Skip to main content
SpringerLink
Log in

Safety evaluation of nanodiamond-doxorubicin complexes in a Naïve Beagle canine model using hematologic, histological, and urine analysis

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

While doxorubicin (DOX) is one of the most common chemotherapeutic drugs for treating cancer, use of DOX must be managed carefully due to dose-related toxicity. Nanodiamond (ND) drug delivery system conjugated with DOX (NDX) has been reported to enhance treatment efficacy and attenuate toxicity in murine cancer models. In addition, extensive biocompatibility studies indicate that NDs seem to be well tolerated in non-human primates. Before the clinical translation of NDX, it is necessary to verify the safety of ND in large mammals. Studies of nanomedicine drug safety for large animal are not commonly reported, and this work represents a key milestone in bridging earlier advances towards clinical assessment. Herein, NDs’ safety as a drug-delivery platform was evaluated in Naïve Beagle dogs. The study is performed with DOX, ND, and NDX in a dual-gender animal model using intravenous (IV) injection and hepatic portal vein (HPV) injection methods. The dogs are monitored for their health phenotype changes in continuous 5 days. Blood and urine obtained are for clinical pathology research. The results indicate that ND drug delivery platform significantly relieves DOX toxicity for Naïve Beagle dog model. This study provides guidance for the pre-clinical safety assessment of NDX therapy at large animal level.

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

Similar content being viewed by others

References

  1. Vasconcelos, I. B.; da Silva, T. G.; Militão, G. C. G.; Soares, T. A.; Rodrigues, N. M.; Rodrigues M. O.; da Costa, N. B. Jr.; Freire, R. O.; Junior, S. A. Cytotoxicity and slow release of the anti-cancer drug doxorubicin from ZIF-8. RSC Adv.2012, 2, 9437–9442.

    Article  CAS  Google Scholar 

  2. Xi, G. F.; Robinson, E.; Mania-Farnell, B.; Vanin, E. F.; Shim, K. W.; Takao, T.; Allender, E. V.; Mayanil, C. S.; Soares, M. B.; Ho, D. et al. Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. Nanomed. Nanotechnol. Biol. Med.2014, 10, 381–391.

    Article  CAS  Google Scholar 

  3. Kunieda, K.; Seki, T.; Nakatani, S.; Wakabayashi, M.; Shiro, T.; Inoue, K.; Sougawa, M.; Kimura, R.; Harada, K. Implantation treatment method of slow release anticancer doxorubicin containing hydroxyapatite (DOX-HAP) complex. A basic study of a new treatment for hepatic cancer. Br. J. Cancer1993, 67, 668–673.

    Article  CAS  Google Scholar 

  4. Li, Y.; Tong, Y.; Cao, R.; Tian, Z.; Yang, B.; Yang, P. In vivo enhancement of anticancer therapy using bare or chemotherapeutic drug-bearing nanodiamond particles. Int. J. Nanomed.2014, 9, 1065–1082.

    Article  Google Scholar 

  5. Chlebowski, R. T. Adriamycin (doxorubicin) cardiotoxicity: A review. West J. Med.1979, 131, 364–368.

    CAS  Google Scholar 

  6. Salaam, A. D.; Hwang, P.; McIntosh, R.; Green, H. N.; Jun, H. W.; Dean, D. Nanodiamond-DGEA peptide conjugates for enhanced delivery of doxorubicin to prostate cancer. Beilstein J. Nanotechnol.2014, 5, 937–945.

    Article  Google Scholar 

  7. Zhang, X. Y.; Hu, W. B.; Li, J.; Tao, L.; Wei, Y. A comparative study of cellular uptake and cytotoxicity of multi-walled carbon nanotubes, graphene oxide, and nanodiamond. Toxicol. Res.2012, 1, 62–68.

    Article  CAS  Google Scholar 

  8. Loh, K. P.; Ho, D.; Chiu, G. N. C.; Leong, D. T.; Pastorin, G.; Chow, E. K. H. Clinical applications of carbon nanomaterials in diagnostics and therapy. Adv. Mater2018, 30, 1802368.

    Article  Google Scholar 

  9. Shimkunas, R. A.; Robinson, E.; Lam, R.; Lu, S.; Xu, X. Y.; Zhang, X. Q.; Huang, H. J.; Osawa, E.; Ho, D. Nanodiamond-insulin complexes as pH-dependent protein delivery vehicles. Biomaterials2009, 30, 5720–5728.

    Article  CAS  Google Scholar 

  10. Larsson, K.; Tian, Y. Effect of surface termination on the reactivity of nano-sized diamond particle surfaces for bio applications. Carbon2018, 134, 244–254.

    Article  CAS  Google Scholar 

  11. Chow, E. K.; Zhang, X. Q.; Chen, M.; Lam, R.; Robinson, E.; Huang, H. J.; Schaffer, D.; Osawa, E.; Goga, A.; Ho, D. Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment. Sci. Transl. Med.2011, 3, 73ra21.

    Article  Google Scholar 

  12. Wang, P.; Su, W. Q.; Ding, X. T. Control of nanodiamond-doxorubicin drug loading and elution through optimized compositions and release environments. Diam. Relat. Mater.2018, 88, 43–50.

    Article  CAS  Google Scholar 

  13. Mochalin, V. N.; Pentecost, A.; Li, X. M.; Neitzel, I.; Nelson, M.; Wei, C. Y.; He, T.; Guo, F.; Gogotsi, Y. Adsorption of drugs on nanodiamond: Toward development of a drug delivery platform. Mol. Pharm.2013, 10, 3728–3735.

    Article  CAS  Google Scholar 

  14. Li, X. X.; Shao, J. Q.; Qin, Y.; Shao, C.; Zheng, T. T.; Ye, L. TAT-conjugated nanodiamond for the enhanced delivery of doxorubicin. J. Mater. Chem.2011, 21, 7966–7973.

    Article  CAS  Google Scholar 

  15. Mochalin, V. N.; Shenderova, O.; Ho, D.; Gogotsi, Y. The properties and applications of nanodiamonds. Nat. Nanotechnol.2012, 7, 11–23.

    Article  CAS  Google Scholar 

  16. Zou, Q.; Wang, M. Z.; Li, Y. G. Analysis of the nanodiamond particle fabricated by detonation. J. Exp. Nanosci.2010, 5, 319–328.

    Article  CAS  Google Scholar 

  17. Astuti, Y.; Saputra, F. D.; Wuning, S.; Arnelli; Bhaduri, G. Enrichment of nanodiamond surfaces with carboxyl groups for doxorubicin loading and release. IOP Conf. Ser.: Mater. Sci. Eng.2017, 172, 012066.

    Article  Google Scholar 

  18. Luo, J. J.; Liu, Y. F.; Wei, H.; Wang, B. L.; Wu, K. H.; Zhang, B. S.; Su, D. S. A green and economical vapor-assisted ozone treatment process for surface functionalization of carbon nanotubes. Green Chem.2017, 19, 1052–1062.

    Article  CAS  Google Scholar 

  19. Zhang, X. Q.; Lam, R.; Xu, X. Y.; Chow, E. K.; Kim, H. J.; Ho, D. Multimodal nanodiamond drug delivery carriers for selective targeting, imaging, and enhanced chemotherapeutic efficacy. Adv. Mater2011, 23, 4770–4775.

    Article  CAS  Google Scholar 

  20. Vaijayanthimala, V.; Lee, D. K.; Kim, S. V.; Yen, A.; Tsai, N.; Ho, D.; Chang, H. C.; Shenderova, O. Nanodiamond-mediated drug delivery and imaging: Challenges and opportunities. Expert Opin. Drug Del.2015, 12, 735–749.

    Article  CAS  Google Scholar 

  21. Moore, L.; Chow, E. K. H.; Osawa, E.; Bishop, J. M.; Ho, D. Diamond-lipid hybrids enhance chemotherapeutic tolerance and mediate tumor regression. Adv. Mater2013, 25, 3532–3541.

    Article  CAS  Google Scholar 

  22. Man, H. B.; Ho, D. Diamond as a nanomedical agent for versatile applications in drug delivery, imaging, and sensing. Phys. Status Solidi (A)2012, 209, 1609–1618.

    Article  CAS  Google Scholar 

  23. Lin, S.; Xie, P. L.; Luo, M.; Li, Q.; Li, L.; Zhang, J. Z.; Zheng, Q. X.; Chen, H.; Nan, K. H. Efficiency against multidrug resistance by co-delivery of doxorubicin and curcumin with a legumain-sensitive nanocarrier. Nano Res.2018, 11, 3619–3635.

    Article  CAS  Google Scholar 

  24. Ma, X. W.; Zhao, Y. L.; Liang, X. J. Nanodiamond delivery circumvents tumor resistance to doxorubicin. Acta Pharmacol. Sin.2011, 32, 543–544.

    Article  CAS  Google Scholar 

  25. Man, H. B.; Lam, R.; Chen, M.; Osawa, E.; Ho, D. Nanodiamond-therapeutic complexes embedded within poly(ethylene glycol) diacrylate hydrogels mediating sequential drug elution. Phys. Status Solidi (A)2012, 209, 1811–1818.

    Article  CAS  Google Scholar 

  26. Xiao, J. S.; Duan, X. P.; Yin, Q.; Zhang, Z. W.; Yu, H. J.; Li, Y. P. Nanodiamonds-mediated doxorubicin nuclear delivery to inhibit lung metastasis of breast cancer. Biomaterials2013, 34, 9648–9656.

    Article  CAS  Google Scholar 

  27. Salaam, A. D.; Hwang, P. T. J.; Poonawalla, A.; Green, H. N.; Jun, H. W.; Dean, D. Nanodiamonds enhance therapeutic efficacy of doxorubicin in treating metastatic hormone-refractory prostate cancer. Nanotechnology2014, 25, 425103.

    Article  Google Scholar 

  28. Moore, L.; Yang, J. Y.; Lan, T. T. H.; Osawa, E.; Lee, D. K.; Johnson, W. D.; Xi, J. Z.; Chow, E. K. H.; Ho, D. Biocompatibility assessment of detonation nanodiamond in non-human primates and rats using histological, hematologic, and urine analysis. ACS Nano2016, 10, 7385–7400.

    Article  CAS  Google Scholar 

  29. Service, P. H. Position statement on use of animals in research. NIH Guide1993, 22.

  30. U.S. Office of Science and Technology Policy. Laboratory animal welfare; U.S. government principles for the utilization and care of vertebrate animals used in testing, research and training; notice. Fed. Regist.1985, 50, 20864–20865.

    Google Scholar 

  31. Wang, H.; Niu, Y. Y.; Si, W.; Li, Y. J.; Yan, Y. Reference data of clinical chemistry, haematology and blood coagulation parameters in juvenile cynomolgus monkeys (Macaca fascicularis). Vet. Med.2012, 57, 233–238.

    Article  Google Scholar 

  32. Huang, H. J.; Pierstorff, E.; Osawa, E.; Ho, D. Active nanodiamond hydrogels for chemotherapeutic delivery. Nano Lett.2007, 7, 3305–3314.

    Article  CAS  Google Scholar 

  33. Ōsawa, E.; Ho, D.; Huang, H. J.; Korobov, M. V.; Rozhkova, N. N. Consequences of strong and diverse electrostatic potential fields on the surface of detonation nanodiamond particles. Diam. Relat. Mater.2009, 18, 904–909.

    Article  Google Scholar 

  34. Man, H. B.; Kim, H.; Kim, H. J.; Robinson, E.; Liu, W. K.; Chow, E. K. H.; Ho, D. Synthesis of nanodiamond-daunorubicin conjugates to overcome multidrug chemoresistance in leukemia. Nanomed. Nanotechnol. Biol. Med.2014, 10, 359–369.

    Article  CAS  Google Scholar 

  35. Bokarev, A. N.; Plastun, I. L. Possibility of drug delivery due to hydrogen bonds formation in nanodiamonds and doxorubicin: Molecular modeling. Nanosyst.: Phys. Chem. Math.2018, 9, 370–377.

    CAS  Google Scholar 

  36. Paciotti, G. F.; Myer, L.; Weinreich, D.; Goia, D.; Pavel, N.; McLaughlin, R. E.; Tamarkin, L. Colloidal gold: A novel nanoparticle vector for tumor directed drug delivery. Drug Deliv.2004, 11, 169–183.

    Article  CAS  Google Scholar 

  37. Kayal, S.; Ramanujan, R. V. Doxorubicin loaded PVA coated iron oxide nanoparticles for targeted drug delivery. Mater. Sci. Eng.: C2010, 30, 484–490.

    Article  CAS  Google Scholar 

  38. Wang, H. D.; Yang, Q. Q.; Niu, C. H. Functionalization of nanodiamond particles with N, O-carboxymethyl chitosan. Diam. Relat. Mater.2010, 19, 441–444.

    Article  CAS  Google Scholar 

  39. Ballet, F.; Vrignaud, P.; Robert, J.; Rey, C.; Poupon, R. Hepatic extraction, metabolism and biliary excretion of doxorubicin in the isolated prefused rat liver. Cancer Chemother. Pharmacol.1987, 19, 240–245.

    Article  CAS  Google Scholar 

  40. Khalid, A.; Mitropoulos, A. N.; Marelli, B.; Tomljenovic-Hanic, S.; Omenetto, F. G. Doxorubicin loaded nanodiamond-silk spheres for fluorescence tracking and controlled drug release. Biomed. Opt. Express2016, 7, 132–147.

    Article  CAS  Google Scholar 

  41. Yuan, Y.; Chen, Y. W.; Liu, J. H.; Wang, H. F.; Liu, Y. F. Biodistribution and fate of nanodiamonds in vivo. Diam. Relat. Mater.2009, 18, 95–100.

    Article  CAS  Google Scholar 

  42. Puzyr, A. P.; Bortnikov, E. V.; Skobelev, N. N.; Tyan, A. G.; Manashev, G. G.; Bondar, V. A possibility of using of intravenous administration of sterile colloids of modified nanodiamonds. Sib. Med. Obzor2005, 1, 20–24.

    Google Scholar 

  43. Polton, G. Appendix I — tables. In Veterinary Hematology: A Diagnostic Guide and Color Atlas; Harvey, J. W., Ed.; Saunders: St. Louis, Mo., 2012; pp 328–335.

    Google Scholar 

  44. Nemzek, J. A.; Lester, P. A.; Wolfe, A. M.; Dysko, R. C.; Myers, D. D. Biology and diseases of dogs. In Laboratory Animal Medicine; Fox, J. G.; Anderson, L. C.; Otto, G. M.; Pritchett-Corning, K. R.; Whary, M. T., Eds.; Academic Press: Boston, 2015; pp 511–554.

    Chapter  Google Scholar 

  45. Forster, G. M.; Stockman, J.; Noyes, N.; Heuberger, A. L.; Broeckling, C. D.; Bantle, C. M.; Ryan, E. P. A comparative study of serum biochemistry, metabolome and microbiome parameters of clinically healthy, normal weight, overweight, and obese companion dogs. Top. Companion Anim. Med.2018, 33, 126–135.

    Article  Google Scholar 

  46. Rizzi, T. E.; Valenciano, A.; Bowles, M.; Cowell, R.; Tyler, R.; DeNicola, D. B. Atlas of Canine and Feline Urinalysis; John Wiley & Sons, Inc.: Hoboken, 2017.

    Book  Google Scholar 

  47. Zou, Q.; Li, Y. G.; Zou, L. H.; Wang, M. Z. Characterization of structures and surface states of the nanodiamond synthesized by detonation. Mater. Charact.2009, 60, 1257–1262.

    Article  CAS  Google Scholar 

  48. Rojas, S.; Gispert, J. D.; Martín, R.; Abad, S.; Menchón, C.; Pareto, D.; Víctor, V. M.; Álvaro, M.; García, H.; Herance, J. R. Biodistribution of amino-functionalized diamond nanoparticles. In vivo studies based on 18F radionuclide emission. ACS Nano2011, 5, 5552–5559.

    Article  CAS  Google Scholar 

  49. Lu, W. J.; Yao, J.; Zhu, X.; Qi, Y. Nanomedicines: Redefining traditional medicine. Biomed. Pharmacother.2021, 134, 111103.

    Article  CAS  Google Scholar 

  50. Cui, Z. F.; Zhang, Y.; Zhang, J. C.; Kong, H. T.; Tang, X. X.; Pan, L.; Xia, K.; Aldalbahi, A.; Li, A. G.; Tai, R. Z. et al. Sodium alginate-functionalized nanodiamonds as sustained chemotherapeutic drug-release vectors. Carbon2016, 97, 78–86.

    Article  CAS  Google Scholar 

  51. Yang, G.; Long, W.; Yan, W.; Huang, H.; Liu, M.; Ouyang, H.; Feng, Y.; Liu, L.; Zhang, X.; Wei, Y. Surface PEGylation of nanodiamond through a facile Michael addition reaction for intracellular drug delivery. J. Drug Deliv. Sci. Tec.2020, 57, 101644.

    Article  CAS  Google Scholar 

  52. Uthappa, U. T.; Arvind, O. R.; Sriram, G.; Losic, D.; Ho-Young-Jung; Kigga, M.; Kurkuri, M. D. Nanodiamonds and their surface modification strategies for drug delivery applications. J. Drug Deliv. Sci. Technol.2020, 60, 101993.

    Article  CAS  Google Scholar 

  53. Moghimi, S. M. Nanomedicine safety in preclinical and clinical development: Focus on idiosyncratic injection/infusion reactions. Drug Discov. Today2018, 23, 1034–1042.

    Article  CAS  Google Scholar 

  54. Singh, A. V.; Ansari, M. H. D.; Rosenkranz, D.; Maharjan, R. S.; Kriegel, F. L.; Gandhi, K.; Kanase, A.; Singh, R.; Laux, P.; Luch, A. Artificial intelligence and machine learning in computational nanotoxicology: Unlocking and empowering nanomedicine. Adv. Healthc. Mater.2020, 9, 1901862.

    Article  CAS  Google Scholar 

  55. Hartung, T. Perspectives on in vitro to in vivo extrapolations. Appl. In Vitro Toxicol.2018, 4, 305–316.

    Article  CAS  Google Scholar 

  56. Zhang, C. Y.; Yan, L.; Wang, X.; Zhu, S.; Chen, C. Y.; Gu, Z. J.; Zhao, Y. L. Progress, challenges, and future of nanomedicine. Nano Today2020, 35, 101008.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work is partially funded by the National Natural Science Foundation of China (No. 81871448), the National Key Research and Development Program of China (Nos. 2017YFC0107603 and 2017ZX10203205-006-002), and the Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (Nos. YG2017QN52, ZH2018QNA54, and ZH2018QNA49).

Author information

Author notes

  1. Liping Wang, Wenqiong Su, Khan Zara Ahmad, and Xin Wang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China

    Liping Wang, Wenqiong Su, Khan Zara Ahmad, Xin Wang, Ting Zhang, Youyi Yu & Xianting Ding

  2. Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore

    Edward Kai-Hua Chow

  3. The N.1 Institute for Health (N.1), National University of Singapore, Singapore, 117456, Singapore

    Edward Kai-Hua Chow & Dean Ho

  4. The Institute for Digital Medicine (WisDM), National University of Singapore, Singapore, 117456, Singapore

    Edward Kai-Hua Chow & Dean Ho

  5. Department of Pharmacology, National University of Singapore, Singapore, 117597, Singapore

    Edward Kai-Hua Chow & Dean Ho

  6. Department of Biomedical Engineering, National University of Singapore, Singapore, 117583, Singapore

    Edward Kai-Hua Chow & Dean Ho

Authors
  1. Liping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenqiong Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Khan Zara Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ting Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Youyi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward Kai-Hua Chow
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dean Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xianting Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Edward Kai-Hua Chow, Dean Ho or Xianting Ding.

Electronic supplementary material

12274_2021_3867_MOESM1_ESM.pdf

Safety evaluation of nanodiamond-doxorubicin complexes in a Naïve Beagle canine model using hematologic, histological, and urine analysis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Su, W., Ahmad, K.Z. et al. Safety evaluation of nanodiamond-doxorubicin complexes in a Naïve Beagle canine model using hematologic, histological, and urine analysis. Nano Res. 15, 3356–3366 (2022). https://doi.org/10.1007/s12274-021-3867-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-021-3867-0

Keywords

Search

Navigation