No abstract

Bladder cancer is the first cancer for which PDT was clinically approved in 1993. Unfortunately, it was unsuccessful due to side effects like bladder contraction. Here, we summarized the recent progress of PDT for bladder cancers, focusing on photosensitizers and formulations. General strategies to minimize side effects are intravesical administration of photosensitizers, use of targeting strategies for photosensitizers and better control of light. Non-muscle invasive bladder cancers are more suitable for PDT than muscle invasive and metastatic bladder cancers. In 2010, the FDA approved blue light cystoscopy, using PpIX fluorescence, for photodynamic diagnosis of nonmuscle invasive bladder cancer. PpIX produced from HAL was also used in PDT but was not successful due to low therapeutic efficacy. To enhance the efficacy of PpIX-PDT, we have been working on combining it with singlet oxygen-activatable prodrugs. The use of these prodrugs increases the therapeutic efficacy of the PpIX-PDT. It also improves tumor selectivity of the prodrugs due to the preferential formation of PpIX in cancer cells resulting in decreased off-target toxicity. Future challenges include improving prodrugs and light delivery across the bladder barrier to deeper tumor tissue and generating an effective therapeutic response in an In vivo setting without causing collateral damage to bladder function.

No abstract

We established a light-activatable prodrug strategy that produces the combination effect of photodynamic therapy (PDT) and site-specific chemotherapy. Prodrugs are activated by singlet oxygen (SO), generated from PS and visible or near IR light, in either intra-or inter-molecular manner. The goal of this study is to evaluate cytotoxic effects of nonmitochondriatargeted prodrugs of a number of anticancer drugs with different mechanisms of action. They were tested in both 2D and 3D in vitro conditions via inter-molecular activation of prodrugs by SO generated in mitochondria by protoporphyrin IX-PDT (PpIX-PDT). Prodrugs of anticancer drugs (paclitaxel, SN-38, combretastatin A4 and mitomycin C) were synthesized using facile and high-yielding reactions. Nonmitochondria-targeted prodrugs showed limited dark toxicity while all of them showed greatly enhanced phototoxicity compared to PpIX-PDT in the 2D culture model. Prodrugs generated up to about 95% cell killing at 2.5 lM when administered with hexylaminolevulinate (HAL) to produce Protoporphyrin IX in cancer cells in both 2D monolayer and 3D spheroids model. The data demonstrate that mitochondria-targeting of prodrugs is not fully essential for our inter-molecular activation prodrug strategy. The prodrug strategy also worked for anticancer drugs with diverse MOAs.

Photodynamic therapy (PDT) initially employed red light, which caused some patients to experience permanent bladder contractions. PDT using the FDA‐approved drug hexaminolevulinate (HAL), which produces protoporphyrin IX (PpIX) in the tumor, showed some promise but has low efficacy in treating non‐muscle‐invasive bladder cancer (NMIBC). We developed singlet oxygen‐activatable prodrugs of two anticancer drugs, paclitaxel and mitomycin C, to enhance the antitumor effect of PpIX‐PDT without producing systemic side effects, by promoting only local release of the active chemotherapeutic agent. Orthotopic NMIBC model was used to compare the efficacy of prodrugs only, PpIX‐PDT, and prodrugs + PpIX‐PDT. 532 nm laser with a total power of 50 mW for 20 min (60 J, single treatment) was used with HAL and prodrugs. Histology and microscopic methods with image analysis were used to evaluate the tumor staging, antitumor efficacy, and local toxicity. Prodrug + PpIX‐PDT produced superior antitumor efficacy than PpIX‐PDT alone with statistical significance. Both PpIX‐PDT alone and combination therapy resulted in mild damage to the bladder epithelium in the normal bladder area with no apparent damage to the muscle layer. Overall, SO‐cleavable prodrugs improved the antitumor efficacy of PpIX‐PDT without causing severe and permanent damage to the bladder muscle layer.