Microenvironment-triggered dual-activation of a photosensitizer- fluorophore conjugate for tumor specific imaging and photodynamic therapy

Abstract

Photodynamic therapy is attracting increasing attention, but how to increase its tumor-specificity remains a daunting challenge. Herein we report a theranostic probe (azo-pDt) that integrates pyropheophorbide α as a photosensitizer and a NIR fluorophore for tumor imaging. The two functionalities are linked with a hypoxic-sensitive azo group. Under normal conditions, both the phototoxicity of the photosensitizer and the fluorescence of the fluorophore are inhibited. While under hypoxic condition, the reductive cleavage of the azo group will restore both functions, leading to tumor specific fluorescence imaging and phototoxicity. The results showed that azo-PDT selectively images BEL-7402 cells under hypoxia, and simultaneously inhibits BEL-7402 cell proliferation after near-infrared irradiation under hypoxia, while little effect on BEL-7402 cell viability was observed under normoxia. These results confirm the feasibility of our design strategy to improve the tumortargeting ability of photodynamic therapy, and presents azo-pDt probe as a promising dual functional agent. Cancer is one of the most common causes of death, and more and more therapeutic strategies against this fatal disease have emerged in the past few decades. Among these strategies, photodynamic therapy has attracted much attention 1. This therapy is based on singlet oxygen produced by photosensitizers under the irradiation with light of a specific wavelength to damage tumor tissues (Fig. 1a). Since the photo-damaging effect is induced by the interaction between a photosensitizer and light, tumor-specific therapy may be realized by focusing the light to the tumor site. Therefore, this therapeutic strategy is supposed to harm healthy tissue less than traditional cytotoxic drugs. Photofrin, the first photodynamic therapy drug approved by the FDA, has been routinely used for the treatment of certain cancers, such as esophageal cancer, lung cancer, bladder cancer, cervical cancer, and skin cancer 2. However, since Photofrin is always ready to undergo photochemical reactions to produce singlet oxygen in the presence of light (630 nm) and also exhibits a long tissue retention time, it may cause long-lasting cutaneous photosensitivity 3. Therefore, patients who have been treated with Photofrin have to avoid sunlight for several weeks, which presents a universal limit for "always on" photosensitizers. To improve the tumor specificity, two strategies are generally utilized 1. The first one is the conjugation of photosensitizers to nanocarriers with tumor-targeted, controlled-release properties. While this strategy has shown promise in preclinical models, it is limited by a complicated formulation process. The second strategy is based on prodrug-like photosensitizers whose photoreactivity can only be activated in tumor-specific environments. Tumor tissues usually demonstrate typical microenvironments that are significantly different from

A New Glutathione-Cleavable Theranostic for Photodynamic Therapy Based on Bacteriochlorin e and Styrylnaphthalimide Derivatives

“…We propose to use a fundamentally different strategy which consists of using two functional components to independently perform the functions of therapy or diagnostics. To the best of our knowledge, one example of such an approach is described in the scientific literature—a conjugate of a photosensitizer and an IR-fluorophore containing a cleavable azo linker [ 20 ]. In this system, the process of energy transfer is realized from the photosensitizer to the fluorophore, which leads to the suppression of the generation of singlet oxygen.…”

The design of small-molecule prodrugs and activatable phototherapeutics for cancer therapy

“…26). 132 With 40 , pyropheophorbide α (PPA, FRET donor) was covalently linked to fluorescent NIR dye SiR-665 (FRET acceptor) via an azo-benzene linker. Due to FRET and the presence of the azo group, 40 exhibited low fluorescence emission and singlet oxygen yield.…”

Hypoxia-Activated Theragnostic Prodrugs (HATPs): Current State and Future Perspectives

“…The utilized dyes can be uniquely selected for different applications based on their photophysical properties, solubility, reactive handles, and permeability. Such representative examples are various cyanines [ 22 ], Si-rhodamine [ 27 ], and Nile blue [ 28 ]. Nevertheless, there are instances where the fluorescent dye may emit fluorescence if the administered anticancer drug itself possesses inherent fluorescence, such as SN-38 or doxorubicin, allowing it to serve both functions concurrently [ 29 ].…”