Advertisement

Nanomedicines for Improved Antiretroviral Therapy in Neuro-AIDS

  • Aarti Belgamwar
  • Shagufta Khan
  • Pramod Yeole
Chapter

Abstract

Human immunodeficiency virus is neurotropic which invades the central nervous system (CNS) in early course of systemic infection and makes the CNS an important dominant reservoir with the capacity to supply virus in low/undetectable viremia. Neuro-AIDS is the major upcoming issue among long-term seropositive survivors as a consequence of incompetence of antiretroviral in complete eradication of HIV from the CNS. Justification behind the low CNS concentration of antiretroviral is anatomical barrier and physicochemical properties of antiretrovirals. Some unmet needs in neuro-AIDS treatment are simplified CNS-targeted treatment regimen and disease-modifying therapies. Target-specific, safe, and controllable nanomedicines have been extensively studied, with particular success, to overcome the natural barriers to the antiretroviral drug delivery posed by the CNS anatomy, histology, and physiology. This chapter insight on current understanding of neuro-AIDS and the pathological mechanisms involved several limitations to the eradication of latent reservoirs and approaches to circumvent these limitations by state-of-the-art nanomedicines.

Keywords

Neuro-AIDS Antiretroviral Nanomedicines HIV CNS 

Nomenclature

ABC

ATP-binding cassette

ADC

AIDS dementia complex

AIDS

Acquired immunodeficiency syndrome

ARV

Antiretroviral

BBB

Blood-brain barrier

BCRP

Breast cancer resistance protein

BCSFB

Blood-cerebrospinal fluid barrier

BMECs

Brain microvessel endothelial cells

BMVECs

Brain microvascular endothelial cells

cART

Combination antiretroviral therapy

CCR5

C-C chemokine receptor type 5

CD4

Cluster of differentiation 4

CNS

Central nervous system

CSF

Cerebrospinal fluid

CSFB

Cerebrospinal fluid-brain barrier

CXCR4

C-X-C chemokine receptor type 4

gp120

Glycoprotein 120

HAART

Highly active antiretroviral therapy

HAND

HIV-associated neurocognitive disorders

hCMEC/D3

Human cerebral microvascular endothelial cell line

HIV

Human immunodeficiency virus

NLCs

Nanostructured lipid carriers

PLA

Polylactic acid

PLGA

Poly(D,L-lactic-co-glycolic acid)

siRNA

Small interfering ribonucleic acid

SIV

Simian immunodeficiency virus

SLN

Solid lipid nanoparticle

Vpr

Viral protein R

References

  1. Albright A, Soldan S, Gonzalez-Scarano F (2003) Pathogenesis of human immunodeficiency virus-induced neurological disease. J Neurovirol 9:222–227PubMedCrossRefPubMedCentralGoogle Scholar
  2. Alghananeem AM, Saeed H, Florence R, Yokel R, Malkawi A (2010) Intranasal drug didanosine-loadedchitosan nanoparticles for brain targeting; an attractive route against ing=fections caused by AIDS viruses. J Drug Targeting 18:381–388Google Scholar
  3. Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13PubMedCrossRefPubMedCentralGoogle Scholar
  4. Barbi M, Carvalho C, Kiill C, Barud H, Santagneli S, Ribeiro S, Gremião M (2015) Preparation and characterization of chitosan nanoparticles for zidovudine nasal delivery. J Nanosci Nanotechnol 15:865–874CrossRefGoogle Scholar
  5. Batrakova E, Li S, Miller D, Kabanov A (1999) Pluronic P85 increases permeability of a broad spectrum of drugs in polarized BBMEC and Caco-2 cell monolayers. Pharm Res 16:1366–1372PubMedCrossRefPubMedCentralGoogle Scholar
  6. Belgamwar A, Khan S, Yeole P (2018) Intranasal chitosan-g-HPβCD nanoparticles of efavirenz for the CNS targeting. Artif Cell Nanomed Biotechnol 46:374–386CrossRefGoogle Scholar
  7. Belgamwar A, Khan S, Yeole P (2019) Intranasal dolutegravir sodium loaded nanoparticles of hydroxypropyl-betacyclodextrin for brain delivery in neuro-AIDS. J Drug Deliv Sci Technol 52:1008–1020CrossRefGoogle Scholar
  8. Bell J (2004) An update on the neuropathology of HIV in the HAART era. Histopathology 45:549–559PubMedCrossRefPubMedCentralGoogle Scholar
  9. Blasi P, Giovagnoli S, Schoubben A, Ricci M, Rossi C (2007) Solid lipid nanoparticles for targeted brain drug delivery. Adv Drug Deliv Rev 59:454–477PubMedCrossRefPubMedCentralGoogle Scholar
  10. Chattopadhyay N, Zastre J, Wong HL, Wu XY, Bendayan R (2008) Solid lipid nanoparticles enhance the delivery of the HIV protease inhibitor, atazanavir, by a human brain endothelial cell line. Pharm Res 25:2262–2271PubMedCrossRefPubMedCentralGoogle Scholar
  11. Chiappetta D, Hocht C, Opezzo J, Sosnik A (2013) Intranasal administration of antiretroviral-loaded micelles for anatomical targeting to the brain in HIV. Nanomedicine 8:223–237PubMedCrossRefPubMedCentralGoogle Scholar
  12. Connor R, Sheridan K, Ceradini D, Choe S, Landau N (1997) Change in coreceotor use correlates with disease progression in HIV-1 infected individuals. J Exp Med 185:621–628PubMedPubMedCentralCrossRefGoogle Scholar
  13. Dalpiaz A, Fogagnolo M, Ferraro L, Capuzzo A, Pavan B, Rassu G, Salis A, Giunchedi P, Gavini E (2015) Nasal chitosan microparticles target a zidovudine prodrug to brain HIV sanctuaries. Antiviral Res 123:146–157PubMedCrossRefPubMedCentralGoogle Scholar
  14. Das M, Chakraborty T (2015) Progress in brain delivery of anti-HIV drugs. J Appl Pharm Sci 5:154–164CrossRefGoogle Scholar
  15. Das S, Ng W, Tan R (2012) Are nanostructured lipid carriers (NLCs) better than solid lipid nanoparticles (SLNs): development, characterizations and comparative evaluations of clotrimazole-loaded SLNs and NLCs? Eur J Pharm Sci 47:139–151PubMedCrossRefPubMedCentralGoogle Scholar
  16. Dash P, Gendelman H, Roy U, Balkundi S, Alnouti Y, Mosley R, Gelbard H, McMillan J, Gorantla S, Poluektova L (2012) Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice. AIDS 26:2135–2144PubMedPubMedCentralCrossRefGoogle Scholar
  17. Date A, Destache C (2013) A review of nanotechnological approaches for the prophylaxis of HIV/AIDS. Biomaterials 34:6202–6228PubMedPubMedCentralCrossRefGoogle Scholar
  18. Destache C, Belgum T, Goede M, Shibata A, Belshan M (2010) Antiretroviral release from poly(DL-lactide-coglycolide) nanoparticles in mice. J Antimicrob Chemother 65:2183–2187PubMedPubMedCentralCrossRefGoogle Scholar
  19. Dhembre G, Moon R, Kshirsagar R (2011) A review on polymeric micellar nanocarriers. Int J Pharm Biol Sci 2:109–116Google Scholar
  20. Doktorovováa S, Araújob J, Garciab M, Rakovský E, Soutoa E (2010) Formulating fluticasone propionate in novel PEG-containing nanostructured lipid carriers (PEG-NLC). Colloids Surf B Biointerfaces 75:538–542CrossRefGoogle Scholar
  21. Dou H, Destache C, Morehead J, Mosley R, Boska M, Kingsley J, Gorantla S, Poluektova L, Nelson J, Chaubal M, Werling J, Kipp J, Rabinow B, Gendelman H (2006) Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery. Blood 108:2827–2835PubMedPubMedCentralCrossRefGoogle Scholar
  22. Dou H, Grotepas CB, McMillan J, Destache C, Chaubal M, Werling J, Kipp J, Rabinow B, Gendelman H (2009) Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS. J Immunol 183:661–669PubMedPubMedCentralCrossRefGoogle Scholar
  23. Dusserre N, Lessard C, Paquette N, Perron S, Poulin L, Tremblay M, Beauchamp D, Désormeaux A, Bergeron M (1995) Encapsulation of foscarnet in liposomes modifies drug intracellular accumulation, in vitro anti-HIV-1 activity, tissue distribution and pharmacokinetics. AIDS 9:833–841PubMedCrossRefPubMedCentralGoogle Scholar
  24. Dutta T, Jain N (2007) Targeting potential and anti-HIV activity of lamivudine loaded mannosylated poly (propyleneimine) dendrimers. Biochim Biophys Acta, Gen Subj 1770:681–686CrossRefGoogle Scholar
  25. Dutta T, Garg M, Jain N (2008) Targeting of efavirenz loaded tuftsin conjugated poly (propyleneimine) dendrimers to HIV infected macrophages in vitro. Eur J Pharm Sci 34:181–189PubMedCrossRefPubMedCentralGoogle Scholar
  26. Fiandra L, Colombo M, Mazzucchelli S, Santini B, Nebuloni M, Capetti A, Rizzardini G, Prosperi D, Corsi F (2015) Nanoformulation of antiretroviral drugs enhances their penetration across the blood brain barrier in mice. Nanomedicine 11:1387–1397PubMedCrossRefPubMedCentralGoogle Scholar
  27. Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5:69–81PubMedCrossRefPubMedCentralGoogle Scholar
  28. Greene W (2007) A history of AIDS: looking back to see ahead. Eur J Immunol 37:94–102CrossRefGoogle Scholar
  29. Gupta S, Kesarla R, Chotai N, Misra A, Omri A (2017) Systematic approach for the formulation and optimization of solid lipid nanoparticles of efavirenz by high pressure homogenization using design of experiments for brain targeting and enhanced bioavailability. Biomed Res Int 2017:5984014PubMedPubMedCentralGoogle Scholar
  30. Hu F, Jiang S, Du Y, Yuan H, Ye Y, Zeng S (2006) Preparation and characteristics of monostearin nanostructured lipid carriers. Int J Pharm 314:83–89PubMedCrossRefPubMedCentralGoogle Scholar
  31. Jain S, Gupta Y, Jain A, Saxena A, Khare P, Jain A (2009) Mannosylated gelatin nanoparticles bearing an anti-HIV drug didanosine for site-specific delivery. Nanomedicine 4:41–48CrossRefGoogle Scholar
  32. Jin S, Bi D, Wang J, Wang Y, Hu H, Deng Y (2005) Pharmacokinetics and tissue distribution of zidovudine in rats following intravenous administration of zidovudine myristate loaded liposomes. Pharmazie 60:840–843PubMedPubMedCentralGoogle Scholar
  33. Jindal S, Bachhav P, Anil B (2017) In situ hybrid nano drug delivery system (IHN-DDS) of antiretroviral drug for simultaneous targeting to multiple viral reservoirs: an in vivo proof of concept. Int J Pharm 521:196–203PubMedCrossRefPubMedCentralGoogle Scholar
  34. Johanson C, Stopa E, McMillan P (2011) The blood-cerebrospinal fluid barrier: structure and functional significance. Methods Mol Biol 686:101–131PubMedCrossRefPubMedCentralGoogle Scholar
  35. Joshy K, Sharma C (2012) Blood compatible nanostructured lipid carriers for the enhanced delivery of azidothymidine to brain. Adv Sci Lett 6:47–55CrossRefGoogle Scholar
  36. Kabanov A, Alakhov V (2002) Pluronic® block copolymers in drug delivery: from micellar nanocontainers to biological response modifiers. Crit Rev Ther Drug Carrier Syst 19:1–72PubMedCrossRefPubMedCentralGoogle Scholar
  37. Kandadi P, Syed M, Goparaboina S, Veerabrahma K (2011) Brain specific delivery of pegylated indinavir submicron lipid emulsions. Eur J Pharm Sci 42:423–432PubMedCrossRefPubMedCentralGoogle Scholar
  38. Kaur A, Jain S, Tiwary A (2008) Mannan-coated gelatin nanoparticles for sustained and targeted delivery of didanosine: in vitro and in vivo evaluation. Acta Pharm 58:61–74PubMedCrossRefPubMedCentralGoogle Scholar
  39. Koopmans P, Ellis R, Best B, Letendre S (2009) Should antiretroviral therapy for HIV infection be tailored for intracerebral penetration? Neth J Med 67:206–211PubMedPubMedCentralGoogle Scholar
  40. Kramer-Hämmerle S, Rothenaigner I, Wolff H, Bell J, Brack-Werner R (2005) Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 111:194–213PubMedCrossRefPubMedCentralGoogle Scholar
  41. Kuo Y, Su F (2007) Transport of stavudine, delavirdine, and saquinavir across the blood–brain barrier by polybutylcyanoacrylate, methylmethacrylate-sulfopropylmethacrylate, and solid lipid nanoparticles. Int J Pharm 340:143–152PubMedCrossRefPubMedCentralGoogle Scholar
  42. Mahajan S, Roy I, Xu G, Yong K, Ding H, Aalinkeel R, Reynolds J, Sykes D, Nair B, Lin E, Prasad P, Schwartz S (2010) Enhancing the delivery of antiretroviral drug “Saquinavir” across the blood brain barrier using nanoparticles. Curr HIV Res 8:396–404PubMedPubMedCentralCrossRefGoogle Scholar
  43. Mahajan S, Law W, Aalinkeel R, Reynolds J, Nair B, Yong K, Roy I, Prasad P, Schwartz S (2012) Nanoparticle-mediated targeted delivery of antiretrovirals to the brain. Methods Enzymol 509:41–60PubMedCrossRefPubMedCentralGoogle Scholar
  44. Mahajan H, Mahajan M, Nerkar P, Agrawal A (2014) Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting. Drug Deliv 21:148–154PubMedCrossRefPubMedCentralGoogle Scholar
  45. Mainardes R, Gremião M, Brunetti I, Fonseca L, Khalil N (2009) Zidovudine-loaded PLA and PLA–PEG blend nanoparticles: influence of polymer type on phagocytic uptake by polymorphonuclear cells. J Pharm Sci 98:257–267PubMedCrossRefPubMedCentralGoogle Scholar
  46. McGee B, Smith N, Aweeka F (2006) HIV pharmacology: barriers to the eradication of HIV from the CNS. HIV Clin Trials 7:142–153PubMedCrossRefPubMedCentralGoogle Scholar
  47. Miller S (2002) HIV life cycle and potential targets for drug activity. South Afr J HIV Med 7:102–103Google Scholar
  48. Morison L (2001) The global epidemiology of HIV/AIDS. Br Med Bull 58:7–18PubMedCrossRefPubMedCentralGoogle Scholar
  49. Nair M, Jayant R, Kaushik A, Sagar V (2016) Getting into the brain: potential of nanotechnology in the management of NeuroAIDS. Adv Drug Deliv Rev 103:202–217PubMedPubMedCentralCrossRefGoogle Scholar
  50. Pardridge W (2002) Brain drug targeting: the future of brain drug development. J Clin Pathol 55(2):158Google Scholar
  51. Rao K, Ghorpade A, Labhasetwar V (2009) Targeting anti-HIV drugs to the CNS. Expert Opin Drug Deliv 6:771–784PubMedPubMedCentralCrossRefGoogle Scholar
  52. Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Jarvinen T, Savolainen J (2008) Prodrugs: design and clinical applications. Nat Rev Drug Discov 7:255–269PubMedCrossRefPubMedCentralGoogle Scholar
  53. Rodriguez M, Kaushik A, Lapierre J, Dever S, El-Hage N, Nair M (2017a) Electro-magnetic nano-particle bound Beclin1 siRNA crosses the blood – brain barrier to attenuate the inflammatory effects of HIV-1 infection in vitro. J Neuroimm Pharmacol 12:120–132CrossRefGoogle Scholar
  54. Rodriguez M, Lapierre J, Ojha C, Kaushik A, Batrakova E, Kashanchi F, Dever S, Nair M, El-Hage N (2017b) Intranasal drug delivery of small interfering RNA targeting Beclin1 encapsulated with polyethylenimine (PEI) in mouse brain to achieve HIV attenuation. Nat Sci Rep 8:71–10Google Scholar
  55. Saiyed M, Gandhi N, Nair M (2010) Magnetic nanoformulation of azidothymidine 5′-triphosphate for targeted delivery across the blood–brain barrier. Int J Nanomedicine 5:157–166PubMedPubMedCentralGoogle Scholar
  56. Shah L, Amiji M (2006) Intracellular delivery of saquinavir in biodegradable polymeric nanoparticles for HIV/AIDS. Pharm Res 23:2638–2645PubMedCrossRefPubMedCentralGoogle Scholar
  57. Sharp P, Hahn B (2012) Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med 1:a006841Google Scholar
  58. Shegokar R, Singh K (2011) Surface modified nevirapine nanosuspensions for viral reservoir targeting: in-vitro and in-vivo evaluation. Int J Pharm 421:341–352PubMedCrossRefPubMedCentralGoogle Scholar
  59. Shegokar R, Jansch M, Singh K, Muller R (2011) In vitro protein adsorption studies on nevirapine nanosuspensions for HIV/AIDS chemotherapy. Nanomed Nanotechnol Biol Med 7:333–340CrossRefGoogle Scholar
  60. Spitzenberger T, Heilman D, Diekmann C, Batrakova E, Kabanov A, Gendelman H, Elmquist W, Persidsky Y (2007) Novel delivery system enhances efficacy of antiretroviral therapy in animal model for HIV-1 encephalitis. J Cereb Blood Flow Metab 27:1033–1042PubMedCrossRefPubMedCentralGoogle Scholar
  61. Trkola A (2004) HIV-host interactions: vital to the virus and key to its inhibition. Curr Opin Microbiol 7:555–559PubMedCrossRefPubMedCentralGoogle Scholar
  62. Varatharajana L, Thomas S (2009) The transport of anti-HIV drugs across blood–CNS interfaces: summary of current knowledge and recommendations for further research. Antivir Res 82:A99–A109CrossRefGoogle Scholar
  63. Vinogradov S, Poluektova L, Makarov E, Gerson T, Senanayake M (2010) Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity. Antivir Chem Chemother 21:1–14PubMedPubMedCentralCrossRefGoogle Scholar
  64. Vyas T, Shah L, Amiji M (2006) Nanoparticulate drug carriers for delivery of HIV/AIDS therapy to viral reservoir sites. Expert Opin Drug Deliv 3:613–628PubMedCrossRefPubMedCentralGoogle Scholar
  65. Wong H, Wu X, Bendayan R (2012) Nanotechnological advances for the delivery of CNS therapeutics. Adv Drug Deliv Rev 64:686–700PubMedCrossRefGoogle Scholar
  66. Zaitseva M, Peden K, Golding H (2003) HIV coreceptors: role of structure, posttranslational modifications, and internalization in viral cell fusion and as targets for entry inhibitors. Biochim Biophys Acta 1614:51–61PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Aarti Belgamwar
    • 1
  • Shagufta Khan
    • 2
  • Pramod Yeole
    • 3
  1. 1.SVKM’s Institute of PharmacyDhuleIndia
  2. 2.Institute of Pharmaceutical Education and Research, Borgaon (Meghe)WardhaIndia
  3. 3.Dr. Babasaheb Ambedkar Marathwada UniversityAurangabadIndia

Personalised recommendations