Date Published: June 23, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Wenting Wu, Xiaodong Shao, Jianzhang Zhao, Mingbo Wu.
With singlet oxygen (1O2) as the active agent, photodynamic therapy (PDT) is a promising technique for the treatment of various tumors and cancers. But it is hampered by the poor selectivity of most traditional photosensitizers (PS). In this review, we present a summary of controllable PDT implemented by regulating singlet oxygen efficiency. Herein, various controllable PDT strategies based on different initiating conditions (such as pH, light, H2O2 and so on) have been summarized and introduced. More importantly, the action mechanisms of controllable PDT strategies, such as photoinduced electron transfer (PET), fluorescence resonance energy transfer (FRET), intramolecular charge transfer (ICT) and some physical/chemical means (e.g. captivity and release), are described as a key point in the article. This review provide a general overview of designing novel PS or strategies for effective and controllable PDT.
Photodynamic therapy (PDT) is a promising noninvasive approach for the treatment of cancer tumors by combining photosensitizer (PS), oxygen molecule and light.1 In clinical applications, a low toxic or non‐toxic PS is delivered to the tumor tissue and cancer cells by active or passive diffusion. Subsequently, PS is excited from its low energy ground state (S0) to an higher energy excited state (S1) by irradiating tumor tissue with long wavelength light (650–900 nm, light in this wavelength range gives good tissue penetration). In the treatment process, reactive oxygen species are responsible for destroying cancer cells, and the first singlet excited state of molecular oxygen (singlet oxygen, 1O2) is the key cytotoxic agent of PDT.21O2 is effective in disrupting biological tissues as a result of its high reactivity.3 It is generated by the triplet‐triplet energy transfer (TTET) between ground‐state oxygen (triplet state) and PS (T1) formed by intersystem crossing (ISC, Figure1).4
PET19 can be used to modulated the generation of 1O2 when compete with others mechanisms, especially ISC. It is well known that 1O2 quantum yield is directly related to the efficiency of ISC (generally, high ISC efficiency results in high 1O2 quantum yield). Usually, PET and ISC are competitive with each other in the process of deactivation of excited states. Therefore, given charge recombination won’t lead to formation of triplet state, inhibition of PET can significantly improve the efficiency of ISC, resulting in an enhancement of 1O2 quantum yield. Therefore, the generation of 1O2 can be controlled by modulating PET process.
FRET was used for the structural analysis of DNA,33 protein,34 targeted therapy,35 fluorescent probe,36 biosensors37 etc.38 When there is a spectral overlap between energy donor (D, emission spectrum) and energy acceptor (A, acceptor absorption), the fluorescence of the donor will be quenched, and the fluorescence of the energy acceptor will be observed (Figure8).39 FRET is achieved upon donor‐acceptor energy transfer based on a long‐range dipole–dipole interaction. Energy transfer includes two main mechanisms: (1) resonance energy transfer (RET) between the singlet state of donor and acceptor, namely Förster resonance energy transfer (FRET); (2) the other is RET between triplet state of the donor and singlet state of acceptor, that is Dexter electron transfer mechanism.40 FRET occurs when: (1) there is a spectral overlap between D and A; (2) proper distance between D‐A, normally less than 10 nm; (3) a relatively high quantum yield in donor.41 The FRET fluorescence quenching always correlates with 1O2 quenching, providing a convenient method to assess activatable photosensitizers.42
ICT has been widely applied in many fields such as fluorescence probe,76 fluorescent chemosensor,77 etc.78 By modulating the properties of the electron donor and acceptor, it is possible to change the efficiency of ICT. ICT can intensely impact the fluorescence and 1O2 quantum yields via competing with other deactivation processes such as ISC and PET. There are many studies of the effect of the different donor and acceptor on ICT efficiency,79 but little was known about the modulation of 1O2 generation with ICT variation.
In the generation of 1O2, there are always several different mechanisms competing with each other, e.g. FRET, PET and ICT. They are mainly from the competition between energy transfer (EET) and electron transfer (PET). Derived from these competition, the emergence of molecular logic gates, emerged to finely tune the 1O2 generation. Molecular logic gates, as a promising strategy,83 was rarely applied to PDT. Combining molecular logic gates with PDT, Akkaya et al.84 reported a controllable and self‐reporting PDT, realized by series logic gate. The cascading of molecular logic gates are composed of two AND logic operation (Figure28). In the first logic gates, light (660 nm) and acidic environment are input signal, 1O2 is the output. BODIPY connected with two nitro (pKa = 6.92) is responsible for Gate 1 ( 16a ). Only in the presence of acid can 1O2 be generated as a result of the protonation of Gate 1. There is no related interpretation mechanism for pH‐controllable PDT. For the second logic gates, 1O2 (the output of gate1) and 520 nm light are the input, the output is 537 nm light. Gate 2 is composed of an EET donor (D) and acceptor (A) portion which are connected to each other by a 1O2‐cleavable linker ((Z)‐1,2‐bis(alkylthio) ethane, 16b). In the absence of 1O2, there is an effective excitation energy transfer (85.0%) between D and A, shutting down the production of 1O2. In contrast, D can emit at 537 nm in the present of 1O2 which can break the linker. Gates 1 and 2 were embedded together into a micelle for a continuous logic operation. When this logic gates are introduced into body, controllable‐PDT efficiency can be revealed by the fluorescence intensity at 537 nm.
In this review, we have summarized the recent developments in controllable photodynamic therapy and some novel strategies of designing activatable PSs. We introduced various regulation methods to control the 1O2 production, such as PET, FRET, ICT, etc. These mechanisms can be employed to modulate the generation of 1O2. It should be noted that the crucial concept of controllable PDT reagents is to selectively generate 1O2 in tumor tissues and to avoid damaging normal tissues and organs. Based on PET mechanism, supramolecular photonic therapeutic reagents, environment‐sensitive PSs and BODIPY derivatives have been reported, achieving 1O2 on/off by pH or polarity variation. Amino protonation is the most used strategy to regulate PET process, and it is necessary to develop new method for effective PET switch. Controlling of FRET is one of the most common mechanism to modulate 1O2 production. The key part of inhibitive FRET is to find a suitable linker, which can be cleaved by tumor‐associated specific conditions such as lower pH and overexpression proteins or enzymes. Except for a cleaveable linker, using nano materials as carrier, combining PS and quencher into a single form is also effective to achieve switching of 1O2 production. By regulating the energy level of FRET‐acceptor, the direction of FRET can be inverted, resulting in an activation and deactivation of PS, respectively. Reversible FRET is becoming a promising strategy to modulate PDT. In addition, the using of photoconversion molecules and molecular logic‐gates is also promising. In a word, by efficient FRET to quench PS, by prohibitive FRET to reactivate PS. Upon competing with ISC directly, ICT can effectively restrain the generation of 1O2. The charge‐transfer (CT) state of donor and acceptor can be influenced by solvent polarity and pH. However, ICT was rarely used to modulate PDT. There is still much room to apply ICT in activatable PDT.
The authors declare no conflict of interest.