Nano-drug delivery systems: a useful approach to improve the biopharmaceutical properties and the pharmacological potential of plant-derived molecules - Nanosistemi per il drug delivery: un valido approccio per migliorare le proprietà biofarmaceutiche e farmacologiche di sostanze di origine vegetale

Recently, the use of herbal drugs has been increased all over the world due to their therapeutic effects and fewer adverse effects as compared to conventional medicines. However, many herbal drugs and herbal extracts demonstrate low in vivo activity due to their poor solubility, improper molecular size or high metabolism, scarce absorption and bioavailability. Novel drug delivery systems open the door towards the development of enhancing bioavailability of plant-derived molecules. The innovative formulations are reported to have remarkable advantages over conventional formulations of plant actives and extracts which include increase of solubility, bioavailability, protection from toxicity, enhancement of pharmacological activity and intracellular uptake, modification of pharmacokinetics and biodistribution, improved tissue macrophages distribution, sustained delivery and protection from physical and chemical degradation. There are numerous examples of the application of the nano-sized drug delivery systems in this field related to isolated compounds or purified extracts. This research concerns the improvement of the biopharmaceutical properties and the pharmacological potential of plant-derived molecules. After the optimization of analytical methods for qualitative and quantitative characterization of the compounds, this work was focused on the development of different nano-drug delivery systems, such as micro- or nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, liposomes, and albumin nanoparticles, for oral and brain delivery of herbal extracts or single molecules. The obtained formulations were physically and chemically characterized by Light Scattering techniques, transmission electron microscopy observations, high performance liquid chromatography, spectrophotometric and calorimetric analyses. All the developed nanocarriers enhanced the solubility of the bioactives when compared with their aqueous suspensions. Chemical and physical stability during storage, in simulated gastrointestinal environment, in the presence of human serum albumin and in rat plasma was tested. The dialysis bag method was employed to evaluate the release of the entrapped molecules in different pH conditions. In vitro permeation, cytotoxicity and uptake studies using different models such as parallel artificial membrane permeability assay (PAMPA), Caco-2 cell line, hCMEC/D3 cells were performed. These in vitro studies could provide useful information about dissolution and permeation/absorption aspects, which further could be correlated to in vivo bioavailability studies. Furthermore, the mucoadhesive properties of chitosan-coated formulations were investigated in vitro, by the turbidimetric method and the evaluation of the -potential and performing ex-vivo experiments using the rabbit nasal mucosa in a Franz-type diffusion apparatus. Besides, to evaluate the ability of the delivery systems to cross the blood-brain barrier and reach brain tissues, in vivo distribution and fate after intravenous administration in healthy rats were studied. Finally, nanostructured lipid carriers designed with silymarin as a payload were studied in a diabetic mouse model as one alternative/complementary remedial in systemic hyperglycemia, hypertriglyceridemia, and neuropathy. Thus, the present research proposed novel and promising strategies based on the development of nano-drug delivery systems to enhance the biopharmaceutical properties of plant active compounds and improve their performance in therapy.