The blood–brain barrier (BBB) is a selective system of endothelial cells, joined through the tight junctions, that protect and maintain the homeostasis of the Central Nervous System (CNS). Only small molecule or drugs, with high lipid solubility and a lower molecular mass under 400–500 Da, can cross the BBB in pharmacologically significant amounts, limiting the uptake of most therapeutic agents into the brain. Currently, the management of neurological with aggressive and invasive techniques (surgery, see Appendix 3), achieves higher therapeutic effect compared to conventional delivery methods, such as systemic administration via intravenous injection or oral administration. However invasive techniques achieve less compliance. This has led to the development of vogue treatments such as nose-to-brain technologies (see Appendix 2), FUS-induced BBB opening, fusion protein chaperones, stem cells, gene therapy, use of natural compounds and neuroprotectants, in order to increase the neuroavailability of various advanced drug delivery systems. These strategies provide promising alternatives that are able to ameliorate the treatment of brain disease. At this purpose, several nanocarriers ranging from the more established systems, e.g. polymeric nanoparticles, liposomes, niosomes and micelles to the newer systems, e.g. nanoemulsions, micro and nano-bubbles, nanosuspensions and nanogels, have been studied for the delivery of therapeutics to CNS. Many of the proposed nanomedicines can be effectively transported across various in vitro and in vivo BBB models by endocytosis and/or transcytosis, and demonstrated early preclinical success for the management of CNS conditions such as brain tumours, HIV encephalopathy, neurodegenerative disease and acute ischemic stroke. Future development of CNS nanomedicines need to focus on increasing their drug-trafficking performance and specificity for brain tissue using novel targeting moieties, improving their BBB permeability and reducing their neurotoxicity. Targeted drug delivery is a means of concentrating drugs at a specific site relative to other parts of the body. It spares the rest of the body from toxic effects of the drug and it is also a potential means of improving therapeutic index. This Ph.D. thesis focused on the study of the formulation of different nanocarriers for brain delivery by two different administration routes: (1) Focused Ultrasound-mediated drug delivery, a technique that offer a unique non-invasive avenue to deliver drugs to the brain through transient opening of the BBB by using of ultrasound in combination with gas-filled bubbles. Our laboratory developed new carriers, the “Bubblesomes”®, able to combine the characteristics of a drug carrier and a contrast agent (theranostic system). When focused ultrasound is applied in presence of drug loaded nanobubbles intravenously administered, inertial cavitation is induced, due to the rapid expansion and violent collapsing of bubbles. This can cause the temporal and fully reversible opening of BBB due to the enhanced endothelial porosity and vascular permeability phenomenon called sonoporation, resulting in an increased drug uptake. (2) Intranasal drug delivery, a non-invasive route to reach directly the brain, circumvent the BBB, from the nose along the olfactory and trigeminal nerve pathways. These nerve pathways initiate in the nasal cavity at olfactory neuroepithelium and terminate in the brain.
Soft nanocarrier development as a versatile approach to brain delivery and targeting / Hanieh, PATRIZIA NADIA. - (2017 Dec 18).
|Titolo:||Soft nanocarrier development as a versatile approach to brain delivery and targeting|
|Data di discussione:||18-dic-2017|
|Appartiene alla tipologia:||07a Tesi di Dottorato|