No need to remind that the blood brain barrier (BBB), the specialized system that separates the brain from systemic circulation, is actually an inviolable defence against molecules not displaying the chemical or receptoral features enabling its crossing. Neurotherapeutic agents are often unable to penetrate into the brain to perform their actions. The major part of the small molecule drugs, and nearly all the large molecule drugs (such as peptides, proteins and nucleic acids) cannot substantially cross this barrier. This selectivity of the BBB highly limits therapies for the cerebral diseases and a great deal of efforts to develop strategies that aid drug passage across the BBB has been made. A starting point for novel therapeutic strategies against neurodegenerative diseases is the Mammalian Target of Rapamycin (mTOR) inhibition, by using mTOR inhibitors such as rapamycin (Rp) or its analogues. mTOR is a serine/threonine kinase that exerts a key-role in cellular metabolism, regulation of cell growth and motility. Rp is currently used in organ-transplanted patients and also in advanced renal cancer because its immunomodulator properties. Recent studies demonstrate that Rp leads to neurological benefits in neurodegenerative diseases such as Alzheimer Disease (AD) and in brain tumors. However, although being able to cross the BBB, the drug shows heavy side effects over long-term treatments owing to systemic immunosuppression. In this regard, we have demonstrated that the administration of the mTOR inhibitor directly in the CNS by using osmotic pumps carries the advantage of limiting systemic exposure to the drug on the one side, fully exploiting the local benefit on the other side. In order to establish a low-invasive therapeutic strategy based on site-specific nanocarriers for i.v. injection able to direct mTOR-I preferentially to the brain, we are exploiting the potentiality of poly(lactic-co-glycolic acid) (PLGA) NPs coated with a short opioid peptide and of solid lipid nanoparticles (SLNs) or drug nanocrystals tailored to present polysorbate 80 (P80) on the surface.
NANOPARTICLE-DRIVEN DRUG DELIVERY TO THE CNS: COMPARISON OF PLGA AND LIPID-BASED NAOPARTICLES IN MOUSE MODEL OF NEURODEGENERATIVE DISEASES
MAGINI, Alessandro;BLASI, PAOLO;GIOVAGNOLI, Stefano;POLCHI, ALICE;TANCINI, Brunella;EMILIANI, Carla
2013
Abstract
No need to remind that the blood brain barrier (BBB), the specialized system that separates the brain from systemic circulation, is actually an inviolable defence against molecules not displaying the chemical or receptoral features enabling its crossing. Neurotherapeutic agents are often unable to penetrate into the brain to perform their actions. The major part of the small molecule drugs, and nearly all the large molecule drugs (such as peptides, proteins and nucleic acids) cannot substantially cross this barrier. This selectivity of the BBB highly limits therapies for the cerebral diseases and a great deal of efforts to develop strategies that aid drug passage across the BBB has been made. A starting point for novel therapeutic strategies against neurodegenerative diseases is the Mammalian Target of Rapamycin (mTOR) inhibition, by using mTOR inhibitors such as rapamycin (Rp) or its analogues. mTOR is a serine/threonine kinase that exerts a key-role in cellular metabolism, regulation of cell growth and motility. Rp is currently used in organ-transplanted patients and also in advanced renal cancer because its immunomodulator properties. Recent studies demonstrate that Rp leads to neurological benefits in neurodegenerative diseases such as Alzheimer Disease (AD) and in brain tumors. However, although being able to cross the BBB, the drug shows heavy side effects over long-term treatments owing to systemic immunosuppression. In this regard, we have demonstrated that the administration of the mTOR inhibitor directly in the CNS by using osmotic pumps carries the advantage of limiting systemic exposure to the drug on the one side, fully exploiting the local benefit on the other side. In order to establish a low-invasive therapeutic strategy based on site-specific nanocarriers for i.v. injection able to direct mTOR-I preferentially to the brain, we are exploiting the potentiality of poly(lactic-co-glycolic acid) (PLGA) NPs coated with a short opioid peptide and of solid lipid nanoparticles (SLNs) or drug nanocrystals tailored to present polysorbate 80 (P80) on the surface.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
