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Apoptotic cell death induced by dendritic derivatives of aminolevulinic acid in endothelial and foam cells co-cultures

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Abstract

Photodynamic therapy (PDT) is an effective procedure for the treatment of lesions diseases based on the selectivity of a photosensitising compound with the ability to accumulate in the target cell. Atherosclerotic plaque is a suitable target for PDT because of the preferential accumulation of photosensitisers in atherosclerotic plaques. Dendrimers are hyperbranched polymers conjugated to drugs. The dendrimers of ALA hold ester bonds that inside the cells are cleaved and release ALA, yielding PpIX production. The dendrimer 6m-ALA was chosen to perform this study since in previous studies it induced the highest porphyrin macrophage: endothelial cell ratio (Rodriguez et al. in Photochem Photobiol Sci 14:1617–1627, 2015). We transformed Raw 264.7 macrophages to foam cells by exposure to oxidised LDLs, and we employed a co-culture model of HMEC-1 endothelial cells and foam cells to study the affinity of ALA dendrimers for the foam cells. In this work it was proposed an in vitro model of atheromatous plaque, the aim was to study the selectivity of an ALA dendrimer for the foam cells as compared to the endothelial cells in a co-culture system and the type of cell death triggered by the photodynamic treatment. The ALA dendrimer 6m-ALA showed selectivity PDT response for foam cells against endothelial cells. A light dose of 1 J/cm2 eliminate foam cells, whereas less than 50% of HMEC-1 is killed, and apoptosis cell death is involved in this process, and no necrosis is present. We propose the use of ALA dendrimers as pro-photosensitisers to be employed in photoangioplasty to aid in the treatment of obstructive cardiovascular diseases, and these molecules can also be employed as a theranostic agent.

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Abbreviations

ALA:

5-Aminolevulinic acid

FBS:

Foetal bovine serum

MTT:

(3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide)

PDT:

Photodynamic therapy

PpIX:

Protoporphyrin IX

PBS:

Buffer phosphate

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Acknowledgements

Work at CIPYP was supported by grants from CONCET (PIP 0237, to AC) and ANPCyT (PICT 2014-0727, to AC). MC thanks INC for a student fellowship. GC thanks CONICET for a doctoral fellowship. The authors are grateful to Vanina Ripoll for her technical support.

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Authors and Affiliations

  1. Centro de Investigaciones Sobre Porfirinas y Porfirias (CIPYP), Hospital de Clínicas José de San Martin, Universidad de Buenos Aires and CONICET, Avenida Córdoba 2351, 1er subsuelo, 1120 AAF, Autonomous City of Buenos Aires, Argentina

    Mariela A. Céspedes, Daniel A. Saénz, Gustavo H. Calvo, Adriana G. Casas & Gabriela M. Di Venosa

  2. Facultad de Ciencias Médicas, Centro Científico Tecnológico La Plata, Instituto de Investigaciones Bioquímica de La Plata (INIBIOLP), Universidad Nacional de La Plata, Calle 60 y 120 s/n, 1900, La Plata, Argentina

    Marina González

  3. Division of Surgery and Interventional Science, University College London, London, UK

    Alexander J. MacRobert

  4. The School of Life Sciences, University of Essex, Colchester, CO4 3SQ, UK

    Sinan Battah

Authors
  1. Mariela A. Céspedes
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  2. Daniel A. Saénz
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  3. Gustavo H. Calvo
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  4. Marina González
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  5. Alexander J. MacRobert
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  6. Sinan Battah
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  7. Adriana G. Casas
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  8. Gabriela M. Di Venosa
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Contributions

GD and AC conceived the biological experiments and wrote the main text. MC, DS, GC and GD carried out the biological experiments. MG carried out the isolation of LDL, preparation of OxLDL AM and SB provide the dendrimer 6m-ALA. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Adriana G. Casas or Gabriela M. Di Venosa.

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Céspedes, M.A., Saénz, D.A., Calvo, G.H. et al. Apoptotic cell death induced by dendritic derivatives of aminolevulinic acid in endothelial and foam cells co-cultures. Photochem Photobiol Sci 20, 489–499 (2021). https://doi.org/10.1007/s43630-021-00025-x

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