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 Guimaraes, Peter Caravan, Lucas Antônio Miranda Ferreira, Ricardo José Alves, Mônica Cristina Oliveira

Research output: Contribution to journalArticle

17 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Bone Development
Cytotoxicity
Doxorubicin
Bone
Neoplasm Metastasis
Bone and Bones
Liposomes
Encapsulation
Tumors
Durapatite
Hydroxyapatite
Differential Scanning Calorimetry
Neoplasms
Toxicity
Differential scanning calorimetry
Bearings (structural)
Cells
Plasmas
Cell Line
Lipid bilayers

Keywords

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

ASJC Scopus subject areas

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

Cite this

Development of a bone-targeted ph-sensitive liposomal formulation containing doxorubicin : Physicochemical characterization, cytotoxicity, and biodistribution evaluation in a mouse model of bone metastasis. / Ferreira, Diêgo dos Santos; Faria, Samilla Dornelas; Lopes, Sávia Caldeira de Araújo; Teixeira, Cláudia Salviano; Malachias, Angelo; Magalhães-Paniago, Rogério; de Souza Filho, José Dias; Oliveira de Jesus Pinto, Bruno Luis; Guimaraes, Alexander; Caravan, Peter; Ferreira, Lucas Antônio Miranda; Alves, Ricardo José; Oliveira, Mônica Cristina.

In: International Journal of Nanomedicine, Vol. 11, 09.08.2016, p. 3737-3751.

Research output: Contribution to journalArticle

Ferreira, DDS, Faria, SD, Lopes, SCDA, Teixeira, CS, Malachias, A, Magalhães-Paniago, R, de Souza Filho, JD, Oliveira de Jesus Pinto, BL, Guimaraes, A, Caravan, P, Ferreira, LAM, Alves, RJ & Oliveira, MC 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, vol. 11, pp. 3737-3751. https://doi.org/10.2147/IJN.S109966
Ferreira, Diêgo dos Santos ; Faria, Samilla Dornelas ; Lopes, Sávia Caldeira de Araújo ; Teixeira, Cláudia Salviano ; Malachias, Angelo ; Magalhães-Paniago, Rogério ; de Souza Filho, José Dias ; Oliveira de Jesus Pinto, Bruno Luis ; Guimaraes, Alexander ; Caravan, Peter ; Ferreira, Lucas Antônio Miranda ; Alves, Ricardo José ; Oliveira, Mônica Cristina. / Development of a bone-targeted ph-sensitive liposomal formulation containing doxorubicin : Physicochemical characterization, cytotoxicity, and biodistribution evaluation in a mouse model of bone metastasis. In: International Journal of Nanomedicine. 2016 ; Vol. 11. pp. 3737-3751.
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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.",
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T1 - Development of a bone-targeted ph-sensitive liposomal formulation containing doxorubicin

T2 - Physicochemical characterization, cytotoxicity, and biodistribution evaluation in a mouse model of bone metastasis

AU - Ferreira, Diêgo dos Santos

AU - Faria, Samilla Dornelas

AU - Lopes, Sávia Caldeira de Araújo

AU - Teixeira, Cláudia Salviano

AU - Malachias, Angelo

AU - Magalhães-Paniago, Rogério

AU - de Souza Filho, José Dias

AU - Oliveira de Jesus Pinto, Bruno Luis

AU - Guimaraes, Alexander

AU - Caravan, Peter

AU - Ferreira, Lucas Antônio Miranda

AU - Alves, Ricardo José

AU - Oliveira, Mônica Cristina

PY - 2016/8/9

Y1 - 2016/8/9

N2 - 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.

AB - 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.

KW - Bisphosphonates

KW - Bone-tumor treatment

KW - Hydroxyapatite-targeted formulations

KW - PH-responsive nanostruc­tures

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