Selective photosensitization through an AND logic response: optimization of the pH and glutathione response of activatable photosensitizers

Abstract

A series of pH and GSH responsive photosensitizers were designed and synthesized. pK a values were optimized by adjusting the inductive contribution of substituents to reach a pH range (6.0-7.4) relevant to the tumour microenvironment. pH-Activatable behaviour and redox mediated release of the quencher from the PS by GSH allow the construction of an AND logic operator for selective photodynamic action in aqueous solutions.The research in molecular logic gates, which was initiated by the seminal work by de Silva, 1 blossomed in the two decades that followed. 2 In addition, the limitations and the potential of this approach has become more clear. A particularly promising application of molecular logic gates may be in the field of information processing therapeutic agents. Incorporation of Boolean logic ideas in the function of therapeutic agents would be very valuable, if the same results cannot be achieved by random optimization studies. Previously, our group and others provided the early examples of the work in that direction. 3 Our first proof of principle work which linked photodynamic sensitization of a Bodipy based photosensitizer (PS) to the concentrations of sodium ions and the acidity was essentially an AND logic gate, but the system required organic solvents and organic acid to function in the desired manner. While it was considered to be noteworthy for that approach to have practical potential, an AND logic gate based enhanced selectivity should be related to cancer related biological parameters, which can generate significant changes in the photophysical character of the sensitizer in aqueous solutions.In this work, we took advantage of two characteristics of the tumour microenvironment, lower pH and higher glutathione concentrations. 4 The difference in pH between cancer tissue and healthy tissue is an easily accessible parameter for use in therapeutic activation. A number of pH-responsive polymeric materials, photosensitizers, and nanocarriers were studied to control drug release or activation. 5 However, extracellular pH of tumor cells drops to a value not below 6.0. 6 Thus, it is challenging to find a smart therapeutic system responsive to pH within the narrow near neutral range and essentially become active at around pH 6.0-6.5 and stay inactive above pH 7.0. Apart from some, 7 most related studies in the literature depend on activation at pH below 5.5, which actually requires nonselective lysosomal activation. 8 In this work, the properties of the PS are optimized for pH activatability by causing rational chemical modification on the pH responsive moiety with electron donating or withdrawing groups to adjust the pK a to the desired near-neutral value and to get enough spectral shift in acidic aqueous solutions such that protonated PSs are exclusively excited species under the conditions of interest. Thus, the overall design (Scheme 1) involves a pH responsive unit, linked to a quencher, which could be cleaved at elevated GSH concentrations. Previously, GSH has been used as a PS activator mostly t...

Disulfide‐Linked Dendritic Oligomeric Phthalocyanines as Glutathione‐Responsive Photosensitizers for Photodynamic Therapy

“…These alkynyl compounds were then conjugated with different numbers of ad isulfide-linked azido zinc(II) phthalocyanine through aC u I -catalyzed alkyne-azide cycloaddition reaction. As shown in Scheme 1, azido phthalocyanine 5 was pre-pared by treating our previously reported alkynyl phthalocyanine PC [15] with al arge excess amount of bis(2-azidoethyl) disulfide [16] also by click chemistry by using CuI and diisopropylethylamine (DIPEA) as the catalyst and base, respectively.U nder similarr eactionc onditions, compound 5 was then clicked with dendritic linkers 1-4 to afford the corresponding disulfide-linked dendritic oligomeric phthalocyanines PC2, PC3, PC4, and PC6i nm oderatey ields. These compounds, except for PC6, were purified by size-exclusion chromatography on Bio-Beads S-X1 beads followed by column chromatography on silica gel.…”

“…The resulting mixture was stirred at room temperature for 16 h. The solvent was then removed under reduced pressure. The residue was purified by column chromatography (silica gel, CH 2 Cl 2 /MeOH 150:1, v/v)t og ive the product as ap ale-yellow solid (238 mg, 82 %): 1 1, 166.6, 159.5, 151.7, 140.1, 132.2, 130.2, 108.3, 108.0, 106.2, 78.8, 78.2, 76.5, 75.8, 67.1, 60.4, 57.4, 52.5, 39.7 Compound 5:Asolution of CuI (2 mg, 11 mmol) and DIPEA (13 mg, 0.10 mmol) in THF (5 mL) was added to am ixture of PC [15] (0.15 g, 0.16 mmol) and bis(2-azidoethyl) disulfide [16] (0.52 g, 2.55 mmol) with continuous stirring at room temperature for 24 h. The solvent was removed under reduced pressure. 2, 154.0, 153.8, 153.7, 152.7, 150.5, 145.1, 139.1, 139.0, 138.6, 129.2, 127.4, 123.0, 122.8, 122.7, 115.1, 72.1, 71.3, 71.0, 70.9, 70.7, 69.8, 69.4, 69.3, 64.6, 59.2, 49.8, 48.6, 37.6, 37.4…”

Redox‐Enabled, pH‐Disabled Pyrazoline–Ferrocene INHIBIT Logic Gates

“…

Pyrazoline-ferrocene conjugatesw ith an "electron-donorspacer-fluorophore-receptor" format are demonstrated as redox-fluorescent two-input INHIBIT logic gates.Molecular logic-basedc omputation is now firmly established as am aturing research discipline with researchers contemplating pragmatic uses for this curiosity-based science. [1][2][3][4][5] Medicalrelated innovations such as photodynamic photosensitizers, [6] drug delivery systems [7] and multi-analyte diagnostics [8] are but af ew envisioned applications. One of our visions is the realization of logic gates responsive to the physiochemical parameters of pH and potential( pE), which are fundamental to understanding metal ion solubility in geology and metallurgy as well as in medicine.

…”

A Dual Colorimetric/Fluorescence System for Determining pH Based on the Nucleophilic Addition Reaction of an o‐Hydroxymerocyanine Dye

“…The secondm ajor designs trategy utilizes molecules containing ap henol moiety the protonation state of which,e stablished by an equilibrium between phenol and phenolate forms, is highly dependent on pH. [22][23][24][25][26][27][28][29] Here,c hanges in the protonation state of the phenol chromophore induces changes in the spectralcharacteristics of the dyes.However,e ach of the above approaches for pH determination has limitations. For example, systems based on reversible protonation of aminen itrogen atoms are restricted to use in acidicp Hr anges owing to the pK a values of ammonium ions.…”