Protoporphyrin IX-β-cyclodextrin bimodal conjugate: Nanosized drug transporter and potent phototoxin

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. The new, water soluble, covalent conjugate of protoporphyrin IX (PpIX) with β-cyclodextrin (PpIX + βCD) was specifically prepared for multimodal application: PpIX + βCD displays phototoxiciy comparable to that of PpIX, preferentially localizes in mitochondria in MCF7 and DU145 cell lines, effectively solubilizes the breast cancer drug tamoxifen metabolite N-desmethyltamoxifen in water and transports it into cells, where it confers cell death through a synergy of photo-and chemo-toxicity while simultaneously its fluorescence serves for imaging purposes. © 2013 The American Society of Photobiology.