Poloxamer 188 functionalized Eudragit RS-nanocarriers as a novel strategy for enhancing loperamide Central Nervous System biodistribution and reducing proteotoxic stress

PONCE, MARÍA FERNANDA ; SILVERO, MARÍA JAZMÍN; CATALAN, JOHANNA; MONTIVERO, AGUSTÍN; PÉREZ, MARIELA F.; CONSTANTIN, MARÍA FLORENCIA; BECERRA, MARÍA CECILIA

Mar del Plata

Congreso; Reunión Anual de Sociedades Biocientíficas; 2020

Brain drug delivery current strategies are of wide scientific interest, mainly for the presence of the blood-brain barrier (BBB). For that matter, we have developed a nanotechnology-based delivery system for brain targeting, after its oral administration. Loperamide was chosen since it does not cross the BBB, but exhibits anti-inflammatory activity, along with its mu-opioid-mediated analgesic effects, and non-mu-receptor associated neuroprotective properties, thus having potential advantages over morphine. Therefore, in this work, we evaluated the capacity of nanocarriers of Eudragit® RS (ERS) covered with poloxamer 188 (P188) and loaded with loperamide (NP-Lop), for crossing the BBB and reduce protein oxidative stress. Methods: Central biodistribution was assessed by evaluating NP-Lop supraspinal analgesic effects in rats naive submitted to the Hot Plate Test, after its oral and intraperitoneal administration. Protein oxidative stress was measure in prefrontal cortex (PFC) of rats submitted to traumatic brain injury (TBI), by advance oxidative protein products (AOPP) colorimetric assay, after NP-Lop intravenous administration. Confidence interval was set at 95%; statistical analysis was performed by t-student comparison or ANOVA and Tukey test. Results: NP-Lop increased maximum possible effect in the Hot Plate test at 30 min, 2 and 24 h after both, ip and vo NP-Lop administration, in about 20 and 60-fold regarding loperamide in solution (Lop/Sol). In addition, NP-Lop reduce AOPP in about 6.7-fold regarding TBI. Conclusion: NP-Lop enhance loperamide CNS biodistribution, and reduces AOPP in a TBI rat model. Finally, the nanocarriers synthesized are potentially a nanopharmaceutical form that may enhance gastrointestinal absorption of drugs like loperamide.