Skip to main content

Advertisement

SpringerLink
Log in

Technological challenges in the preclinical development of an HIV nanovaccine candidate

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Despite a very active research in the field of nanomedicine, only a few nano-based drug delivery systems have reached the market. The “death valley” between research and commercialization has been partially attributed to the limited characterization and reproducibility of the nanoformulations. Our group has previously reported the potential of a peptide-based nanovaccine candidate for the prevention of SIV infection in macaques. This vaccine candidate is composed of chitosan/dextran sulfate nanoparticles containing twelve SIV peptide antigens. The aim of this work was to rigorously characterize one of these nanoformulations containing a specific peptide, following a quality-by-design approach. The evaluation of the different quality attributes was performed by several complementary techniques, such as dynamic light scattering, nanoparticle tracking analysis, and electron microscopy for particle size characterization. The inter-batch reproducibility was validated by three independent laboratories. Finally, the long-term stability and scalability of the manufacturing technique were assessed. Overall, these data, together with the in vivo efficacy results obtained in macaques, underline the promise this new vaccine holds with regard to its translation to clinical trials.

Graphical abstract

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.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Niu Z, Conejos-Sánchez I, Griffin BT, O’Driscoll CM, Alonso MJ. Lipid-based nanocarriers for oral peptide delivery. Adv Drug Deliv Rev. 2016;106:337–54.

    Article  CAS  PubMed  Google Scholar 

  2. Yu M, Wu J, Shi J, Farokhzad OC. Nanotechnology for protein delivery: overview and perspectives. J Control Release. 2016;240:24–37.

    Article  CAS  PubMed  Google Scholar 

  3. Santalices I, Gonella A, Torres D, Alonso MJ. Advances on the formulation of proteins using nanotechnologies. J Drug Deliv Sci Technol. 2017;42:155–80.

    Article  CAS  Google Scholar 

  4. Samaridou E, Alonso MJ. Nose-to-brain peptide delivery – the potential of nanotechnology. Bioorg Med Chem. 2018;26:2888–905.

    Article  CAS  PubMed  Google Scholar 

  5. Li Z, Rana TM. Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov. 2014;13:622–38.

    Article  CAS  PubMed  Google Scholar 

  6. Liu Y, Xu C-F, Iqbal S, Yang X-Z, Wang J. Responsive nanocarriers as an emerging platform for cascaded delivery of nucleic acids to cancer. Adv Drug Deliv Rev. 2017;115:98–114.

    Article  CAS  PubMed  Google Scholar 

  7. Saraiva SM, Castro-López V, Pañeda C, Alonso MJ. Synthetic nanocarriers for the delivery of polynucleotides to the eye. Eur J Pharm Sci. 2017;103:5–18.

    Article  CAS  PubMed  Google Scholar 

  8. Kaczmarek JC, Kowalski PS, Anderson DG. Advances in the delivery of RNA therapeutics: from concept to clinical reality. Genome Med. 2017;9:60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Irvine DJ, Hanson MC, Rakhra K, Tokatlian T. Synthetic nanoparticles for vaccines and immunotherapy. Chem Rev. 2015;115:11109–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cordeiro AS, Alonso MJ. Recent advances in vaccine delivery. Pharm Pat Anal. 2015;5:49–73.

    Article  PubMed  CAS  Google Scholar 

  11. Dacoba TG, Olivera A, Torres D, Crecente-Campo J, Alonso MJ. Modulating the immune system through nanotechnology. Semin Immunol. 2017;34:78–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gause KT, Wheatley AK, Cui J, Yan Y, Kent SJ, Caruso F. Immunological principles guiding the rational design of particles for vaccine delivery. ACS Nano. 2017;11:54–68.

    Article  CAS  PubMed  Google Scholar 

  13. Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res. 2016;33:2373–87.

    Article  CAS  PubMed  Google Scholar 

  14. Anselmo AC, Mitragotri S. Nanoparticles in the clinic. Bioeng Transl Med. 2016;1:10–29.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ventola CL. Progress in nanomedicine: approved and investigational nanodrugs. P T. 2017;42:742–55.

    PubMed  PubMed Central  Google Scholar 

  16. Desai N. Challenges in development of nanoparticle-based therapeutics. AAPS J. 2012;14:282–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ragelle H, Danhier F, Préat V, Langer R, Anderson DG. Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures. Expert Opin Drug Deliv. 2017;14:851–64.

    Article  CAS  PubMed  Google Scholar 

  18. Hua S, de Matos MBC, Metselaar JM, Storm G. Current trends and challenges in the clinical translation of nanoparticulate nanomedicines: pathways for translational development and commercialization. Front Pharmacol. 2018;9:1–14.

    Article  CAS  Google Scholar 

  19. Dormont F, Rouquette M, Mahatsekake C, Gobeaux F, Peramo A, Brusini R, et al. Translation of nanomedicines from lab to industrial scale synthesis: the case of squalene-adenosine nanoparticles. J Control Release. 2019;307:302–14.

    Article  CAS  PubMed  Google Scholar 

  20. Gabizon A, Bradbury M, Prabhakar U, Zamboni W, Libutti S, Grodzinski P. Cancer nanomedicines: closing the translational gap. Lancet. 2014;384:2175–6.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16:771–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wicki A, Witzigmann D, Balasubramanian V, Huwyler J. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J Control Release. 2015;200:138–57.

    Article  CAS  PubMed  Google Scholar 

  23. Agrahari V, Agrahari V. Facilitating the translation of nanomedicines to a clinical product: challenges and opportunities. Drug Discov Today. 2018;23:974–91.

    Article  PubMed  Google Scholar 

  24. Zamboni WC, Torchilin V, Patri AK, Hrkach J, Stern S, Lee R, et al. Best practices in cancer nanotechnology: perspective from NCI nanotechnology alliance. Clin Cancer Res. 2012;18:3229–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pallagi E, Ambrus R, Szabó-Révész P, Csóka I. Adaptation of the quality by design concept in early pharmaceutical development of an intranasal nanosized formulation. Int J Pharm. 2015;491:384–92.

    Article  CAS  PubMed  Google Scholar 

  26. Rose F, Wern JE, Ingvarsson PT, van de Weert M, Andersen P, Follmann F, et al. Engineering of a novel adjuvant based on lipid-polymer hybrid nanoparticles: a quality-by-design approach. J Control Release. 2015;210:48–57.

    Article  CAS  PubMed  Google Scholar 

  27. Shah B, Khunt D, Bhatt H, Misra M, Padh H. Intranasal delivery of venlafaxine loaded nanostructured lipid carrier: risk assessment and QbD based optimization. J Drug Deliv Sci Technol. 2016;33:37–50.

    Article  CAS  Google Scholar 

  28. Raina H, Kaur S, Jindal AB. Development of efavirenz loaded solid lipid nanoparticles: risk assessment, quality-by-design (QbD) based optimisation and physicochemical characterisation. J Drug Deliv Sci Technol. 2017;39:180–91.

    Article  CAS  Google Scholar 

  29. Marto J, Ruivo E, Lucas SD, Gonçalves LM, Simões S, Gouveia LF, et al. Starch nanocapsules containing a novel neutrophil elastase inhibitor with improved pharmaceutical performance. Eur J Pharm Biopharm. 2018;127:1–11.

    Article  CAS  PubMed  Google Scholar 

  30. Simões A, Veiga F, Figueiras A, Vitorino C. A practical framework for implementing quality by design to the development of topical drug products: nanosystem-based dosage forms. Int J Pharm. 2018;548:385–99.

    Article  PubMed  CAS  Google Scholar 

  31. Faria M, Björnmalm M, Thurecht KJ, Kent SJ, Parton RG, Kavallaris M, et al. Minimum information reporting in bio–nano experimental literature. Nat Nanotechnol. 2018;13:777–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vicente S, Peleteiro M, Díaz-Freitas B, Sanchez A, González-Fernández Á, Alonso MJ. Co-delivery of viral proteins and a TLR7 agonist from polysaccharide nanocapsules: a needle-free vaccination strategy. J Control Release. 2013;172:773–81.

    Article  CAS  PubMed  Google Scholar 

  33. Correia-Pinto JF, Csaba N, Schiller J, Alonso MJ. Chitosan-poly (I:C)-PADRE based nanoparticles as delivery vehicles for synthetic peptide vaccines. Vaccines. 2015;3:730–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. González-Aramundiz JV, Presas E, Dalmau-Mena I, Martínez-Pulgarín S, Alonso C, Escribano JM, et al. Rational design of protamine nanocapsules as antigen delivery carriers. J Control Release. 2017;245:62–9.

    Article  PubMed  CAS  Google Scholar 

  35. Crecente-Campo J, Lorenzo-Abalde S, Mora A, Marzoa J, Csaba N, Blanco J, et al. Bilayer polymeric nanocapsules: a formulation approach for a thermostable and adjuvanted E. coli antigen vaccine. J Control Release. 2018;286:20–32.

    Article  CAS  PubMed  Google Scholar 

  36. Li H, Nykoluk M, Li L, Liu LR, Omange RW, Soule G, et al. Natural and cross-inducible anti-SIV antibodies in Mauritian cynomolgus macaques. PLoS One. 2017;12:e0186079.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Dacoba TG, Omange RW, Li H, Crecente-Campo J, Luo M, Alonso MJ. Polysaccharide nanoparticles can efficiently modulate the immune response against an HIV peptide antigen. ACS Nano. 2019;13:4947–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li H, Omange RW, Liang B, Toledo N, Hai Y, Liu LR, et al. bioRxiv. 2019.

  39. Rathore AS, Winkle H. Quality by design for biopharmaceuticals. Nat Biotechnol. 2009;27:26–34.

    Article  CAS  PubMed  Google Scholar 

  40. European Medicines Agency. ICH guideline Q8 (R2) on pharmaceutical development [Internet]. 2017 [cited 2019 Dec 5]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002872.pdf.

  41. Li H, Omange RW, Plummer FA, Luo M. A novel HIV vaccine targeting the protease cleavage sites. AIDS Res Ther. 2017;14:51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. England RJA, Homer JJ, Knight LC, Ell SR. Nasal pH measurement: a reliable and repeatable parameter. Clin Otolaryngol. 1999;24:67–8.

    Article  CAS  PubMed  Google Scholar 

  43. U.S. Food and Drug Administration. Guidance for industry: nasal spray and inhalation solution, suspension, and spray drug products — chemistry, manufacturing, and controls documentation [Internet]. 2002 [cited 2019 Dec 1]. Available from: https://www.fda.gov/media/70857/download.

  44. May JC, Wheeler RM, Etz N, Del Grosso A. Measurement of final container residual moisture in freeze-dried biological products. Dev Biol Stand. 1992;74:153–64.

    CAS  PubMed  Google Scholar 

  45. International Organization for Standardization. Particle size analysis — Dynamic light scattering (DLS) (ISO/DIS Standard No. 22412). 2017.

  46. Hartig SM. Basic image analysis and manipulation in ImageJ. Curr Protoc Mol Biol. 2013;102:1–12.

    Article  Google Scholar 

  47. Klein M, Menta M, Dacoba TG, Crecente-Campo J, Alonso MJ, Dupin D, et al. Advanced nanomedicine characterization by DLS and AF4-UV-MALS: application to a HIV nanovaccine. J Pharm Biomed Anal. 2020;179:113017.

    Article  PubMed  CAS  Google Scholar 

  48. Rapalli VK, Khosa A, Singhvi G, Girdhar V, Jain R, Dubey SK. Application of QbD principles in nanocarrier-based drug delivery systems. In: Beg S, Hasnain MS, editors. Pharm Qual by Des. Amsterdam: Elsevier; 2019. p. 255–96.

    Chapter  Google Scholar 

  49. Cordeiro AS, Alonso MJ, de la Fuente M. Nanoengineering of vaccines using natural polysaccharides. Biotechnol Adv. 2015;33:1279–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Prego C, Paolicelli P, Díaz B, Vicente S, Sánchez A, González-Fernández Á, et al. Chitosan-based nanoparticles for improving immunization against hepatitis B infection. Vaccine. 2010;28:2607–14.

    Article  CAS  PubMed  Google Scholar 

  51. Rose F, Wern JE, Gavins F, Andersen P, Follmann F, Foged C. A strong adjuvant based on glycol-chitosan-coated lipid-polymer hybrid nanoparticles potentiates mucosal immune responses against the recombinant Chlamydia trachomatis fusion antigen CTH522. J Control Release. 2018;271:88–97.

    Article  CAS  PubMed  Google Scholar 

  52. Sharma S, Mukkur TK, Benson HA, Chen Y. Enhanced immune response against pertussis toxoid by IgA-loaded chitosan–dextran sulfate nanoparticles. J Pharm Sci. 2012;101:233–44.

    Article  CAS  PubMed  Google Scholar 

  53. Correia-Pinto JF, Csaba N, Alonso MJ. Vaccine delivery carriers: insights and future perspectives. Int J Pharm. 2013;440:27–38.

    Article  CAS  PubMed  Google Scholar 

  54. Stano A, Nembrini C, Swartz MA, Hubbell JA, Simeoni E. Nanoparticle size influences the magnitude and quality of immune response after intranasal immunization. Vaccine. 2012;30:7541–6.

    Article  CAS  PubMed  Google Scholar 

  55. Kaur IP, Kakkar V, Deol PK, Yadav M, Singh M, Sharma I. Issues and concerns in nanotech product development and its commercialization. J Control Release. 2014;193:51–62.

    Article  CAS  PubMed  Google Scholar 

  56. Maguire CM, Rösslein M, Wick P, Prina-Mello A. Characterisation of particles in solution – a perspective on light scattering and comparative technologies. Sci Technol Adv Mater. 2018;19:732–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Caputo F, Clogston J, Calzolai L, Rösslein M, Prina-Mello A. Measuring particle size distribution of nanoparticle enabled medicinal products, the joint view of EUNCL and NCI-NCL. A step by step approach combining orthogonal measurements with increasing complexity. J Control Release. 2019;299:31–43.

    Article  CAS  PubMed  Google Scholar 

  58. European Nanomedicine Characterisation Laboratory. Measuring batch mode DLS [Internet]. 2016 [cited 2019 Dec 5]. Available from: http://www.euncl.eu/about-us/assay-cascade/PDFs/Prescreening/EUNCL-PCC-001.pdf?m=1468937875&.

  59. Shang J, Gao X. Nanoparticle counting: towards accurate determination of the molar concentration. Chem Soc Rev. 2014;43:7267–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lakkireddy HR, Bazile D. Building the design, translation and development principles of polymeric nanomedicines using the case of clinically advanced poly(lactide(glycolide))–poly(ethylene glycol) nanotechnology as a model: an industrial viewpoint. Adv Drug Deliv Rev. 2016;107:289–332.

    Article  CAS  PubMed  Google Scholar 

  61. European Medicines Agency. Questions and answers on the supply situation of Caelyx [Internet]. 2013 [cited 2019 Dec 5]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2013/04/WC500142510.pdf.

  62. Vetten MA, Yah CS, Singh T, Gulumian M. Challenges facing sterilization and depyrogenation of nanoparticles: effects on structural stability and biomedical applications. Nanomedicine. 2014;10:1391–9.

    Article  CAS  PubMed  Google Scholar 

  63. Tsukada Y, Hara K, Bando Y, Huang CC, Kousaka Y, Kawashima Y, et al. Particle size control of poly(DL-lactide-co-glycolide) nanospheres for sterile applications. Int J Pharm. 2009;370:196–201.

    Article  CAS  PubMed  Google Scholar 

  64. Masson V, Maurin F, Fessi H, Devissaguet JP. Influence of sterilization processes on poly(ε-caprolactone) nanospheres. Biomaterials. 1997;18:327–35.

    Article  CAS  PubMed  Google Scholar 

  65. U.S. Food and Drug Administration. Guidance for industry Q1A(R2) stability testing of new drug substances and products [Internet]. ICH Guidel. 2003 [cited 2019 Dec 5]. Available from: https://www.fda.gov/media/71707/download.

  66. Szymańska E, Winnicka K. Stability of chitosan – a challenge for pharmaceutical and biomedical applications. Mar Drugs. 2015;13:1819–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Valencia PM, Farokhzad OC, Karnik R, Langer R. Microfluidic technologies for accelerating the clinical translation of nanoparticles. Nat Nanotechnol. 2012;7:623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Stroock AD. Chaotic mixer for microchannels. Science. 2002;295:647–51.

    Article  CAS  PubMed  Google Scholar 

  69. Samaridou E, Walgrave H, Salta E, Álvarez DM, Castro-López V, Loza M, et al. Nose-to-brain delivery of enveloped RNA - cell permeating peptide nanocomplexes for the treatment of neurodegenerative diseases. Biomaterials. 2020;230:119657.

    Article  CAS  PubMed  Google Scholar 

  70. Roces CB, Christensen D, Perrie Y. Translating the fabrication of protein-loaded poly(lactic-co-glycolic acid) nanoparticles from bench to scale-independent production using microfluidics. Drug Deliv Transl Res. 2020.

  71. Paliwal R, Babu RJ, Palakurthi S. Nanomedicine scale-up technologies: feasibilities and challenges. AAPS PharmSciTech. 2014;15:1527–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Authors would like to thank the RIAIDT-USC analytical facilities, for the microscopy imaging. All the icons used in the graphical abstract were designed by Freepick at www.flaticon.com.

Funding

This work was supported by the European Union’s Horizon 2020 research program (NanoPilot project – grant agreement number 646142) and by Xunta de Galicia’s Grupos de referencia competitiva (grant number ED431C 2017/09). T.G. Dacoba acknowledges a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sports (grant number FPU14/05866).

Author information

Authors and Affiliations

  1. Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), IDIS Research Institute, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain

    Tamara G. Dacoba, Desirée Teijeiro-Osorio, María J. Alonso & José Crecente-Campo

  2. Department of Pharmacology, Pharmacy and Pharmaceutical Technology, School of Pharmacy, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain

    Tamara G. Dacoba, Desirée Teijeiro-Osorio, María J. Alonso & José Crecente-Campo

  3. CIDETEC, Basque Research and Technology Alliance (BRTA), Parque Científico y Tecnológico de Gipuzkoa, 20014, Donostia-San Sebastián, Spain

    Luisa Ruiz-Gatón, Ana Benito, Damien Dupin & Iraida Loinaz

  4. Ultra Trace Analyses Aquitaine (UT2A/ADERA), Technopôle Hélioparc Pau-Pyrénées, 64053, Pau Cedex 9, France

    Marlène Klein & Mathieu Menta

  5. Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada

    Ma Luo

Authors
  1. Tamara G. Dacoba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luisa Ruiz-Gatón
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Benito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marlène Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Damien Dupin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ma Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mathieu Menta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Desirée Teijeiro-Osorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Iraida Loinaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. María J. Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. José Crecente-Campo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to María J. Alonso or José Crecente-Campo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 544 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dacoba, T.G., Ruiz-Gatón, L., Benito, A. et al. Technological challenges in the preclinical development of an HIV nanovaccine candidate. Drug Deliv. and Transl. Res. 10, 621–634 (2020). https://doi.org/10.1007/s13346-020-00721-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-020-00721-8

Keywords

Search

Navigation