A polyethyleneimine-driven self-assembled nanoplatform for fluorescence and MR dual-mode imaging guided cancer chemotherapy
Introduction
Cancer remains one of the leading causes of mortality worldwide and has attracted extensive concern [1], [2]. Multifunctional nanoplatforms with diagnostic and drug-delivery abilities are at the forefront of scientific research because of their potential applications in combating cancer [3], [4], [5], [6]. A nanoplatform with effective imaging ability can precisely locate tumors and monitor therapeutic effects during treatment [7], [8], [9]. Alternatively, a nanoplatform with a tumor-targeting drug-delivery role can enhance the specificity of anti-cancer drugs, and improve local concentrations at tumor site, while mitigating systemic toxicity [10], [11], [12]. To design an effective imaging nanoplatform, high spatial resolution and imaging sensitivity should be comprehensively considered to obtain a more precise tumor diagnosis [13], [14], [15], [16], [17], [18]. Magnetic resonance imaging (MRI) plays an important role in clinical diagnosis of cancer due to its penetration depth, noninvasiveness and high spatial resolution [19], [20]. However, MRI has poor sensitivity for detecting small tumor nodules [14], [21], [22]. Fluorescence imaging could be an effective tool for detecting small tumors because of its superior sensitivity but is limited by its unsatisfactory tissue penetration [23], [24], [25]. Therefore, the development of fluorescence/MR dual-mode imaging techniques is necessary to provide complementary information and enable the precise location of tumors.
As is known, lanthanides are also important elements to maintain the functionalities of proteins and enzymes in many physiological processes and can facilitate cellular uptake of certain drugs by increasing the cell permeability [26]. Besides, because of f-f intra orbital electronic transitions, lanthanide ions could lead to the photoluminescence of doped nanoparticles [27]. Lanthanides (e.g., Gd and Eu)-doped inorganic fluorides have been widely used for fluorescence/MR imaging because of their excellent fluorescence properties and paramagnetic properties [28], [29], [30], [31]. CaF2 crystals with good biocompatibility are an ideal host material because of their high lattice match with rare earth ions and high stability [29], [30], [31], [32]. Although many lanthanide-doped inorganic fluorides have been used for fluorescence and MR imaging, the use of polyethyleneimine (PEI) as a template to drive the self-assembly of CaF2 nanocrystals and prepare porous CaF2 nanoclusters has been not reported. As we know, PEI, a commonly used surfactant [33], can easily coordinate metal ions on the nanocrystal surface via its amino groups, thereby altering the crystal growth behavior for the synthesis of nanomaterials [34], [35], [36]. In addition, the amino groups of PEI on nanomaterials can coordinate with cisplatin (CDDP). This interaction can be easily destroyed under acidic conditions because the hydrogen proton can occupy the lone-pair electrons of the amino group, enabling pH-responsive drug-release behavior [6], [34], [37], [38].
Here, a PEI-driven self-assembled Gd-/Eu-doped CaF2 nanocluster (GECN) was successfully fabricated. The application of this nanoplatform for fluorescence/MR imaging and cancer chemotherapy was explored by loading CDDP, followed by coating with polyethylene glycol (PEG)-coupled folic acid (FA). The nanoplatform displayed good fluorescence/MR imaging effects in both in vitro and in vivo experiments. The systemic delivery of this nanoplatform in vivo could effectively suppress the tumor growth while mitigating the side effects of anticancer drugs on vital organs. Thus, this multifunctional nanoplatform is expected to be a promising candidate for simultaneous cancer diagnosis and chemotherapy.
Section snippets
Materials
Ethylene glycol, diethylene glycol, triethanolamine, FA, and dimethyl sulfoxide were provided by Sinopharm Co. (Shanghai, China). Gd(NO3)3·6H2O, Eu(NO3)3·6H2O, Ca(NO3)2·4H2O, NaBF4, PEI (MW: 10000), methoxypolyethylene glycol amine (PEG-NH2, MW: 10000), N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide (EDC), and N-hydroxysuccinimide (NHS) were provided by Aladdin Co. (Shanghai, China). CDDP was purchased from Sigma-Aldrich. Co. (USA). All of these chemicals were analytical grade and used without
Synthesis and characterization of GECN@CDDP@PEG-FA
The detailed synthesis of the prepared nanoplatform is summarized in Fig. 1a. First, the self-assembled GECN nanoparticles were prepared using a facile hydrothermal method. Subsequently, the nanoplatform was loaded with CDDP and further modified by PEG-FA to enhance its blood circulation time and tumor targeting. This nanoplatform, which combined excellent fluorescence/MR imaging and drug delivery role, could be a promising candidate for simultaneous cancer diagnosis and chemotherapy.
The TEM
Conclusions
In summary, we successfully synthesized a PEI-driven self-assembled Gd-/Eu-doped CaF2 nanocluster for use as a drug carrier and fluorescence/MR imaging agent. CDDP was chosen as the model drug and was effectively loaded into this nanoplatform. The release of CDDP was triggered by adjusting the pH. In addition, this nanoplatform showed a high r1 relaxation rate (4.91 mM−1 s−1) and fluorescence imaging ability. CLSM and TEM observation indicated that the nanoplatform was effectively internalized
Acknowledgments
The authors acknowledge financial support from the National Natural Science Foundation of China (Nos. 21407151, 31370983), the Science and Technology Major Project of Anhui Province (No. 17030701051), the Key Program of Chinese Academy of Sciences (No. KSZD-EW-Z-022-05), the Youth Innovation Promotion Association of Chinese Academy of Sciences (No. 2015385), and the Science and Technology Service Programs of Chinese Academy of Sciences (Nos. KFJ-STS-ZDTP-002 and KFJ-SW-STS-143), Anhui Science
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These authors contributed equally to this work.