Skip to main content

Advertisement

SpringerLink
Log in

Permeability and in vivo distribution of poly(Ɛ-caprolactone) nanoparticles loaded with zidovudine

  • Research Paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

Zidovudine (AZT) is one of first choice drugs for the treatment of acquired immunodeficiency syndrome (AIDS). Despite its efficacy to control virus replication, the extent of adverse effects and the therapeutic regimen are directly related to patients’ non-compliance. In this work, we evaluated the permeability and in vivo distribution of AZT incorporated into poly(Ɛ-caprolactone), PCL, nanoparticles (AZT-NP) aiming to reduce the normally observed side effects and increase the drug bioavailability. AZT-NP were obtained by interfacial deposition of preformed polymer. The mean diameter of the nanoparticles was 283.4 nm ± 17.0 with a polydispersity index of 0.232 ± 0.073. The nanoparticles presented a zeta potential of − 32.4 mV ± 3.3, entrapment rate of 53.11% ± 9.25, and were stable for at least 7 days. The drug and the polymer showed no incompatibility in thermal analysis. The permeability of AZT across Caco-2 cells was 22-fold higher for AZT-NP compared to the drug solution. The nanoparticles were able to release AZT in vivo after oral administration in mice, and the plasma levels of labeled AZT-NP were higher and more constant when compared to free labeled AZT. Thus, AZT-NP demonstrated superior performance compared to the drug solution in vivo and in vitro, showing the potential of this system for the treatment of AIDS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ait Slimane T, Hoekstra D (2002) Sphingolipid trafficking and protein sorting in epithelial cells. FEBS Lett 529(1):54–59

    Article  Google Scholar 

  • Araújo AAS, Storpirtis S, Mercuri LP, Carvalho FMS, Dos Santos Filho M, Matos JR (2003) Thermal analysis of the antiretroviral zidovudine (AZT) and evaluation of the compatibility with excipients used in solid dosage forms. Int J Pharm 260(2):303–314

    Article  Google Scholar 

  • Awasthi VD, Garcia D, Goins BA, Phillips WT (2003) Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits. Int J Pharm 253(1–2):121–132

    Article  Google Scholar 

  • Badowski ME, Pérez SE, Biagi M, Littler JA (2016) New antiretroviral treatment for HIV. Infect Dis Ther 5(3):329–352

    Article  Google Scholar 

  • Barbanti SH, Zavaglia CAC, Duek EAR (2006) Accelerated degradation of poly(ε-caprolactone) and poly(D,L-lactic acid-co-glycolic acid) scaffolds in alkaline medium. Polímeros 16(2):141–148

    Article  Google Scholar 

  • Binaschi M, Supino R, Gambetta RA, Giaccone G, Prosperi E, Capranico G, Catalog I, Zunino F (1995) MRP gene overexpression in a human doxorubicin-resistant SCLC cell line: alterations in cellular pharmacokinetics and in pattern of cross-resistance. Int J Cancer 62(1):84–89

    Article  Google Scholar 

  • Blum MR, Liao SHT, Good SS, de Miranda P (1988) Pharmacokinetics and bioavailability of zidovudine in human. Am J Med 85(2A):189–194

    Google Scholar 

  • Celia C, Trapasso E, Cosco D, Paolino D, Fresta M (2009) Turbiscan Lab® expert analysis of the stability of ethosomes® and ultradeformable liposomes containing a bilayer fluidizing agent. Colloids Surf B: Biointerfaces 72(1):155–160

    Article  Google Scholar 

  • Chai GH, Xu Y, Chen SQ, Cheng B, Hu FQ, You J, du YZ, Yuan H (2016) Transport mechanisms of solid lipid nanoparticles across Caco-2 cell monolayers and their related cytotoxicology. ACS Appl Mater Interfaces 8(9):5929–5940

    Article  Google Scholar 

  • Cho EJ, Holback H, Liu KC, Abouelmagd SA, Park J, Yeo Y (2013) Nanoparticle characterization: state of the art, challenges, and emerging technologies. Mol Pharm 10(6):2093–2110

    Article  Google Scholar 

  • Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Mehendale S, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Wang L, Makhema J, Mills LA, de Bruyn G, Sanne I, Eron J, Gallant J, Havlir D, Swindells S, Ribaudo H, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano D, Essex M, Fleming TR, HPTN 052 Study Team (2011) Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 365(6):493–505

    Article  Google Scholar 

  • Collins JM, Unadkat JD (1989) Clinical pharmacokinetics of zidovudine: an overview of current data. Clin Pharmacokinet 17(1):1–9

    Article  Google Scholar 

  • Dalpiaz A, Contado C, Mari L, Perrone D, Pavan B, Paganetto G et al (2013) Development and characterization of PLGA nanoparticles as delivery systems of a prodrug of zidovudine obtained by its conjugation with ursodeoxycholic acid. Drug Deliv 7544:1–12

    Google Scholar 

  • Dalpiaz A, Fogagnolo M, Ferraro L, Capuzzo A, Pavan B, Rassu G et al (2015) Nasal chitosan microparticles target a zidovudine prodrug to brain HIV sanctuaries. Antiviral Res 123:146–157

    Article  Google Scholar 

  • Dalpiaz A, Paganetto G, Pavan B, Fogagnolo M, Medici A, Beggiato S et al (2012) Zidovudine and ursodeoxycholic acid conjugation: design of a new prodrug potentially able to bypass the active efflux transport systems of the central nervous system. Mol Pharm 9:957–968

    Article  Google Scholar 

  • Dash TK, Konkimalla VB (2012) Poly-є-caprolactone based formulations for drug delivery and tissue engineering: a review. J Control Release 158(1):15–33

    Article  Google Scholar 

  • De Barros ALB, Das Graças Mota L, Coelho MMA, Corrêa NC, De Góes AM, Oliveira MC et al (2015) Bombesin encapsulated in long-circulating pH-sensitive liposomes as a radiotracer for breast tumor identification. J Biomed Nanotechnol 11(2):342–350

    Article  Google Scholar 

  • Driscoll DF (2006) Lipid injectable emulsions: pharmacopeial and safety issues. Pharm Res 23(9):1959–1969

    Article  Google Scholar 

  • Dubernet C (1995) Thermoanalysis of microspheres. Thermochim Acta 24:259–269

    Article  Google Scholar 

  • Duek EAR, Zavaglia CAC, Belangero WD (1999) In vitro study of poly (lactic acid) pin degradation. Polymer 40(23):6465–6473

    Article  Google Scholar 

  • Espuelas MS, Legrand P, Irache JM, Gamazo C, Orecchioni AM, Devissaguet JP, Ygartua P (1997) Poly(ε-caprolactone) nanospheres as an alternative way to reduce amphotericin-B toxicity. Int J Pharm 158(1):19–27

    Article  Google Scholar 

  • Feng S, Huang G (2001) Effects of emulsifiers on the controlled release of paclitaxel (Taxol®) from nanospheres of biodegradable polymers. J Control Release 71(1):53–69

    Article  Google Scholar 

  • Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S (1989) Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm 55(1):1–4

    Article  Google Scholar 

  • Fischl MA, Parker CB, Pettinelli C (1990) A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N Engl J Med 323(15):1009–1014

    Article  Google Scholar 

  • Gajbhiye V, Ganesh N, Barve J, Jain NK (2013) Synthesis, characterization and targeting potential of zidovudine loaded sialic acid conjugated-mannosylated poly(propyleneimine) dendrimers. Eur J Pharm Sci 48(4–5):668–679

    Article  Google Scholar 

  • Gao Y, Kraft JC, Yu D, Ho RJY (2018) Recent developments of nanotherapeutics for targeted and long-acting, combination HIV chemotherapy. Eur J Pharm Biopharm. https://doi.org/10.1016/j.ejpb.2018.04.014

  • Gari S, Doig-Acuña C, Smail T, Malungo JR, Martin-Hilber A, Merten S (2013) Access to HIV/AIDS care: a systematic review of socio-cultural determinants in low and high income countries. BMC Health Serv Res 13:198

    Article  Google Scholar 

  • Giacalone G, Bochot A, Fattal E, Hillaireau H (2013) Drug-induced nanocarrier assembly as a strategy for the cellular delivery of nucleotides and nucleotide analogues. Biomacromolecules 14(3):737–742

    Article  Google Scholar 

  • Gomes MJ, Das Neves J, Sarmento B (2014) Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system. Int J Nanomedicine 9(1):1757–1769

    Google Scholar 

  • Gunaseelan S, Gunaseelan K, Deshmukh M, Zhang X, Sinko PJ (2010) Surface modifications of nanocarriers for effective intracellular delivery of anti-HIV drugs. Adv Drug Deliv Rev 62(4–5):518–531

    Article  Google Scholar 

  • He B, Lin P, Jia Z, Du W, Qu W, Yuan L et al (2013) The transport mechanisms of polymer nanoparticles in Caco-2 epithelial cells. Biomaterials 34(25):6082–6098

    Article  Google Scholar 

  • Hillaireau H, Le Doan T, Besnard M, Chacun H, Janin J, Couvreur P (2006) Encapsulation of antiviral nucleotide analogues azidothymidine-triphosphate and cidofovir in poly(iso-butylcyanoacrylate) nanocapsules. Int J Pharm 324(1):37–42

    Article  Google Scholar 

  • Hu L, Tang X, Cui F (2004) Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs. J Pharm Pharmacol 56(12):1527–1535

    Article  Google Scholar 

  • Jorajuria S, Dereuddre-Bosquet N, Becher F, Martin S, Porcheray F, Garrigues A, Mabondzo A, Benech H, Grassi J, Orlowski S, Dormont D, Clayette P (2004) ATP binding cassette multidrug transporters limit the anti-HIV activity of zidovudine and indinavir in infected human macrophages. Antivir Ther 9(4):519–528

    Google Scholar 

  • Joshi SA, Chavhan SS, Sawant KK (2010) Rivastigmine-loaded PLGA and PBCA nanoparticles: preparation, optimization, characterization, in vitro and pharmacodynamic studies. Eur J Pharm Biopharm 76(2):189–199

    Article  Google Scholar 

  • Joshy KS, George A, Jose J, Kalarikkal N, Pothen LA, Thomas S (2017) Novel dendritic structure of alginate hybrid nanoparticles for effective anti-viral drug delivery. Int J Biol Macromol 103:1265–1275

    Article  Google Scholar 

  • Kumar A, Sawant K (2013) Encapsulation of exemestane in polycaprolactone nanoparticles: optimization, characterization, and release kinetics. Cancer Nanotechnol 4(4–5):57–71

    Article  Google Scholar 

  • Kumar P, Lakshmi YS, Bhaskar C, Golla K, Kondapi AK (2015) Improved safety, bioavailability and pharmacokinetics of zidovudine through lactoferrin nanoparticles during oral administration in rats. PLoS One 10(10):1–18

    Google Scholar 

  • Lande MB, Priver NA, Zeidel ML (1994) Determinants of apical membrane permeabilities of barrier epithelia. Am J Phys 267(2 Pt 1):367–374

    Article  Google Scholar 

  • Lee CM, Jeong HJ, Kim DW, Sohn MH, Lim ST (2012) The effect of fluorination of zinc oxide nanoparticles on evaluation of their biodistribution after oral administration. Nanotechnology 23(20):205102

    Article  Google Scholar 

  • Lince F, Marchisio DL, Barresi AA (2008) Strategies to control the particle size distribution of poly-ε-caprolactone nanoparticles for pharmaceutical applications. J Colloid Interface Sci 322(2):505–515

    Article  Google Scholar 

  • Lu Z, Mao C, Meng M, Liu S, Tian Y, Yu L, Sun B, Li CM (2014) Fabrication of CeO2 nanoparticle-modified silk for UV protection and antibacterial applications. J Colloid Interface Sci 435:8–14

    Article  Google Scholar 

  • Mainardes RM, Urban MC, Cinto PO, Chaud MV, Evangelista RC, Gremião MP (2006) Liposomes and micro/nanoparticles as colloidal carriers for nasal drug delivery. Curr Drug Deliv 3(3):275–285

  • Mainardes RM, Gremião MP, Brunetti IL, da Fonseca LM, Khalil NM (2009) Zidovudine-loaded PLA and PLA–PEG blend nanoparticles: influence of polymer type on phagocytic uptake by polymorphonuclear cells. J Pharm Sci 98(1):257–267

    Article  Google Scholar 

  • Mane V, Muro S (2012) Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice. Int J Nanomedicine 7:4223–4237

    Google Scholar 

  • Malikmammadov E, Tanir TE, Kiziltay A, Hasirci V, Hasirci N (2018) PCL and PCL-based materials in biomedical applications. J Biomater Sci Polym Ed 29(7–9):863–893

    Article  Google Scholar 

  • Moore KHP, Raasch RH, Brouwer KLR, Opheim K, Cheeseman SH, Eyster E et al (1995) Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group Protocol 062). Antimicrob Agents Chemother 39(12):2732–2737

    Article  Google Scholar 

  • Mora-Huertas CE, Fessi H, Elaissari A (2010) Polymer-based nanocapsules for drug delivery. Int J Pharm 385(1–2):113–142

    Article  Google Scholar 

  • Palumbo PJ, Fogel JM, Hudelson SE, Wilson EA, Hart S, Hovind L et al (2017) HIV drug resistance in adults receiving early versus delayed antiretroviral therapy: Hptn 052. J Acquir Immune Defic Syndr 77(5):484–491

    Article  Google Scholar 

  • Perloff ES, Duan SX, Skolnik PR, Greenblatt DJ, Von Moltke LL (2005) Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos 33(6):764–770

    Article  Google Scholar 

  • Petri N, Tannergren C, Rungstad D, Lennernas H (2004) Transport characteristics of fexofenadine in the Caco-2 cell model. Pharm Res 21(8):1398–1404

    Article  Google Scholar 

  • Pople PV, Singh KK (2013) Development and evaluation of colloidal modified nanolipid carrier: application to topical delivery of tacrolimus. Part II—in vivo assessment, drug targeting, efficacy, and safety in treatment for atopic dermatitis. Eur J Pharm Biopharm 84(1):72–83

    Article  Google Scholar 

  • Pople PV, Singh KK (2011) Development and evaluation of colloidal modified nanolipid carrier: application to topical delivery of tacrolimus. Eur J Pharm Biopharm 79:82–94

    Article  Google Scholar 

  • Quevedo MA, Nieto LE, Briñón MC (2011) P-glycoprotein limits the absorption of the anti-HIV drug zidovudine through rat intestinal segments. Eur J Pharm Sci 43(3):151–159

    Article  Google Scholar 

  • Rachlis A, Fanning MM (1993) Zidovudine toxicity. Clinical features and management. Drug Saf 8(4):312–320

    Article  Google Scholar 

  • Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Hirsch MS, Jackson GG, Durack DT, Nusinoff-Lehrman S, The AZT Collaborative Working Group (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 317(4):192–197

    Article  Google Scholar 

  • Rodriguez-Emmenegger C, Jäger A, Jäger E, Stepanek P, Alles AB, Guterres SS et al (2011) Polymeric nanocapsules ultra stable in complex biological media. Colloids Surf B: Biointerfaces 83(2):37681

    Article  Google Scholar 

  • Saiyed ZM, Gandhi NH, Nair MPN (2009) AZT 5′-triphosphate nanoformulation suppresses human immunodeficiency virus type 1 replication in peripheral blood mononuclear cells. J Neuro-Oncol 15(4):343–347

    Google Scholar 

  • Saravanan M, Asmalash T, Gebrekidan A, Gebreegziabiher D, Araya T, Hilekiros H, Barabadi H, Ramanathan K (2018) Nano-medicine as a newly emerging approach to combat human immunodeficiency virus (HIV). Pharm Nanotechnol 6:17–27

    Article  Google Scholar 

  • Shamsipur M, Pourmortazavi SM, Beigi AAM, Heydari R, Khatibi M (2013) Thermal stability and decomposition kinetic studies of acyclovir and zidovudine drug compounds. AAPS Pharm Sci Technol 14(1):287–293

    Article  Google Scholar 

  • Shiraki N, Hamada A, Yasuda K, Fujii J, Arimori K, Nakano M (2000) Inhibitory effect of human immunodeficiency virus protease inhibitors on multidrug resistance transporter P-glycoprotein. Biol Pharm Bull 23(12):1528–1531

    Article  Google Scholar 

  • Silva JO, Fernandes RS, Lopes SCA, Cardoso VN, Leite EA, Cassali GD, Marzola MC, Rubello D, Oliveira MC, de Barros ALB (2016) pH-sensitive, long-circulating liposomes as an alternative tool to deliver doxorubicin into tumors: a feasibility animal study. Mol Imaging Biol 18(6):898–904

    Article  Google Scholar 

  • Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J (2007) Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol 73(10):1573–1581

    Article  Google Scholar 

  • Tamir Z, Alemu J, Tsegaye A (2018a) Anemia among HIV infected individuals taking ART with and without zidovudine at Addis Ababa, Ethiopia. Ethiop J Health Sci 28(1):73–82

    Article  Google Scholar 

  • Thrall JH, Ziessman HA (2003) Medicina nuclear, 2nd edn. Guanabara Koogan, Rio de Janeiro

    Google Scholar 

  • Troutman MD, Thakker DR (2003) Efflux ratio cannot assess P-glycoprotein-mediated attenuation of absorptive transport: asymmetric effect of P-glycoprotein on absorptive and secretory transport across Caco-2 cell monolayers. Pharm Res 20(8):1200–1209

    Article  Google Scholar 

  • Tamir Z, Alemu J, Tsegaye A (2018b) Anemia among HIV infected individuals taking ART with and without zidovudine at Addis Ababa, Ethiopia. Ethiop J Health Sci 28(1):73–82

    Article  Google Scholar 

  • Tyagi P, Subramony JA (2018) Nanotherapeutics in oral and parenteral drug delivery: Key learnings and future outlooks as we think small. J Control Release 272:159–168

  • Venturini CG, Jäger E, Oliveira CP, Bernardi A, Battastini AMO, Guterres SS, Pohlmann AR (2011) Formulation of lipid core nanocapsules. Colloids Surf A Physicochem Eng Asp 375(1–3):200–208

    Article  Google Scholar 

  • Wang F, Miao MX, Sun BB, Wang ZJ, Tang XG, Chen Y, Zhao KJ, Liu XD, Liu L (2017) Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp. Acta Pharmacol Sin 38(11):1554–1565

    Article  Google Scholar 

  • Wang H, Wolock TM, Carter A, Nguyen G, Kyu HH, Gakidou E et al (2016) Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2015: the Global Burden of Disease Study 2015. Lancet HIV 3(8):e361–e387

    Article  Google Scholar 

  • WHO (2017) Fact sheet on HIV/AIDS. World Health Organization HIV/AIDS Department. http://www.who.int/mediacentre/factsheets/fs360/en/. Accessed 2 Febr 2018

  • Woodruff MA, Hutmacher DW (2010) The return of a forgotten polymer—polycaprolactone in the 21st century. Prog Polym Sci 35(10):1217–1256

    Article  Google Scholar 

  • Yameen B, Choi WI, Vilos C, Swami A, Shi J, Farokhzad OC (2014) Insight into nanoparticle cellular uptake and intracellular targeting. J Control Release 190:485–499

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank CNPq/MCT (Brazil) and FAPEMIG (Brazil) for financial support. This study is part of the National Institute of Science and Technology in Pharmaceutical Nanotechnology: a transdisciplinary approach INCT-NANOFARMA, which is supported by São Paulo Research Foundation (FAPESP, Brazil) Grant #2014/50928-2, and by “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq, Brazil) Grant # 465687/2014-8. The authors would like to acknowledge the Center of Microscopy at the Federal University of Minas Gerais (http://www.microscopia.ufmg.br) for providing the equipment and technical support for experiments involving electron microscopy.

Author information

Author notes

  1. A. Silva-Cunha and S.L. Fialho are joint senior authors.

  2. Milena C. R.S. Magalhães and Brenda F. M. Castro equally contributed as first authors.

Authors and Affiliations

  1. Faculty of Pharmacy, Federal University of Minas Gerais, Avenida Presidente Antônio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Milena C. R. S. Magalhães, Brenda F. M. Castro, Andre L. B. Barros, Renata S. Fernandes & Armando Silva-Cunha

  2. Pharmaceutical Research and Development, Ezequiel Dias Foundation, Rua Conde Pereira Carneiro, 80, Gameleira, Belo Horizonte, Minas Gerais, 30510-010, Brazil

    Milena C. R. S. Magalhães & Sílvia L. Fialho

  3. Faculty of Pharmacy, Federal University of São João Del Rei, Rua Sebastião Gonçalves Coelho, 400, Chanadour, Divinópolis, Minas Gerais, 35501-296, Brazil

    Whocely V. de Castro

Authors
  1. Milena C. R. S. Magalhães
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brenda F. M. Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Whocely V. de Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andre L. B. Barros
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Renata S. Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Armando Silva-Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sílvia L. Fialho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sílvia L. Fialho.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Magalhães, M.C.R.S., Castro, B.F.M., de Castro, W.V. et al. Permeability and in vivo distribution of poly(Ɛ-caprolactone) nanoparticles loaded with zidovudine. J Nanopart Res 20, 176 (2018). https://doi.org/10.1007/s11051-018-4280-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-018-4280-9

Keywords

Search

Navigation