Rapamycin (Rp) is an mammalian target of rapamycin-inhibitor (mTOR-I) approved by the U.S. Food and Drug Administration for clinical use as an immunosuppressant. It is currently used to induce tolerance in organ-transplanted patients, but also in oncology for treatment of advanced renal cancer. Recent studies demonstrate that Rp leads to benefits also in neurological diseases. In fact, a prolonged Rp treatment gives rise to the rescue of the learning deficit and the reduction of the intraneural Aβ in an Alzheimer’s Disease mouse model [1]. In 2006, Franz DN et coworkers reported the regression of subependymal giant cell astrocytomas in the brain of patients affected by the Tuberous Sclerosis Complex (TSC) after a prolonged oral Rp administration [2]. Unfortunately systemic administration of Rp, and more generally of mTOR-Is, even are though it offers significant benefits, produces a number of side effects that may impair their therapeutic efficacy, especially upon chronic administration [2,3]. The administration of mTOR-Is directly to central nervous system (CNS) carry the advantage of limiting systemic exposure to the drug and, in addition, it allows to fully exploiting the local benefit [4]. In our work, we administered everolimus, an Rp analogs, directly to the CNS of symptomatic 3xTgAD mice via intracerebroventricular infusion. We showed that everolimus, administered for a short period, caused the improvement of behavioral, biochemical and pathological dysfunctions of 3xTg-AD mice, allowing their preservation for a relatively long time. Alternatively to the invasive CNS administration, we are developing site-specific nanocarriers for intravenous injection with the aim to pass the blood-brain barrier (BBB) and release therapeutic mTOR-Is doses directly to the CNS. In this regard, we prepared Rp-loaded solid lipid nanoparticles (SLNs) functionalized with polysorbate 80 (P80) on the surface and demonstrated their ability to be internalized into the cell and to release an efficacious dose of drug to inhibit mTOR activity [6, 7]. Moreover, Rp-SLNs increased stability/integrity of the drug thus prolonging its bioavailability in the cells. Thus, Rp-SLNs could represent a promising tool for the treatment of diseases with neurological involvement. Acknowledgments Work supported by Cassa di Risparmio di Perugia Foundation, Italy (Grant no.2016-0050.021 to Carla Emiliani) References [1] Caccamo et al. (2010) J Biol Chem 285, 13107-20 [2] Franz et al., (2006) Ann Neurol 59, 490-498 [3] Krueger et al. (2010) N Engl J Med 363,1801-11 [4] Patent EP2846770A15 [5] Giovagnoli et al. (2015) J Chromatogr B Analyt Technol Biomed Life Sci. 985, 155-63 [6] Mazurik J et al. (2016) Colloids Surf A Physicochem Eng Asp. 502, 54-65 [7] Polchi et al (2016) Nanomaterials (Basel) 6(5). pii: E87

Drug delivery strategies for mTOR inhibitors therapy in neurodegenerative and neuro-oncologic disease.

Alessandro Magini;Alice Polchi;Danila Di Meo;Carla Emiliani
2017-01-01

Abstract

Rapamycin (Rp) is an mammalian target of rapamycin-inhibitor (mTOR-I) approved by the U.S. Food and Drug Administration for clinical use as an immunosuppressant. It is currently used to induce tolerance in organ-transplanted patients, but also in oncology for treatment of advanced renal cancer. Recent studies demonstrate that Rp leads to benefits also in neurological diseases. In fact, a prolonged Rp treatment gives rise to the rescue of the learning deficit and the reduction of the intraneural Aβ in an Alzheimer’s Disease mouse model [1]. In 2006, Franz DN et coworkers reported the regression of subependymal giant cell astrocytomas in the brain of patients affected by the Tuberous Sclerosis Complex (TSC) after a prolonged oral Rp administration [2]. Unfortunately systemic administration of Rp, and more generally of mTOR-Is, even are though it offers significant benefits, produces a number of side effects that may impair their therapeutic efficacy, especially upon chronic administration [2,3]. The administration of mTOR-Is directly to central nervous system (CNS) carry the advantage of limiting systemic exposure to the drug and, in addition, it allows to fully exploiting the local benefit [4]. In our work, we administered everolimus, an Rp analogs, directly to the CNS of symptomatic 3xTgAD mice via intracerebroventricular infusion. We showed that everolimus, administered for a short period, caused the improvement of behavioral, biochemical and pathological dysfunctions of 3xTg-AD mice, allowing their preservation for a relatively long time. Alternatively to the invasive CNS administration, we are developing site-specific nanocarriers for intravenous injection with the aim to pass the blood-brain barrier (BBB) and release therapeutic mTOR-Is doses directly to the CNS. In this regard, we prepared Rp-loaded solid lipid nanoparticles (SLNs) functionalized with polysorbate 80 (P80) on the surface and demonstrated their ability to be internalized into the cell and to release an efficacious dose of drug to inhibit mTOR activity [6, 7]. Moreover, Rp-SLNs increased stability/integrity of the drug thus prolonging its bioavailability in the cells. Thus, Rp-SLNs could represent a promising tool for the treatment of diseases with neurological involvement. Acknowledgments Work supported by Cassa di Risparmio di Perugia Foundation, Italy (Grant no.2016-0050.021 to Carla Emiliani) References [1] Caccamo et al. (2010) J Biol Chem 285, 13107-20 [2] Franz et al., (2006) Ann Neurol 59, 490-498 [3] Krueger et al. (2010) N Engl J Med 363,1801-11 [4] Patent EP2846770A15 [5] Giovagnoli et al. (2015) J Chromatogr B Analyt Technol Biomed Life Sci. 985, 155-63 [6] Mazurik J et al. (2016) Colloids Surf A Physicochem Eng Asp. 502, 54-65 [7] Polchi et al (2016) Nanomaterials (Basel) 6(5). pii: E87
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1423752
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