Counterion Tuning of Near-Infrared Organic Salts Dictates Phototoxicity to Inhibit Tumor Growth

Abstract

Photodynamic therapy (PDT) has the potential to improve cancer treatment by providing dual selectivity through the use of both photoactive agent and light, with the goal of minimal harmful effects from either the agent or light alone. However, current PDT is limited by insufficient photosensitizers (PSs) that can suffer from low tissue penetration, insufficient phototoxicity (toxicity with light irradiation), or undesirable cytotoxicity (toxicity without light irradiation). Recently, we reported a platform for decoupling optical and electronic properties with counterions that modulate frontier molecular orbital levels of a photoactive ion. Here, we demonstrate the utility of this platform in vivo by pairing near-infrared (NIR) photoactive heptamethine cyanine cation (Cy+), which has enhanced optical properties for deep tissue penetration, with counterions that make it cytotoxic, phototoxic, or nontoxic in a mouse model of breast cancer. We find that pairing Cy+ with weakly coordinating anion FPhB– results in a selectively phototoxic PS (CyFPhB) that stops tumor growth in vivo with minimal side effects. This work provides proof of concept that our counterion pairing platform can be used to generate improved cancer PSs that are selectively phototoxic to tumors and nontoxic to normal healthy tissues.

Structure–Properties Correlations in the Range of Cationic Spiropyrans as Analogues of Cyanine Dyes

“…[9] Though, this type of structural modification is extremely important in some cases. [10][11][12] Due to structural similarity, the merocyanine (Mc) forms of spiropyrans (SPPs) can also be considered as analogues of trimethine Cys in most cases (Figure 1). However, the structure of Mc form of SPP salts with conjugated vinyl-3H-indolium fragment is similar to HMCys, [13] especially to IR-786 widely used in bioimaging.…”

“…Wherein, only slight changes in absorption properties have been observed during anion variations in polar solvents [9] . Though, this type of structural modification is extremely important in some cases [10–12] …”

Synthesis of Near-Infrared-Absorbing Anionic Heptamethine Cyanine Dyes with Trifluoromethyl Groups

“…These dyes are particularly important as they allow us to take advantage of NIR light, a resource that has yet to be fully exploited. Among them, heptamethine cyanine (HMC) dye [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ] is an organic dye that absorbs NIR light with excellent optical properties, such as selective absorption in the NIR region and a high molar absorption coefficient. Figure 1 illustrates the two categories of HMC dyes—cationic and anionic.…”