Multiple strategies for brain drug delivery: in vitro and in vivo analysis of P-glycoprotein inhibition by nanocarriers covered with poloxamer 188, and glucose quantum dots functionalization effects over preferential brain distribution.

JOHANNA CATALAN; GONZALES, PABLO M.; PÉREZ, MARIELA F.; ÓRDENES, NICOLÁS; MORALES, JAVIER O.; CONTRERAS, PILAR; PÉREZ-DONOSO, JOSÉ MANUEL

Mar del Plata

Congreso; Reunión Anual de Sociedades Biocientíficas; 2019

Sociedad Argentina Investigación Clínica

The treatment of Central Nervous System (CNS) disorders has limited efficacy due to the Blood Brain Barrier (BBB). Thus, drugs with CNS therapeutic potential are not being used mainly because of pharmacokinetic limitations. For example, loperamide (Lop) is a µ-opioid agonist that poorly penetrates the CNS since it is a hydrophobic drug and P-glycoprotein (Pgp) substrate; however, it has potential neuroprotective effects. Thus, in this work, we evaluated the capacity of nanocarriers of Eudragit® RS (ERS) covered with poloxamer 188 (P188) for the passive delivery of Lop (NP-Lop) to the CNS. NP-Lop were developed for increasing Lop water dispersion, and P188 was used for the inhibition of Pgp. Finally, under fasting conditions, preferential brain delivery was assessed by the conjugation of Quantum-Dots (QDs) with glucose, since it has been shown that glucose transporters exhibit a relative brain overexpression during hypoglycemia. Methods: NP-Lop effects over Pgp we evaluated by uptake and transport assays in MDCK-MDR1 cells. Central distribution was assessed by evaluating Lop supraspinal analgesic effects in mice submitted to a Hot Plate Test. Glucose functionalization effects over QDs biodistribution was evaluated by determining the fluorescence of mice organs using a multi-modal in vivo imaging system. All treatments were intravenously adminstered. Confidence interval was set at 95%; statistical analysis was performed by ANOVA and Holm-Sidak or Tukey test. Results: NP-Lop increased Lop uptake 2.1 times, while Lop efflux was decreased 10 times, regarding Lop in solution. Maximum possible effect in the Hot Plate test obtained with NP-Lop was 7.2 higher than the observed for Lop in solution. QDs conjugated with glucose showed to be preferentially distributed to the brain under fasting condition. Conclution: NP-Lop decrease Lop efflux and favour its transport towards the CNS. Glucose conjugation may induce a preferential brain distribution.