Elsevier

Dyes and Pigments

Volume 186, February 2021, 108926
Dyes and Pigments

Sphere–like aggregates of porphyrin as phototherapeutic agent for synergistic cancer treatment

https://doi.org/10.1016/j.dyepig.2020.108926Get rights and content

Highlights

  • A photosensitizers aggregates (TNP) was firstly constructed in this study.

  • TNP possesses a good photo-therapeutic performance irradiated by 650 nm laser.

  • TNP exhibited an excellent photo-therapeutic effect in vitro and in vivo.

  • TNP also showed a better biocompatible and safe for biomedical applications.

Abstract

Nowadays, “all–in–one” nano–agent combing various phototherapeutic effects into one nano–system has been attracted more attention in cancer therapy. Herein, a new kind of photosensitizers (PSs) aggregate is designed and constructed. Tetra (4–carboxy phenyl) porphyrin (TCPP), acted as element, is used to form a sphere–like TCPP nanoparticles (TNP) by the self–assembly process. The obtained TNP not only shows good hydrophilia, but also possesses a high photothermal conversion efficiency (η = 31%) which the excessive energy from the excited singlet state (Sn) to the ground state (S0) can be converted into heat. Moreover, TNP is served as photodynamic therapy (PDT) agent because of their components. The synergistic effect of PDT and photothermal therapy (PTT) gives TNP to superior antitumor performance under NIR laser irradiation. Meanwhile, TNP also exhibit an excellent biocompatible and safe for biomedical applications. This work provides novel insight for developing an outstanding phototherapeutic agent based on PSs aggregates to synergistically treat cancer.

Graphical abstract

Upon the 650 nm laser irradiation, the smart “all-in-one” tetrakis (4–carboxy phenyl) porphyrin (TCPP) aggregates (named as TNP) demonstrates excellent synergistic anticancer efficiency in vitro and in vivo. The photodynamic therapy (PDT) performance of TNP is derived from their components (TCPP) to generate toxic 1O2 irradiated by the NIR laser. Synchronously, their photothermal effect is acquired by a mechanism that the excited molecules can also be converted to the ground state via releasing heat.

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Introduction

Cancer, a terrible disease, become a major public health problem and the second cause of death for human in the world [[1], [2], [3], [4], [5]]. Many scientists paid more attention to dealing with the server issue and developing new better therapeutic treatments. Nowadays, phototherapy become a promising therapeutic method to treat various kinds of cancers. In contrast with traditional cancer therapy such as surgery, chemotherapy and radiation therapy, the treated patients after phototherapy show a high survival rate and low side–effect [[6], [7], [8], [9], [10], [11]]. PDT as a type of phototherapy is clinically treated for skin disease, cancer treatment and bacterial infection, which is generated from the combination of PS, light and oxygen [[12], [13], [14], [15], [16]]. Moreover, PTT is a new–found clinical phototherapy for antitumor treatment by using of the combination of NIR light and photothermal agent [[17], [18], [19], [20], [21], [22]]. Whereas, the therapeutic efficiency of phototherapy is severely restricted because of the depth of the excitation light and the singlet therapeutic effect. Therefore, to design a “all–in–one” nano–agent containing multimode phototherapy would be a challenge and opportunity for cancer treatment.

Porphyrin derivatives were widely used for antitumor treatment via their PDT properties because they possessed high extinction coefficients, good biocompatibility and stable photochemical properties [[23], [24], [25], [26]]. However, the chief drawbacks of such porphyrin derivatives are the absorption location of laser and low photostability, which are severely inhibited their use in phototherapy. To overcome the problems, these π–conjugated organic molecules will be formed the self–assembly structure through π–π interaction so as to obtain good water–solubility and redshift of Q band absorption [[27], [28], [29]]. Furthermore, the aggregates also possess good photothermal properties, which the excessive energy from the excited singlet state to the ground state will be converted into heat [[30], [31], [32], [33], [34]]. In especial, there are few reports on the use of porphyrin aggregates with various phototherapy under NIR laser irradiation.

In this work, we designed and constructed an excellent photo–therapeutic agent (TNP) for antitumor treatment, which showed a good PDT and PTT effect under 650 nm laser irradiation. At first, we chose TCPP as component of TNP because the hydrophilic groups like –OH, –COOH and –SH were much easier to synthesize the sphere–like aggregates. The special structure of TNP could increase the π–conjugated system to obtain a large Q band absorption. Meanwhile, not only did TNP show PDT effect, but also the PCE of TNP was much higher than those of other traditional PTT agents such as graphene oxide (GO) [35], Au nanorods [36,37] or MoS2 [38,39]. In addition, TNP had a good solubility in aqueous solutions and smaller size so as to easily enter tumor cells via enhanced permeability and retention (EPR) effect. Therefore, the designed TNP showed several obvious advantages, including (1) well–defined self–assembly obtained from only one small organic molecule (TCPP), (2) good PTT properties with high PCE (31%), and (3) simple synthetic method by using of π–π interaction without adding any other reagents. Combined with PDT and PTT performance co–enhanced collaborative treatment, our prepared TNP will be a promising choice for cancer therapy in the future.

Section snippets

Reagents and materials

The methyl p–formylbenzoate, pyrrole and propionic acid were acquired from Innochem (China). 3–(4,5–dimethyl–2–thiazolyl)–2,5–diphenyl–2H–tetrazolium bromide (MTT), N, N–dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 2,7–dichlorofluorescin diacetate (DCFH–DA) and propidium iodide were purchased from Aladdin Reagents.

Cells and experimental animals

HeLa cells, L929 cells and U14 cells were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). The experimental Kunming female mice (20 g) were

Synthesis and characterization of TNP

As shown in Scheme 1, the structures of the precursor and TCPP were synthesized and characterized (Fig. 1A and B). Then, the synergistic therapeutic process of TNP was illustrated in Scheme 2, which TNP was fabricated by the self–assembly of TCPP. As shown in Fig. 1C, the critical micelle concentration (CMC) curve of TNP was acquired from the dynamic light scattering (DLS) spectra. As shown in Fig. 1D, the average size of TNP that the concentration was 20 μM was still unchanged after 48 h.

Conclusions

In summary, a good phototherapeutic agent (TNP) have been designed and constructed, which was acted as an all–in–one nano–system for cancer treatment. The aggregates were constructed with TCPP as building elements, and fabricated by π–π stacking of TCPP. TNP not only showed higher NIR photothermal performance with NIR laser irradiation, but also still had obvious PDT effect originated from TCPP. Furthermore, TNP would be suitable for biomedical applications because of their good

CRediT authorship contribution statement

Bingyu Xu: Conceptualization, Methodology, Software, Data curation, Writing - original draft. Zhao Wang: Writing - review & editing. Weimin Zhao: Software, Visualization, Validation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors are grateful to the Foundation of Binzhou University (2020Y14 and 2016Y07) and National Natural Science Foundation of China (Grant Nos. 21905029) for the Financial support.

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      Conventional chemotherapy agents used for cancer treatment suffer from several limitations including poor bioavailability, nonspecific selectivity, low accumulation in tumours and severe multidrug resistance (MDR) [1]. Photodynamic therapy (PDT) has been recognized as a promising alternative to traditional cancer treatments in clinic [2–4] owing to its spatiotemporal selectivity, wide-spectrum anticancer effect, enabling repeated treatments without initiating resistance and its possible combination with other therapeutic modalities [5–7]. PDT involves exposure of photosensitizer to appropriate wavelength of light which generates short lived, highly cytotoxic reactive oxygen species (ROS), including hydroxyl radical, superoxide ion, hydrogen peroxide and singlet oxygen (1O2).

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