Chlorin e6: a promising photosensitizer of anti-tumor and anti-inflammatory effects in PDT

ABSTRACT

Photodynamic therapy (PDT) involves the activation of photosensitizers (PSs) by visible laser light at the target site to catalyze the production of reactive oxygen species, resulting in tumor cell death and blood vessel closure. The efficacy of PDT depends on the PSs, the amount of oxygen, and the intensity of the excitation laser. PSs have been extensively researched, and great efforts have been made to develop an ideal photosensitizer. Chlorin-e6 is an FDA-approved second-generation PSs that has attracted widespread research interest in the medical field, especially with respect to antitumor and anti-inflammatory activity. Chlorin-e6 possesses the advantages of a large absorption coefficient, high strength, low residue in the body, and relatively high safety and thus has promising application prospects. Here we review the use of chlorin-e6 in PDT and discuss the prospects of further development of this technology.

1. Introduction

Chlorin-e6 (Ce6) is a chlorophyll degradation product obtained from natural chlorophyll in silkworm excrement and algae; the natural Ce6 is isolated, purified, and modified for the targeted application. Prepared Ce6 (chemical structure shown in Figure 1) is a dark green powder with absorbent, oxidizing, and hydrophobic properties.

Figure 1.

The chemical structure of Ce6.

Ce6 is a second-generation photosensitizer (PS) that when activated by the appropriate intensity of laser irradiation catalyzes the production of reactive oxygen species (ROS), thereby inducing tumor cell death and vascular closure. Despite its hydrophobicity and tendency to aggregate [1], Ce6 shows promise as an antitumor and anti-inflammatory agent. Researchers are currently employing various methods to address the limitations in Ce6 operability of this material.

2. Photodynamic therapy

Photodynamic therapy (PDT) is a form of light therapy that involves laser light (600–800 nm) and laser-sensitized chemicals that bind to molecular oxygen and cause cell death [2]. PSs play a crucial role in PDT. The use of laser-absorbing chemicals in biological systems dates back to 1900 when Raab reported the lethal effects of exposure to laser and acridine dyes on the paramecia [3]. Subsequently, laser-sensitive substances have been widely used.

2.1. PSs in PDT

From 1900 to the last few years, the evolution of PS technology can be described as occurring over three distinct periods or generations of research and development [4] (Figure 2).

Figure 2.

The development of PSs.

The first generation involved hematoporphyrin and its derivatives, which are mainly used in the treatment of breast cancer, bladder cancer, and in other areas of medical research [5]. However, more widespread use of Ce6 was hindered by a number of problems: phototoxicity [6], long-term skin photosensitivity, as well as insufficient penetration of deep tumors and inaccurate positioning [7].

Second-generation PS compounds include Ce6, as well as porphyrin, chlorin, chlorocyanide, and anthocyanidins. These substances absorb relatively long-wavelength laser emissions and have been shown to have a high yield of singlet oxygen with low toxicity in vivo [8]. However, there are some drawbacks, such as a lack of target specificity [9,10] and poor water solubility [11], which seriously hinder any further development of the second-generation PSs.

In the development of third-generation PSs, researchers have focused on several aspects to improve Ce6 functionality: drug delivery systems to improve site targeting, improved water solubility, and the use of nanocomposites. The third-generation PSs discussed in the present study include materials such as Foslip® [12], PcMAb [13], G-chlorin [14] and so on. However, the issue of aggregation persists [15]. To overcome this drawback, nanoscale metal-organic frameworks (NMOFs) are connected to metal nanomaterials or metal oxides/perovskites [16]. Since 2014, photosensitive materials have been used in metal-organic frameworks [17]. Researchers have connected metal ions to a photosensitive material to form an NMOF (Zr-porphyrin NMOF [18], Fe-porphyrin NMOF [19], Ti-porphyrin NMOF [20], or PSs loaded onto NMOF [21–23]; these advanced technologies have evidently improved the effect of PDT by increasing phototoxicity.

2.2. Ce6 in PDT

Ce6 is a second-generation PS with an absorption range of 650 to 680 nm [24]. Currently, Ce6 in PDT is mainly illuminated with a 660-nm laser [25–27], which causes the electrons to transition from the ground state to the excited state. Subsequently, Ce6 is activated and catalyzes ROS production, leading to tumor cell death and reduced expression of inflammatory factors [28,29]. However, Ce6 is characterized by poor solubility and low selectivity [30], seriously impeding its broader application in antitumor and anti-inflammatory treatments.

3. Photodynamic therapy with Ce6 nanomaterials

With the development of biotechnology, chemical modifications, nanotechnology, and combination therapy, the efficiency of Ce6 in anti-malignant tumors and anti-inflammation treatments can be significantly improved. The application of nanomaterials in PDT is promising for three reasons: nanomaterials can achieve actively targeted treatment for specific modifications, improve the solubility of hydrophobic photosensitizers, and maintain the sustained release of photosensitizers.

3.1. PDT with Ce6 in the anti-tumor field

Researchers have found that further investigation of the tumor microenvironment (TME) is necessary to advance antitumor research. Particular aspects of the TME under investigation include the tumor hypoxic environment (PO₂, below 5–10 mmHg), mildly acidic conditions (pH, 5.5–6.5), high levels of intracellular glutathione (GSH, 0.5 ~ 10 × 10⁻³ M), excessive hydrogen peroxide (H₂O₂, 50–100 × 10⁻⁶ M), functional evasion, cellular vascular remodeling, and communication between tumor cells and cells in the surrounding environment [31–38]. These factors reduce the effectiveness of treatment and promote tumor progression. To alleviate this situation, researchers have used effective PDT methods.Increased ROS production can, to some degree, overcome the limitations imposed by the TME. Under appropriate laser irradiation, the electrons of Ce6 jump from the ground state to the excited state, resulting in the production of ROS, which play an important role in killing cancer cells and activating immunity (Figure 3). The beneficial effects of PDT are twofold. PDT mitigates the hypoxia condition at the tumor site, thus promoting tumor cell death. As well, the cells exposed to PDT release signals that activate the immune system and promote the anti-tumor activity of the inflammatory cells [39,40]. Currently, Ce6 has received considerable attention in the field of antitumor therapy. In the following sections we discuss physical encapsulation of Ce6, chemical conjugation, and other assembly methods.

Figure 3.

ROS generation mechanism in PDT after Ce6 activation.

3.1.1. Physical encapsulation

There are three main advantages to using nanocarriers in PDT with Ce6: more targeted delivery of Ce6 to disease area, improved solubility (mitigating the hydrophobic Ce6), and the maintenance of a constant release rate of Ce6. At present, researchers have used liposomes, micelles, nanovesicles, and MOFsas carriers of the Ce6 cargo (Figure 4).

Figure 4.

Schematic illustration of various delivery systems for photosensitizers. (a) Liposomes, (b) Micelles, (c) Nanovesicles, (d) Metal−organic frameworks, (e) Polymeric nanoparticles.

Kostryukova et al. [41] prepared nanovesicles of Ce6-PC, which resulted in greater accumulation of Ce6 in tumor tissues compared to results using free Ce6; as well, the phototoxicity and accumulation of Ce6 in the skin were reduced. Ryu et al. [42] synthesized the nanophotosensitizer Pe6, composed of MePEG and Ce6, which was shown to enhance cell uptake, phototoxicity, and ROS generation in vitro and improved the infiltration and accumulation in tumor tissue in live animal experiments. Liposomes (LP) integrated with both the photosensitizer Ce6 and TP (triptolide) (TP/Ce6-LP) were designed by Yu et al. [43] with the aim of controlling drug release and PDT, which showed better therapeutic effects on tumor cells and tissues after laser irradiation than did the free TP group. Yang et al. [44] developed BP@PEG/Ce6, which when packaged with nanoparticles was found to efficiently generate ROS, thus relieving the hypoxic tumor environment. Zhu, Y et al. [45] generated a nanozyme-promoted PDT nanoformula (Ce6/Ftn@MnO₂) for tumor therapy, which increased the accumulation of Ce6 in the tumor and decreased the expression of hypoxia-inducible factor (HIF)-1α. In Table 1 are summarized the Ce6 nanoformulations prepared via physical encapsulation.

Table 1.

Ce6 nanoformulations prepared by physical encapsulation for anti-tumor.

No.	Nanocarrier	Chemotherapeutic agent	Laser wavelength (nm)	Size (nm)	Encapsulation efficiency (EE, %)	Drug loading (DL, %)	Cell lines	Ref
1	Nanobubbles	Soluble programmed cell death protein 1 (sPD-1)	620	282.97 ± 21.80	Ce6:40.85 ± 3.09	Ce6:1.32 ± 0.10	H22	[46]
2	MnO2 nanosheets	/	660	271 ± 26.7	/	/	PC3, L929	[47]
3	Hollow mesoporous silica nanospheres	Doxorubicin (DOX)	660	160	/	DOX:14 Ce6:36	Hela	[48]
4	Liposomes	Doxorubicin (DOX)	660	162.95 ± 2.45	DOX: 82.82 ± 1.37 Ce6:74.06 ± 0.22	DOX: 21.93 ± 0.36, Ce6:0.393 ± 0.001	Hela	[49]
5	virosomes	/	665	/	/	/	Human OSCC, CAL-27	[50]
6	Micelles	Resveratrol (RES)	660	120	/	/	Cal 27	[51]
7	MOF	/	660	/	/	Ce6:15.3 ± 2.9 (Ce6@CMOF) 14.9 ± 2.7 (Ce6@RMOF)	4T1	[52]
8	Mesoporous silica NPs	Curcumin (Cur)	650	120	/	/	CAL-27	[53]
9	Nanoparticles	Doxorubicin (DOX)	650	46.5 ± 1.2	/	/	OSCC	[54]
10	Micelles	/	633	189.6 ± 14.32	75	/	Hela, A549	[55]
11	Nanoparticles	/	664	169 ± 29	/	/	HCT-116	[56]
12	Micelles	/	660	189 ± 19	/	4.1 ± 0.5	LLC	[57]
13	Nanoparticles	Sorafenib	660	97.02	/	/	Hep3B,SMMC7721	[58]
14	Nanoparticles	Doxorubicin (DOX)	808	122.4	/	DOX:5.8	HSC-3, SCC-9, CAL-27, HCM	[59]
15	Nanoparticles	Cabozantinib (CAB)	660	208 ± 6	CAB:92.35 ± 2.33 Ce6:73.95 ± 1.94	CAB:78.6 ± 3.5 Ce6:76.3 ± 2.8	HepG2	[60]
16	Nanoparticles	/	606	237.2	97.45	/	4T1	[61]
17	Nanoparticles	Doxorubicin (DOX)	/	20	/	Ce6:13.6 DOX:14.5	MCF-7	[62]
18	Micelles	/	666	167.45 ± 3.65	82.23 ± 4.92%	7.47 ± 0.72	B16F10;FaDu	[63]

3.1.2. Chemical conjugation

By analyzing the structure of Ce6, researchers have found that the carboxyl groups or other reactive groups on Ce6 can easily form chemical bonds with other materials. These chemical bonds include amides, disulfides, esters, and diselenide bonds. Common chemical bonds used in anticancer drugs are discussed below. As shown in Table 2, Ce6 is connected to other materials through different chemical bonds.

Table 2.

Ce6 was connected by chemical bond in anti-tumor.

No.	Chemical bond	Chemical conjugate	Intermediate	Reaction condition	Cell lines	Ref
1	Amide bond	Ce6-MS	/	/	MGH-U1	[64]
2		FA-Au-CH	/	EDC/NHS	HCT 116	[65]
3		MPEG- Ce6	/	EDAC/NHS	HCT116	[66]
4		Ce6-biotin	/	DECI DIPEA DMF N2	Hela	[67]
5		Ce6-BN	/	/	TNBC, MCF 10A	[68]
6		Ce6-DEVD-MMAE	Asp-Glu-Val-Asp	/	SCC7	[69]
7		FC-Ce6	/	EDC/NHS	Cal-27	[70]
8		Cdot-Ce6-HA	/	EDC/NHS PBS	B16F10	[71]
9		HA-PDA-Ce6	/	HOBt, DIPEA, CH2Cl2	HCT-116	[72]
10		CMPNs	DETA	/	A549	[73]
11		Au@Pt-Ce6-HN-1	/	EDC/NHS	SCC9	[74]
12		DMC-CD/Ad-ss-pep-Ce6 (DACss)	/	EDC/NHS	4T1	[75]
13		Gd−Ce6−FFVLGGGC-PEG (GdCPP)	/	EDC/NHS	C666–1	[76]
14	Diselenide bond	FAPEGbCDseseCe6	Selenocystamine	EDAC NHS	Hela	[77]
15	Ester bond	Ce6-PEG-HKN15 NPs	PEG	DCC&DMAOP, DMSO 60℃	4T1	[78]
16		HPEE-ce6	/	PH < 7, 37℃	CAL-27	[79]

3.1.2.1. Amide bond (–CO–NH–)

The amide bond – a common structure in organic molecules and biomolecules such as peptides, proteins, DNA, and RNA – is highly stable [80]. The formation of amide bonds primarily connects the carboxyl groups of Ce6 to the amino groups of other materials. To obtain Ce6 with long-wave absorption, good water-lipid solubility, and high selectivity for tumor tissues, the multi-substituted basic carbon framework of Ce6 has been chemically and structurally modified. Meng et al. [81] prepared a Ce6-amino acid conjugate that exhibited a relatively high singlet oxygen quantum yield, high dark toxicity/phototoxicity ratio, good water solubility, and excellent in vivo PDT antitumor efficacy. Song et al. [82] connected Ce6 with PEG through an amide bond to form a shell loaded with cisplatin (CDDP) and metformin (chemotherapeutic sensitizer). The nanoparticles reached the target site and released the drug in situ after laser irradiation, thus achieving a synergistic antitumor effect and exhibiting less systemic toxicity. Kook et al. [83] connected folic acid to Ce6 through the intermediate PEG3500 and cysteamine, which resulted in a higher Ce6 uptake ratio, ROS production, and cellular cytotoxicity against oral epidermoid carcinoma cells (KB cells) and human lung squamous cell carcinoma cells (YD-38 cells) compared with the action of free Ce6.

3.1.2.2. Disulfide bond (–S–S–)

The disulfide bond can be stabilized in the extracellular environment: Upon entering cancer cells, it undergoes a sulfhydryl-disulfide exchange reaction with glutathione (GSH) in the cytoplasm, leading to disulfide bond cleavage [84]. GSH is a tripeptide of glutamate, cysteine, and glycine and is found at high concentrations in virtually all mammalian tissues [85]. GSH is involved in scavenging ROS, thus maintaining antioxidant defenses and regulating redox-dependent cell signaling [86]. GSH is highly expressed in tumor cells, resulting in tumor cell growth and resistance to tumor cell death [87–90]. Focusing on the disulfide bond, Zhao et al. [91] were able to conjugate Ce6 to β-cyclodextrin (β-CD), which was found to release 50% more Ce6 after 24 h in deoxidizer dithiothreitol compared with Ce6 in the absence of deoxidizer. Kumari et al. [92] conjugated Ce6 to methoxy – poly (ethyleneglycol) – poly (D,L-lactide) through disulfide bonds, which prevented Ce6 aggregation. The use of these conjugates resulted in significant inhibition of tumor growth and enhanced phototoxicity compared to the results from free Ce6.

3.1.2.3. Diselenide bond (–Se–Se–)

The diselenide bond has been proven to be a dynamic covalent bond that enables diselenide metathesis under visible laser irradiation [93,94]. The diselenide bond (-Se-Se-) can be selectively cleaved by an abnormally high reduced potential in the TME, releasing the prototype drug [95]. Li et al. [96] conjugated Ce6 to hyaluronic acid (HA) via a diselenide bond, which only dissociated under high redox conditions in tumor tissues, thus providing both high antitumor effect and reduced skin phototoxicity. Chen et al. [97] linked cRGD to Ce6 via a bridge between poly(ethylene glycol) and diselenide bonds, which can break the diselenide bond to expose a neural-targeting peptide (Tet1) after laser irradiation; this allows for more precise targeting.

3.1.2.4. Ester bond (–COO–)

The carboxyl groups of Ce6 react with the hydroxyl groups of other materials to form ester bonds, which are unstable and prone to hydrolysis, thus reducing the photodynamic effect of Ce6 on tumors. Park et al. [98] assembled a Ce6 conjugate to Pluronic F127 to decrease the hydrophilic lipophilic balance, causing the drug to be more easily internalized into tumor cells. Narumi et al. [99] linked Ce6 and maltose (Mal3) with intermediate propylpentanolamine and tetraethylene glycol derivatives to form ester bond linkages, which increased the solubility of glucose and Ce6, thereby reducing the damage caused by intravenous injection and improving its antitumor ability.

3.1.3. Self-assembly mechanics for Ce6

The double bond-based conjugated and planar structures of Ce6 provide potential interactions with other molecules through hydrophobic interactions, π - π stacking interactions, and electrostatic interactions [100] (Table 3) Furthermore, the carboxyl group has been shown to promote potential electrostatic interactions and hydrogen bonding with amino groups on other molecules. Zhang et al. [108] carried out self-assembly of Ce6 and genistein (Gen) to form nanoparticles through hydrophobic interactions and hydrogen bonding, which inhibited tumor glucose uptake and reduced the amount of oxygen consumed by tumor respiration to increase Ce6-mediated photodynamic therapy. Xu et al. [109] made use of Sorafenib (Sor), Ce6, and Fe³⁺ self-assembly co-delivery nanoparticles through π-π stacking interactions and hydrogen bonding. In addition to producing ROS through Fenton reaction, Fe³⁺ also supplies O₂ from Fenton reaction, thus increasing the effect of PDT and enhancing the production of ROS.

Table 3.

Self-assembly mechanic for Ce6.

No.	Interactions	Nanoparticles	Size (nm)	Cell lines	Ref
1	π-π stacking and hydrogen bond interaction	Ce6-YSL	75 ± 3.5	SMMCC-7721	[110]
2	hydrophobic interactions	BSC	102.29 ± 11.08	4T1	[111]
3	hydrophobic interactions	HSA-Ce6@HSA-RGD	100	U87MG	[101]
4	hydrophobic interactions, hydrogen bonding	SN38/Ce6	154.87 ± 1.82	4T1	[102]
5	π-π stacking, hydrophobic and electrostatic interactions	D-KCD/A	250	4T1	[103]
6	hydrophobic interactions,	Ce6@P(EG-a-CPBE)	61.2	MCF-7	[104]
7	π-π stacking, hydrophobic interactions	PhotoSyn	78.74 ± 1.38	MCF-7	[105]
8	hydrophobic interactions	GosCe	97.3	4T1	[106]
9	π-π stacking	Ce6/Epa NPs	144.9 nm	MDA MB-231	[107]

3.2. Anti-inflammatory photodynamic therapy with Ce6

Ce6 has also been used in photodynamic therapy to treat inflammation and reduce inflammatory responses caused by antitumor and antibacterial treatments. Thus, Ce6 is more effective in the clinical treatment of arthritis, osteomyelitis, keratitis, atherosclerosis, and antibiotic-induced inflammation. Ce6 in PDT- inactivated M1 or M1-type macrophages is polarized into M2-type macrophages [112–114]. M1 cells can release mediators – such as IL-12, IL-23, TNF-α and IL-1β—and can be able to increase ROS production [115]. M2 macrophages, given that they produce high levels of anti-inflammatory cytokines, such as IL-10 and TGF-β, and are involved in tissue repair and remodeling, played anvital role in suppressing the immune response [116] (Figure 5). Thus, macrophages are indispensable for anti-inflammatory action.

Figure 5.

Direction of macrophage polarization and major functions.

3.2.1. Free Ce6

By utilizing this fluorescence property, the accumulation of Ce6 in vivo can be detected and the amount necessary for anti-inflammatory activity determined. Zharova et al. [117] developed a rabbit model of arthritis and injected Ce6 (1.25 mg/kg) via the auricular vein; on the 21st day after PDT, the synovial membrane possessed a noticeable villous structure, and no inflammatory cells were observed.

3.2.2. Physical encapsulation

The hydrophobicity of Ce6 affects its application in PDT to a great extent. Physical encapsulation is an effective method for mitigating the hydrophobicity of Ce6 and its tendency to aggregate. Because of its suitable particle size, controllable quality, and favorable results, Ce6 has been widely used for PDT (Table 4). Han et al. [121] developed up-converting nanoparticles loaded with Ce6 (UCNPs-Ce6), which were shown to generate ROS during PDT, which in turn activates autophagy and inhibits the expression of proinflammatory factors in M1 peritoneal macrophages via the PI3K/AKT/mTOR signaling pathway. Du et al. [122] developed decoy nanozymes (MCeC@MΦ) which consisted of mesoporous silica nanoparticle cores loaded with CeO₂ and Ce6 and biomimetic shells of macrophage membrane. Ce6 loading not only has a bactericidal effect but also interacts with nanoenzymes to balance endotoxins and pro-inflammatory cytokines.

Table 4.

Ce6 nanoformulations prepared by physical encapsulation in anti-inflammatory.

No.	Nanocarrier	Laser wavelength (nm)	Size (nm)	Encapsulation efficiency, (EE,%)	Drug loading (DL,%)	Ref
1	CD68-Ce6-mediated liposomes	660	214.8	68.71	3.67	[118]
2	Ce6@M-Lip	650	111.37 ± 2.28	97.61	1.12	[119]
3	UCNPs-Ce6@Silane	660	78 ± 2	/	/	[120]

3.2.3. Chemical conjugation

The chemical conjugation method makes full use of the carboxyl groups or intermediates linked to amide bonds (Table 5). Li et al. [127] reported that hydrophobic Ce6 was modified via an amide bond with the TAT peptide to improve its solubility, and exerted remarkable synergistic anti-periodontitis effects with PDT and antibiotic therapy. Sun et al. [128] fabricated Ce6 on nanoceria using 3-aminopropyltriethoxysilane (APTES) to achieve sterilization and inflammation elimination, which has been shown to downregulate M1 polarization (pro-inflammatory) and upregulate M2 polarization (anti-inflammatory and regenerative) in macrophages.

Table 5.

Ce6 was connected by chemical bond in anti-inflammation.

No	Chemical bond	Chemical conjugate	Laser wavelength (nm)	Size (nm)	Ref
1	Amide bond	MA-Ce6	665	/	[123]
2		BSA-Ce6-mal	670	/	[124]
3		MMP-S NPs	660	60	[125]
		MAN-PEG-Ce6	670	200.6	[126]

3.2.4. Self-assembly mechanics for Ce6

Self-assembly also has applications in the anti-inflammatory field. Because antitumor agents produce a corresponding inflammatory response, Ce6 self-assembly with anti-inflammatory drugs can significantly reduce the PDT-induced inflammatory response in vivo and enhance tumor therapy through inflammation inhibition. Li et al. [129] developed self-assembled Ce6 with the COX-2 inhibitor indomethacin (Indo) to form Celndo through hydrophobic and electrostatic interactions, which significantly reduced PDT-induced inflammatory responses in vivo, leading to elevated feedback tumor suppression.

4. Combination of Ce6-based PDT with other therapeutic modes

4.1. Anti-tumor

Combination therapy with Ce6-based PDT has been extensively researched and developed for antitumor applications, including PDT-based immunotherapy and photothermal therapy (PTT). Shu et al. [130] developed a novel combined chemo/photodynamic therapy with nanoparticles loaded with the chemotherapy drug Ce6/sorafenib (SRF): the release of SRF was enhanced due to a large amount of ROS (induced by Ce6) which exerted an anti-tumor synergistic therapy. Palanikumar et al. [131] designed multifunctional nanospheres comprising a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium, and gadolinium) and PTA bismuth selenide (NaYF₄:Yb/Er/Gd,Bi₂Se₃). After laser irradiation, Ce6 was excited, which generated cytotoxic ROS, and Bi₂Se₃ was efficiently converted to heat, realizing the PDT-PTT combination. Zhang et al. [132] developed nanoparticles that self-assembled from BMS-202 and Ce6 via hydrogen bonds, which enhanced the maturation of dendritic cells (DCs) and maturation and infiltration of antigen-specific T cells into the tumor. In conclusion, combination therapy has great potential in antitumor treatment.

4.2. Anti-inflammation

The combination of PDT with other therapeutic modes of anti-inflammation is usually used to treat atherosclerosis and relieve inflammatory pain. Lei et al. [133] constructed ROS-responsive nanomicelle-encapsulated Ce6 and lidocaine (LC), which relieved pain by inhibiting excessive inflammation. Liu et al. [134] prepared Ce6-loaded carbon nanocages and observed that PTT accelerated the release of Ce6, thereby improving the accumulation of Ce6 in the atherosclerotic plaque area and thus the efficiency of PDT. In conclusion, combination therapies to treat inflammation are worthy of more in-depth study.

5. Conclusion

In summary, Ce6 is widely used as a PS owing to its antitumor and anti-inflammatory activities. With the development of PSs, their shortcomings, such as poor targeting, low water solubility, tendency to aggregate, and short cycle times, have been addressed to a large degree, especially in terms of antitumor and anti-inflammatory activities. In addition to its application in PDT, Ce6 can be used in combination with other therapies, such as chemotherapy, PTT, immunotherapy, and sonodynamic therapy. Currently, researchers have made great efforts to continuously optimize the size, shape, and specificity of Ce6-nanoparticles complexes, which enhances Ce6-based PDT combinations. Physical encapsulation and chemical conjugation are the two main methods used to modify PSs. Physical encapsulation decreases the inherent hydrophobicity (resulting in higher solubility) and improves the biocompatibility nd targeting ability of Ce6. Chemical conjugation involves both direct and indirect processes. Direct conjugation utilizing chemical bonds such as amides, disulfides, esters, and diselenides can improve the water solubility and efficacy of the drug. Indirect conjugation can make full use of the bonded compounds to introduce chemical bonds corresponding to the tumor environment. In anti-inflammatory agents, indirect conjugation chemical bonds are dominated by amide bonds that are highly stable and refractory to hydrolysis or pyrolysis, thus maintaining their structure and function within the organism. Other chemical bonds are not as frequently used for anti-inflammatory purposes because they are unstable and dissociate in aqueous solutions or are insensitive to the inflammatory environment. The self-assembly of Ce6 with other chemicals is also an effective strategy for ameliorating Ce6 defects. This method does not involve complex procedures, and the drug and Ce6 are prone to self-assembly to form nanoparticles through non-covalent bonds. The construction of self-assembly based on π-π stacking between drugs and carriers has the advantage of improving the stability and loading capacity of the drugs as well as increasing hydrophilicity and biosafety [135].

Physical encapsulation, chemical conjugation, and self-assembly have played significant roles in the antitumor and anti-inflammatory fields. However, the method of physical encapsulation results in a low drug load; therefore, the purification of nano-reagents is an urgent problem to be solved. Chemical conjugation requires the use of more organic solvents, which tends to increase the toxicity of the prepared nanoparticles, creating safety concerns. Reducing the toxicity and increasing the biocompatibility and safety of nanoparticles is an urgent challenge for chemical conjugation. In future research and development in the field of anti-inflammation, it is likely involve that additional chemical bonds will be used. Although the method of preparing nanoparticles by self-assembly is simple, the nanoparticles obtained are poorly stabilized, prone to decomposition, exert poor medicinal effects, and rely only on the noncovalent connection between the drug or chemical compound and Ce6. Therefore, surface modification of nanoparticles is one way to improve their stability.

Although nanomaterials have shown good efficacy in animal (in vivo) and cellular (in vitro) experiments, their clinical application has not been well verified owing to species variance and environmental complexity in vivo. Furthermore, the security issue remains unanswered [136]. In the future, the clinical translation of Ce6-based PDT will be realized in the field of anti-tumor and anti-inflammation with the collaborative efforts of clinicians, scientists, and biotech companies.

6. Future perspectives

In the near future, Ce6-based PDT will likely show outstanding progress in treating cancers and inflammation. Although Ce6-based PDT has mainly been applied in anti-atherosclerosis and osteoarthritis treatments, anti-inflammatory effects are comparatively understudied. Therefore, researchers should focus on other inflammatory diseases, such as dermatitis, hepatitis, and carditis. At the same time, more stable carriers with precise targeting should be explored to enhance the accumulation of Ce6 at the disease site, thus improving the therapeutic role of both PDT and the combination modes of Ce6-based PDT.

Funding Statement

This paper was not funded.

Article highlights

Enhanced photodynamic efficiency

• The synthesis of nanomaterials by Ce6 through physical encapsulation, chemical conjugation, and self-assembly not only improves the water solubility and toxicity of Ce6, but also targets more Ce6 to tumor and inflammatory sites, thus enhancing its photodynamic efficiency.

Enhanced targeting

• The traditional detection and treatment has disadvantages such as insufficient targeting and limited sensitivity, so the surface modification of Ce6 nanoparticles can enhance the targeting of nanoparticles.

Synergistic therapies

• Combining PDT with other treatments such as photothermal therapy, chemotherapy therapy and so on can significantly enhance its anti-tumor and anti-inflammatory effects.

Author contributions

Hairong Yu designed the manuscript, figures and was responsible for the writing of abstract and introduction. Ziling Huang and Jiale Wu were responsible for the writing of PDT in anti-tumor. Ziming Zhao and Yabing Hua were responsible for the writing of PDT in anti-inflammation. Yihua Yang revised the manuscript and gave the final approval of the version to be published.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.