Enzyme-Activated Multifunctional Prodrug Combining Site-Specific Chemotherapy with Light-Triggered Photodynamic Therapy

Abstract

Combination treatments are more effective than conventional monotherapy in combating cancer. Herein, a multifunctional prodrug BDP-L-CPT was rationally engineered and prepared by the conjugation of a boron dipyrromethene (BDP)-based photosensitizer (PS) to the active site of the chemotherapeutic drug camptothecin (CPT) via a phenyl benzoate group. After modification, the cytotoxicity of CPT was locked. Moreover, the fluorescence emission at 430 nm from the CPT component in the prodrug was substantially inhibited through the intramolecular fluorescence resonance energy transfer process. The phenyl benzoate linker in BDP-L-CPT could be selectively cleaved by exogenous carboxylesterase in phosphate-buffered saline solution and endogenous carboxylesterase overexpressed in cancer cells, which was followed by selfimmolation to release free CPT. The drug release process could be monitored by the turn-on of CPT fluorescence in solution and cells. Owing to the combination of site-specific chemotherapy with light-driven photodynamic therapy, the IC 50 values of the prodrug BDP-L-CPT against HepG2 human hepatocellular carcinoma and HeLa human cervical carcinoma cells were lower than those of the controls, BDP-COOH and CPT. The combined antitumor effects of the prodrug BDP-L-CPT were also observed in the mice bearing H22 tumors. Furthermore, BDP-L-CPT had a more prolonged blood circulation time in mice than CPT, which is beneficial to persistent therapy. This study may provide a promising strategy for a selective combination cancer treatment by conjugating a prodrug to a PS.

Enzyme-activated prodrugs and their release mechanisms for the treatment of cancer

“…When the prodrug interacts with carboxylesterases, the ester bond can be broken, releasing the PS and CPT anticancer drugs, and then the PS can play its therapeutic role under UV radiation. In cell assay and in vivo experiments, prodrug 42 against human hepatocellular carcinoma (HepG2) and human cervical carcinoma cells (HeLa) were lower than those of the controls, 83 BDP-COOH, and CPT (Fig. 25).…”

“…In addition, Liu et al 83 reported enzyme-activated multifunctional prodrug 42 . This prodrug can provide three functions: imaging of drug release, photodynamic therapy, and chemotherapy.…”

Overview of Nanoparticle-Based Approaches for the Combination of Photodynamic Therapy (PDT) and Chemotherapy at the Preclinical Stage

“…Among the TI category and in the field of anticancer nanomedicines, the natural drug camptothecin (CTP) (see Section 4.4 ) is particularly appealing to be modified and synthetized in the form of prodrugs, often in combination with PSs [ 149 , 150 , 151 ], and to be further utilized for the formation of carrier-free NPs [ 152 , 153 ]. As an example, Chu and co-workers reported on the synthesis of a novel ROS-responsive nanosystem (MPEG-(TK-CPT)-PPa) derived from the self-assembly of a prodrug of CPT and pyropheophorbide (PPa) both conjugated to a PEG methyl ether (MPEG) via a TK and lipid linkage, respectively [ 109 ].…”

Recent Advances in the Enzyme‐Activatable Organic Fluorescent Probes for Tumor Imaging and Therapy

“…The CE activity was then effectively evaluated in orthotopic HepG2 tumor‐bearing mice under different conditions and 3D imaging in vivo. To afford the cancer‐killing ability, Zhang and colleagues developed a CE‐triggered multifunctional prodrug BDP−L−CPT (Figure 13) by the conjugation of a boron dipyrromethene (BDP)‐based PS to the active site of the chemotherapeutic drug camptothecin (CPT) [79] . The activity of CPT was effectively shielded in the prodrug by chemical modification.…”