepared using a saturated phospholipid and structurally related cationic or analogue N-oxide surfactants and showed different properties, based on their composition. In particular, ex-vivo permeability tests using porcine nasal mucosa were performed, denoting that subtle variations of the lipids structure can significantly affect the delivery of LD to the target site.

Quatsomes Formulated with l-Prolinol-Derived Surfactants as Antibacterial Nanocarriers of (+)-Usnic Acid with Antioxidant Activity.

The efficacy of the treatment of bacterial infection is seriously reduced because of antibiotic resistance; thus, therapeutic solutions against drug-resistant microbes are necessary. Nanoparticle-based solutions are particularly promising for meeting this challenge because they can offer intrinsic antimicrobial activity and sustained drug release at the target site. Herein, we present a newly developed nanovesicle system of the quatsome family, composed of l-prolinol-derived surfactants and cholesterol, which has noticeable antibacterial activity even on Gram-negative strains, demonstrating great potential for the treatment of bacterial infections. We optimized the vesicle stability and antibacterial activity by tuning the surfactant chain length and headgroup charge (cationic or zwitterionic) and show that these quatsomes can furthermore serve as nanocarriers of pharmaceutical actives, demonstrated here by the encapsulation of (+)-usnic acid, a natural substance with many pharmacological properties.

Structurally Related Liposomes Containing N-Oxide Surfactants: Physicochemical Properties and Evaluation of Antimicrobial Activity in Combination with Therapeutically Available Antibiotics.

Although liposomes are largely investigated as drug delivery systems, they can also exert a pharmacological activity if devoid of an active principle as a function of their composition. Specifically, charged liposomes can electrostatically interact with bacterial cells and, in some cases, induce bacterial cell death. Moreover, they also show a high affinity toward bacterial biofilms. We investigated the physicochemical and antimicrobial properties of liposomes formulated with a natural phospholipid and four synthetic l-prolinol-derived surfactants at 9/1 and 8/2 molar ratios. The synthetic components differ in the nature of the polar headgroup (quaternary ammonium salt or N-oxide) and/or the length of the alkyl chain (14 or 16 methylenes). These differences allowed us to investigate the effect of the molecular structure of liposome components on the properties of the aggregates and their ability to interact with bacterial cells. The antimicrobial properties of the different formulations were assessed against Gram-negative and Gram-positive bacteria and fungi. Drug-drug interactions with four classes of available clinical antibiotics were evaluated against Staphylococcus spp. The target of each class of antibiotics plays a pivotal role in exerting a synergistic effect. Our results highlight that the liposomal formulations with an N-oxide moiety are required for the antibacterial activity against Gram-positive bacteria. In particular, we observed a synergism between oxacillin and liposomes containing 20 molar percentage of N-oxide surfactants onStaphylococcus haemolyticus, Staphylococcus epidermidis, andStaphylococcus aureus. In the case of liposomes containing 20 molar percentage of the N-oxide surfactant with 14 carbon atoms in the alkyl chain for S. epidermidis, the minimum inhibitory concentration was 0.125 µg/mL, well below the breakpoint value of the antibiotic.

Cyclic and Acyclic Amine Oxide Alkyl Derivatives as Potential Adjuvants in Antimicrobial Chemotherapy against Methicillin-Resistant Staphylococcus aureus with an MDR Profile.

The dramatic intensification of antimicrobial resistance occurrence in pathogenic bacteria concerns the global community. The revitalisation of inactive antibiotics is, at present, the only way to go through this health system crisis and the use of antimicrobial adjuvants is turning out the most promising approach. Due to their low toxicity, eco-friendly characteristics and antimicrobial activity, amphoteric surfactants are good candidates. This study investigated the adjuvant potentialities of commercial acyclic and newly cyclic N-oxide surfactants combined with therapeutically available antibiotics against MDR methicillin-resistant Staphylococcus aureus (MRSA). The safety profile of the new cyclic compounds, compared to commercial surfactants, was preliminarily assessed, evaluating the cytotoxicity on human peripheral mononuclear blood cells and the haemolysis in human red blood cells. The compounds show an efficacious antimicrobial activity strongly related to the length of the carbon atom chain. In drug-drug interaction assays, all surfactants act synergistically, restoring sensitivity to oxacillin in MRSA, with dodecyl acyclic and cyclic derivatives being the most effective. After evaluating the cytotoxicity and considering the antimicrobial action, the most promising compound is the L-prolinol amine-oxide C12NOX. These findings suggest that the combination of antibiotics with amphoteric surfactants is a valuable therapeutic option for topical infections sustained by multidrug-resistant S. aureus.

Fluorescent molecular rotors as sensors for the detection of thymidine phosphorylase.

Three new fluorescent molecular rotors were synthesized with the aim of using them as sensors to dose thymidine phosphorylase, one of the target enzymes of 5-fluorouracil, a potent chemotherapic drug largely used in the treatment of many solid tumors, that acts by hindering the metabolism of pyrimidines. 5-Fluorouracil has a very narrowtherapeutic window, in fact, its optimal dosage is strictly related to the level of its target enzymes that vary significantly among patients, and it would be of the utmost importance to have an easy and fast method to detect and quantify them. The three molecular rotors developed as TP sensors differ in the length of the alkylic spacer joining the ligand unit, a thymine moiety, and the fluorescent molecular rotor, a [4-(1-dimethylamino)phenyl]-pyridinium bromide. Their ability to trigger an optical signal upon the interaction with thymidine phosphorylase was investigated by fluorescent measurements.

Cationic Amphiphiles Bearing a Diacetylenic Function in the Headgroup: Aggregative Properties and Polymerization.

In the wide panorama of diacetylenic lipids, the photoresponsive conjugated 1,3-diyne function is usually encased into the hydrocarbon chain of the amphiphile at a variable distance from the headgroup. Therefore, the polydiacetylene network obtained by polymerization upon UV irradiation of the corresponding liposomes, exploited as sensing function, is embedded in the hydrophobic region of liposomes. Structurally related cationic diacetylenic amphiphiles featuring the conjugated triple bonds proximate to charged nitrogen were synthesized and evaluated in their ability to polymerize under aggregative conditions. The occurrence of polymerization only in certain aggregating conditions was rationalized by nuclear magnetic resonance (NMR) and Langmuir trough experiments.

Correlation of Physicochemical and Antimicrobial Properties of Liposomes Loaded with (+)-Usnic Acid.

(+)-Usnic acid (UA) is a natural substance that displays pharmacological activity, but it is barely soluble in water, so it was included in liposomes in order to study its properties. First, the effects of phospholipid structure and loading methodology on UA entrapment efficacy were evaluated. Then, the physicochemical and biological properties (UA delivery efficacy to Staphylococcus aureus bacterial cells) of different liposome formulations containing structurally related amphiphiles derived from L-prolinol were fully investigated. Entrapment efficiency of UA with passive loading by incubation was 80-100 molar percentage, which is related to lipophilicity of the drug and to the packing and fluidity of the bilayer. Some of the investigated formulations show the potential of UA in delivery systems (minimum inhibitory concentration of liposomal UA: 8 µg/mL) and even subtle variations of the molecular structure of lipids can significantly affect the liposomes' physicochemical properties and efficiency of drug release.

Influence of structurally related micelle forming surfactants on the antioxidant activity of natural substances.

Physicochemical properties of micelles, like other lipid aggregates, mostly depend on the composition and on the structure of the surfactants used as monomers. The preparation and the characterization of three cationic L-prolinol derivative surfactants with different chain lengths and their corresponding N-oxide are described. UV measurements were carried out to investigate the effect of the inclusion in micelles on the degradation of L-ascorbic acid and (+)-usnic acid. An influence on antioxidant activity was exerted to an extent strictly dependent on i) surfactant chain length, ii) charge, iii) pH (in the case of (+)-usnic acid) and iv) on the hydrophilicity of the solute, determinant parameter for their location in the aggregates. In general the extent of the antioxidant activity of the system in the case of N-oxides micelles depends on surfactant chain length. On the other hand, cationic micelles formed by the surfactant with the shortest chain behave more like N-oxides ones rather than those formed by its relative structural homologues featuring longer alkyl chains, probably as a consequence of a concentration effect.