​Organic dye-based photosensitizers for fluorescence imaging-guided cancer phototheranostics

Author links open overlay panelRui Wang【王蕊】 a b,Siwei Hua【滑思炜】 b,Yanlong Xing【邢艳珑】 a b,Rui Wang【王锐】 a b,Huimin Wang【王慧敏】 a,Tongmeng Jiang【蒋童蒙】 a b,Fabiao Yu 【于法标】a b

• a

• Key Laboratory of Hainan Trauma and Disaster Rescue, Key Laboratory of Haikou Trauma, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China

• b

• Engineering Research Center for Hainan Bio-Smart Materials and Bio-Medical Devices, Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China

Received 2 January 2024, Revised 6 March 2024, Accepted 5 April 2024, Available online 2 May 2024, Version of Record 2 May 2024.

https://doi.org/10.1016/j.ccr.2024.215866

Highlights

• •Four types of photosensitizers with fluorescence imaging functions were summarized.

• •Design strategies for fluorescence-imaging guided phototherapy were highlighted.

• •Challenges and future opportunities of imaging-guided phototherapy were presented.

Abstract

Precise diagnosis and treatment of tumors is the current hotspot, which has also given rise to a new subject named “theranostics”. It is an ideal precision treatment strategy if the agent can provide effective treatment while visually monitoring tumor occurrence and providing timely feedback on the efficacy. Fluorescence imaging-guided phototherapy technology is a non-invasive, simple-to-operate, highly safe and non-drug-resistant visual treatment method that can accurately monitor tumor sites, perform efficient phototherapy and feedback on tumor treatment effects. Photosensitizers with fluorescence imaging capabilities play a decisive role in the entire diagnosis and treatment process. In this review, we focus on four commonly used photosensitizers with fluorescence imaging functions, including cyanine, tetrapyrrole structures, BODIPY, and AIEgens. The design strategies and principles for improving imaging or/and therapeutic functions were highlighted based on these four organic molecular monomers or their nanoaggregates, nanocomposites, etc. The challenges and future opportunities of fluorescence imaging-guided phototherapy in the clinical translation of precision tumor treatment are also presented.

Keywords

Fluorescence imaging-guided phototheranostics

Cancer treatment

Photosensitizers

Monomers

Nanoparticals

1. 1. Introduction

2. 2. Design strategy for efficient phototheranostic agents

3. 3. Cyanine-based fluorescence imaging-guided theranostics for cancer therapy

• 3.1.1. Type II PDT

• 3.1.2. Type I PDT

• 3.1. Heavy atom effect enhanced PDT

• 3.2. Heavy atom-free effect enhanced PDT

• 3.3. Overcome tumor hypoxia enhanced PDT

• 3.4. Activatable properties for enhanced PTT

• 3.5. Regulation the aggregation state for enhanced PTT

• 3.6. Tumor or/and subcellular organelle-specific targeted enhanced PTT

• 3.7. Other methods for enhanced PTT

• 3.8. Molecule structure for combined PDT and PTT

• 3.9. Nanomaterials based on small molecule structures for combined PDT and PTT

4. 4. Tetrapyrrole structures-based fluorescence imaging-guided theranostics for cancer therapy

• 4.1. Overcome the hypoxia enhanced PDT

• 4.2. Tumor or/and subcellular organelle targeting enhanced PDT

• 4.3. Self-assembly to construct nanomaterials for enhanced PDT

• 4.4. Protein/nucleic acid regulate aggregation state for enhanced PDT

• 4.5. Other methods for enhanced PDT

• 4.6. Phthalocyanine nanomaterials for combined PDT and PTT

5. 5. BODIPY-based fluorescence imaging-guided theranostics for cancer therapy

• 5.1. Heavy atoms enhanced PDT

• 5.2. Heavy atom-free effect enhanced PDT

• 5.3. BODIPY-based nanoparticles for PTT

• 5.4. BODIPY-based nanomaterials for combined PDT and PTT

6. 6. AIEgens −based fluorescence imaging-guided theranostics for cancer therapy

• 6.1. Tetraphenylethylene-based phototheranostic agents for PDT

• 6.2. Triphenylamine-based phototheranostic agents for PDT

• 6.3. Other AIEgens for PDT

• 6.4. AIEgens for PTT

7. 7. Conclusions and perspectives

8. Declaration of competing interest

9. Acknowledgements

10. Data availability

11. References

1. Introduction

Tumors have the characteristics of high incidence rate, strong concealment in the early stage, complexity and heterogeneity of the occurrence and development process, as well as easy recurrence and metastasis, making them a killer that seriously reduces the quality of life and endangers life and health [1], [2], [3]. Traditional single or combined treatment methods such as surgery, chemotherapy, and radiotherapy are still the conventional means of clinical treatment of tumors [4], [5]. Frustratingly, the above-mentioned treatments still face shortcomings such as high invasiveness, low targeting, and high side effects [6], [7]. They are also unable to achieve real-time visual diagnosis of tumors and timely feedback on therapeutic effects. Therefore, the development of new imaging-guided, non-invasive and low-side-effect theranostic methods is of great significance for the precise treatment of tumors [8], [9], [10].

The non-invasive, highly selective, and low-drug-resistant phototherapy has attracted widespread attention from medical workers and scientific researchers since it was used in the clinical treatment of various types of tumors more than 40 years ago [4], [11]. Photodynamic therapy (PDT) and photothermal therapy (PTT) are important components of phototherapy, which can selectively treat diseased areas and have great therapeutic effects on various types of tumors [12]. Not only that, phototherapy does not conflict with other treatments, and each treatment takes less time, making life more convenient [13], [14].

Light, photosensitizers (PSs), oxygen (or other adjacent substrates) are indispensable and vital components of PDT [15], [16]. After the PS in the ground state (S0) absorbs excitation light of a specific wavelength, it produces toxic reactive oxygen species (ROS), damaging prominent proteins and subcellular organelles, thereby inducing apoptosis of tumor cells [17], [18]. PDT is used for anti-tumor treatment in three interrelated ways: (1) directly killing tumor cells; (2) damaging tumor blood vessels; (3) activating the immune system [19]. Different from PDT, the PS absorbs laser of a specific wavelength and reaches to the excited state from the S0, and then returns to the S0 through non-vibrational relaxation is called PTT process [20]. At the same time, it releases enough heat to damage the membrane structure of tumor cells or cause the inactivation of proteins and other substances, thereby achieving the purpose of tumor elimination [21], [22].

Since phototherapy has inherent selectivity for disease treatment, it only needs to give light to the lesion, thereby reducing damage to normal tissue and reducing side effects [4], [23]. Based on this, the best treatment timing can be determined by real-time monitoring of the distribution of PSs in the body and its enrichment time at the tumor site, so as to achieve the lowest drug dose and the best therapeutic effect. Fluorescence imaging technology is a high-profile non-invasive imaging method with great sensitivity and resolution [24], [25], [26], [27]. By combining fluorescence imaging technology and phototherapy, the targeting effect, therapeutic efficiency and metabolic effect of PSs on tumor sites can be determined, thereby clarifying the entire dynamic process of PSs in the body and laying a theoretical foundation for clinical translation [28]. As an essential part of fluorescence imaging, fluorophores can emit fluorescence by absorbing light of specific wavelengths [29]. Fortunately, many fluorophores have been structurally modified to possess phototherapeutic properties [30]. Therefore, the development of these PSs with fluorescence imaging properties provides a feasible strategy for real-time diagnosis and precise treatment of tumors [31], [32].

The performance of phototheranostic agents directly determines the effects of fluorescence imaging and phototherapy. Hundreds of PSs, including porphyrins, phthalocyanines, boron dipyrromethene (BODIPY), etc., have been used in clinical research on various solid tumors [33], [34], [35]. An ideal PS should have the following properties [33], [36], [37]: (1) High operability, many sites that can be modified, and simple structural modification; (2) It can possess excellent tumor targeting by itself or after modification; (3) The absorption mainly in the near-infrared region (NIR, 700–1350 nm; NIR I and NIR II), which is beneficial to reducing the interference of biological autofluorescence background and decreasing the inconvenience of life caused by the strictly avoiding light after treatment; (4) Superior quantum yield of ROS for PDT and excellent photothermal conversion efficiency (PCE) for PTT; (5) Strong safety, no dark toxicity, high biocompatibility, and easily metabolized out of the body. To meet the above requirements, researchers have designed and synthesized a series of organic molecules with fluorescent diagnostic and therapeutic functions, or constructed nanoaggregates, nanocomposites, and nanomaterials based on these functional molecules through self-assembly or co-assembly for fluorescence imaging-guided phototherapy of tumors [38].

In this review, we focus on these fluorescent therapeutic molecules or fluorescent therapeutic aggregates, fluorescent therapeutic nanocomposites based on organic molecular structures, for phototherapy of tumors. According to the different parent structures of organic parents, they are mainly divided into cyanine, tetrapyrrole structure, BODIPY, and AIEgens, which can be used for fluorescence imaging-guided PDT, PTT, and PDT combined PTT against cancers (Fig. 1). In addition, we have in-depth summarized the impact of structural modification (molecular level) or regulated aggregation mode (nano-level) on energy dissipation, providing feasible strategies for constructing PSs that meet both imaging and therapeutic effects. Moreover, we also elaborated on the ways in which molecular structure or nanostructured phototheranostic agents can enhance the effect of phototherapy, which will provide strategies for the subsequent construction of phototheranostic agents with precise tumor imaging and treatment.

Fig. 2. Schematic of the Jablonski diagram.

Table 1. Summary of fluorescence, therapeutic modalities, advantages and disadvantages of representative PSs among cyanine-based molecular or nanomaterials.

Photosensitizer	Fl.	Ther. Mod.	Advantages	Disadvantages	Ref.
heavy-atomized cyanine structures	NIR I	PDT (type II)	broad absorption; enhanced 1O2 generation	Φf is relatively reduced; O2-dependent	[45], [46]
halogen-modified heptamethine cyanine	NIR I	PDT (type I)	activatable fluorescence; anti-hypoxic PDT; ALP-overexpressed cancer targeting	lower Φf (CyI)	[52]
introduced TEMPO into Cy7	NIR I	PDT (type II)	extremely high ФΔ andlow dark cytotoxicity	weakening of fluorescence	[55]
modification of acetophenone at thiopentamethylcyanine	NIR I	PDT (type II)	enhancement of fluorescence and ROS generation; tumor-targeted imaging	O2-dependent	[60]
fluorination of a squarylium indocyanine	NIR I	PDT (type II)	enhanced ROS generation; ER-targeting; O2 supply	the synthesis is relatively complex	[67]
nitro imidazole modified IR-1048 dye	NIR II	PTT	hypoxia-activated PTT; high imaging penetration depth	relatively poor water solubility	[73]
pyrene or TPE modified Cy7	NIR I	PTT	enhanced PCE; improved tumor-targeting	low Φf; relatively poor water solubility	[80]
hydrophilic quaternary stereo-specific cyanine and polypeptide based nanoparticles	NIR II	PTT	increased water solubility; improved biocompatibility and PCE	requires relatively high laser intensity	[82]
tamoxifen modified cyanine	NIR I	PTT	breast cancer targeted; enhanced tumor inhibition rate	relatively low fluorescence penetration depth	[86]
biotin modified cyanine	NIR I	PDT & PTT	ratiometric fluorescence; tumor-targeting; pH activated phototherapy	relatively low fluorescence penetration depth and photostability	[102]
dimeric heptamethine cyanine with an aromatic diphenol linker	NIR I	PDT & PTT	bright fluorescence, excellentROS generation capability; improvedphotostability	requires relatively high laser intensity; relatively poor water solubility	[103]
nanoaggregates based on twistable TPE structure between two IR780s	NIR I	PDT & PTT	tumor targeting; mitochondria targeted disassembly; high PCE;	relatively poor water solubility	[43]
crizotinib modified IR808 self-assembled with BSA	NIR II	PDT & PTT	excellent biocompatibility and biosafety; colorectal cancer targeting	requires relatively high laser intensity	[116]

Fl., fluorescence; Ther. Mod., therapeutic modalities; Ref., reference; Φf, fluorescence quantum yield; TEMPO, 2,2,6,6-tetramethylpiperidinyloxy; ФΔ, singlet oxygen quantum yield; TPE, tetraphenylethene; Cy7, heptamethine cyanine; PCE, photothermal conversion efficiency.

Fig. 3. (a) Chemical structures of CY-C4, I-CY-C4, Br-CY-C4, and COOH-CY-C4. (b) Chemical structures of 6a and 6b.

Fig. 4. (a) Chemical structures of CyH, CyBro, CyBr, and CyI. (b) Chemical structures and reaction of CyBrP with ALP.

Fig. 5. (a) Chemical structure of dye 2. (b) Chemical structures of C2-R. (c) Fluorescence emission spectra of the various dyes in DCM. (d) Normalized DPBF absorbance decrease at 415 nm. (e) The reaction of C2-NO2 to C2-NH2 in the presence of NTR. (f) Fluorescence imaging of tumor-bearing mice after different treatments. (g) Relative tumor volume of mice over time after different treatments. Reprinted with permission from Ref. [60], copyright © 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH.

Fig. 6. Chemical structures of (a) RhoSSCy and (b) HCL1-3.

Fig. 7. Chemical structures of Cy-NTR-CB and Cy-NH2 (a), FCy (b); Ru-Cyn-1, Ru-Cyn-2, Ru-Cyn-3 (c).

Fig. 8. (a) Chemical structures of Cy-830, NSCy-975, NSCy-980 and NSCy-1015 and their design stratagem; (b) The response mechanism of NSCy-1050; (c) Time-dependent whole-body NIR-II fluorescence imaging of 4T1 tumor-bearing mice after i. v. injection of NSCy-1050; (d) Ex vivo NIR-II fluorescence imaging of organs; (e) In vivo photothermal images of 4T1 tumor-bearing mice after laser irradiation various times; (f) Photographs of the tumors from different groups after therapy. Reprinted with permission from Ref. [70], copyright © 2023 Wiley‐VCH GmbH.

Fig. 9. (a) Chemical structure and response mechanism of IR1048-MZ; (b) Chemical structures of IR1-IR4 and the response mechanism of them.

Fig. 10. (a) Chemical structure of Cy-CO2Bz; (b) Chemical structures of Indocyanine and Quinoline cyanine; (c) Chemical structures of Cy7-TPE and Cy7-Pyrene; (d) Chemical structure of CY5-664; (e) Chemical structure of HQS-Cy.

Fig. 11. (a) Chemical structure of CyT, Cy and TAM; In vivo (b) and ex vivo (c) fluorescence imaging of tumor-bearing mice (b) and tumors (c) with different treatments. (d) Time-depended temperature changes at the tumor sites after laser irradiation. (e) Tumor weight of tumor-bearing mice with different treatment. Reprinted with permission from Ref. [86], copyright © 2020 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Fig. 12. (a) Chemical structure of Met-IR-782; (b) Chemical structure of response mechanism of IR-PY and its reaction in different pH; (c) Chemical structure of IR825-Cl.

Fig. 13. Chemical structure, photophysical and chemical properties of CydtPy, Mn2+-chelated CydtPy and Fe2+-chelated CydtPy. Reprinted from Ref. [92], copyright © 2023 Junfei Zhu et al. Distributed under a CC BY 4.0.

Fig. 14. Chemical structures of ICG (a), IR-52 and IR-83 (b), Cy-Bio-O (c), 26NA-NIR and 44BP-NIR (d).

Fig. 15. (a) Chemical structures of Icy-NBF and Icy-NH2. (b) Schematic illustration of O2-dependend energy dissipation. (c) Confocal imaging of calcein-AM and PI-labeled Hela cells with different treatments. (d) In vivo fluorescence imaging of tumor-bearing mice with Icy-NBF. (e) Photographs of mice in the different groups after 0, 12, and 24 days treatment. Reprinted with permission from Ref. [105] (b-e), copyright © 2020, American Chemical Society.

Fig. 16. (a) Chemical structure and its nanoaggregates of T780T; schematic illustration of the application of T780T nanoaggregates in tumor. Reprinted with permission from Ref. [43], copyright © 2021, American Chemical Society. (b) Chemical structure and its self-assembly of BTH-Cy7-TCF; schematic illustration of the application of BTH-Cy7-TCF NPs in tumor. Reprinted with permission from Ref. [110], copyright © 2023 Wiley‐VCH GmbH.

Fig. 17. Chemical structures of (a) BSS-Et and BAC808 (b). (c) The chemical structure of Crizotinib-IR808 and its self-assembly. Reprinted with permission from Ref. [116], copyright © 2023, American Chemical Society.

Table 2. Summary of fluorescence, therapeutic modalities, advantages and disadvantages of representative PSs among tetrapyrrole structures-based molecular or nanomaterials.

Photosensitizer	Fl.	Ther. Mod.	Advantages	Disadvantages	Ref.
morpholine modified SiPc	NIR I	PDT (type I)	pH activatable fluorescence; anti-hypoxic PDT; improved biocompatibility	one-time treatment effect is relatively poor	[121]
lipid-modified porphyrin-based nanomaterials	NIR I	PDT (type II)	hypoxia relief; highly fluorescence; inhibit tumor growth and liver metastasis	preparation of nanomaterials is relatively complicated	[123]
DNBS and cRGD graft onto ZnPc	NIR I	PDT (type II)	enhanced tumor targeting; activatable fluorescence and ROS	relatively poor water solubility	[131]
modifying biotin on SiPc	NIR I	PDT (type II)	enhanced tumor targeting	easy to aggregate	[133]
4-sulfophenoxy mono-α-substituted ZnPc	NIR I	PDT (type II)	turn-on fluorescence; tumor targeted imaging	O2-dependent	[147]
co-assembly of ZnPc and anti-cancer drug MA	NIR I	PDT (type II)	nucleic acid-responsive fluorescence and ROS; improved anticancer effect	O2-dependent	[152]
self-assembly peptide modified ZnPc	NIR I	PDT & PTT	photoactivity changes before and after transmembrane	reduced fluorescence intensity	[156]

Fl., fluorescence; Ther. Mod., therapeutic modalities; Ref., reference; SiPc, silicon phthalocyanine; ZnPc, zinc (II) phthalocyanine; DNBS, 2,4-dinitrobenzene sulfonic acid; cRGD, cyclic arginine-glycine-aspartic acid; MA, mitoxantrone.

Fig. 18. (a) Chemical structures of PcM and NanoPcM. Reprinted with permission from Ref. [121], copyright © 2022, American Chemical Society. (b) Chemical structures of porphyrin with O-linked cationic side chains. (c) The formation processes and biological applications of O2@PFOB@PGL NPs. Reprinted with permission from Ref. [123], copyright © 2020, American Chemical Society. (d) The formation processes of ATO/ZnPc-CA@DA. Reprinted with permission from Ref. [124], copyright © 2023 Elsevier Inc. All rights reserved.

Fig. 19. (a) Chemical structure of Ac-DEVDD-TPP and its self-assembly. Reprinted with permission from Ref. [125], copyright © 2023, American Chemical Society. (b) Chemical structure of 6. (c) Chemical structures of SiPc-biotin and compound 1.

Fig. 20. Chemical structures of P1, P2 (a) and Pt-1(b).

Fig. 21. (a) Chemical structure of PcS and its self-assembly. (b) In vivo fluorescence images of HepG2 tumor-bearing mice after post-injection of MB and NanoPcS. (c) Tumor growth of mice after various treatments. Reprinted with permission from Ref. [147], copyright © 2019, American Chemical Society. Chemical structures of PcN4 (d), ZnPcS8, ZnPcS4, ZnPcS2, ZnPcN4 and ZnPcN12 (e).

Fig. 22. Chemical structure of ZnPc-FF and its self-assembly. The spatiotemporally coupled photoactivity of PF self-assemblies is also presented. Reprinted with permission from Ref. [156], copyright © 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Table 3. Summary of fluorescence, therapeutic modalities, advantages and disadvantages of representative PSs among BODIPY structures-based molecular or nanomaterials.

Photosensitizer	Fl.	Ther. Mod.	Advantages	Disadvantages	Ref.
iodine disubstituted BODIPY modified erlotinib	NIR I	PDT (type II)	high molar absorption coefficient and tumor inhibition rate; EGFR-positive tumors target	O2-dependent PDT	[162]
covalently connected cationic rhodamine and diiodo-substituted BODIPY	NIR I	PDT (type II)	high tumor targeting; increased light-harvesting ability; mitochondrial anchoring ability	O2-dependent PDT; the tendency for dark toxicity	[164]
dibromo-substituted BODIPY grafted acetazolamide	NIR I	PDT (type II)	relieve hypoxia; CAIX-overexpressing tumor cells targeting; inhibit tumor angiogenesis	synthesis steps are relatively complex	[167]
thienopyrrole-fused BODIPY	NIR I	PDT (type II)	increased extinction coefficient and ФΔ	relatively low fluorescence penetration depth	[170]
multipolar triphenylamine-BODIPY	two photon	PDT (type I and II)	higher ФΔ and better Φf; enhanced imaging depth	relatively poor water solubility	[173]
glycosylated Aza-BODIPY self-assembled into nanofibers	NIR I	PDT (type I)	tumor-targeted ability; anti-hypoxia; long retention; cell membrane damage	relatively low fluorescence penetration depth	[51]
BODIPY modified with trifluoromethyl and CPT	NIR I	PTT	improved PCE; enhanced biocompatibility	synthesis steps are relatively complex	[178]
morpholine modified aza-BODIPY based nanoparticles	NIR I	PDT & PTT	increased water solubility; high cytotoxicity for tumor cells; rapid metabolic kinetics	relatively poor tumor targeting ability	[181]
rigid coplanar aza-BODIPY modified tetrastyrene	NIR II	PDT & PTT	enhanced imaging penetration depth; improved PCE and ROS generation;	unable to inhibit tumor metastasis and recurrence	[186]

Fl., fluorescence; Ther. Mod., therapeutic modalities; Ref., reference; EGFR, epidermal growth factor receptor; CAIX, carbonic anhydrase IX; ФΔ, singlet oxygen quantum yield; Φf, fluorescence quantum yield; CPT, camptothecin; PCE, photothermal conversion efficiency.

Fig. 23. (a) Chemical structure of CatER. (b) In vivo whole-body fluorescence imaging of tumor-bearing mice after injection of BDP or CatER. (c) Tumor growth of mice after various treatments. Reprinted with permission from Ref. [162] (a-c), Copyright © 2022 the Author(s). Published by PNAS. Distributed under CC BY-NC-ND 4.0 DEED. Chemical structure of MBDP (d), RDM-BDP (e), pH-BODIPY (f), and AZ-BPS (g).

Fig. 24. Chemical structure of SBDPiR688 (a), Lyso-BDP (b), and (c) T-BDPn (n = 1, 2, 3). (d) Chemical structure of LMBP. (e) Chemical structure of BY-I2, BY-I8, BY-I12, BY-I16, BY-I18 and their nanoform. Reprinted with permission from Ref. [176], copyright © 2023 Wiley‐VCH GmbH.

Fig. 25. Chemical structure of BAC.

Fig. 26. Chemical structure of MAB (a), (b) TAB, TAB-I, and TAB-Br; (c) BDPN, BDPI, BDPC, and BDPJ; (d) CCNU-1060; (e) BDP 2 − 7.

Table 4. Summary of fluorescence, therapeutic modalities, advantages and disadvantages of representative PSs among AIEgens-based molecular or nanomaterials.

Photosensitizer	Fl.	Ther. Mod.	Advantages	Disadvantages	Ref.
tetrastyrene derivative combined with 1O2-cleavable AA and cRGD	NIR I	PDT (type II)	high tumor targeting; monitoring of 1O2 generation; early evaluation of the therapeutic effect	synthesis steps are relatively complex; no in vivo applications	[192]
alkoxyl-branched TPE modified with Br	NIR I	PDT (type I and II)	membrane staining; efficient ROS generation	relatively poor in vivo application	[196]
N,N-dimethyl-substituted TPE modified with 4-vinylpyridine	NIR II	PDT (type I)	relieve hypoxia; cancerous mitochondria-targeting; hybrid apoptosis and ferroptosis	unable to inhibit tumor metastasis and recurrence	[202]
TPA skeleton modified with pyridine and biotin	NIR I	PDT (type I and II)	large stokes shift; tumor cells and mitochondrial targeting; sufficient ROS production	relatively low fluorescence penetration depth	[207]
TPA skeleton modified with quinolinium salt	NIR I	PDT (type I)	time-dependent subcellular organelles target; excellent type I ROS generation	relatively low fluorescence penetration depth	[208]
TPA combined with thiophene and benzothiazole 2-acetonitrile	NIR I	PDT (type I and II)	lipid droplets detection; high bioactivity and stability; enhanced ROS generation	relatively poor water solubility	[213]
5,5′-(6,7-diphenyl-[1,2,5]thiadiazolo[3,4–g]quinoxaline-4,9-diyl)bis(4-hexyl-N,N-bis(4-methoxyphenyl)thiophen-2-amine)	NIR II	PTT	increased fluorescence penetration depth and control of PCE; enhanced photostability and tumor targeting	the construction of nanomaterials is more complicated	[222]
6, 7-diphenyl-[1,2,5]thiadiazolo[3,4g]quinoxaline as the acceptor, thiophene as the π bridge, phenothiazine serves as the acceptor, and a triphenylamine rotor donor is added to the phenothiazine	NIR II	PTT	highest PCE (73.32 %); increased fluorescence penetration depth; noticeable therapeutic efficiency and biocompatibility	relatively poor water solubility; complex synthesis steps	[223]

Fl., fluorescence; Ther. Mod., therapeutic modalities; Ref., reference; AA, aminoacrylate; cRGD, cyclic arginine-glycine-aspartic acid; TPE, tetraphenylethylene; TPA, triphenylamine; PCE, photothermal conversion efficiency.

Fig. 27. Chemical structure of TPECM-1TPP, TPECM-2TPP (a), (b) TPE-TThPy, TPE-TPys; (c) TPTB; (d) TPE-PTB.

Fig. 28. (a) Chemical structure of TPEQM-DMA. (b) 1O2 detection by using SOSG as probe. (c) OH• detection by using HPF as probe. (d) The live/dead cell staining assays under normoxic and hypoxic conditions. (e) In vivo NIR-I and NIR-II fluorescence imaging of tumor-bearing mice after injection of TPEQM-DMA. (f) Tumor growth of mice after various treatments. Reprinted with permission from Ref. [202], copyright © 2023, American Chemical Society.

Fig. 29. Chemical structure of (a) TPATrzPy-3+; (b) DCMT; (c) TBTCP; (d) TSBPy-OH; (e) TSPy-B; (f) CTQ-S; (g) MTOTPy; (h) ADB; (i) TTVP; (j) MeTTSN; (k) DPP-BPYS.

Fig. 30. Chemical structure of (a) DCMa, DCls, DCPy and DCFu; (b) DSABBT; (c) DPpy, DMPpy and DMPSI.

Fig. 31. (a) Chemical structure of NHTDP and nanostructure of NHTDP@M. (b) Photothermal effect and photostability of DHTDP NP@M (c) In vivo NIR-II fluorescence imaging of tumor-bearing mice after injection of DHTDP NP and DHTDP NP@M. (d) Time-depended photothermal imaging in vivo. (e) Tumor growth of mice after various treatments. Reprinted with permission from Ref. [222], copyright © 2023 Wiley‐VCH GmbH.

Fig. 32. (a) Chemical structure of TPTQ and nanostructure of TPTQ NPs. (b) Photothermal effect TPTQ NPs (c) In vivo NIR-II fluorescence imaging of tumor-bearing mice after injection of TPTQ NPs. (d) Time-depended photothermal imaging in vivo. (e) Tumor growth of mice after various treatments. Reprinted with permission from Ref. [223], copyright © 2023 Elsevier B.V. All rights reserved.

7. Conclusions and perspectives

In this review, we summarized the organic molecules inculding cyanines, porphyrins, phthalocyanines, BODIPY, and AIEgens or nanoaggregates and nanocomposite based on these organic molecules for fluorescence imaging-guided phototherapy. Special attention is paid to the strategy of visual elimination of tumors through molecular structure modification, controlled aggregation, and assembly of functionalized nanomaterials. Obviously, this integrated approach to diagnosis and treatment demonstrates the huge potential for clinical transformation of precision tumor treatment. However, fluorescence imaging-guided phototherapy for tumor elimination still faces great challenges: (1) There is currently no fully mature method that can accurately control the fluorescence, photodynamic or photothermal intensity of all kinds of PSs. The strategies used by different PSs molecules are not completely consistent, and the design methods need to be adjusted according to the structure. (2) Maintaining photostability of fluorescence after continuous high-intensity output is a huge challenge. Meanwhile, fluorescence imaging will also face interference from background. To solve the above problems, some afterglow luminescent structures have been studied. Such structures store the energy of the illuminated light and then slowly emit photons. Song et al. have achieved tumor glycolysis and chemotherapy resistance by constructing afterglow structure; [224] in addition, this kind of materials can also quantify and image targets such as pH, superoxide anion, and aminopeptidase [225]. (3) Quantitatively evaluating the accuracy of detecting early tumor lesions through fluorescence intensity and the effectiveness of phototherapy is still limited. (4) The problem of penetration depth. There is an urgent need to further expand the fluorescence emission wavelength so that it can be used for the visual treatment of deep-seated solid tumors. Currently, photoacoustic imaging is favored due to its deeper penetration depth [226]. In addition to tumors, diseases such as atherosclerosis can also be diagnosed early through photoacoustic imaging [227], [228]. (5) Phototherapy has the disadvantage of locality, and metastatic tumors are difficult to detect or treat through this method. In this case, phototherapy needs to be used in conjunction with systemic treatments such as chemotherapy and immunotherapy to enhance the therapeutic effect of metastatic tumors.

Collectively, the use of fluorescence-imaging guided phototherapy for anti-tumor is a promising strategy. This review summarizes the progress made in this field in recent years as well as the opportunities and challenges faced. We believe that with the continuous efforts of scientific researchers and clinicians, fluorescence imaging-guided phototherapy will become a prominent feature in the field of precision tumor treatment in the future.

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