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Angela Bonaccorso,1,2,* Alessandro Ortis,3,* Teresa Musumeci,1,2 Claudia Carbone,1,2 Mazhar Hussain,3 Valentina Di Salvatore,1 Sebastiano Battiato,3 Francesco Pappalardo,1,2 Rosario Pignatello1,2 1Department of Drug and Health Sciences, University of Catania, Catania, Italy; 2NANOMED–Research Centre for Nanomedicine and Pharmaceutical Nanotechnology, University of Catania, Catania, 95125, Italy; 3Department of Mathematics and Computer Science, University of Catania, Catania, Italy*These authors contributed equally to this workCorrespondence: Teresa Musumeci, Email teresa.musumeci@unict.itBackground: In the last few decades, nose-to-brain delivery has been investigated as an alternative route to deliver molecules to the Central Nervous System (CNS), bypassing the Blood–Brain Barrier. The use of nanotechnological carriers to promote drug transfer via this route has been widely explored. The exact mechanisms of transport remain unclear because different pathways (systemic or axonal) may be involved. Despite the large number of studies in this field, various aspects still need to be addressed. For example, what physicochemical properties should a suitable carrier possess in order to achieve this goal? To determine the correlation between carrier features (eg, particle size and surface charge) and drug targeting efficiency percentage (DTE%) and direct transport percentage (DTP%), correlation studies were performed using machine learning.Methods: Detailed analysis of the literature from 2010 to 2021 was performed on Pubmed in order to build “NANOSE” database. Regression analyses have been applied to exploit machine-learning technology.Results: A total of 64 research articles were considered for building the NANOSE database (102 formulations). Particle-based formulations were characterized by an average size between 150– 200 nm and presented a negative zeta potential (ZP) from − 10 to − 25 mV. The most general-purpose model for the regression of DTP/DTE values is represented by Decision Tree regression, followed by K-Nearest Neighbors Regressor (KNeighbor regression).Conclusion: A literature review revealed that nose-to-brain delivery has been widely investigated in neurodegenerative diseases. Correlation studies between the physicochemical properties of nanosystems (mean size and ZP) and DTE/DTP parameters suggest that ZP may be more significant than particle size for DTP/DTE predictability.Keywords: nanomedicine, intranasal administration, pharmacokinetic, DTE, DTP, machine learning

In this paper, two medusa-like ACyDs, modified at the primary rim bearing four (ACyD4) and eight carbons (ACyD8) acyl chain length, and one bouquet-like CyD, modified at primary side with thiohexyl and at secondary one with oligoethylene moiety (SC6OH), were investigated for their ability to assemble in nanostructures or to form hybrid dipalmitoylphosphatidylcholine (DPPC)/ACyDs systems. The lipophilicity of these molecules and the different preparation methods used in this study (thin layer evaporation and nanoprecipitation method) significantly affect the aggregation behaviour in aqueous medium. Except for the shortest medusa-like ACyD4, the other ACyDs formed stable nanoaggregates for at least 45 days. The effect of ACyDs on the thermotropic behaviour of DPPC liposomes was also studied by differential scanning calorimetry analysis, thus elucidating their interaction with liposomes to afford hybrid liposome/ACyDs systems. The medusa-like ACyD4 cannot be used to realize nanosystems because it quickly aggregates or it induces a complete destabilization of the liposomes. At the highest concentration investigated (0.01 molar fraction), both ACyD8 and SC6OH interacted with DPPC liposomes, forming ACyD/DPPC or SC6OH/DPPC hybrid vesicular carriers. [ABSTRACT FROM AUTHOR]

This study proposes polymeric micelles produced using new amphiphilic conjugates between amino- or carboxy-mPEG2000 and three different α-lipoamino acids (PEG-LAA). The characterization of these colloidal systems showed CMC values, in the order of 10−5 M, that are interesting in the view of an in vivo administration. The PEG-LAA micelles also showed a good stability at 37 °C and upon dilution in aqueous media. Using a colored probe as a model lipophilic compound, the loading efficiency and in vitro release profile were also outlined. [ABSTRACT FROM AUTHOR]

Contact with many different biological membranes goes along the destiny of a drug after its systemic administration. From the circulating macrophage cells to the vessel endothelium, to more complex absorption barriers, the interaction of a biomolecule with these membranes largely affects its rate and time of biodistribution in the body and at the target sites. Therefore, investigating the phenomena occurring on the cell membranes, as well as their different interaction with drugs in the physiological or pathological conditions, is important to exploit the molecular basis of many diseases and to identify new potential therapeutic strategies. Of course, the complexity of the structure and functions of biological and cell membranes, has pushed researchers toward the proposition and validation of simpler two- and three-dimensional membrane models, whose utility and drawbacks will be discussed. This review also describes the analytical methods used to look at the interactions among bioactive compounds with biological membrane models, with a particular accent on the calorimetric techniques. These studies can be considered as a powerful tool for medicinal chemistry and pharmaceutical technology, in the steps of designing new drugs and optimizing the activity and safety profile of compounds already used in the therapy. [ABSTRACT FROM AUTHOR]

Hydrogels for the buccal application of the anesthetic drug lidocaine hydrochloride (LDC) were prepared using chitosan glutamate (CHG), a soluble salt of chitosan, or a binary mixture of CHG and glycerin, at different weight ratios. The in vitro drug release was studied at the pH value of saliva to assess the effect of the different formulations on drug delivery. The anesthetic activity of mucoadhesive LDC-CHG hydrogels was assessed in vivo after application on the buccal mucosa, compared to commercial semisolid formulations containing the same drug. LDC-loaded hydrogels can be proposed for the symptom relief of aphthosis or other painful mouth diseases. [ABSTRACT FROM AUTHOR]

Chitosan (CH) was used as a biocompatible and bioadhesive polymer material to prepare solid dispersions as well as hydrogels loaded with dexamethasone sodium phosphate (DSP), a steroidal anti-inflammatory agent clinically used for treatment of different mouth diseases. Binary solid dispersions at various drug-to-polymer weight ratios were prepared by freeze-drying; their direct compression gave tablets which were characterized for the swelling behaviour and drug release in vitro. Similarly, DSP-loaded hydrogels composed of CH and glycerine were prepared and characterized. CH and DSP showed a good physical compatibility. A slow and prolonged release of the drug was observed in vitro from both kinds of systems. The swelling properties of the polymer seemed to be the main parameter affecting the drug release profile from both tablets and hydrogels at the pH value of mouth. In vivo buccal application of both the systems allowed to obtain a prolonged release of DSP, as compared with a glycerine solution of the drug. From the in vitro swelling studies and in vivo test, the 2:1 CH-DSP solid dispersion in particular can be designated for further investigation. [ABSTRACT FROM AUTHOR]

In a previous paper the preparation has been described, by three different techniques, of microparticles made of Eudragit RS 100 and RL 100 containing a NSAI agent, Tolmetin. Freely flowing microparticles failed to affect significantly the in vitro drug release, which displayed a similar dissolution profile after micro-encapsulation to the free drug powder. Microparticles were then converted into tablets and the effect of compression on drug delivery, as well as that of the presence of co-additives, was studied in the present work. Furthermore, microparticles were also prepared by adding MgO to the polymer matrix, to reduce the sensitivity of the drug to pH changes during its dissolution. Similarly, magnesium stearate was also used for microparticle formation as a droplet stabilizer, in order to reduce particle size and hinder rapid drug release. A mathematical evaluation, by using two semi-empirical equations, was applied to evaluate the influence of dissolution and diffusion phenomena upon drug release from microparticle tablets. [ABSTRACT FROM AUTHOR]

Purpose Neovascular diabetic retinopathy (DR) and age-related macular degeneration (AMD) are characterized by increased VEGF signaling. VEGF can be targeted using monoclonal antibody-based drugs (e.g. ranibizumab, aflibercept) or by modified oligonucleotides (e.g. pegaptanib). The main difference between the two classes is that antibodies recognize all VEGF isoforms while oligonucleotides may be more specific for certain isoform such as VEGF165. New ways of intervention stem out from the observation that VEGF expression can be post-transcriptionally regulated by the RNA-binding HuR/Elav-like1 protein. We evaluated if targeting HuR is a potential tool to hinder VEGF overexpression. Methods 2.5 µM HuR si RNA (naked or delivered by nanocarriers) was intravitreally administered in a DR model. Rats were sacrificed 48 h after si RNA injection and retinal tissues collected for Western blot, ELISA, histological examination. Results HuR si RNA treatment blunts both HuR and VEGF increase, restating normal VEGF content in DR retina. HuR si RNA exerts its protective effect when included in liposomal nanocarriers, since the naked molecule does not prevent diabetic retinal damage. Conclusions An HuR-based strategy may be a target in the chain of events controlling VEGF expression synergizing with oligonucleotide-based interventions having the potential to modulate the expression of VEGF without fully blocking it. [ABSTRACT FROM AUTHOR]

Abstract Background PTX is one of the most widely used drug in oncology due to its high efficacy against solid tumors and several hematological cancers. PTX is administered in a formulation containing 1:1 Cremophor® EL (polyethoxylated castor oil) and ethanol, often responsible for toxic effects. Its encapsulation in colloidal delivery systems would gain an improved targeting to cancer cells, reducing the dose and frequency of administration. Methods In this paper PTX was loaded in PLGA NS. The activity of PTX-NS was assessed in vitro against thyroid, breast and bladder cancer cell lines in cultures. Cell growth was evaluated by MTS assay, intracellular NS uptake was performed using coumarin-6 labelled NS and the amount of intracellular PTX was measured by HPLC. Results NS loaded with 3% PTX (w/w) had a mean size < 250 nm and a polydispersity index of 0.4 after freeze-drying with 0.5% HP-Cyd as cryoprotector. PTX encapsulation efficiency was 30% and NS showed a prolonged drug release in vitro. An increase of the cytotoxic effect of PTX-NS was observed with respect to free PTX in all cell lines tested. Conclusion These findings suggest that the greater biological effect of PTX-NS could be due to higher uptake of the drug inside the cells as shown by intracellular NS uptake and cell accumulation studies.