Oxaprozin-Loaded Lipid Nanoparticles towards Overcoming NSAIDs Side-Effects
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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.
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.
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.
The developed nanoparticles enclose a great potential for oxaprozin oral administration with significant less gastric side-effects.
KEY WORDSCaco-2 permeability study folate functionalization in vitro release study nanoparticles characterization oxaprozin
Disteroylphosphatidylethanolamine-poly(ethylene glycol)2000-folic acid
- FA-NLCs + Oxa
DSPE-PEG2000-FA functionalized oxaprozin loaded nanostructured lipid carriers NLCs
DSPE-PEG2000-FA functionalized placebo nanostructured lipid carriers
Nanostructured lipid carriers
- NLCs Placebo
Non-functionalized placebo nanostructured lipid carriers
- NLCs + Oxa
Non-functionalized oxaprozin loaded nanostructured lipid carriers
Non-steroidal Anti-inflammatory drugs
Solid lipid nanoparticles
Transepithelial electrical resistance
ACKNOWLEDGMENTS AND DISCLOSURES
This work was funded by FEDER funds through the Operational Programme for Competitiveness Factors - COMPETE and by National Funds through FCT - Foundation for Science and Technology under the Pest-C/EQB/LA0006/2013 and FCOMP-01-0124-FEDER-3728. The work also received financial support from the European Union (FEDER funds) under the framework of QREN through Project NORTE-07-0162-FEDER-000088. To all financing sources the authors are greatly indebted. JLA, ARN and CN also acknowledge the FCT for financial support through the Research grant PD/BI/105914/2014, PhD grant SFRH/BD/73379/2010 and Post-Doc Grant SFRH/BPD/81963/2011.
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