A lysosome-localized thionaphthalimide as a potential heavy-atom-free photosensitizer for selective photodynamic therapy
Graphical abstract
Introduction
Photodynamic therapy (PDT), a noninvasive medical technique that relies on the use of a combination of a photosensitizer (PS) and light in the presence of molecular oxygen, has received significant attention in cancer treatment over the past decades [1]. Ideally, light-activated PSs should efficiently generate reactive oxygen species (ROS) without involving any heavy atoms in their structures to avoid dark toxicity[2], maintain excellent therapeutic efficacy under hypoxia in solid tumors [3], and display switchable photoactivities [4].
Other factors also need to be addressed when developing cancer phototheranostic agents [5]. Since, ROS have a short lifetime and undergo limited diffusion in biological systems, their phototherapeutic outcome strongly depends on the subcellular location of PSs [6]. To date, many PSs that can specifically localize to mitochondria, nucleus, and lysosomes have been intensively studied to gain a better understanding of cell death pathways [7], especially studies on lysosome-targeted photodynamic therapeutic agents are in high demand for enhanced PDT because lysosomes display a critical role in ensuring the functioning of living cells [8,9].
The abovementioned considerations motivated us to search for novel heavy-atom-free PSs targeting lysosomes for PDT. Recently, a new molecular design strategy based on naphthalimide derivatives for developing efficient heavy-atom-free photosensitizers have been reported and it was demonstrated that oxygen-to-sulfur substitution in the naphthalimide backbone along with the introduction of an electron-donating group to the 4-position of naphthalimide are key factors in ensuring such functions [10]. However, further studies are still required to clarify that intriguing finding. The morpholine group is a good electron donor owing to its lone pair electrons[11], and it is recognized as the most effective group for rapid accumulation of traditional fluorophores in the lysosome to overcome nonspecific interactions with other organelles [12]. Thus, the incorporation of a dual-functional morpholine group (electron-donating and lysosome-targeting) into sulfur-substituted naphthalimide may be suitable for our purpose, in the hope that this compound can be internalized in the lysosomes of cancer cells for effective and selective PDT. Promisingly, cellular results showed that LSNI-S could generate a considerable amount of ROS in the lysosomes of HeLa cells to cause cell death upon light irradiation. This work provides the basis for further molecular design of sulfur-substituted carbonyl fluorophores.
Section snippets
General considerations
All operations were performed under an inert nitrogen atmosphere using standard Schlenk techniques. Anhydrous-grade solvents were used as received from Aldrich. Spectrophotometric-grade solvents were used as received. Commercial reagents were used without further purification after purchase. LSNI-O was synthesized according to the modified literature procedures [13]. Deuterated solvents from Cambridge Isotope Laboratories were used. NMR spectra were recorded on a Bruker AM 300 (300.13 MHz for 1
Synthesis
LSNI-S was simply synthesized from commercially available 4-bromo-1,8-naphthalic anhydride following a modified literature method (Fig. 1a). LSNI-O was treated with Lawesson's reagent (4.0 equiv.) in toluene under reflux for 18 h h to afford LSNI-S and was used as the reference compound in this study. The target LSNI-S was fully characterized by multinuclear 1H and 13C NMR, elemental analyses, as well as EI-mass spectra with high purity.
Photophysical properties
The photophysical properties of naphthalimide derivatives
Conclusion
We have successfully designed and synthesized sulfur-substituted naphthalimide as a lysosome-targeting photosensitizer, in which a morpholine moiety plays the dual roles of an electron-donating and lysosome-targeting species. The substitution of oxygen atoms by sulfur atoms in a naphthalimide platform is crucial to promote the intersystem crossing (ISC) of LSNI-S from the excited singlet state to excited triplet state and follows the enhancement of ROS generation capability. LSNI-S could
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.
Acknowledgment
This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (No. 2012R1A3A2048814 for J. Y.). Mass spectral data were obtained from the Korea Basic Science Institute (Daegu) on a Jeol JMS 700 high-resolution mass spectrometer.
References (25)
- et al.
Structural effects on the pH-dependent fluorescence of naphthalenic derivatives and consequences for sensing/switching
Photochem Photobiol Sci
(2012) - et al.
2,4-Dithiothymine as a potent UVA chemotherapeutic agent
J Am Chem Soc
(2014) - et al.
Ultrafast triplet formation in thionated perylene diimides
J Phys Chem C
(2014) - et al.
Achieving efficient photodynamic therapy under both normoxia and hypoxia using cyclometalated Ru(II) photosensitizer through type I photochemical process
Chem Sci
(2018) - et al.
Photodynamic therapy and anti-tumour immunity
Nat Rev Canc
(2006)et al.Supramolecular photosensitizers rejuvenate photodynamic therapy
Chem Soc Rev
(2018)et al.Supramolecular antibacterial materials for combatting antibiotic resistance
Adv Mater
(2019) - et al.
Designing excited states: theory-guided access to efficient photosensitizers for photodynamic action
Angew Chem Int Ed
(2011) - et al.
Phthalocyanine-assembled nanodots as photosensitizers for highly efficient type I photoreactions in photodynamic therapy
Angew Chem Int Ed
(2018) - et al.
Facile supramolecular approach to nucleic-acid-driven activatable nanotheranostics that overcome drawbacks of photodynamic therapy
ACS Nano
(2018) - et al.
Nanoparticles in photodynamic therapy
Chem Rev
(2015)et al.Molecularly precise self-assembly of theranostic nanoprobes within a single-molecular framework for in vivo tracking of tumor-specific chemotherapy
Chem Sci
(2018)(c)Guo Z, Yan C, Zhu W. High-performance quinoline-malononitrile core as diversity-orientated AIEgens. Angew Chem Int... - et al.
Highly charged ruthenium(II) polypyridyl complexes as lysosome-localized photosensitizers for two-photon photodynamic therapy
Angew Chem Int Ed
(2015)
Enhanced efficiency of cell death by lysosome-specific photodamage
Sci Rep
A smart perylene derived photosensitizer for lysosome-targeted and self-assessed photodynamic therapy
Chem Commun
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Contributed equally to this work.