Oxaprozin-Loaded Lipid Nanoparticles towards Overcoming NSAIDs Side-Effects.
OBJECTIVE
Nanostructured Lipid Carriers (NLCs) loading oxaprozin were developed to address an effective drug packaging and targeted delivery, improving the drug pharmacokinetics and pharmacodynamics properties and avoiding the local gastric side-effects. Macrophages actively phagocyte particles with sizes larger than 200 nm and, when activated, over-express folate beta receptors - features that in the case of this work constitute the basis for passive and active targeting strategies.


METHODS
Two formulations containing oxaprozin were developed: NLCs with and without folate functionalization. In order to target the macrophages folate receptors, a DSPE-PEG2000-FA conjugate was synthesized and added to the NLCs.


RESULTS
These formulations presented a relatively low polydispersity index (approximately 0.2) with mean diameters greater than 200 nm and zeta potential inferior to -40 mV. The encapsulation efficiency of the particles was superior to 95% and the loading capacity was of 9%, approximately. The formulations retained the oxaprozin release in simulated gastric fluid (only around 10%) promoting its release on simulated intestinal fluid. MTT and LDH assays revealed that the formulations only presented cytotoxicity in Caco-2 cells for oxaprozin concentrations superior to 100 μM. Permeability studies in Caco-2 cells shown that oxaprozin encapsulation did not interfered with oxaprozin permeability (around 0.8 × 10(-5) cm/s in simulated intestinal fluid and about 1.45 × 10(-5) cm/s in PBS). Moreover, in RAW 264.7 cells NLCs functionalization promoted an increased uptake over time mainly mediated by a caveolae uptake mechanism.


CONCLUSIONS
The developed nanoparticles enclose a great potential for oxaprozin oral administration with significant less gastric side-effects.
UCIBIO, REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
José
J
Lopes-de-Araújo
UCIBIO, REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
Ana Rute
AR
Neves
UCIBIO, REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
Virgínia M
VM
Gouveia
UCIBIO, REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
Catarina C
CC
Moura
UCIBIO, REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal. cdnunes@ff.up.pt.
Cláudia
C
Nunes
UCIBIO, REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
Salette
S
Reis
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry*; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D000077431:Oxaprozin; D010539:Permeability; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011422:Propionates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000894:Anti-Inflammatory Agents, Non-Steroidal; D004337:Drug Carriers; D010714:Phosphatidylethanolamines; D011422:Propionates; D011092:Polyethylene Glycols; D005492:Folic Acid; D000077431:Oxaprozin
Caco-2 permeability study; folate functionalization; in vitro release study; nanoparticles characterization; oxaprozin