Nanostructured functionalized magnetic platforms for the sustained delivery of cisplatin: Synthesis, characterization and in vitro cytotoxicity evaluation
Graphical abstract
Novel nanocarriers consisting of core–shell silica-coated iron oxide nanoparticles functionalized with dicarboxylic acid groups for controlled release of cisplatin have been synthesized and their in vitro biological properties have been evaluated.
Introduction
Platinum(II) drugs are effective anticancer metallodrugs against solid tumors. Cisplatin or cis-dichlorodiaminoplatinum(II) (CDDP) is one of the Pt(II) metallodrugs most widely used in chemotherapy, owing to its ability to bind to genomic DNA. However, as most of small-molecule anticancer drugs, its clinical use is conditioned due to high toxicity and severe side effects, namely nephrotoxicity and neurotoxicity as well as high incidence of Pt associated drug resistance. In addition, CDDP is nonselective and, hence, DNA replication of malignant and non-malignant cells is equally affected [[1], [2], [3]].
The development of nanotechnology and nanomedicine in the past decades has prompt the research of nanostructured systems with potential to address some of the most challenging problems regarding anticancer metallodrugs [4]. Nanostructured platforms can act as vectors for the delivery of metallodrugs or simply as protectors of active species of the coordination compounds for amplifying their activities, reducing degradation, and promoting controlled or sustained release [5,6]. Therefore, the new generation of nanomedicine can cross the biological, biophysical and biomedical barricades that the human body enforces against conventional anticancer agents [5].
Several nanostructured systems have been developed to improve the chemotherapeutic effectivity of CDDP and its derivatives. Examples of nanocarriers that have been proposed for CDDP delivery include gold nanoparticles [[7], [8], [9]], magnetic iron oxide nanomaterials [[10], [11], [12], [13], [14], [15]], carbon nanotubes [16], silica nanoparticles [17,18] and polymer-based systems [19,20]. The advantage of using nanosystems is own to their unique physicochemical properties (that arise from tunable architectures and surface functionalities), variety of chemical composition and large surface to volume ratio [4]. Among nanocarriers, magnetic iron oxides (e.g. magnetite – Fe3O4) are of great interest because of their response to an externally applied magnetic field. This can be used to guide the loaded carrier remotely to the tumors, providing localized drug delivery to maximize the drug efficiency while side effects are alleviated. Furthermore, owing to their magnetic features, magnetic iron oxides also find application in hyperthermia treatment that could be combined with chemotherapeutics, and as contrast agents in Magnetic Resonance Imaging (MRI) for cancer diagnosis [[21], [22], [23], [24], [25], [26]]. The possible combination of such functionalities in a single platform make magnetic iron oxide nanoparticles very attractive for theranostic applications [27].
Although significant progress has been made, additional investigations are still needed to obtain magnetic platforms offering improved efficacy and with reduced toxicity and frequency of administration of conventional anticancer drugs [6]. Demonstrating that metallodrugs can be tethered to nanoparticles and that the resulting conjugates can promote their sustained release is a crucial step in the long and intricate approval process of nanomedicines. To be successful at this step, it is essential to ensure the proper surface functionalization of the magnetic nanoparticles [28]. Magnetic cisplatin carriers reported so far include mostly Fe3O4 nanoparticles functionalized with synthetic and natural polymers [10,12,14,15,[29], [30], [31]] through polymerization reactions requiring extensive preparatory procedures or the use of crosslinkers and further purifications steps. To the best of our knowledge, simple functionalization strategies employing dicarboxylated alkoxysilanes as coupling agents have not been explored for the development of cisplatin magnetic carriers. Pancreatic cancer is a devastating disease with the incidence increasing at an alarming rate, and survival rates have not improved substantially during the past three decades [32]. With one of the highest mortality-to-incidence ratios, pancreatic cancer is the eighth leading cause of cancer-related death in men worldwide and the ninth in women [33]. This disease is usually detected at advanced stages, carrying a poor prognosis regardless of treatment, and is associated with debilitating symptoms. After the initial diagnosis, most patients have a median survival of about 6 months with treatment [32]. Even in cases where the cancer is diagnosed at an early resectable stage, the 5-year survival is still only 22% [34]. Chemotherapy plays an integral role in the management of all stages of pancreatic cancer, with gemcitabine and fluoropyrimidines being the leading agents employed. Chemotherapy with a single agent is usually only used locally in advanced pancreatic cancer and combined chemotherapy in the metastatic disease [32,35]. Although an enormous effort has been made for comprehensive treatment of this disease, little or no survival improvement have been obtained. Thus, it is mandatory to develop novel therapeutic strategies effective for pancreatic cancer.
Herein, the aim of this work was the synthesis of novel nanosized magnetic carriers, for the transport and controlled delivery of CDDP. These carriers encompassed Fe3O4 nanoparticles encapsulated within amorphous silica shells, chemically modified with a succinic anhydride silane derivative (following a simple one-step chemical strategy) to provide adequate functional groups (dicarboxylic acid groups) for conjugation with CDDP. The resulting materials were characterized using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), and zeta potential measurements. The nanoparticles were conjugated with CDDP and the drug release was monitored along time at physiological pH at 37 °C. In vitro cytotoxicity of the resulting cisplatin conjugates, against malignant and non-malignant human cells, was also investigated. Overall, the results revealed the efficacy of the nanoconjugates against a pancreatic cancer cell line. Furthermore, the nanoparticles conjugated with cisplatin exhibited a lower toxicity, when compared with free CDDP, regarding nonmalignant human pancreatic duct cells.
Section snippets
Materials
All chemicals were reagent grade and used without further purification unless otherwise specified. Iron(II) sulfate heptahydrate (FeSO4.7H2O, >99%) and ethanol (>99%) were purchased from Panreac. Potassium nitrate (KNO3) (>99%), tetraethyl orthosilicate (TEOS, 99.99%) and phosphate buffered saline (PBS, pH = 7) were acquired from Sigma-Aldrich. 3-Triethoxysilylpropylsuccinic anhydride (TESPSA, 95%) from Gelest, and cis-diclorodiaminoplatinum(II) (CDDP, 99.99%) from Acros. Ammonia solution (25%
Synthesis and characterization of the magnetic carriers
In the present work, magnetic iron oxide nanoparticles were prepared, coated with amorphous silica and further functionalized with dicarboxylic acid chelating moieties at the surface, aiming their application as CDDP drug delivery systems. These three synthetic steps are schematically represented in the Scheme 1a. Note that the last step comprises simultaneously the hydrolytic condensation of TESPSA to the surface of the nanoparticles and the hydrolysis of the succinic anhydride at the end of
Conclusions
In recent years nanostructured systems have shown potential for more effective applications of therapeutic agents in cancer treatment. Chemotherapy based on drug-nanoparticles magnetic systems can be used to ensure that drugs are targeted mostly to solid tumors, thereby leaving healthy tissues intact and greatly reducing the typical side-effects associated with conventional chemotherapy. In this work Fe3O4@SiO2 core@shell type nanoparticles whose surface was functionalized with dicarboxylic
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.
Acknowledgements
The costs resulting from the FCT hiring is funded by national funds (OE), through FCT – Fundação para a Ciência e a Tecnologia, I.P., in the scope of the framework contract foreseen in the numbers 4, 5 and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19. This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, financed by national funds through the FCT/MEC and when
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