Two novel silicon(IV) phthalocyanines substituted axially with two BODIPY or mono-styryl BODIPY moieties have been synthesised, which exhibit predominantly a photo-induced energy or electron-transfer process in toluene depending on the axial substituents.

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Coencapsulation of chemotherapeutic agents and photosensitizers into nanocarriers can help to achieve a combination of chemotherapy and photodynamic therapy for superior antitumor effects. However, precise on-demand drug release remains a major challenge. In addition, the loaded photosensitizers usually tend to aggregate, which can significantly weaken their fluorescent signals and photodynamic activities. To address these issues, herein, a smart nanocarrier termed as singlet oxygen-responsive nanoparticle (SOR-NP) was constructed by introducing singlet oxygen (1O2)-sensitive aminoacrylate linkers into amphiphilic mPEG-b-PCL copolymers. Boron dipyrromethene (BDP) and paclitaxel (PTX) as model therapeutic agents were coloaded into an 1O2-responsive nanocarrier for realizing light-controlled drug release and combination cancer treatment. This polymeric nanocarrier could substantially relieve the aggregation of encapsulated BDP due to the presence of a long hydrophobic chain. Therefore, the formed SOR-NPBDP/PTX nanodrug could generate bright fluorescent signals and high levels of 1O2, which could mediate cell death via PDT and rupture aminoacrylate linker simultaneously, leading to collapse of SOR-NPBDP/PTX and subsequent PTX release. The light-triggered drug release and combined anticancer effects of SOR-NPBDP/PTX were validated in HepG2 and MCF-7 cancer cells and H22 tumor-bearing mice. This study provides a promising strategy for tumor-specific drug release and selective photodynamic–chemo combination treatment.

Hypoxia-activated prodrugs (HAPs) have drawn increasing attention for improving the antitumor effects while minimizing side effects. However, the heterogeneous distribution of the hypoxic region in tumors severely impedes the curative effect of HAPs. Additionally, most HAPs are not amenable to optical imaging, and it is difficult to precisely trace them in tissues. Herein, we carefully designed and synthesized a multifunctional therapeutic BAC prodrug by connecting the chemotherapeutic drug camptothecin (CPT) and the fluorescent photothermal agent boron dipyrromethene (BODIPY) via hypoxia-responsive azobenzene linkers. To enhance the solubility and tumor accumulation, the prepared BAC was further encapsulated into a human serum albumin (HSA)-based drug delivery system to form HSA@BAC nanoparticles. Since the CPT was caged by a BODIPY-based molecule at the active site, the BAC exhibited excellent biosafety. Importantly, the activated CPT could be quickly released from BAC and could perform chemotherapy in hypoxic cancer cells, which was ascribed to the cleavage of the azobenzene linker by overexpressed azoreductase. After irradiation with a 730 nm laser, HSA@BAC can efficiently generate hyperthermia to achieve irreversible cancer cell death by oxygen-independent photothermal therapy. Under fluorescence imaging-guided local irradiation, both in vitro and in vivo studies demonstrated that HSA@BAC exhibited superior antitumor effects with minimal side effects.

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.