Abstract
BackgroundThe first-line chemotherapy drug that is used to treat pancreatic ductal adenocarcinoma is gemcitabine. Unfortunately, its effectiveness is hampered by its chemo-resistance, low vascularization and drug biodistribution limitations in the tumor microenvironment. Novel nanotherapeutics must be developed in order to improve the prognosis for patients with pancreatic cancer.ResultsWe developed a synthetic methodology for obtaining a water-soluble nanoconjugate of a [60]fullerene-glycine derivative with the FDA-approved drug gemcitabine (nanoC60GEM). The proposed synthetic protocol enables a highly water-soluble [60]fullerene-glycine derivative (6) to be obtained, which was next successfully conjugated with gemcitabine using the EDCI/NHS carbodiimide protocol. The desired nanoconjugate was characterized using mass spectrometry and DLS, IR and XPS techniques. The photogeneration of singlet oxygen and the superoxide anion radical were studied by measuring 1O2 near-infrared luminescence at 1270 nm, followed by spin trapping of the DMPO adducts by EPR spectroscopy. The biological assays that were performed indicate that there is an inhibition of the cell cycle in the S phase and the induction of apoptosis by nanoC60GEM.ConclusionIn this paper, we present a robust approach for synthesizing a highly water-soluble [60]fullerene nanoconjugate with gemcitabine. The performed biological assays on pancreatic cancer cell lines demonstrated cytotoxic effects of nanoC60GEM, which were enhanced by the generation of reactive oxygen species after blue LED irradiation of synthesized fullerene nanomaterial.
Highlights
The first-line chemotherapy drug that is used to treat pancreatic ductal adenocarcinoma is gemcitabine
We expected that the carboxylic groups, which are present in that compound would be much more reactive toward the aromatic amines in contrast to the malonic acid derivatives, which are closely connected the [60]fullerene scaffold, based on literature findings (Wang et al 2015)
The desired [60]fullerene monoadduct 4 was created in a high yield by in situ generation of α-brominated malonate 2 in the presence of C Br4/DBU at room temperature in a time-controlled reaction, where monoadducts were formed up to 3 h
Summary
The first-line chemotherapy drug that is used to treat pancreatic ductal adenocarcinoma is gemcitabine. Novel nanotherapeutics must be developed in order to improve the prognosis for patients with pancreatic cancer. The rapid development of nanotechnology is of great interest to researchers focused on translational medicine and novel targeted cancer treatment (Kim et al 2010). Engineered nanoparticles, including carbon nanomaterials, can enter tumors via their leaky vessels and remain there due to the weak drainage in the tumor microenvironment. This phenomenon is called the enhanced permeability and retention effect (EPR effect) and does not occur in normal tissues (Fang et al 2011; Maeda et al 2016). In our recently published article, we demonstrated that fluorescently labeled fullerenes (C60-serPF) can be used as a model delivery system for biodistribution studies in a breast cancer model, due to their preferred biokinetic profile (Lapin et al 2017a)
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