Type I AIE PSs for Antitumor Applications: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 3 by Conner Chen.

In modern medicine, precision diagnosis and treatment using optical materials, such as fluorescence/photoacoustic imaging-guided photodynamic therapy (PDT), are becoming increasingly popular. Photosensitizers (PSs) are the most important component of PDT. Different from conventional PSs with planar molecular structures, which are susceptible to quenching effects caused by aggregation, the distinct advantages of AIE (aggregation-induced emission) fluorogens open up new avenues for the development of image-guided PDT with improved treatment accuracy and efficacy in practical applications. PDT has been actively used as a noninvasive treatment in clinical practice for some superficial skin cancers such as skin cancer and bladder cancer.  Although many PSs have been developed for tumor treatment, type II photosensitizers are predominant. Since type II photodynamic therapy is highly oxygen-dependent and its therapeutic effect on anaerobic tumors is inhibited, the development of low oxygen-dependent type I PDT can effectively mitigate this problem.

  • photodynamic therapy
  • aggregation-induced emission
  • intersystem crossing
  • type I photosensitizers

1. Single Type I PDT for Antitumor

As elaborated above, the efficiency in photodynamic therapy (PDT) is expected to be enhanced because cationization can promote the type I photoreactive pathway of AIE (aggregation-induced emission) photosensitizers (PSs) to produce more toxic type I reactive oxygen species (ROS), such as OH•−. It is worth mentioning that the cationization also endows the mitochondria-targeting capacity of AIE PSs, which can further enhance the PDT effect due to the fact that mitochondria are the primary target of ROS during PDT. Such mitochondrial-targeted type I PDT is demonstrated with DTPAPyPF6 and DTPANPF6. The cationic AIE PSs (DTPAPyPF6 and DTPANPF6) have negligible toxicity to cancer cells under dark. However, the viabilities of HeLa cancer cells have a significant decrease along with increased PS concentrations after white light irradiation (20 mWcm−2, 10 min). In addition, these two cationic type I AIE PSs showed significant tumor inhibition in solid hypoxia tumor upon light irradiation. Both in vitro and in vivo results show the excellent antitumor PDT feature of the cationic AIE PSs. Although PSs that target the cell membrane are unable to enter the nucleus, they can cause nonapoptotic cell death and indirectly affect DNA integrity, resulting in an effective anticancer effect [1][2]. In 2022, Zhao et al. reported two AIE PSs used triphenylamine (TPA) as the rotor and D moiety, and a novel electron acceptor 2-(4-methyl-8-(pyridin-4-ylethynyl) [3][4] dithiolo [4’,5’:4,5] ben-zo [1,2c] [1,2,5] thiadiazol-6-ylidene)malononitrile as a strong A moiety, named the resultant aggregation-induced emission fluorogens (AIEgens) with cationic TBMPEI and noncationic TBMPE, respectively [5]. Cationization could effectively reduce ΔEST and promote intersystem crossing (ISC) while also increasing ROS generation, particularly for type I ROS. The free radical generation ability of TBMPEI is superior to that of some commercial PSs (Chlorin e6 (Ce6) and Rose bengal (RB)). Furthermore, the membrane-specific targeting ability of TBMPEI improved its potential to destroy cancer cells when exposed to light by cell necrosis, cell membrane rupture, and DNA destruction. Finally, TBMPEI was successfully used for fluorescence image-guided PDI in vivo with excellent therapeutic performance.
The nucleus is also critical for PDT implementation and plays a critical role in cancer cell resistance to cell death, invasion, and metastasis [6]. Wang et al. created two AIE PSs of type I (TFMN and TTFMN) for nucleus-targeted PDT [7]. TFMN was built with a strong donor–acceptor (D-A) structure based on the TPA moiety with D and the furan moiety as an auxiliary D and π-bridge and dicyano units as A. Furthermore, TPE, a well-known AIE-active group, was introduced into TFMN via refined molecular structure tuning to produce TTFMN. The ΔEST value of TTFMN (0.20 eV) was slightly lower than that of TFMN (0.24 eV). In addition, it was determined that the Gibbs free energy changes of the electron transfer processes of TFMN and TTFMN were −0.218 and −0.359 eV, respectively, indicating that TTFMN has better ISC and intramolecular charge transfer (ICT) processes for type I ROS (OH•−) generation. Furthermore, PLA12k-PEG5k-TATSA, a widely used lysosomal acid-activated TAT peptide-modified amphiphilic polymer, was employed to encapsulate TTFMN for nucleus targeting to enhance the PDT effectiveness of type I ROS. Driven by this “good steel used in the blade” tactic, tumor growth was significantly inhibited by the precise type I PDT.

2. PDT-PTT for Synergistic Antitumor

In clinical practice, PDT typically produces unsatisfactory therapeutic results, which are hampered by the hypoxic microenvironment within solid tumors and the limited light penetration depth. Recently, photothermal therapy (PTT) has been receiving more and more attention as an emerging and efficient mode of tumor treatment [8][9]. PTT uses light energy to kill cancer cells by converting it to heat energy via a nonradiative relaxation pathway. PTT does not face the drawbacks of being oxygen-dependent like PDT and has inherent advantages in the treatment of solid tumors in hypoxic environments. Therefore, the synergistic therapy of PTT and PDT could largely enhance the ablation capability of tumors in vivo. Wang et al. developed two NIR-II emission AIEgens (CTBT and DCTBT) via employing carbazole- or TPA-modified carbazole moieties as D, alkyl chain-modified thiophene groups as auxiliary D and π-bridge, and benzo [1,2-c:4,5-c’] bis ([1,2,5] thiadiazole) (BBT) as A, respectively [10]. The creation of strong D-A architecture facilitates narrowing the S1-S0 bandgap to achieve the long-wavelength absorption as well as emission, which also favors highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) separation. To achieve a small ΔEST and efficient ISC process, TPA was introduced as the rotors to nonradiatively dissipate the excited energy for heat generation. Moreover, the introduction of long alkyl chain on thiophene units contributes to providing the steric hindrance to twist the molecular geometry to improve the twisted intramolecular charge transfer (TICT) effect for DCTBT, thus further red-shifting the emission wavelength and accelerating the ISC processes. As a consequence, DCTBT-based nanoparticles showed predominate type I ROS generation and an excellent photothermal performance with a photothermal conversion efficiency (PCE) of 59.6%. After intravenous injection into tumor-bearing mice, DCTBT nanoparticles showed effective tumor accumulation at tumor sites. Benefitting from the synergistic cooperation of type I PDT and PTT, DCTBT exhibited excellent tumor inhibition performance on subcutaneous PANC-1 tumor-bearing mice as well as on the orthotopic pancreatic tumor-bearing mice.
The clever introduction of donor groups with strong electron-donating capability and large spatial spins can facilitate the ISC process as well as increase the nonradiative decay path of the aggregated state, thereby simultaneously improving the ROS generation capability and photothermal performance. Wang and coworkers reported four AIEgens for realizing a synergistic antitumor effect though type I PDT and PTT via an acceptor planarization and donor rotation strategy [11]. Thiophene-modified diketopyrrolopyrrole (DPP) was conjugated with the electron-donors via a metal-catalyzed cross-coupling reaction in previous works. This work utilizes methyl (as a new derivation site of DPP) to replace thiophene (traditional derivatization site of DPP), which was further modified through Knoevenagel condensation reaction to obtain 2TPAVDPP, TPATPEVDPP, and 2TPEVDPP. The introduction of vinyl linkers as both sides of DPP could enlarge the acceptor planarity and π conjugation to facilitate the strong D-A interaction, thus promoting the ISC process as well as changing the type of PS pathways. As compared to the thiophene-linked TPA-DPP, which showed predominate type II ROS generation, the vinyl linked 2TPAVDPP, TPATPEVDPP, and 2TPEVDPP only showed type I ROS generation with negligible production of type II ROS. DFT calculation further revealed the T1 state energy level of TPA-DPP was located at 1.01 eV, while the T1 levels for the other three PSs were all below 0.77 eV. With the singlet oxygen energy level located at 0.98 eV, the lower T1 energy levels of 2TPAVDPP, TPATPEVDPP, and 2TPEVDPP made them unable to undergo energy transfer to ground state oxygen (O2) to generate singlet oxygen, and hence, they mainly produced type I ROS. In contrast, the PCE values increased with the number of free rotating units, and 2TPEVDPP nanoparticles possessed the highest PCE value of 66% among these analogues. As a consequence, 2TPEVDPP nanoparticles achieved synergistic treatment of type I PDT as well as PTT under both normoxic and hypoxic environments. This molecular strategy of donor rotation and acceptor planarization provides a model for the development of AIE PSs with photothermal effects.
Multimodal imaging provides additional visualization for tumor treatment. When photon energy is converted to heat, the resulting acoustic wave can be used for photoacoustic imaging (PAI) with increased penetration depth and signal-to-noise ratio. Moreover, PAI can be a powerful supplemental imaging approach to fluorescence imaging (FLI), especially for NIR-II FLI, due to its advantages of clear contouring of deep tumor histology and clear microspatial resolution. Therefore, multimodal imaging of FLI and PAI will possess more potential for precision tumor treatment. Tang et al. recently developed three simple AIE-active phototheranostic agents (TPEDCPy, TPEDCQu, and TPEDCAc) with a D-A system and mitochondria-targeting ability through an electron acceptor engineering strategy for NIR II FLI/PAI guided diagnosis and efficient type I PDT and PTT combination phototherapy [12]. High twisted tetraphenylethylene (TPE) and diphenylamine (DPA) moieties were constructed to the molecules as D and rotors. Furthermore, the electron-rich carbazole was employed as the π-bridge. With such a molecular design, the TICT effect was significantly increased, resulting in fluorescence emission from the NIR I region red-shifting to NIR II through enhancing the capacity of A moiety of the acceptors from quinolinium and pyridinium to acridinium. Moreover, this molecular design strategy can regulate the energy gap from 2.61 eV (TPEDCPy) to 2.33 eV (TPEDCAc), which makes TPEDCAc more conducive to accelerate the ISC process and enhance the type I ROS production capability. In addition, the large feature of acridinium improved the intramolecular motions; thus, TPEDCAc showed the highest PCE (44.1%) under the irradiation of 660 nm laser (0.3 W cm−2) among these analogues and other commercial photothermal agents (cyanine dyes ≈ 26.6% and ICG ≈ 3.1%) [13][14]. Importantly, TPEDCAc was successfully used in NIR II FLI/PAI guided PDT and PTT combination therapy on MCF 7 tumor bearing mice. Recently, Tang and coworkers reported three compounds (TI, TSI, and TSSI) for efficient multimodal imaging-guided tumor therapy [15]. The introduction of thiophene units as the π-bridge increased D-A interaction and promoted the ISC process and the type I ROS (OH•−) production. Additionally, TSSI also showed the best photothermal performance among these three analogues. Upon 660 nm laser irradiation (0.3 W cm−2, 5 min), the temperature of TSSI rapidly plateaued at 61 °C, higher than TI (47 °C) and TSI (54 °C). The PCE of TSSI nanoparticles was calculated to be ~46.0%, which provides a solid foundation for subsequent oncology treatment. The excellent photothermal conversion efficiency of TSSI nanoparticles also endows it with strong PA capability in vivo. Based on these advantages, TSSI nanoparticles are successfully used for multimodal imaging-guided PDT-PTT combination tumor therapy.

3. PDT-CDT for Synergistic Antitumor

Chemodynamic therapy (CDT) is similar to photodynamic therapy (PDT). It can generate ROS in the tumor microenvironment (TME) to kill tumor cells via external stimuli or endogenous triggers. The endogenous triggers are usually several kinds of transition metal ions, such as Fe, Cu, Mn, Co, etc., which are capable of transforming the endogenous H2O2 to the highly toxic OH•− by Fenton or Fenton-like reactions under mildly acidic TME. More importantly, CDT, unlike PDT, does not require external stimuli and does not require the consumption of oxygen. Therefore, the synergistic treatment of PDT and CDT will effectively enhance the effect of tumor treatment with a lower dose and cost than PDT or CDT alone. Multifunctional nanoplatform development has been proposed as a promising strategy for effective PDT/CDT combination. In 2021, Wang and Tang et al. developed a smart TME-responsive multifunctional nanoplatform (MUM nanoparticles) for FLI-MRI guided PDT and CDT combination tumor therapy under both hypoxia-tolerance and deep-penetration conditions [16]. The powerful nanoplatform was constructed from type I AIE PSs (MeOTTI), MnO2 and upconversion nanoparticles (UCNPs). This nanoplatform realized triple-jump photodynamic theranostics: (1) Type I ROS generated by MUM nanoparticles under 980 nm laser irradiation. (2) The overexpressed GSH in the TEM can reduction MnO2 to Mn2+; subsequently, Mn2+ converts H2O2 to OH•− through a Fenton-like reaction [17], and this process can be used as CDT. Furthermore, Mn2+ can also be used for T1-weighted MRI in cancer treatments [18]. (3) Type I ROS generated by MeOTTI under white light irradiation. MnO2 has the catalase-like capability, which can decompose H2O2 to O2, mitigating intracellular hypoxia. Surprisingly, the released Mn2+ can be used in cancer theranostics via T1-weighted magnetic resonance imaging (MRI). Furthermore, the excitation wavelength was shifted from the UV-vis region to the NIR region and was obtained using the FRET mechanism between MeOTTI and UCNPs, which obviously enhances the tissue penetration depth of phototherapy and OH•− generation. This triple-jump PDT and CDT synergistic therapy strategy effectively inhibits tumor growth.

4. PDT-CDT-CT for Synergistic Antitumor

Chemotherapy, as one of the most common treatment strategies, is frequently associated with severe side effects and drug resistance, and patients experience excruciating pain, although it has a certain efficacy in tumor treatment. Therefore, combining charge-transfer (CT) with PDT-CDT will yield further therapeutic effects in oncology treatment. Recently, Wang and Tang developed a smart phototheranostic system via a multicomponent complementary-assembled strategy based on Cu2+-engineered aminosilica [19]. The tumor-targeted activatable aggregates (AD-Cu-DOX-HA) were prepared by coordinating previous reported AIE-active type I/II PS (MeOTTVP) [20] with Cu2+ (catalyze H2O2 to generate extremely poisonous OH•− via the Fenton-like reaction) and further loading doxorubicin (DOX, as efficient drug for CT). Initially, the fluorescence of both MeOTTVP and DOX was in an “off” state because of the presence of Cu2+; however, after specific accumulation in tumor, hyaluronic acid (HA) in the surface layer of the aggregates was easily activated by acidic TME, further leading to stimuli-responsive PSs/DOX/Cu2+ release. The fluorescence signal of released PS (MeOTTVP) was recovered (over 10-fold) for accurate diagnosis and used in FLI-guided combinatorial therapy of type I PDT. The released Cu2+ further catalyzed H2O2 to generate highly toxic OH•− for CDT. In addition, the released DOX was utilized for CT. The combination of these three treatment modalities has a significant effect on tumor growth inhibition. This work provides a new paradigm for smart and activable phototheranostic system.

5. PDT-Gas Therapy for Synergistic Antitumor

In recent years, gas (e.g., CO, NO, H2S) therapy has received increasing attention because these gases have few side effects and can be used as effective therapeutic agents [21][22][23][24][25]. These gases play a crucial role as endogenous signaling molecules in many physiological and pathophysiological events, and the combination of PDT with gas therapy is expected to further improve the efficacy of tumor treatment, especially when gas therapy is also initiated by light treatment. Very recently, Tang and Huang et al. developed a TSH hydrogel system for continuous type I ROS production after light irradiation for antitumor therapy application [26]. This multifunctional hydrogel platform was constructed by loading the (NH4)2S (a famed H2S donor) and type I AIE-active PS (TDCAc) into the injectable hydrogel. Moreover, TDCAc has a high PCE value of 43.5% and thermal stability, which plays a key role for its rapid heating under laser irradiation to soften TSH hydrogels for controllable release of (NH4)2S and TDCAc into the TME. Interestingly, the continual production of H2S by (NH4)2S in TME increases the amount of H2S that diffuses into cancer cells and inhibits the activity of catalase (CAT), effectively promoting the CDT effect (promote the Fenton-like reaction). In contrast, the uninterrupted H2O2 produced by TDCAc can bind the labile iron pool (LIP) in cells and promote the Fenton reaction to produce highly toxic hydroxyl radicals uninterrupted, which provides the demand of free radicals for subsequent tumor treatment. This work effectively enhances the tumor treatment effect and provides a new strategy of synergistic and efficient gas therapy based on type I AIE PSs.

6. PDT-Immunotherapy for Synergistic Antitumor

Immunotherapy has evolved into a promising cancer treatment strategy over the last few decades because it can assist the immune system in fighting cancer [27][28]. Immunogenic cell death (ICD) is a form of apoptotic cell death, providing an important theoretical rationale for modern clinical cancer immunotherapy [29]. Despite there being a limited number of PSs (e.g., pheophorbide A (PPa), Ce6, temoporfin, and hypericin) that can be employed as ICD initiators, these elicitors have not achieved satisfactory results for achieving ICD immunotherapy [30]. As a result, developing high-efficiency ICD initiators is critical for improving the efficacy of tumor immunotherapy. Ding’s group was the first to focus on mitochondrial oxidative stress and use AIE PSs to induce ICD in synergistic treatment of PDT and immunotherapy. Thereafter, numerous AIE PSs have been developed as ICD initiators to promote immunotherapy [31][32][33][34][35][36][37]. Although these reported AIE PSs (the majority of which are type II AIE PSs) are effective in initiating immunotherapy, the relationship between types of ROS and corresponding immune response is unknown. Very recently, several type I AIE-active PSs were successfully used in the synergistic treatment of tumors of PDT and immunotherapy.
Li et al. rationally developed three AIE type I PSs via the D-A effect for efficient facilitation of the reprogramming of macrophages to M1 phenotype for immunotherapy [38]. n-Butyl-substituted TPA and electron acceptors of different strengths (including ID, DCR, and BCI) were employed as the building blocks to construct the D-A structured molecules. tTDCR showed the smallest ΔEST with a value of 0.06 eV among these three analogues, which is far less than the appropriate value (<0.3 eV) for triggering the ISC process [39]. Hence, tTDCR displayed more efficient type I ROS generation capability than tTDI and tTBCI. The extracellular generation of ROS from tTDCR nanoparticles could significantly upregulate the secretion of typical proinflammatory cytokines (TNF-α, a famed marker of M1) from macrophages, with significantly higher activation than other experimental groups and control groups at all concentrations. Moreover, Western blot (WB) experimental results suggested the tTDCR nanoparticles possess the excellent capacity to downregulate CD206 (M2 marker) and upregulate phosphorylation of nuclear factor-κ-gene-binding (NF-κB)  (M1 marker) over other analogues. All the experimental results clearly indicated that extracellular ROS generated by type I AIE PS can efficiently stimulate nonpolarized macrophages to M1 phenotype, and the stimulation efficiency improves with enhanced ROS generation ability (tTBCI < tTID < tTDCR). In addition, single treatment with tTDCR and light can achieve complete tumor ablation without recurrence within 20 days without the help of any immune adjuvants as the type I ROS overcomes the limitation of hypoxia and maintains highly efficient macrophage polarization even in anaerobic tumors. Overall, this work indicates that highly effective type I AIE PSs provide new insights in PDT-mediated immunotherapy by inducing macrophage polarization.
Recently, Tang and coworkers developed a biomimetic nanoplatform (CTTPA-G) via loading a type I AIE PS (TTPA) and glutamine antagonist in cancer cell membranes (CC-Ms) as well as mesoporous silica nanoparticles (MSNs) for improving antitumor immunotherapy [40]. The D-A structured AIE PS was constructed by TPA moiety and dicycanovinyl-modified indanone moiety. superoxide anions (O2•−) and hydroxyl radicals (OH•−) are the main ROS species of TTPA upon light irradiation. Strong surface-exposed calreticulin (CRT) signaling and increased levels of extracellular high mobility group protein B1 (HMGB1) as well as adenosine triphosphate (ATP) secretion suggest that CTTPA-G can efficiently induce ICD process and activate DCs and specific T-cell responses. CTTPA-G stimulated the maturation of CD80+CD86+ of bone marrow dendritic cells DCs (BMDCs), indicating it can successfully activate the antitumor immune system. Flow cytometry results further indicated that type I ROS can effectively enhance the percentage of antitumor M1-like tumor-associated macrophages TAMs (CD11b+F4/80+CD86+), which also suggests that CTTPA-G can efficiently remodel the tumor immunosuppressive microenvironment. Ultimately, both the primary tumor and distal tumor growth were significantly inhibited. In addition, tumor hypoxia was significantly relieved, mainly because CTTPA-G reduced cancer cell nutrition, improved TME, reshaped tumor metabolism, inhibited tumor proliferation, and obtained efficient antitumor immune responses. Moreover, CTTPA-G has a vaccine-like function that further synergistically inhibits tumor proliferation.

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