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Protoporphyrin IX–β-Cyclodextrin Bimodal Conjugate: Nanosized Drug Transporter and Potent Phototoxin

Authors

  • Chrysie Aggelidou,

    1. Institute of Advanced Materials, Physicochemical Processes, Nanotechnology & Microsystems, National Center for Scientific Research “Demokritos”, Aghia Paraskevi, Attiki, Greece
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  • Theodossis A. Theodossiou,

    Corresponding author
    • Institute of Advanced Materials, Physicochemical Processes, Nanotechnology & Microsystems, National Center for Scientific Research “Demokritos”, Aghia Paraskevi, Attiki, Greece
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  • Konstantina Yannakopoulou

    Corresponding author
    • Institute of Advanced Materials, Physicochemical Processes, Nanotechnology & Microsystems, National Center for Scientific Research “Demokritos”, Aghia Paraskevi, Attiki, Greece
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Corresponding authors email: dyanna@chem.demokritos.gr (Konstantina Yannakopoulou) theo@chem.demokritos.gr (Theodossis A. Theodossiou)

Abstract

Topical or systemic administration of 5-aminolevulinic acid (ALA) and its esters results in increased production and accumulation of protoporphyrin IX (PpIX) in cancerous lesions allowing effective application of photodynamic therapy (PDT). The large concentrations of exogenous ALA practically required to bypass the negative feedback control exerted by heme on enzymatic ALA synthesis and the strong dimerization propensity of ALA are shortcomings of the otherwise attractive PpIX biosynthesis. To circumvent these limitations and possibly enhance the phototoxicity of PpIX by adjuvant chemotherapy, covalent bonding of PpIX with a drug carrier, β-cyclodextrin (βCD) was implemented. The resulting PpIX + βCD product had both carboxylic termini of PpIX connected to the CD. PpIX + βCD was water soluble, was found to preferentially localize in mitochondria rather than in lysosomes both in MCF7 and DU145 cell lines while its phototoxiciy was comparable to that of PpIX. Moreover, PpIX + βCD effectively solubilized the breast cancer drug tamoxifen metabolite N-desmethyltamoxifen (NDMTAM) in water. The PpIX + βCD/NDMTAM complex was readily internalized by both cell lines employed. Furthermore, the multimodal action of PpIX + βCD was demonstrated in MCF7 cells: while it retains the phototoxic profile of PpIX and its fluorescence for imaging purposes, PpIX + βCD can efficiently transport tamoxifen citrate intracellularly and confer cell death through a synergy of photo- and chemotoxicity.

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