Self-assembly of methylene violet-conjugated perylene diimide with photodynamic/photothermal properties for DNA photocleavage and cancer treatment
Graphical abstract
Introduction
Cancer is one of the great threatens to human beings’ life. The traditional methods, including surgery, chemotherapy, and radiotherapy are demonstrated to be great success to cure cancer [1,2]. However, their shortcomings such as serious side effects [3,4], drug resistance and recurrence impel the exploration of new treatment with noninvasiveness and high efficiency [[5], [6], [7], [8], [9], [10]]. Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT) [9,11], has emerged as a noninvasive and efficient method to treat cancer because the toxic species (heat or singlet oxygen) are only triggered by the light irradiation [[12], [13], [14], [15], [16]]. Nowadays, there is increasing clinical interest in PDT and PTT phototherapies for cancer as they could provide better outcomes with fewer adverse effects [17]. In the process of PTT, the tumor cells are damaged by local heat effect, triggered by photothermal agents (PTAs) upon laser irradiation in the near-infrared (NIR) region [8,13,18]. As to PDT, the tumor tissues are ablated by reactive oxygen species (ROS) produced by photosensitizer in the presence of oxygen and light irradiation [19]. Owing to the hypoxic microenvironment of tumor site, PTT is expected to have higher treatment efficiency relative to that of PDT as it greatly relies on the surrounding molecular oxygen. To data, most of the developed photothermal agents have focused on inorganic materials, such as carbon-based nanomaterials, gold nanorods, and metal nanostructures [20]. However, the nonbiodegradable characteristic of these materials will cause long-term toxicity to organisms and thus hamper their further clinical translation. In contrast, the organic photothermal agents with good biocompatibility and biodegradability are more suitable in (pre)clinical PTT [12,21,22]. Therefore, it is of great importance to explore the organic therapeutic agents with intense NIR absorption and high photothermal conversion efficiency (PCE) [10,23,24].
PDI (perylene diimide) and its derivatives, as the popular organic chromophores, have been widely used in the field of cancer theranostic in recent years because of their large π-π conjugated system, high fluorescence quantum yield, excellent photochemical properties, and high thermalstability [[25], [26], [27], [28]]. However, the extreme hydrophobicity and weak absorption in NIR region severely inhibit their potential applications in PTT [[29], [30], [31]]. Recently, the self-assembly of amphiphilic organic molecules into related organic nanomaterials with ideal biocompatibility has attracted great attention [32,33]. Moreover, the self-aggregation of molecules in nanostructures could enhance the NIR light absorption and energy conversion efficiency, facilitating their great potential as photothermal agents.
In this context, here we design and synthesize a new small organic molecule (PRX) based on the conjugation of PDI with methylene violet (RAX). Methylene violet bearing the planar phenazine structure, can be used a potential photosensitizer in PDT because of its ability to generate ROS under light irradiation, as indicated in the previous reported literatures [[34], [35], [36]]. Moreover, methylene violet displays the electron-donating characteristic. After conjugation with PDI, featuring with electron-withdrawing ability, to form PRX, it will exhibit a typical donor (D)-acceptor (A) structure. The organic compounds with d-A structure could lower their bandgap, resulting in the redshift of absorption. Furthermore, the good water solubility of methylene violet and the introduction of alkyl chains endow PRX with amphiphilic characteristic, facilitating the self-assembly of organic molecules into related nanoparticles (PRX NPs) through π-π stacking and hydrophobic interaction without addition of extra polymer (Scheme 1). Comparing with that of organic molecule PRX, PRX NPs displayed the broadened and red-shifted absorption with maximum peak at 756 nm. Under a single NIR laser (808 nm) irradiation, PRX NPs could generate photodynamic and photothermal effects simultaneously, with photothermal conversion efficiency as high as 59%. Due to bearing the positive zeta potential, PRX NPs interacts efficiently with DNA and could cleave plasmid DNA in the presence of light. The biocompatibility and photocytotoxicity of PRX NPs are demonstrated by MTT assay using A549 cells as model. These results suggest the as-prepared PDI-based nanomaterials are promising photodynamic/photothermal agents for cancer treatment.
Section snippets
Synthesis and characterization
The synthetic route for PRX was illustrated in Scheme 2. In brief, methylene violet (RAX) was synthesized according to the previous reported method [35,37]. Perylene diimide (1) was synthesized by reacting 3, 4, 9, 10-tetracarboxylic dianhydride and 1-hexylheptylamine in the presence of imidazole with subsequent addition of the mixed solution of hydrochloric acid/ethanol. After bromination with liquid bromine in CDCl3, the monobrominated PDI (2) was obtained in medium yield. Finally, PRX was
Conclusion
In conclusion, we designed and synthesized a new small molecule (PRX) by conjugation of PDI and methylene violet. With the feature of typical d-A structure, PRX displayed efficient absorption in NIR region and quenching fluorescence due to the intramolecular electron transfer. After self-assembly into nanoparticle, PRX NPs exhibited red-shifted absorption with maximum peak at 756 nm. Under 808 nm laser irradiation, PRX NPs could generate ROS and heat simultaneously. The PCE of PRX NPs was
Materials and characterization
The chemical reagents were purchased from Tianjin Fuyu Reagent Company or Sinopharm. Calf-thymus DNA (ct-DNA) was purchased from Sigma company. 1H NMR spectrum were obtained from a Varian Mercury-VX 400 spectrometer. UV–vis absorption and PL spectrum were collected from shimadzu Model UV-1700 spectrometer and Perkin-Elmer LS 55 spectrometer, respectively.
Synthesis of methylene violet (RAX)
10 g of p-aminophenylethylene diamine, 11.34 g of aniline, and 12 g of concentrated hydrochloric acid were dissolved in 50 mL water. K2CrO4
CRediT authorship contribution statement
Haolan Li: Methodology, Investigation, Formal analysis, Data curation, Writing - original draft, Writing - review & editing. Liangliang Yue: Conceptualization, Methodology, Data curation. Ming Wu: Conceptualization, Writing - review & editing, Funding acquisition. Fengshou Wu: Conceptualization, Supervision, Funding acquisition, Writing - review & editing.
Declaration of Competing Interest
The authors reported no declarations of interest.
Acknowledgements
We are grateful for the support from National Natural Science Foundation of China (21601142).
References (46)
- et al.
Functionalized graphene nanocomposites for enhancing photothermal therapy in tumor treatment
Adv. Drug Deliver. Rev.
(2016) - et al.
Organic small molecular nanoparticles based on self-assembly of amphiphilic fluoroporphyrins for photodynamic and photothermal synergistic cancer therapy
Colloids Surf. B Biointerfaces
(2019) - et al.
Platinated porphyrin as a new organelle and nucleus dual-targeted photosensitizer for photodynamic therapy
Org. Biomol. Chem.
(2017) - et al.
Photocytotoxicity, cellular uptake and subcellular localization of amidinophenylporphyrins as potential photodynamic therapeutic agents: an in vitro cell study
Bioorg. Med. Chem. Lett.
(2015) - et al.
Optoelectronic properties of a perylene substituted (cholesteryl)benzoateethynylene co-polymer
Mater. Chem. Phy.
(2014) - et al.
A novel water-soluble perylenetetracarboxylic diimide as a fluorescent pH probe: chemosensing, biocompatibility and cell imaging
Dye. Pigment.
(2019) - et al.
Self-assembled naphthalimide conjugated porphyrin nanomaterials with D-A structure for PDT/PTT synergistic therapy
Bioconjug. Chem.
(2020) - et al.
Visible-light driven photocatalytic degradation of methylene-violet by rGO/Fe3O4/ZnO ternary nanohybrid structures
J. Alloys. Compd.
(2016) - et al.
Mitochondria-targeting Pt/Mn porphyrins as efficient photosensitizers for magnetic resonance imaging and photodynamic therapy
Dye. Pigment.
(2019) - et al.
Functional nanomaterials for phototherapies of cancer
Chem. Rev.
(2014)
Cancer diagnosis and imaging-guided photothermal therapy using a dual-modality nanoparticle
ACS Appl. Mater. Interfaces
Near-infrared-Light-Activatable nanomaterial-mediated phototheranostic nanomedicines: an emerging paradigm for Cancer treatment
Adv. Mater.
Self-assembled peptide- and protein-based nanomaterials for antitumor photodynamic and photothermal therapy
Adv. Mater.
Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer
Chem. Soc. Rev.
Highly stable organic small molecular nanoparticles as an advanced and biocompatible phototheranostic agent of tumor in living mice
ACS Nano
Synthesis, singlet oxygen generation, photocytotoxicity and subcellular localization of azobisporphyrins as potentially photodynamic therapeutic agents in vitro cell study
J. Porphyr. Phthalocya.
Supramolecular photosensitizers rejuvenate photodynamic therapy
Chem. Soc. Rev.
Organic molecule-based photothermal agents: an expanding photothermal therapy universe
Chem. Soc. Rev.
Terrylenediimide-based intrinsic theranostic nanomedicines with high photothermal conversion efficiency for photoacoustic imaging-guided Cancer therapy
ACS Nano
Photosensitizer-conjugated hyaluronic acid-shielded polydopamine nanoparticles for targeted photomediated tumor therapy
ACS Appl. Mater. Interfaces
Highly effective dual-function near-infrared (NIR) photosensitizer for fluorescence imaging and photodynamic therapy (PDT) of Cancer
J. Med. Chem.
Clinical development and potential of photothermal and photodynamic therapies for cancer
Nat. Rev. Clin. Oncol.
Biological photothermal nanodots based on self-assembly of peptide-porphyrin conjugates for antitumor therapy
J. Am. Chem. Soc.
Cited by (25)
Novel 3RAX-based fluorescent probe for hydrogen sulfide detection and photodynamic therapy
2023, Journal of LuminescenceDevelopment of novel hydrogen sulfide depletion aided platform for photodynamic therapy with enhanced anticancer performance
2023, Journal of Photochemistry and Photobiology B: BiologyAsymmetric anionic [O⋯H⋯N]<sup>−1</sup> -type strong H-bond constructed new near-infrared organic photothermal materials with high molar absorptivity and high amount of temperature rise
2022, Dyes and PigmentsCitation Excerpt :As an organic dye, perylene diimide (PDI) not only has good photostability and thermal stability, but also has the advantages of adjustable structure and easy accessibility, which makes it stand out in many photothermal materials. The following methods are mainly used to construct PDI-based NIR photothermal materials which could make the UV–Vis spectra of PDI red shift to the near-infrared region: (1) Designing new structure of donor and acceptor for PDI [20–24]. ( 2) Controlling the aggregation modes of PDI [25–27]. (
Bacteria-triggered radical anions amplifier of pillar[5]arene/perylene diimide nanosheets with highly selective antibacterial activity
2022, Chemical Engineering JournalCitation Excerpt :Perylene diimide (PDI) derivatives, with high molar extinction coefficients, superior photostability and prominent visible-light response, have been widely exploited as advanced photo-relevant materials for electron and energy-transfer [18,19]. It has been found that PDI derivative could behavior as a photosensitizer to promote singlet oxygen (1O2) generation for photodynamic therapy [20,21]. Besides, the PDI motif can be easily reduced to its radical anions with strong absorption bands in near-infrared region (NIR), which displays excellent photothermal conversion ability.
- 1
These authors contributed equally to this work.