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Nanostructured Lipid Carrier Co-loaded with Doxorubicin and Docosahexaenoic Acid as a Theranostic Agent: Evaluation of Biodistribution and Antitumor Activity in Experimental Model

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Abstract

Purpose

Nanotheranostic platforms, i.e., the combination of both therapeutic and diagnostic agents on a single platform, are emerging as an interesting tool for the personalized cancer medicine. Therefore, the aim of this work was to evaluate the in vivo properties of a Tc-99m-labeled nanostructured lipid carrier (NLC) formulation, co-loaded with doxorubicin (DOX) and docosahexaenoic acid (DHA), for theranostic applications.

Procedures

NLC-DHA-DOX were prepared busing the hot melting homogenization method using an emulsification-ultrasound and were radiolabeled with Tc-99m. Biodistribution studies, scintigraphic images, and antitumor activity were performed in 4T1 tumor-bearing mice.

Results

NCL was successfully radiolabeled with Tc-99m. Blood clearance showed a relatively long half-life, with blood levels decaying in a biphasic manner (T1/2 α = 38.7 min; T1/2 β = 516.5 min). The biodistribution profile and scintigraphic images showed higher tumor uptake compared to contralateral muscle in all time-points investigated. Antitumor activity studies showed a substantial tumor growth inhibition ratio for NLC-DHA-DOX formulation. In addition, the formulation showed more favorable toxicity profiles when compared to equivalent doses of free administered drugs, being able to reduce heart and liver damage.

Conclusions

Therefore, NLC-DHA-DOX formulation demonstrated feasibility in breast cancer treatment and diagnosis/monitoring, leading to a new possibility of a theranostic platform.

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References

  1. Stewart BW, Wild CP (2014) World cancer report 2014 latest world cancer statistics. International Agency for Research on Cancer, Lyon

    Google Scholar 

  2. Livi L, Meattini I, de Cardillo CL et al (2009) Non-pegylated liposomal doxorubicin in combination with cyclophosphamide or docetaxel as first-line therapy in metastatic breast cancer: a retrospective analysis. Tumori 95:422–426

    Article  CAS  PubMed  Google Scholar 

  3. Shi Y, Moon M, Dawood S et al (2011) Mechanisms and management of doxorubicin cardiotoxicity. Herz 36:296–305

    Article  CAS  PubMed  Google Scholar 

  4. Primeau AJ, Rendon A, Hedley D et al (2005) The distribution of the anticancer drug doxorubicin in relation to blood vessels in solid tumors. Clin Cancer Res 27:8782–8788

    Article  Google Scholar 

  5. Trédan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454

    Article  PubMed  Google Scholar 

  6. Carvalho C, Santos RX, Cardoso S et al (2009) Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem 16:3267–3285

    Article  CAS  PubMed  Google Scholar 

  7. Jassem J, Pieńkowski T, Płuzańska A et al (2001) Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707–1715

    Article  CAS  PubMed  Google Scholar 

  8. Germain E, Chajès V, Cognault S et al (1998) Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MDA-MB-231: relationship to lipid peroxidation. Int J Cancer 75:578–583

    Article  CAS  PubMed  Google Scholar 

  9. Colas S, Mahéo K, Denis F et al (2006) Sensitization by dietary docosahexaenoic acid of rat mammary carcinoma to anthracycline: a role for tumor vascularization. Clin Cancer Res 12:5879–5886

    Article  CAS  PubMed  Google Scholar 

  10. Siddiqui RA, Harvey KA, Xu Z et al (2011) Docosahexaenoic acid: a natural powerful adjuvant that improves efficacy for anticancer treatment with no adverse effects. Biofactors 37:399–412

    Article  CAS  PubMed  Google Scholar 

  11. Mahéo K, Vibet S, Steghens JP et al (2005) Differential sensitization of cancer cells to doxorubicin by DHA: a role for lipoperoxidation. Free Radic Biol Med 39:742–751

    Article  PubMed  Google Scholar 

  12. Hardman WE, Avula CP, Fernandes G, Cameron IL (2001) Three percent dietary fish oil concentrate increased efficacy of doxorubicin against MDA-MB 231 breast cancer xenografts. Clin Cancer Res 7:2041–2049

    CAS  PubMed  Google Scholar 

  13. Parhi P, Mohanty C, Sahoo SK (2012) Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy. Drug Discov Today 17:1044–1052

    Article  CAS  PubMed  Google Scholar 

  14. Mamot C, Drummond DC, Hong K et al (2003) Liposome-based approaches to overcome anticancer drug resistance. Drug Resist Update 6:271–279

    Article  CAS  Google Scholar 

  15. Muller RH, Mader K, Gohla D (2000) Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm 50:161–177

    Article  CAS  PubMed  Google Scholar 

  16. Mehnert W, Mader K (2001) Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev 47:165–196

    Article  CAS  PubMed  Google Scholar 

  17. Janib SM, Moses AS, MacKay JA (2010) Imaging and drug delivery using theranostic nanoparticles. Adv Drug Deliv Rev 62:1052–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jo SD, SH K, Won Y-Y et al (2016) Targeted nanotheranostics for future personalized medicine: recent progress in cancer therapy. Theranostics 6:1362–1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Choi KY, Liu G, Lee S, Chen X (2012) Theranosticnanoplatforms for simultaneous cancer imaging and therapy: current approaches and future perspectives. Nano 4:330–342

    CAS  Google Scholar 

  20. Xie J, Chen X (2010) Nanoparticle-based theranostic agents. Adv Drug Deliv Rev 62:1064–1079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang DJ, Kim C, Schechter NR et al (2003) Imaging with 99mTc-ECDG targeted at the multifunctional glucose system: feasibility studies with rodents. Radiology 226:465–473

    Article  PubMed  Google Scholar 

  22. Saha GB (2010) Radiopharmaceuticals and methods of radiolabeling. In: Fundamentals of nuclear pharmacy. Springer, New York, pp 83–113

    Chapter  Google Scholar 

  23. Mussi SV, Sawant R, Perche F et al (2014) Novel nanostructured lipid carrier co-loaded with doxorubicin and docosahexaenoic acid demonstrates enhanced in vitro activity and overcomes drug resistance in MCF-7/Adr cells. Pharm Res 8:1882–1890

    Article  Google Scholar 

  24. Mussi SV, Silva RC, Oliveira MC et al (2013) New approach to improve encapsulation and antitumor activity of doxorubicin loaded in solid lipid nanoparticles. Eur J Pharm Sci 48:282–290

    Article  CAS  PubMed  Google Scholar 

  25. Fernandes RS, Silva JO, Lopes SCA et al (2016) Technetium-99m-labeled doxorubicin as an imaging probe for murine breast tumor (4T1 cell line) identification. Nucl Med Commun 37:307–312

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  27. Souza CM, Carvalho LF, Vieira TS et al (2012) Thalidomide attenuates mammary cancer associated-inflammation, angiogenesis and tumor growth in mice. Biomed Pharmacother 66:491–498

    Article  Google Scholar 

  28. Li Y, Wang J, Wientjes MG, JL A (2012) Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor. Adv Drug Deliv Rev 64:29–39

    Article  CAS  PubMed  Google Scholar 

  29. Maeda H, Wu J, Sawa J, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65:271–284

    Article  CAS  PubMed  Google Scholar 

  30. Torchilin V (2011) Tumor delivery of macromolecular drugs based on the EPR effect. Adv Drug Deliv Rev 63:131–135

    Article  CAS  PubMed  Google Scholar 

  31. Reddy LH, Sharma LK, Chuttani K et al (2005) Influence of administration route on tumor uptake and biodistribution of etoposide loaded solid lipid nanoparticles in Dalton’s lymphoma tumor bearing mice. J Control Release 105:185–198

    Article  CAS  Google Scholar 

  32. Beloqui A, Solinis MA, Delgado A et al (2013) Biodistribution of nnostructured lipid carriers (NLCs) after intravenous administration to rats: influence of technological fators. Eur J Pharm Biopharm 84:309–314

    Article  CAS  PubMed  Google Scholar 

  33. Torchilin V (2009) Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur J Pharm Biopharm 71:431–444

    Article  CAS  PubMed  Google Scholar 

  34. Yuan F, Dellian M, Fukumura D et al (1995) Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55:3752–3756

    CAS  PubMed  Google Scholar 

  35. Leu AJ, Berk DA, Lymboussaki A et al (2000) Absence of functional lymphatics within murine sarcoma: molecular and functional evaluation. Cancer Res 60:4324–4327

    CAS  PubMed  Google Scholar 

  36. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:246–257

    Article  Google Scholar 

  37. Munn II (2003) Aberrant vascular architecture in tumors and its importance in drug-based therapies. Drug Discov Today 8:396–403

    Article  PubMed  Google Scholar 

  38. Gosh K, Thodeti CK, Dudley AC et al (2008) Tumor-derived endothelial cells exhibit aberrant Rhon-mediated mechanosensing and abnormal angiogenesis in vitro. Proc Natl Acad Sci U S A 105:11305–11310

    Article  Google Scholar 

  39. Mastria EM, Chen M, McDaniel JR (2015) Doxorubicin-conjugated polypeptide nanoparticles inhibit metastasis in two murine models of carcinoma. J Control Release 118:52–58

    Article  Google Scholar 

  40. Sun L, Deng X, Yang X et al (2014) Co-delivery of doxorubicin and curcumin by polymeric micelles for improving antitumor efficacy on breast carcinoma. RSC Adv 4:46737–46750

    Article  CAS  Google Scholar 

  41. Wang J, Ma W, Tu W (2015) Synergistically improved anti-tumor efficacy by co-delivery doxorubicin and curcumin polymeric micelles. Macromol Biosci 15:1252–1261

    Article  CAS  PubMed  Google Scholar 

  42. Guffy MM, North JA, Burns CP (1984) Effect of cellular fatty acid alteration on adriamycin sensitivity in cultured L1210 murine leukemia cells. Cancer Res 44:1863–1866

    CAS  PubMed  Google Scholar 

  43. Wissing SA, Kayser O, Muller RH (2004) Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev 56:1257–1272

    Article  CAS  PubMed  Google Scholar 

  44. Haley B, Frenkel E (2008) Nanoparticles for drug delivery in cancer treatment. Urol Oncol 26:57–64

    Article  CAS  PubMed  Google Scholar 

  45. O’Brien MER, Wigler N, Inbar M et al (2004) Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX™/Doxil®) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 26:440–449

    Article  Google Scholar 

  46. Shuhendler AJ, Prasad P, Zhang RX et al (2014) Synergistic nanoparticulate drug combination overcomes multidrug resistance, increases efficacy, and reduces cardiotoxicity in a nonimmuno compromised breast tumor model. Mol Pharmaceutics 14:2659–2674

    Article  Google Scholar 

Download references

Financial Support

The authors thank Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG-Brazil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Brazil) for their financial support and fellowships.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Renata S. Fernandes, Juliana O. Silva, Samuel V. Mussi, Sávia C. A. Lopes, Elaine A. Leite, Valbert N. Cardoso, Lucas A. M. Ferreira & André L. B. de Barros

  2. Biological Science Institute, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Geovanni D. Cassali

  3. Department of Drug Discovery and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA

    Danyelle M. Townsend

  4. Department of Radiology, University of Southern California, Los Angeles, CA, USA

    Patrick M. Colletti

  5. Department of Nuclear Medicine, Radiology, NeuroRadiology, Medical Physics, Clinical Pathology & Molecular Biology, Santa Maria della Misericordia Hospital, Via Tre Martiri, 140, 45100, Rovigo, Italy

    Domenico Rubello

Authors
  1. Renata S. Fernandes
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  2. Juliana O. Silva
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  3. Samuel V. Mussi
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  4. Sávia C. A. Lopes
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  5. Elaine A. Leite
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  6. Geovanni D. Cassali
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  7. Valbert N. Cardoso
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  8. Danyelle M. Townsend
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  9. Patrick M. Colletti
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  10. Lucas A. M. Ferreira
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  11. Domenico Rubello
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  12. André L. B. de Barros
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Corresponding authors

Correspondence to Domenico Rubello or André L. B. de Barros.

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Fernandes, R.S., Silva, J.O., Mussi, S.V. et al. Nanostructured Lipid Carrier Co-loaded with Doxorubicin and Docosahexaenoic Acid as a Theranostic Agent: Evaluation of Biodistribution and Antitumor Activity in Experimental Model. Mol Imaging Biol 20, 437–447 (2018). https://doi.org/10.1007/s11307-017-1133-3

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  • DOI: https://doi.org/10.1007/s11307-017-1133-3

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