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.

Novel β-cyclodextrin–eosin conjugates

“…For PDT applications CDs have been conjugated with porphyrin [7] and protoporphyrin (5-aminolevulinic acid) [8] in order to enhance the membrane penetration of the PS (or its prodrug), to increase the aqueous solubility and to prevent the undesired aggregation of the PS inside the cell. Another advantage offered by the covalently connected CD–PS systems is the encapsulation of hydrophobic photoactivatable drug molecules in the CD cavity, enabling thereby the application of these systems in combined phototherapies.…”

Synthesis of Water-Soluble Non-Aggregated Porphyrin-β-Cyclodextrin Tetraconjugate

“…One of these systems intensively studied in the recent years is the conjugates of porphyrins (Por) with cyclodextrins (CD). [1][2][3][4][5][6][7][8][9][10][11][12] The specific biological (tendency to accumulate in cancer tissues) and spectroscopic (high molar absorption, strong fluorescence and good quantum yields) properties of porphyrins predetermine their medical applications mostly focused on photodynamic diagnostic and photodynamic therapy (PDT). [13][14][15][16] The photoactivity of many photosensitizers in PDT is affected by their poor solubility and aggregation, which leads to a decrease in their singlet oxygen production.…”

“…Moreover, the presence of porphyrin unit in conjugate with cyclodextrin gives the possibility of additional accurate spectroscopic detectability of the supramolecular systems before and after complexation with guests into cyclodextrin cavities. [1][2][3][4][5][6][7][8][9][10][11][12]19,21] The several porphyrin derivatives covalently linked with cyclodextrins were synthesized and investigated. [2][3][4][6][7][8][9][10][11][12]20,[22][23][24][25][26][27][28][29][30][31][32][33][34] Most of these conjugates contain one or two cyclodextrin units on periphery of porphyrin macrocycle.…”

A versatile δ-aminolevulinic acid (ΑLA)-cyclodextrin bimodal conjugate-prodrug for PDT applications with the help of intracellular chemistry

“…Compound 1 is a polar, zwitterionic compound, with inherently poor cell permeability and consequently challenging pharmaceutical formulations [5]. We have recently published [6] the covalent conjugation of PpIX to β-cyclodextrin (β-CD), a water-soluble cyclic oligosaccharide host capable of carrying hydrophobic molecules, such as drugs, in its hydrophobic cavity [7]. The cyclodextrins (CDs) are a notable family of semi-natural carbohydrate molecules approved as pharmaceutical excipients that improve the solubility and bioavailability of drugs through molecular encapsulation.…”

“…The cyclodextrins (CDs) are a notable family of semi-natural carbohydrate molecules approved as pharmaceutical excipients that improve the solubility and bioavailability of drugs through molecular encapsulation. We demonstrated [6] the conjugate’s (PpIX-CD) bimodal action of transporting the chemotherapeutic agent tamoxifen intracellularly to engage its targets while simultaneously acting as a PS. In this sense we created a bimodal system with adequate water solubility (several μM) able to inflict significant chemo- and phototoxicity on cancer cells.…”