Novel nanoformulation to mitigate co-effects of drugs of abuse and HIV-1 infection: towards the treatment of NeuroAIDS
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Drug abuse (e.g., methamphetamine—Meth or cocaine—Coc) is one of the major risk factors for becoming infected with HIV-1, and studies show that in combination, drug abuse and HIV-1 lead to significantly greater damage to CNS. To overcome these issues, we have developed a novel nanoformulation (NF) for drug-abusing population infected with HIV-1. In this work, a novel approach was developed for the co-encapsulation of Nelfinavir (Nel) and Rimcazole (Rico) using layer-by-layer (LbL) assembled magnetic nanoformulation for the cure of neuroAIDS. Developed NF was evaluated for blood-brain barrier (BBB) transmigration, cell uptake, cytotoxicity and efficacy (p24 assay) in HIV-1 infected primary astrocyte (HA) in presence or absence of Coc and Meth. Developed magnetic nanoformulation (NF) fabricated using the LbL approach exhibited higher amounts of drug loading (Nel and Rico) with 100% release of both the therapeutic agents in a sustained manner for 8 days. NF efficacy studies indicated a dose-dependent decrease in p24 levels in HIV-1-infected HA (~55%) compared to Coc + Meth treated (~50%). The results showed that Rico significantly subdued the effect of drugs of abuse on HIV infectivity. NF successfully transmigrated (38.8 ± 6.5%) across in vitro BBB model on the application of an external magnetic field and showed >90% of cell viability with efficient cell uptake. In conclusion, our proof of concept study revealed that sustained and concurrent release of sigma σ1 antagonist and anti-HIV drug from the developed novel sustained release NF can overcome the exacerbated effects of drugs of abuse in HIV infection and may solve the issue of medication adherence in the drug-abusing HIV-1 infected population.
KeywordsNeuroAIDS Drugs of abuse Magnetic nanoparticle Sustain release formulation Blood-brain-barrier (BBB)
We would like to acknowledge the financial support from NIH grant nos. R01-DA040537, R01-DA037838, R01-DA042706, for (MN). We also like to acknowledge NIH-AIDS Research Program for the ARV drug and HIV-1 virus. The authors also would like to acknowledge Roozbeh Nikkhah-Moshaie and the facility support of the Advanced Materials Engineering Research Institute (AMERI), FIU.
RDJ conducted all of the key measurements including NF preparation, characterization, in vitro drug release, BBB, and efficacy studies. VA helped in designing dose optimization, cellular uptake, cell culture studies, and p24 assays. AY and SPK helped with flow cytometer analysis. AK and ST helped with TEM, DLS, and MTT cytotoxicity studies. MN supervised the whole project.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Atluri VSR, Hidalgo M, Samikkannu T, Kurapati KRV, Jayant RD, Sagar V, Nair MP (2015) Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update. Front Cell Neurosci 9:212. doi: 10.3389/fncel.2015.00212
- Bing EG, Burnam M, Longshore D, Fleishman JA, Sherbourne CD, London AS, Turner BJ, Eggan F, Beckman R, Vitiello B, Morton SC, Orlando M, Bozzette SA, Ortiz-Barron L, Shapiro M (2001) Psychiatric disorders and drug use among human immunodeficiency virus infected adults in the united states. Arch gen Psychiatry 58:721–728CrossRefPubMedGoogle Scholar
- Borgmann K, Ghorpade A (2015) HIV-1, methamphetamine and astrocytes at neuroinflammatory crossroads. Front Microbiol 6:1143. doi: 10.3389/fmicb.2015.01143
- Conigliaro J, Madenwald T, Bryant K, Braithwaite S, Gordon A, Fultz SL, Maisto S, Samet J, Kraemer K, Cook R, Day N, Roach D, Richey S, Justice A (2004) The veterans aging cohort study: observational studies of alcohol use, abuse, and outcomes among human immunodeficiency virus–infected veterans. Alcohol Clin Exp res 28:313–321CrossRefPubMedGoogle Scholar
- Díaz L, Martínez-Bonet M, Sánchez J, Fernández-Pineda A, Jiménez JL, Muñoz E, Moreno S, Álvarez S, Muñoz-Fernández MÁ (2015) Bryostatin activates HIV-1 latent expression in human astrocytes through a PKC and NF-ĸB-dependent mechanism. Scientific Reports 5:12442. doi: 10.1038/srep12442
- Jayant RD, Madhavan N (2016) Materials and methods for sustained release of active compounds. In: US Patent App. 15/082,611Google Scholar
- Kaushik A, Jayant RD, Nikkhah-Moshaie R, Bhardwaj V, Roy U, Huang Z, Ruiz A, Yndart A, Atluri V, El-Hage N (2016a) Magnetically guided central nervous system delivery and toxicity evaluation of magneto-electric nanocarriers. Sci Rep 6:25309. doi: 10.1038/srep25309
- Ramesh G, MacLean AG, Philipp MT (2013) Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediat Inflamm 2013:480739. doi: 10.1155/2013/480739
- Ramirez SH, Potula R, Fan S, Eidem T, Papugani A, Reichenbach N, Dykstra H, Weksler BB, Romero IA, Couraud PO (2009) Methamphetamine disrupts blood–brain barrier function by induction of oxidative stress in brain endothelial cells. J Cereb Blood Flow Metab 29:1933–1945CrossRefPubMedPubMedCentralGoogle Scholar
- Tomitaka A, Arami H, Raymond A, Yndart A, Kaushik A, Jayant RD, Takemura Y, Cai Y, Toborek M, Nair M (2017) Development of magneto-plasmonic nanoparticles for multimodal image-guided therapy to the brain. Nano 9:764–773Google Scholar