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Oxaprozin-Loaded Lipid Nanoparticles towards Overcoming NSAIDs Side-Effects

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Abstract

Purpose

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.

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Abbreviations

DSPE-PEG2000-FA:

Disteroylphosphatidylethanolamine-poly(ethylene glycol)2000-folic acid

EE:

Encapsulation efficiency

FA-NLCs + Oxa:

DSPE-PEG2000-FA functionalized oxaprozin loaded nanostructured lipid carriers NLCs

FA-NLCs:

DSPE-PEG2000-FA functionalized placebo nanostructured lipid carriers

FR:

Folate receptor

GI:

Gastrointestinal

LC:

Loading capacity

LNs:

Lipid nanoparticles

NLCs:

Nanostructured lipid carriers

NLCs Placebo:

Non-functionalized placebo nanostructured lipid carriers

NLCs + Oxa:

Non-functionalized oxaprozin loaded nanostructured lipid carriers

NSAIDs:

Non-steroidal Anti-inflammatory drugs

Oxa:

Oxaprozin

SLN:

Solid lipid nanoparticles

TEER:

Transepithelial electrical resistance

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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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Authors and Affiliations

  1. UCIBIO, REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal

    José Lopes-de-Araújo, Ana Rute Neves, Virgínia M. Gouveia, Catarina C. Moura, Cláudia Nunes & Salette Reis

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  1. José Lopes-de-Araújo
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  2. Ana Rute Neves
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Correspondence to Cláudia Nunes.

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Lopes-de-Araújo, J., Neves, A.R., Gouveia, V.M. et al. Oxaprozin-Loaded Lipid Nanoparticles towards Overcoming NSAIDs Side-Effects. Pharm Res 33, 301–314 (2016). https://doi.org/10.1007/s11095-015-1788-x

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  • DOI: https://doi.org/10.1007/s11095-015-1788-x

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