Spectroscopy, Binding to Liposomes and Production of Singlet Oxygen by Porphyrazines with Modularly Variable Water Solubility

Abstract

Three novel classes of porphyrazine-like structures were synthesized to form modular structures in which lipophilicity and water solubility can be tuned. Subtle modification of solubility is an important criterion in selecting a compound for biological photosensitization. The general structure takes the form H2[pz(AnB4-n)], where the core is a porphyrazine (pz) group, A is a pyrrole ring with two sulfide linkages (SR moieties) and B is a pyrrole fused with a 4,7-bis(isopropyloxy)benzo group, with n=4, 3 and 2. These molecules possess their longest wavelength absorption band between 700 and 810 nm, hence laser beams of higher tissue penetration depth could be used to illuminate them in photodynamic therapy (PDT). Armed with absorption bands in the far-red and near-infrared (near-IR), and a capability to tune the solubility, these molecules could make for better sensitizers because of optimized uptake by lipidic membranes and better optical properties. We tested several derivatives of the A4, A3B and A2B2 structures for their singlet oxygen quantum yields in methanol and in liposomes, using 9,10-dimethyl anthracene (DMA) as a singlet oxygen target. Singlet oxygen quantum yields in liposomes ranged from 0.01 to 0.44, with the A2B2 group showing the most promise. In the binding assay to find the equilibrium binding constant, Kb, we detected fluorescence changes due to a change in environment. Peripheral long-chain moieties (the R group in the SR moieties) dominate lipid binding. These moieties range in the hydrophobicity that they induce from C8H17 and benzene, which rendered the molecule totally insoluble in water, to polyethylene glycol (PEG) and carboxylate groups, which imparted water solubility. Each molecule had between 4 and 8 such identical chains. Chains bearing an ether or ester link resulted in measurable equilibrium constants, with a higher Kb for ether substituents. Results for Kb ranged from 0.23 to 26.52 (mg mL(-1))(-1). A delicate balance exists between water solubility and good partitioning to membranes. In general, a higher oxygen-to-carbon ratio in the chains improves binding. Fewer chains and a centrally coordinated zinc ion further improve binding and singlet oxygen production.

Chiral porphyrazine near-IR optical imaging agent exhibiting preferential tumor accumulation

“…The optical properties of 247 are similar to those of analogous heteroatom-functionalized pzs, the H 2 ½pzðtrans-A 2 B 2 Þ pzs, where A and B represent two types of moieties appended trans to each other on the pz periphery (13,14); for 247, A ¼ ð2R; 3RÞ 2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene; B ¼ α; α 0 -diisopropoxy benzo (15). Pz 247 exhibits three major optical absorptions, the Soret band (329 nm) and two NIR Q-bands, Q x ¼ 702 and Q y ¼ 629 nm (Fig.…”

“…As the need for LDL-bound cholesterol is elevated in highly proliferative tumor cells over nontumorigenic cells, 247 has a potential application for any highly proliferative tumor (32)(33)(34)(35). Alternatively, 247 and other pzs bind to lipid vesicle models (14,22) that can act as delivery vehicles to tumors (36).…”

Chiral bis‐Acetal Porphyrazines as Near‐infrared Optical Agents for Detection and Treatment of Cancer

“…The quantum yield of singlet oxygen production is measured by monitoring the rate of oxidation of 9,10‐dimethylanthracene (DMA) (15). The efficiency of photosensitized destruction of DMA, which also is membrane‐bound, reflects not only the unknown sensitizer’s intrinsic yield but also its vertical location in the membrane.…”

“…These studies have established a pz structurefunction relationship revealing the M[pz(trans-A 2 B 2 )] core as the most promising agent with the highest fluorescence quantum yields for M = H 2 and the highest yields of singlet oxygen generation for M = Zn (14). Pzs of this type with polyethylene glycol R-groups bind well with phosphatidyl choline (PC) liposomes (15), which provide a photophysical model for biological lipid bilayers (16) and have attracted attention as delivery vehicles to cancer targets (17)(18)(19) (20,21). Liposome binding constants for pzs reflect the size of pz payload attached and its amphiphilic character which, as mentioned above, has been shown to dictate tumor-specific uptake of porphyrinoids.…”

The binding of analogs of porphyrins and chlorins with elongated side chains to albumin

“…The fluorescence of DMA disappears when it is oxidized by singlet oxygen and so the kinetics of the decrease of its fluorescence is measured for each studied sensitizer, in comparison to that generated by Rose Bengal, a standard sensitizer whose singlet oxygen yield is known. This method was described by us before (Sholto et al 2008). …”