Graphene oxide covalently grafted upconversion nanoparticles for combined NIR mediated imaging and photothermal/photodynamic cancer therapy
Introduction
The growing demand for advancement in cancer diagnosis and therapy has triggered significant research efforts to construct theranostics nanoplatforms integrating imaging and therapy into a single system for imaging-guided, visualized cancer therapy due to the higher therapeutic efficiency and reduced side effects [1], [2]. Imaging probes, as the tool to identify the location of cancer cell, monitor the biodistribution of nanocomposites and assess the therapeutic efficacy, are one of the most important parts of the theranostic nanoplatform. Recently, upconversion nanoparticles (UCNPs), particularly lanthanide-doped rare-earth nanocrystals, have been proposed as new generation of fluorescent probes with great potential in biomedical imaging since they have shown several significant advantages such as a sharp emission bandwidth, long lifetime, tunable emission, high photostability, and low cytotoxicity [3], [4], [5], [6]. More importantly, UCNPs utilize near infrared (NIR) excitation within the “optical transmission window” of biological tissues (700–1000 nm), thereby significantly enhancing penetration depths and minimizing background autofluorescence, photobleaching as well as photodamage to biological specimens [7], [8], [9], [10], [11]. Benefiting from such unique advantages, UCNPs have been successfully employed as promising contrast agents for in vitro cell imaging and in vivo whole-animal imaging [3], [6], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24].
Lately, the construction of theranostics nanoplatform composed of UCNPs and various therapeutic agents, such as anti-cancer drugs [25], photosensitizers (PS) [26], [27] and gold nanostructures [28], [29], for potential therapeutic applications, especially noninvasive photodynamic therapy (PDT) and photothermal therapy (PTT) has been a research hotspot in the forefront of materials science. However, there exist several scientific and technical challenges of UCNPs-based theranostics nanoplatform for application in the clinic. First, the therapeutic effect of UCNPs-based PDT is unsatisfactory owing to the low upconversion luminescence (UCL) emission quantum yield (less than 1%) and limited resonance energy transfer efficiency [30]. Second, the strategies of direct combination of photothermal agent to UCNPs also need more investigation because the photothermal agents often quench the emission of the UCNPs. For example, coating gold nanoshells on the surface of UCNPs has been reported that it greatly suppressed the emission due to the strong scattering of the excitation irradiation [28], [29]. Finally, nanocarriers used for constructing multifunctional nanoplatform, including liposomes, polymers, micelles, mesoporous silica etc. [31], are only the container of the incorporated therapeutic agents. In this respect, they themselves don't own any therapeutic function, resulting in sophisticated preparation process to assemble multiple treatment modalities nanoplatform. Over the years, extensive efforts have been devoted to addressing the first challenge, by developing core–shell structured UCNPs [32], [33] and grafting PS on the surface of UCNPs [34], in an attempt to enhance the UCL emissions and improve the resonance energy transfer efficiency. However, insufficient emphasis has been placed on dealing with the latter two challenges. Along this line, if nanographene oxide (NGO), which can be used as both carrier for PS and photothermal agent for PTT due to its large surface area and intrinsic high NIR absorbance [35], [36], [37], [38], [39], [40], [41], is combined with core–shell structured UCNPs via long-chain joint molecule, the resulting theranostic nanoplatform will exhibit both high fluorescent intensity for imaging and improved therapeutic effect owing to the combination of PDT and PTT.
Building from these ideas, herein we design and develop a multifunctional nanocomposite, which is synthesized by covalently grafting core–shell structured UCNPs with NGO via bifunctional polyethylene glycol (PEG), and then loading phthalocyanine (ZnPc) on the surface of NGO. Benefiting from the unique hybrid nanostructure, this nanocomposite integrates the multifunctions of PDT, PTT and UCL imaging into a single nanoplatform, which could act as an integrated theranostic probe for UCL image-guided combinatorial PDT/PTT of cancer (Scheme 1). Remarkably, both imaging and dual-mode treatments in this nanoplatform are stimulated by light, which exhibits remarkable advantages in terms of enhancing cancer killing specificity and reducing side effects since only the tumor lesion exposed to the light, in comparison to conventional cancer therapies. Moreover, a synergistic effect of combined noninvasive photodynamic and photothermal therapy is expected to improve the therapeutic efficiency, decrease the dosage-limiting toxicity and tissue damage by over-heating.
Section snippets
Materials
Rare-earth oxides RE2O3 (99.99%) (RE = Y, Yb, Er, Tm) were purchased from Science and Technology Parent Company of Changchun Institute of Applied Chemistry. Oleic acid (>90%), 1-octadecene (ODE; >90%), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), poly(allylamine) and zinc phthalocyanine were purchased from Aldrich. Amino carboxylic PEG was purchased from Sunbio Inc. All above chemicals were used directly without further purification. Rare earth chloride (RECl3) stock
Preparation and characterization
For highly efficient UCL, core–shell structured Tm3+/Er3+/Yb3+ co-doped NaYF4@NaYF4 nanocrystals were synthesized as fluorescent probe using previously reported method [42], [43], [44]. The average diameters of the core and core–shell UCNPs were determined to be 28 nm and 40 nm by transmission electron microscopy (TEM), respectively, as presented in Fig. S1 (Supporting Information). The X-ray diffraction (XRD) pattern showed that the nanoparticles were hexagonal β-NaYF4 (Fig. S2). The UCNPs
Conclusions
We have prepared UCNPs-NGO/ZnPc as a theranostic platform for UCL image-guided combinatorial PDT/PTT of cancer. Cytotoxicity assays demonstrated good biocompatibility and low toxicity of the UCNPs-NGO/ZnPc. The nanocomposite could be used as UCL imaging probe of cells and whole-body animals with high contrast for diagnosis. At the same time, significantly greater cell killing was obtained because UCNPs-NGO/ZnPc was not only excellent nanocarrier to load ZnPc for PDT, also could kill cells by a
Acknowledgments
The authors are grateful to the financial aid from the National Natural Science Foundation of China (Grant Nos. 21001101, 21071140, 91122030 and 21210001), ‘863’-National High Technology Research and Development Program of China (Grant No. 2011AA03A407) and National Natural Science Foundation for Creative Research Group (Grant No. 21221061). We wish to thank Prof. F. Y. Li (FU) for kindly providing UCL imaging measurements.
References (50)
- et al.
Combination therapy: opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines
Adv Drug Deliv Rev
(2009) - et al.
Tracking transplanted cells in live animal using upconversion fluorescent nanoparticles
Biomaterials
(2009) - et al.
Synthesis, characterization, and in vivo targeted imaging of amine-functionalized rare-earth up-converting nanophosphors
Biomaterials
(2009) - et al.
Neurotoxin-conjugated upconversion nanoprobes for direct visualization of tumors under near-infrared irradiation
Biomaterials
(2010) - et al.
Drug delivery with upconversion nanoparticles for multi-functional targeted cancer cell imaging and therapy
Biomaterials
(2011) - et al.
Near-infrared light induced in vivo photodynamic therapy of cancer based on upconversion nanoparticles
Biomaterials
(2011) - et al.
The influence of surface chemistry and size of nanoscale graphene oxide on photothermal therapy of cancer using ultra-low laser power
Biomaterials
(2012) Designer combination therapy for cancer
Nat Biotechnol
(2006)- et al.
Non-blinking and photostable upconverted luminescence from single lanthanide-doped nanocrystals
Proc Natl Acad Sci U S A
(2009) - et al.
Nonblinking and nonbleaching upconverting nanoparticles as an optical imaging nanoprobe and T1 magnetic resonance imaging contrast agent
Adv Mater
(2009)
Multicolor core/shell-structured upconversion fluorescent nanoparticles
Adv Mater
Sub-10 nm hexagonal lanthanide-doped NaLuF4 upconversion nanocrystals for sensitive bioimaging in vivo
J Am Chem Soc
Upconversion and anti-stokes processes with f and d ions in solids
Chem Rev
Recent advances in the chemistry of lanthanide-doped upconversion nanocrystals
Chem Soc Rev
Upconversion nanoparticles in biological labeling, imaging, and therapy
Analyst
Upconverting nanoparticles
Angew Chem Int Ed
Upconversion nanophosphors for small-animal imaging
Chem Soc Rev
High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared upconversion in Tm3+ and Yb3+ doped fluoride nanophosphors
Nano Lett
Biocompatibility of silica coated NaYF(4) upconversion fluorescent nanocrystals
Biomaterials
Facile epoxidation strategy for producing amphiphilic up-converting rare-earth nanophosphors as biological labels
Chem Mater
High contrast upconversion luminescence targeted imaging in vivo using peptide-labeled nanophosphors
Anal Chem
Laser scanning up-conversion luminescence microscopy for imaging cells labeled with rare-earth nanophosphors
Anal Chem
Surface modification of upconverting NaYF4 nanoparticles with PEG-phosphate ligands for NIR (800 nm) biolabeling within the biological window
Langmuir
In vivo multiple color lymphatic imaging using upconverting nanocrystals
J Mater Chem
Immunolabeling and NIR-excited fluorescent imaging of HeLa cells by using NaYF4:Yb, Er upconversion nanoparticles
ACS Nano
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