NIR light-controlled mitochondria-targeted delivery of carbon monoxide combined with histone deacetylase inhibition for synergistic anticancer therapy
Graphical abstract
A multifunctional APIPB-MnCO@TPP@N,P-GQDs nanoplatform {APIPB = N-(2-aminophen-yl)-4-(1H-imidazo[4,5-f] [1, 10] phenanthrolin-2-yl) benzamide, TPP = triphenylphosphine and GQDs = graphene quantum dots} exhibited mitochondria-targeted CO delivery together with inhibition of histone deacetylases activity under 808 nm near IR light irradiation, showing the synergistic anticancer therapy.
Introduction
Histones are one of the most important components of eukaryotic chromosomes, as their acetylated and deacetylated forms regulate gene expression via key transcription and modification. Histone acetylation weakens the binding of DNA and histones, and can promote the binding of transcription-related enzymes to promoters [1]. However, histone deacetylase (HDACs) will increase histone deacetylation [[2], [3], [4]]. In normal cells, the acetylation and deacetylation of histones are in a dynamic balance. When the balance is broken, it may lead to the occurrence of tumors. In cancer cells, over-expressed HDACs increase histone deacetylation and make histones bind tightly to deoxyribonucleic acid (DNA), which is not conducive to the expression of tumor suppressor genes [5,6]. Histone deacetylase inhibitors (HDACIs), a new class of potential anti-tumor drugs [7], regulate the expression and stability of apoptosis and differentiation-related proteins by increasing the level of acetylation in specific regions of the chromatin, ultimately inducing cell apoptosis and differentiation [[8], [9], [10]]. Although HDACIs have been proven to exhibit good anticancer effects, most of them are only used to treat malignant tumors in the hematological system [11], with the impact that they have on solid tumors being relatively weak. Therefore, combining HDACIs with chemo [[12], [13], [14]]/radiation [15,16]/immune [[17], [18], [19]]/photodynamic [20,21]/nitric oxide (NO) therapy [22,23] presents an effective strategy to enhance their anticancer activity.
As an emerging gas molecule for use in therapeutic treatments, carbon monoxide (CO) has attracted widespread attention for the treatment of cancer, owing to its multifaceted regulation of cellular function and the tumor microenvironment [24]. CO targets mitochondrial activity in cancer cells and accelerates cellular respiration (including O2 consumption and the overproduction of reactive oxygen species (ROS)), adenosine triphosphate (ATP) depletion, mitochondrial collapse, and other proapoptotic effects [25]. Moreover, as CO can freely traverse various biological membranes and tumor interstitium [26], it holds great potential in complementing other anticancer treatments, such as photodynamic therapy (PDT) [[27], [28], [29], [30]], sonodynamic therapy (SDT) [31], chemodynamic therapy (CDT) [32,33], chemotherapy [34], and photothermal therapy (PTT) [35]. However, the combination of CO with HDACIs for cancer therapy has been rarely reported. Recently, we reported a novel bifunctional complex [MnBr(CO)3(APIPB)] (APIPB = N-(2-aminophen-yl)-4-(1H-imidazo[4,5-f] [1, 10] phenanthrolin-2-yl)benzamide) that exhibits inhibitory HDAC activity and visible light-controlled CO delivery [36]. However, its lack of targeted CO delivery, small tissue permeability, and phototoxicity of visible light limit its therapeutic effect.
In this study, a multifunctional nanoplatform APIPB–MnCO@TPP@N, P-GQDs (TPP = triphenylphosphine, N,P-GQDs = nitrogen and phosphorus-doped graphene quantum dots), nanoplatform (1), is reported for near-infrared (NIR) light-controlled mitochondria-targeted CO delivery together with the inhibitory activity of an HDAC (Fig. 1), wherein a manganese carbonyl complex [MnBr(CO)3(APIPB)] with an HDACI moiety and a mitochondrial-targeting TPP derivative are covalently attached to the surface of up-conversion N,P-GQDs. When incubated with HeLa cells, nanoplatform (1) specifically localized in the mitochondria, wherein it instantly released CO under 808 nm laser irradiation together with the synergistic inhibition of HDAC, thus inducing cell apoptosis.
Section snippets
Chemicals
All reagents were used as purchased commercially without further purification unless otherwise noted. 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-N-phenylbenzamide (PIPB), N-(2-aminophen-yl)-4-(1H-imidazo[4,5-f] [1, 10] phenanthrolin-2-yl)benzamide) (APIPB), [MnBr(CO)3(APIPB)] (APIPB-MnCO) and [MnBr(CO)3(PIPB)] (PIPB-MnCO) [36], (TPPCOOH) [37], N,P-GQDs [38] and fluorescent CO probe (FL-CO-1) [39] were synthesized according to the previously reported literatures.
Characterization techniques
Transmission electron
Preparation and characterization of nanoplatform (1)
Nanoplatform (1) was prepared according to the procedures shown in Scheme 1, isonicotinic acid (IA) and TPP were first covalently functionalized to N, P-GQDs by forming an amide bond, and then through coordination with the nitrogen atom from IA to further anchor the CO donor [Mn(CF3SO3)(CO)3(APIPB)] with HADC inhibitory effect. The morphology of nanoplatform (1) was observed by transmission electron microscopy (TEM). In the TEM images, nanoplatform (1) is made up of spherical nanoparticles that
Conclusions
In summary, a mitochondria-targeted multifunctional nanoplatform (1), which combines NIR laser-controlled CO release with HDAC inhibition, was prepared via the covalent attachment of the CO donor APIPB–MnCO with a ZBG and a TPP directing group on a fluorescent N,P-GQD carrier. Nanoplatform (1) is fluorescence-trackable and capable of targeting the mitochondria of cancer cells to which CO is delivered. Cytotoxicity assays reveal that nanoplatform (1) exhibits the highest lethality toward HeLa
Abbreviations
APIPB N-(2-aminophen-yl)-4-(1H-imidazo[4,5-f] [1, 10] phenanthrolin-2-yl)benzamide ATP Adenosine triphosphate CO Carbon monoxide DAPI 4′, 6′-Diamidino-2-phenylindole DMEM Dulbecco's modified Eagle's medium EDC 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide GQDs Graphene quantum dots Hb Hemoglobin HbCO Carboxyhemoglobin HDAC Histone deacetylase HDACI HDAC inhibitor IA 4-picolinic acid JC-1 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethyl-benzimidazolylcarbocyanine iodide MMP Mitochondrial membrane potential MTT
Author statement
This manuscript or its contents in other forms has not been published previously and/or is not under consideration for publication elsewhere at the time of submission.
Declaration of Competing Interest
The authors have no competing interests to declare.
Acknowledgements
This study was financially supported by the National Nature Science Foundation of China (No. 21571062 to JGL), the Program for Professor of Special Appointment (Eastern Scholar) at the Shanghai Institutions of Higher Learning to JGL, and the Fundamental Research Funds for the Central Universities (No. 222201717003).
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