Regular ArticleTransferrin modified ruthenium nanoparticles with good biocompatibility for photothermal tumor therapy
Graphical abstract
Schematic illustration of the preparation of Tf modified RuNPs. Cell uptake of Tf-RuNPs is mediated by Tf receptor-mediated endocytosis. Upon the NIR laser irradiation, the internalized Tf-RuNPs can expeditious convert the absorbed light energy to local heat for PTT.
Introduction
Nowadays, the growing and aging of world population may be responsible for the increasing cancer-causing behaviours. After all, cancer is still a disturbing and global health problem [1], [2], [3]. There is one thing that demands our focal attention that cancers were conventionally treated by traditional methods such as chemotherapy, surgery, radiation therapy, etc [4]. Unfortunately, these methods are restricted because of the adverse effects. In recent years, a growing number of scientists focus on the exploitation of nanomaterials for photothermal therapy (PTT), a minimally invasive and selective treatment of cancer. In this PTT protocol, photo-absorbing nanomaterials convert photon energy to heat, producing a local hyperthermia to burn cancer cells and tissues. As for the light source, near-infrared (NIR, 700 to 1100 nm) laser is being widely used. Because it can reach several centimetres in biological tissues due to the relatively low absorption of hemoglobin and water as well as less damage to normal tissues [5]. Hence, strong absorption in the NIR region of nanomaterials will be beneficial for the application of PTT.
There are quiet a few, different types of photothermal agents, such as metal nanostructures [6], [7], [8], [9], [10], [11], [12], [13], [14], organic compounds [15], [16], carbon materials [17], [18], [19]. Actually, a multitude of them have been investigated up to now. There are quiet a few different shapes of gold, for typical examples, nanospheres, nanorods, nanoshells, and nanocages, obviously, all of them will bewell-suited to various biomedical applications [20], [21]. Even though, almost all the researches pay excessive attention on the narrow range of metal elements like gold, silver, or palladium. On the contrary, studies on the light and heat properties of the precious metal ruthenium (Ru) are rarely reported. According to this, we have studied the photothermal effect of ruthenium nanoparticles with simple spherical morphology. Gold nanomaterials feature the high cost, poor bioassay and thermal stability, while carbon nanomaterials featurepoorly dispersible and may induce oxidative stress as well as immune response, contrarily, the ruthenium nanoparticles have good biocompatibility and exhibit outstanding photothermal effect.
Insufficient intracellular particle delivery may be the main obstacle that prevents the using of metal nanoparticles in the fight against cancerous cells [22]. Considering this, nanoscale modification technology was invented timely. More specifically, it is a promising pathway to enhance the accumulation of nanoparticles. Different ligands have been modified into nanoparticles and significantly enhanced the cellular ability of absorbing via receptor-mediated pathways, such as folic acid [23], hyaluronic acid [24], peptides [25], etc. Transferrin (Tf), as a serum protein which is non-toxic, non-immunogenic, and biodegradable: it has been widely studied as a cancer-targeting agent [26]. There is an ocean of Transferrin receptor (TfR) existing on the surface of proliferating and malignant cancer cells [27], [28], [29]. Tf/TfR-mediated endocytosis has been proved to be an effective strategy to enhance the nanoparticles accumulation in tumor sites [30]. A host of investigations have indicated that different material modified by Tf extends the blood circulation time and achieves a high selectivity for cancer cells, [32], [33].
Collectively, the purpose of this study was to investigate the activity of Ruthenium (Ru) nanoparticles in photothermal therapy against cancer cells. In view of this, we envisage to make Tf modified on the surface of Ru nanoparticles. so that the synthesis of Ru nanoparticles would get prone to be absorbed by cells (Scheme 1). Beyond that, the cellular uptake mechanisms of Tf-RuNPs were detected in cell assays. Also, the photothermal effects of Tf-RuNPs on A549 cells were measured by MTT assay. Furthermore, we observed and assessed the photothermal effects of Tf-RuNPs on tumor-bearing mice. Afterwards, it is demonstrated that Tf-RuNPs exhibit excellent capability to kill cancer cells, with less side effects owing to the use of Tf-RuNPs. Simply put, these new nanoparticles could be successfully used for highly efficient in vivo PTT under NIR irradiation.
Section snippets
Materials
All reagents and solvents were purchased commercially and used without further purification unless specially noted, and Ultrapure MilliQ water (18.2 MW) was used in all experiments. polyvinyl pyrrolidone (PVP), Cetyltrimethylammonium bromide (CTAB), HAuCl4·3H2O, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), RuCl3·nH2O, NaBH4, thioglycolate, N-Hydroxysuccinimide (NHS), thiazolyl blue tetrazolium bromide (MTT), DAPI, Transferrin were purchased Sigma-Aldrich Chemical Co.
Preparation of RuNPs, Tf-RuNPs and gold nanorods
In a
Preparation, characterization, and photothermal effect of RuNPs
The RuNPs were synthesised by a simple preparation procedure mentioned above. Fig. 1A showed TEM image of the RuNPs with a uniform size about 70 nm. To detect the absorption properties of RuNPs, the UV–vis-NIR absorbance of the RuNPs were measured (in water) at the mass concentration of 10 μg mL−1 (Fig. 1B). The RuNPs in water showed monotonically rising absorbance from the NIR to the UV–vis region, although the surface plasmon resonance of RuNPs is not located in the vis-NIR region, but the notable
Conclusion
In this work, we firstly investigated the photothermal effect of RuNPs. As a new photothermal agent, RuNPs showed the high absorption under NIR irradiation and the efficient heat transformation for photothermal therapy. We successfully synthesised Ru nanoparticles modified by Tf, and then we investigated their photothermal cancer treatment effect in vitro and in vivo. the modification of Tf remarkably enhanced cellular uptake of RuNPs via caveolae-mediated endocytosis and clathrin-mediated
Acknowledgements
This work was supported by the National Natural Science Foundation of China (21171070, 21371075), the Natural Science Foundation of Guangdong Province (2014A030311025) and the Planned Item of Science and Technology of Guangdong Province (2016A020217011).
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Both authors contribute equally to this work.