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Early Stage HIV Management and Reduction of Stavudine-Induced Hepatotoxicity in Rats by Experimentally Developed Biodegradable Nanoparticles

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Abstract

The objectives of this research work were to develop optimized nanoparticulate formulations of poly (d,l-lactic-co-glycolic acid) (PLGA) (85:15) with an anti-AIDS drug stavudine and to evaluate their in-vitro uptake by the macrophages and hepatotoxicity in-vivo. Nanoparticles were prepared by nanoprecipitation method based on a factorial design with varying parameters such as the amounts of polymer and stabilizer used. Physicochemical characterizations such as drugexcipient interaction, surface morphology, particle size, and zeta potential measurements were carried out. The best formulation was selected and tagged with fluorescein isothiocyanate (FITC) for cellular uptake study of the formulation. In-vitro uptake of nanoparticles by macrophages was carried out. Formulation-induced hepatotoxicity was assessed by analyzing some serum hepatotoxic parameters and hepatic histology following 10-day treatment in comparison with the free drug. Nanoparticles exhibited smooth surface with particle size 84–238 nm, high entrapment efficiency (approx 85%), and negative surface charge. Formulations showed a sustained drug release pattern over the study period. In-vitro uptake study by macrophages exhibited a time-dependent profile. In-vivo studies on rats showed improvement in the serum parameters and maintenance of the integrity of the hepatic architecture indicating decreased hepatotoxicity with the formulations as compared to the free drug. The experimental results showed a positive outcome in the development of antiretroviral drug carrier exhibiting sustained drug release, macrophage-targeted delivery characteristics, and having reduced hepatoxicity. This could be beneficial for the management of early stage of HIV infection besides reducing the drug load for effective treatment, thereby offering an attractive option in AIDS therapy.

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References

  1. Shi J, Votruba AR, Farokhzad OC, Langer R. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 2010;10(9):3223–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release. 2011;153(3):198–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ramanaa LN, Anand AR, Sethuramana S, Krishnana UM. Targeting strategies for delivery of anti-HIV drugs. J Control Release. 2014;192(10):271–83.

    Article  Google Scholar 

  4. Kraft JC, Freeling JP, Wang Z, Ho RJ. Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. J Pharm Sci. 2014;103(1):29–52.

    Article  CAS  PubMed  Google Scholar 

  5. Ito F, Fujimori H, Makino V. Factors affecting the loading efficiency of water-soluble drugs in PLGA microspheres. Colloids Surf B: Biointerfaces. 2008;61(1):25–9.

    Article  CAS  PubMed  Google Scholar 

  6. Avgoustakis K. Pegylatedpoly(lactide) and poly (lactide-coglycolide) nanoparticles: preparation, properties and possible applications in drug delivery. Curr Drug Deliv. 2004;1(4):321–33.

    Article  CAS  PubMed  Google Scholar 

  7. Barratt GM. Therapeutic applications of colloidal drug carriers: physical structure to therapeutic applications. Pharm Sci Technol Today. 2000;3(5):163–71.

    Article  CAS  PubMed  Google Scholar 

  8. Barlet DW, Davis ME. Physicochemical and biological characterization of targeted nucleic acid-containing nanoparticles. Bioconjug Chem. 2007;18(2):456–68.

    Article  Google Scholar 

  9. Gomes MJ, Neves JD, Sarmento B. Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system. Int J Nanomedicine. 2014;9:1757–69.

    PubMed  PubMed Central  Google Scholar 

  10. Mehta AK, Yadav KS, Sawant KK. Nimodipine loaded PLGA nanoparticles: formulation optimization using factorial design, characterization and in vitro evaluation. Curr Drug Deliv. 2007;4(3):185–93.

    Article  CAS  PubMed  Google Scholar 

  11. Chen X, Young TJ, Sarkari M, Williams RO, Johnston KP. Preparation of cyclosporine A nanoparticles by evaporative precipitation into aqueous solution. Int J Pharm. 2002;242(1–2):3–14.

    Article  CAS  PubMed  Google Scholar 

  12. Anton N, Benoit JP, Saulnier P. Design and production of nanoparticles formulated from nano-emulsion templates—a review. J Control Release. 2008;128(3):185–99.

    Article  CAS  PubMed  Google Scholar 

  13. Barichello JM, Morishita M, Takayama K, Nagai T. Encapsulation of hydrophilic and lipophillic drugs in PLGA nanoparticles by the nanoprecipitation method. Drug Dev Ind Pharm. 1999;25(4):471–6.

    Article  CAS  PubMed  Google Scholar 

  14. Bilati U, Allémann E, Doelker E. Development of a nanoprecipitation method intended for the entrapment of hydrophilic drugs into nanoparticles. Eur J Pharm Sci. 2005;24(1):67–75.

    Article  CAS  PubMed  Google Scholar 

  15. Das S, Roy P, Auddy RG, Mukherjee A. Silymarin nanoparticle prevents paracetamol induced hepatotoxicity. Int J Nanomedicine. 2011;6:1291–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Govender T, Stolnik S, Garnett MC, Illum L, Davis SS. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J Control Release. 1999;57(2):171–85.

    Article  CAS  PubMed  Google Scholar 

  17. Basu S, Mukherjee B, Chowdhury SR, Paul P, Choudhury R, Kumar A, et al. Colloidal gold-loaded, biodegradable, polymer-based stavudine nanoparticles uptake by macrophages: an in vitro study. Int J Nanomedicine. 2012;7:6049–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Freeling JP, Koehn J, Shu C, Sun J, Ho RJY. Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates. AIDS Res Hum Retrovir. 2015;31(1):107–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alexaki A, Liu Y, Wigdahl B. Cellular reservoirs of HIV-1 and their role in viral persistence. Curr HIV Res. 2008;6(5):388–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nicholas PK, Kemppainen JK, Canaval GE, Corless IB, Sefcik EF, Nokes KM, et al. Symptom management and self-care for peripheral neuropathy in HIV/AIDS. AIDS Care. 2007;19(2):179–89.

    Article  CAS  PubMed  Google Scholar 

  21. Alimonti JB, Ball TB, Fowke KR. Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS. J Gen Virol. 2003;84(7):1649–61.

    Article  CAS  PubMed  Google Scholar 

  22. Knoll B, Lassmann B, Temesgen Z. Current status of HIV infection: a review for non HIV treating physicians. Int J Dermatol. 2007;46(12):1219–28.

    Article  CAS  PubMed  Google Scholar 

  23. Edagwa BJ, Zhou T, McMillan JM, Liu XM, Gendelman HE. Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies. Curr Med Chem. 2014;21(36):4186–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Garg M, Dutta T, Jain NK. Reduced hepatic toxicity enhanced cellular uptake and altered pharmacokinetics of stavudine loaded galactosylated liposomes. Eur J Pharm Biopharm. 2007;67(1):76–85.

    Article  CAS  PubMed  Google Scholar 

  25. Bala I, Hariharan S, Kumar R. PLGA nanoparticles in drug delivery: the state of the art. Crit Rev Ther Drug Carrier Syst. 2004;21(5):387–422.

    Article  CAS  PubMed  Google Scholar 

  26. Deneka M, Pelchen-Matthews A, Byland R, Ruiz-Mateos E, Marsh M. In macrophages, HIV-1 assembles into an intracellular plasma membrane domain containing the tetraspanins CD81, CD9, and CD53. J Cell Biol. 2007;177(2):329–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Maji R, Dey NS, Satapathy BS, Mukherjee B, Mondal S. Preparation and characterization of Tamoxifen citrate loaded nanoparticles for breast cancer therapy. Int J Nanomedicine. 2014;9:3107–18.

    PubMed  PubMed Central  Google Scholar 

  28. Pattnaik G, Sinha B, Mukherjee B, Ghosh S, Basak S, Mondal S, et al. Submicron-size biodegradable polymer-based didanosine particles for treating HIV at early stage: an in vitro study. J Microencapsul. 2012;29(7):666–76.

    Article  CAS  PubMed  Google Scholar 

  29. Roy P, Das S, Bera T, Mondal S, Mukherjee A. Andrographolide nanoparticles in leishmaniasis: characterization and in vitro evaluation. Int J Nanomedicine. 2010;5:1113–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Piscitelli SC, Kelly G, Walker RE, Kovacs J, Falloon J, Davey Jr RT, et al. A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1999;43(3):647–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cunha-Filho MS, Martinez-Pacheco R, Landin M. Compatibility of the antitumoral beta lapachone with different solid dosage forms excipients. J Pharm Biomed Anal. 2007;45(4):590–8.

    Article  CAS  PubMed  Google Scholar 

  32. Sahoo SK, Panyam J, Prabha S, Labhasetwar V. Residual polyvinyl alcohol associated with poly (D,L-lactide-coglycolide) nanoparticles affects their physical properties and cellular uptake. J Control Release. 2002;82(1):105–14.

    Article  CAS  PubMed  Google Scholar 

  33. Núñez M. Hepatic toxicity of antiviral agents. In: Kaplowitz N, DeLeve LD, editors. Drug-induced liver disease. Amsterdam: Elsevier; 2013. p. 505–18.

    Chapter  Google Scholar 

  34. Kim H, Cheng C, Kim Y, Chee Y. Preparation and hydrolytic degradation of semi-interpenetration networks of poly (3-hydroxyundecenoate) and poly(lactide-co-glycolide). Int J Biol Macromol. 2005;37(5):221–6.

    Article  CAS  PubMed  Google Scholar 

  35. Rudra A, Manasadeepa R, Ghosh MK, Ghosh S, Mukherjee B. Doxorubicin-loaded phosphatidylethanolamine-conjugated nanoliposomes: in vitro characterization and their accumulation in liver, kidneys, and lungs in rats. Int J Nanomedicine. 2011;5:811–23.

    Google Scholar 

  36. Mukherjee B, Roy G, Santra K, Sahana K. Lactide-glycolide polymers as nanodimensional carriers of drugs. Int J Biomed Nanosci Nanotechnol. 2010;1(2):230–46.

    Article  CAS  Google Scholar 

  37. Mukherjee B, Patra B, Layek B, Mukherjee A. Sustained release of acyclovir from nano-liposomes and nano-niosomes. Int J Nanomedicine. 2007;2(2):213–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. De S, Robinson DH. Particle size and temperature effect on the physical stability of PLGA nanospheres and microspheres containing Bodipy. AAPS PharmSciTech. 2004;5(4), e53.

    Article  PubMed  Google Scholar 

  39. Yoo JW, Chambers E, Mitragotri S. Factors that control the circulation time of nanoparticles in blood: challenges, solutions and future prospects. Curr Pharm Des. 2010;16(21):2298–307.

    Article  CAS  PubMed  Google Scholar 

  40. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med. 1995;1(5):417–22.

    Article  CAS  PubMed  Google Scholar 

  41. Abrescia N, D’Abbraccio M, Figoni M, Busto A, Maddaloni A, De Marco M. Hepatotoxicity of antiretroviral drugs. Curr Pharm Des. 2005;11(28):3697–710.

    Article  CAS  PubMed  Google Scholar 

  42. Spengler U, Lichterfeld M, Rockstroh JK. Antiretroviral drug toxicity—a challenge for the hepatologist? J Hepatol. 2002;36(2):283–94.

    Article  CAS  PubMed  Google Scholar 

  43. Rahman K. Studies on free radicals, antioxidants, and co-factors. Clin Interv Aging. 2007;2(2):219–36.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We are indebted to the Indian Council of Medical Research (Grant no 45/6/2013/Nan/BMS) for partially funding the research work.

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Correspondence to Biswajit Mukherjee.

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Ghosh, S., Mondal, L., Chakraborty, S. et al. Early Stage HIV Management and Reduction of Stavudine-Induced Hepatotoxicity in Rats by Experimentally Developed Biodegradable Nanoparticles. AAPS PharmSciTech 18, 697–709 (2017). https://doi.org/10.1208/s12249-016-0539-6

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  • DOI: https://doi.org/10.1208/s12249-016-0539-6

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