Rapamycin-loaded solid lipid nanoparticles for brain targeting

Neurodegenerative diseases are very debilitating conditions with an increasing impact on the world population and as yet without an effective remedy. Therefore, the development of new strategies for early diagnosis and treatment of these diseases is becoming a priority. The selectivity of the blood-brain barrier (BBB) strictly limits the number of therapeutic substances able to reach the brain and therefore, in recent years, many studies have been directed to the development of systems that facilitate the passage of drugs to the central nervous system (CNS). One of the most crucial protein complexes, that regulates vital processes within signal transduction, proliferation and autophagy pathways, is the mammalian target of rapamycin (Rp) complex (mTOR). Specific inhibition of mTOR by Rp in-feed administration has been recently demonstrated to ameliorate the cognitive behavior in an Alzheimer’s mice model [1]. Rp is an immunosuppressive drug that can pass the BBB, but its systemic administration produces a number of side effects that may impair its therapeutic efficacy [2]. Nanoparticles represent one of the most innovative and noninvasive approaches for drug targeting. In particular, due to an average size below 100 nm and lipophilic properties, the use of P80-coated solid lipid nanoparticles (SLNs) can overcome the BBB and allow accumulation of drugs directly into the brain tissue, through the apolipoprotein blood-to-brain pathway. Here, we report the development of a novel formulation of Rp loaded SLNs and the investigation of the effect upon treatment of SHSY5Y neuroblastoma cells. Our results show that Rp loaded SLNs are able to inhibit mTOR activity over a longer period of time compared to free Rp. This prolonged action is rather evident even at concentrations as low as 2 nM and it is consistent with a longer retention of Rp due to a slower release from the SLNs. On the basis of the data obtained, we will perform experiments to assay in vivo the ability of Rp-SLNs to deliver Rp therapeutic doses to the CNS, limiting systemic exposure to the drug side effects.