Development of a bone-targeted ph-sensitive liposomal formulation containing doxorubicin: Physicochemical characterization, cytotoxicity, and biodistribution evaluation in a mouse model of bone metastasis

Diêgo dos Santos Ferreira, Samilla Dornelas Faria, Sávia Caldeira de Araújo Lopes, Cláudia Salviano Teixeira, Angelo Malachias, Rogério Magalhães-Paniago, José Dias de Souza Filho, Bruno Luis Oliveira de Jesus Pinto, Alexander Ramos Guimarães, Peter Caravan, Lucas Antônio Miranda Ferreira, Ricardo José Alves, Mônica Cristina Oliveira

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Background: Despite recent advances in cancer therapy, the treatment of bone tumors remains a major challenge. A possible underlying hypothesis, limitation, and unmet need may be the inability of therapeutics to penetrate into dense bone mineral, which can lead to poor efficacy and high toxicity, due to drug uptake in healthy organs. The development of nanostructured formulations with high affinity for bone could be an interesting approach to overcome these challenges. Purpose: To develop a liposomal formulation with high affinity for hydroxyapatite and the ability to release doxorubicin (DOX) in an acidic environment for future application as a tool for treatment of bone metastases. Materials and methods: Liposomes were prepared by thin-film lipid hydration, followed by extrusion and the sulfate gradient-encapsulation method. Liposomes were characterized by aver­age diameter, ζ-potential, encapsulation percentage, X-ray diffraction, and differential scanning calorimetry. Release studies in buffer (pH 7.4 or 5), plasma, and serum, as well as hydroxyapatite-affinity in vitro analysis were performed. Cytotoxicity was evaluated by MTT assay against the MDA-MB-231 cell line, and biodistribution was assessed in bone metastasis-bearing animals. Results: Liposomes presented suitable diameter (~170 nm), DOX encapsulation (~2 mg/mL), controlled release, and good plasma and serum stability. The existence of interactions between DOX and the lipid bilayer was proved through differential scanning calorimetry and small-angle X-ray scattering. DOX release was faster when the pH was in the range of a tumor than at physi­ological pH. The bone-targeted formulation showed a strong affinity for hydroxyapatite. The encapsulation of DOX did not interfere in its intrinsic cytotoxicity against the MDA-MB-231 cell line. Biodistribution studies demonstrated high affinity of this formulation for tumors and reduction of uptake in the heart. Conclusion: These results suggest that bone-targeted pH-sensitive liposomes containing DOX can be an interesting strategy for selectively delivering this drug into bone-tumor sites, increas­ing its activity, and reducing DOX-related toxicity.

Original languageEnglish (US)
Pages (from-to)3737-3751
Number of pages15
JournalInternational journal of nanomedicine
Volume11
DOIs
StatePublished - Aug 9 2016

Keywords

  • Bisphosphonates
  • Bone-tumor treatment
  • Hydroxyapatite-targeted formulations
  • PH-responsive nanostruc­tures

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Ferreira, D. D. S., Faria, S. D., Lopes, S. C. D. A., Teixeira, C. S., Malachias, A., Magalhães-Paniago, R., de Souza Filho, J. D., Oliveira de Jesus Pinto, B. L., Guimarães, A. R., Caravan, P., Ferreira, L. A. M., Alves, R. J., & Oliveira, M. C. (2016). Development of a bone-targeted ph-sensitive liposomal formulation containing doxorubicin: Physicochemical characterization, cytotoxicity, and biodistribution evaluation in a mouse model of bone metastasis. International journal of nanomedicine, 11, 3737-3751. https://doi.org/10.2147/IJN.S109966