Indinavir-Loaded Nanostructured Lipid Carriers to Brain Drug Delivery: Optimization, Characterization and Neuropharmacokinetic Evaluation

Author(s): Mohammad Nasiri, Amir Azadi, Mohammad Reza Saghatchi Zanjani, Mehrdad Hamidi*.

Journal Name: Current Drug Delivery

Volume 16 , Issue 4 , 2019

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Abstract:

Purpose: As an anti-retroviral Protease Inhibitor (PI), Indinavir (IDV) is part of the regimen known as Highly Active Anti-Retroviral Therapy (HAART) widely used for Human Immunodeficiency Virus (HIV) infection. The drug efficiency in treatment of the brain manifestations of HIV is, however, limited which is mainly due to the efflux by P-glycoprotein (P-gp) expressed at the Blood-Brain Barrier (BBB).

Methods: To overcome the BBB obstacle, NLCs were used in this study as carriers for IDV, which were optimized through two steps: a “one-factor-at-a-time” screening followed by a systematic multiobjective optimization. Spherical smooth-surfaced Nanoparticles (NPs), average particle size of 161.02±4.8 nm, Poly-Dispersity Index (PDI) of 0.293±0.07, zeta potential of -40.62±2.21 mV, entrapment efficiency of 93±1.58%, and loading capacity of 9.15±0.15% were obtained after optimization which were, collectively, appropriate in terms of the objective of this study.

Result: The surface of the optimized NPs was, then, modified with human Transferrin (TR) to improve the drug delivery. The particle size, zeta potential, and PDI of the TR-modified NLCs were 185.29±6.7nm, -28.68±3.37 mV, and 0.247±0.06, respectively. The in vitro release of IDV molecules from the NPs was best fitted to the Weibull model indicating hybrid diffusion/erosion behavior.

Conclusion: As the major in vivo findings, compared to the free drug, the NLCs and TR-NLCs displayed significantly higher and augmented concentrations in the brain. In this case, NLC and TR-NLC were 6.5- and 32.75-fold in their values of the brain uptake clearance compared to free drug.

Keywords: Blood-Brain Barrier (BBB), Nanostructured Lipid Carriers (NLC), indinavir, transferrin, neuropharmacokinetic analysis, Highly Active Anti-Retroviral Therapy (HAART).

[1]
Joint United Nations Programme on HIV/AIDS. Global HIV&AIDS statistics - 2018 fact sheet. Available from: http://www.unaids.org/en/resources/fact-sheet
[2]
Letendre, S. Central Nervous System Complications in HIV Disease: HIV-Associated Neurocognitive Disorder. Top. Antivir. Med., 2011, 19(4), 137-142.
[3]
Al-Ghananeem, A.M.; Smith, M.; Coronel, M.L.; Tran, H. Advances in brain targeting and drug delivery of anti-HIV therapeutic agents. Expert Opin. Drug Deliv., 2013, 10(7), 973-985.
[4]
Price, R.W.; Spudich, S. Antiretroviral therapy and central nervous system HIV type 1 infection. J. Infect. Dis., 2008, 197(3), 294-306.
[5]
Johnson, T.P.; Nath, A. New insights into HIV neuropathogenesis in: HIV and the Brain: New challenges in the modern era; Springer, 2009, pp. 17-27.
[6]
Prabhakar, K.; Afzal, S.M.; Kumar, P.U.; Rajanna, A.; Kishan, V. Brain delivery of transferrin coupled indinavir submicron lipid emulsions-pharmacokinetics and tissue distribution. Colloids Surf. B Biointerfaces, 2011, 86(2), 305-313.
[7]
Wohlfart, S.; Gelperina, S.; Kreuter, J. Transport of drugs across the blood–brain barrier by nanoparticles. J. Control. Release, 2012, 161(2), 264-273.
[8]
Hamidi, M. Role of P-glycoprotein in tissue uptake of indinavir in rat. Life Sci., 2006, 79(10), 991-998.
[9]
Rao, K.S.; Ghorpade, A.; Labhasetwar, V. Targeting anti-HIV drugs to the CNS. Expert Opin. Drug Deliv., 2009, 6(8), 771-784.
[10]
Saraiva, C.; Praca, C.; Ferreira, R.; Santos, T.; Ferreira, L.; Bernardino, L. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases. J. Control. Release, 2016, 235, 34-47.
[11]
Patel, T.; Zhou, J.; Piepmeier, J.M.; Saltzman, W.M. Polymeric nanoparticles for drug delivery to the central nervous system. Adv. Drug Deliv. Rev., 2012, 64(7), 701-705.
[12]
Bondi, M.L.; Di Gesu, R.; Craparo, E.F. Lipid nanoparticles for drug targeting to the brain. Methods Enzymol., 2012, 508, 229-251.
[13]
Hamidi, M. Simple and sensitive high-performance liquid chromatography method for the quantitation of indinavir in rat plasma and central nervous system. J. Sep. Sci., 2006, 29(5), 620-627.
[14]
Tapeinos, C.; Battaglini, M.; Ciofani, G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. J. Control. Release, 2017, 264, 306-332.
[15]
Azadi, A.; Hamidi, M.; Khoshayand, M.R.; Amini, M.; Rouini, M.R. Preparation and optimization of surface-treated methotrexate-loaded nanogels intended for brain delivery. Carbohydr. Polym., 2012, 90(1), 462-471.
[16]
Azadi, A.; Hamidi, M.; Rouini, M.R. Methotrexate-loaded chitosan nanogels as ‘Trojan Horses’ for drug delivery to brain: Preparation and in vitro/in vivo characterization. Int. J. Biol. Macromol., 2013, 62, 523-530.
[17]
Azadi, A.; Rouini, M.R.; Hamidi, M. Neuropharmacokinetic evaluation of methotrexate-loaded chitosan nanogels. Int. J. Biol. Macromol., 2015, 79, 326-335.
[18]
Hamidi, M. Central nervous system distribution kinetics of indinavir in rats. J. Pharm. Pharmacol., 2007, 59(8), 1077-1085.


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Article Details

VOLUME: 16
ISSUE: 4
Year: 2019
Page: [341 - 354]
Pages: 14
DOI: 10.2174/1567201816666190123124429
Price: $58

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