Bi-Yuan Zheng

Recent progress in development of new sonosensitizers for sonodynamic cancer therapy.

Developing an effective treatment for cancer is still a challenge. Despite great success with traditional cancer therapies, there are numerous disadvantages for conventional treatments such as systemic toxicity, low selectivity, drug resistance and potential long-term side effects. Recently, photodynamic therapy (PDT) has been widely applied in clinical settings. However, this approach suffers from the major shortcoming derived from the limited penetrability of visible light. Sonodynamic therapy (SDT) utilizing ultrasound combined with a sonosensitizer represents a novel noninvasive approach for cancer therapy, which is deemed to overcome the disadvantage of PDT. In this review, we extensively summarize the recent progress in the discovery of new sonosensitizers for SDT and discuss the future directions for the development of novel sonosensitizers.

A Tumor-pH-Responsive Supramolecular Photosensitizer for Activatable Photodynamic Therapy with Minimal In Vivo Skin Phototoxicity

A major challenge in photodynamic therapy (PDT) is the development of new tumor-targeting photosensitizers. The tumor-specific activation is considered to be an effective strategy for designing these photosensitizers. Herein, we describe a novel tumor-pH-responsive supramolecular photosensitizer, LDH-ZnPcS8, which is not photoactive under neutral conditions but is precisely and efficiently activated in a slightly acidic environment (pH 6.5). LDH-ZnPcS8 is prepared by using a simple coprecipitation method based on the electrostatic interaction between negatively charged octasulfonate-modified zinc(II) phthalocyanine (ZnPcS8) and cationic hydroxide layers of layered double hydroxide (LDH). The in vitro photodynamic activities of LDH-ZnPcS8 in cancer cells are dramatically enhanced relative to those of ZnPcS8 alone. The results of in vivo fluorescence imaging demonstrate that the nanohybrid is activated in tumor tissues, where it displays an excellent PDT effect resulting in 95.3% tumor growth inhibition. Furthermore, the minimal skin phototoxicity of LDH-ZnPcS8 highlights its high potential as a novel photosensitizer for activatable PDT.

Highly positive-charged zinc(II) phthalocyanine as non-aggregated and efficient antifungal photosensitizer.

A new tetra-α-substituted zinc(II) phthalocyanine containing dodeca-amino groups (compound 4) and its quaternized analogue (compound 5) have been prepared and evaluated for their photoactivities against Candida albicans. Compared with the dodeca-amino phthalocyanine 4, the dodeca-cationic phthalocyanine 5 exhibits a higher photodynamic inactivation against C. albicans with an IC90 value down to 1.46 μM, which can be attributed to its non-aggregated nature in aqueous environments and more efficient cellular uptake. More interestingly, 5 shows a higher photodynamic inactivation on C. albicans due to its stronger affinity to C. albicans cells than mammalian cells. These results suggest that the highly positive-charged phthalocyanine 5 is a potential non-aggregated antifungal photosensitizer, which shows some selectivity toward the fungus.

Preparation and sonodynamic activities of water-soluble tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine and its bovine serum albumin conjugate.

Sonodynamic therapy (SDT) is a new approach for cancer treatment, involving the synergistic effect of ultrasound and certain chemical compounds termed as sonosensitizers. A water-soluble phthalocyanine, namely tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine (ZnPcC4), has been prepared and characterized. The interactions between ZnPcC4 and bovine serum albumin (BSA) were also investigated by absorption and fluorescence spectroscopy. It was found that there were strong interactions between ZnPcC4 and BSA with a binding constant of 6.83×10(7)M(-1). A non-covalent BSA conjugate of ZnPcC4 (ZnPcC4-BSA) was prepared. Both ZnPcC4 and ZnPcC4-BSA exhibited efficient sonodynamic activities against HepG2 human hepatocarcinoma cells. Compared with ZnPcC4, conjugate ZnPcC4-BSA showed a higher sonodynamic activity with an IC50 value of 7.5μM. Upon illumination with ultrasound, ZnPcC4-BSA can induce an increase of intracellular reactive oxygen species (ROS) level, resulting in cellular apoptosis. The results suggest that the albumin conjugates of zinc(II) phthalocyanines functionalized with carboxyls can serve as promising sonosensitizers for sonodynamic therapy.

A tumor-targeted activatable phthalocyanine-tetrapeptide-doxorubicin conjugate for synergistic chemo-photodynamic therapy

Chemo-photodynamic therapy is a promising strategy for cancer treatments. However, it remains a challenge to develop a chemo-photodynamic therapeutic agent with little side effect, high tumor-targeting, and efficient synergistic effect simultaneously. Herein, we report a zinc(II) phthalocyanine (ZnPc)-doxorubicin (DOX) prodrug linked with a fibroblast activation protein (FAP)-responsive short peptide with the sequence of Thr-Ser-Gly-Pro for chemo-photodynamic therapy. In the conjugate, both photosensitizing activity of ZnPc and cytotoxicity of DOX are inhibited obviously. However, FAP-triggered separation of the photosensitizer and DOX can enhance fluorescence emission, singlet oxygen generation, dark- and photo-cytotoxicity significantly, and lead to a synergistic anticancer efficacy against HepG2 cells. The prodrug can also be specifically and efficiently activated in tumor tissue of mice. Thus, this prodrug shows great potential for clinical application in chemo-photodynamic therapy.

Silicon(IV) phthalocyanines substituted axially with different nucleoside moieties. Effects of nucleoside type on the photosensitizing efficiencies and in vitro photodynamic activities.

A series of new silicon(IV) phthalocyanines (SiPcs) di-substituted axially with different nucleoside moieties have been synthesized and evaluated for their singlet oxygen quantum yields (ΦΔ) and in vitro photodynamic activities. The adenosine-substituted SiPc shows a lower photosensitizing efficiency (ΦΔ=0.35) than the uridine- and cytidine-substituted analogs (ΦΔ=0.42-0.44), while the guanosine-substituted SiPc exhibits a weakest singlet oxygen generation efficiency with a ΦΔ value down to 0.03. On the other hand, replacing axial adenosines with chloro-modified adenosines and purines can result in the increase of photogenerating singlet oxygen efficiencies of SiPcs. The formed SiPcs 1 and 2, which contain monochloro-modified adenosines and dichloro-modified purines respectively, appear as efficient photosensitizers with ΦΔ of 0.42-0.44. Both compounds 1 and 2 present high photocytotoxicities against HepG2 and BGC823 cancer cells with IC50 values ranging from 9nM to 33nM. The photocytotoxicities of these two compounds are remarkably higher than the well-known anticancer photosensitizer, chlorin e6 (IC50=752nM against HepG2 cells) in the same condition. As revealed by confocal microscopy, for both cell lines, compound 1 can essentially bind to mitochondria, while compound 2 is just partially localized in mitochondria. In addition, the two compounds induce cell death of HepG2 cells likely through apoptosis.

Synthesis and biological characterization of novel rose bengal derivatives with improved amphiphilicity for sono-photodynamic therapy

Sono-Photodynamic therapy (SPDT) utilizing ultrasound and light has been demonstrated that this novel approach can lower dosage resulting in reduction of the potential side effects caused by sensitizers. Recently, a new formulation of rose bengal (RB) as an intralesional injection has completed clinical trials phase II for PDT treatment of melanoma cancer. However, the inherent unfavorable pharmacological properties of RB hindered its extensive clinical development. With the aim to identify new RB derivatives (RBDs) with enhanced photodynamic and sonodynamic anticancer efficiency, a series of amphiphilic RBDs have been designed, synthesized and biological characterized. Among them, RBD4 significantly improved cellular uptake and enhanced intracellular ROS generation efficiency upon light and ultrasound irradiation, resulting in dramatically improved anticancer potency. Notably, RBD4 has a relative potency similar to sinoporphyrin sodium (DVDMS), indicating its further potential application for SPDT.

Progress in the development of nanosensitizers for X-ray-induced photodynamic therapy

In recent years, photodynamic therapy has been applied in cancer treatment because of its high selectivity and marginal invasion properties. However, the excitation light used has limited ability to penetrate tissue, which creates a stumbling block for its future development. To overcome this, X-rays have been introduced to transmit energy to deeper tissues. Given that a large number of X-ray-induced sensitizers have been designed to facilitate X-ray excitation and generate reactive oxygen species (ROS), this has led to the concept of X-ray-induced photodynamic therapy (X-PDT). After 10 years of development, this treatment now shows good therapeutic effects as well as shortcomings. Going forward, it will be important to improve tumor targeting and a standard deep-seated tumor model should be established.