Iron oxide-carbon core-shell nanoparticles for dual-modal imaging-guided photothermal therapy
Graphical abstract
Introduction
Photothermal therapy (PTT) is a cancer treatment recourse whose efficacy primarily depends on the ability of the deployed phototherapeutic agents to absorb electromagnetic radiation from a known source and convert it into localized heat [1,2]. The current standard of cancer remediation typically involves surgical resection, which does not always result in the utter removal of cancerous tissue, followed by the administration of chemotherapeutics and radiation therapy, which are both toxic to healthy tissues. In contrast to the nonselective cellular destruction attendant to chemotherapy and radiotherapy, PTT capitalizes on the human body's translucency to near-infrared (NIR) light allowing a laser to penetrate deep into tissues noninvasively and energize phototherapeutic agents exposed to photons to increase the temperature in their vicinity to above a threshold at which cell death occurs [3,4]. Thermal ablation of healthy tissue is thus minimized in PTT by spatially controlling the NIR light source to illuminate only pre-defined regions. Spatial regulation of NIR exposure paired with the ability of prudently designed phototherapeutics to passively and actively target cancerous lesions discriminately over normal tissue reinforces PTT with another layer of specificity that chemotherapy and radiotherapy lack. To bring PTT out of the realm of the laboratory and into the clinic, phototherapeutic agents with the following properties must be made available: high photothermal energy conversion efficiency, low tissue toxicity, and tumor-targeting capability [4,5]. Additionally, it would be highly advantageous to be able to monitor the location, distribution profile, and retention and secretion properties of phototherapeutics over the course of the therapy with an noninvasive imaging technique such as fluorescence (FL) or magnetic resonance imaging (MRI) [[6], [7], [8]]. The combination of phototherapeutic and imaging capabilities in a single particle would allow for the precise identification of tumor regions and verification that phototherapeutics are within cancer lesions during the treatment process of PTT [[9], [10], [11], [12], [13]].
A number of materials have been investigated as phototherapeutic agents for PTT including gold nanoparticles [14,15], copper sulfide nanocrystals (CuS) [16], molybdenum sulfide nanosheets (MoS2) [17,18], carbon materials [[19], [20], [21], [22]], conjugated polymers [23], metal-organic frameworks [13], and iron oxide nanoparticles [24,25]. Many of these thermo-optically active nanomaterials demonstrated to be highly effective in ablating cancer in preclinical animal models [26,27]. However, most of the reported phototherapeutic agents serve only as photon absorbers that convert light into heat without imaging capability, or vice versa, or they are toxic to cells and tissues in nature limiting their application in medicine [23,28,29]. A low tissue toxic phototherapeutic agent coupled with an imaging capacity such as MRI or an FL imaging or both would be highly desirable in clinical settings. MRI is a pervasive imaging modality used in cancer detection because of its high-spatial resolution and safe profile [30]. In order to accurately distinguish lesions from healthy tissues, MRI contrast agents are commonly employed [31,32]. In FL imaging, an exogenous light source is used to excite fluorophores residing in regions of interest being imaged. These fluorophores absorb energy from the light source and in response emit photons of a different wavelength than the source photons. FL imaging has been used in image-guided surgery wherein fluorescent probes aid surgeons to better view the boundaries of malignant tissues being removed [33].
Here, we report on the development of a bifunctional nanoparticle (BFNP) formulation that demonstrates efficient photothermal energy conversion for PTT while providing contrast enhancement for both MRI and fluorescence imaging. The BFNP is comprised of an Fe3O4 core and a carbon shell, with an average diameter of approximately 16 nm, which is considerably smaller than all the Fe3O4 cluster/carbon core/shell NPs reported thus far (>100 nm) and is highly desirable for vivo application [34]. BFNPs are synthesized by a simple one-pot high-yield process. These BFNPs demonstrate photoluminescence property and have thus the potential to serve as a detectable optical marker in FL imaging. Similarly, the superparamagnetic iron oxide cores of BFNPs provide a source of T2 contrast enhancement in T2-weighted MRI. In vitro experiments and in vivo experiments were performed to test their cytotoxicity and tissue toxicity, respectively. Finally, BFNPs are tested for their ability to kill tumor cells in vitro and inhibit tumor growth in vivo via photothermal therapy.
Section snippets
Synthesis of BFNPs
Ferrocene (0.01 g, Aldrich) was dissolved in acetone (30 mL, Aldrich) in a 50 mL beaker covered with a foil to avoid the volatilization of acetone. After intense sonication (42 kHz, EW- 08891-21 sonicator, Cole-Parmer) for 30 min at room temperature, 1.0 mL of 30% H2O2 (Aldrich) solution was slowly added using a pipette within 30 min while stirring. The resultant mixture solution was further stirred for 30 min with a magnetic stirring apparatus. This precursor solution was transferred to a
Results and discussion
The morphology and structure of BFNPs are examined with transmission electron microscopy (TEM), high-resolution TEM (HRTEM) and selected-area electron diffraction (SAED). Fig. 1a shows that BFNPs are virtually spheroidal and quite uniform in size with an average diameter of about 16 nm. An HRTEM image of a single BFNP (Fig. 1b) reveals the architecture of BFNPs as consisting of a crystalline iron oxide core (9.1 nm in diameter) surrounded by a carbon shell with a thickness of 3.4 nm.
Conclusions
Theranostic hybrid nanostructures based on Fe3O4 nanocrystal cores with carbon shells were synthesized using a one-pot solvothermal method with ferrocene as the sole precursor. The resultant BFNPs have a uniform size of about 16 nm and excellent stability in solution due to the presence of hydrophilic carboxyl groups on the surface of carbon shell. The carbon shell in BFNPs exhibits excitation wavelength-tunable photoluminescence, which allow BFNPs to serve as an optical maker for confocal,
Acknowledgements
This work was supported by NIH grants R01CA161953 and R01EB026890. We acknowledge the use of resources at the University of Washington's Department of Chemistry and Molecular Engineering and Science Institute's molecular analysis facility. We acknowledge the support from NIH to UW W. M. Keck Microscopy Center grant (S10 OD016240) and two photon fluorescence imaging study supported in part by a gift to the Institute for Stem Cell and Regenerative Medicine at the University of Washington.
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