Far-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel Chemotherapy

Abstract

Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and non-small cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer. Unfortunately, PDT is often followed by recurrence, due to incomplete ablation of tumors. To overcome these problems, we prepared the far-red light-activatable prodrug of PTX by conjugating photosensitizer via singlet oxygen-cleavable aminoacrylate linker. Tubulin polymerization enhancement and cytotoxicity of prodrugs were dramatically reduced. However, once illuminated with far-red light, the prodrug effectively killed SKOV-3 ovarian cancer cells through the combined effects of PDT and locally released PTX. Ours is the first PTX prodrug that can be activated by singlet oxygen using tissue penetrable and clinically useful far-red light, which kills the cancer cells through the combined effects of PDT and site-specific PTX chemotherapy.

Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system

“…1C), were designed for this study, as previously described [17]. Pc-(L-PTX) 2 is the SO-cleavable PTX prodrug that releases PTX upon light activation.…”

“…The plates were placed without lids on an orbital shaker (Lab-line, Barnstead International) and were illuminated using a diode laser (690 nm) at 5.6 mW/cm 2 for 30 min to achieve a light dose of 10 J/cm 2 . Then, the plates were placed back into the incubator for another 72 h. After the incubation, MTT assay was performed as previous described [17]. …”

“…In the present study, the illumination lasted for 30 min and a first-order release rate constant ( k r ) was used to describe the PTX release, where k r is set to zero when there is no light illumination. K r was calculated based on the time-dependent release kinetics of PTX [17]. We assume a 90% release during the 30-min illumination (release efficacy F r = 0.9), because our previous study showed > 90% PTX release [17].…”

“…K r was calculated based on the time-dependent release kinetics of PTX [17]. We assume a 90% release during the 30-min illumination (release efficacy F r = 0.9), because our previous study showed > 90% PTX release [17]. Both prodrugs are stable under dark conditions until 72 h (Fig S4).…”

“…As a model system, we used near-infrared (NIR)-responsive prodrugs (Figure. 1), which utilize the photochemistry of photosensitizers (PS), NIR-absorbing materials that generate singlet oxygen (SO) when illuminated, to trigger the release of chemotherapeutic molecules [17]. For example, silicon phthalocyanine (Pc) is conjugated with paclitaxel (PTX) via an SO-cleavable linker to treat local or regional cancers.…”