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Iodine-125-labeled cRGD-gold nanoparticles as tumor-targeted radiosensitizer and imaging agent
© Su et al.; licensee Springer. 2015
- Received: 12 January 2015
- Accepted: 16 March 2015
- Published: 2 April 2015
Research interests on radiosensitive property of gold nanoparticles (GNPs) are rapidly raised because of the extensively proved in vitro effectiveness and clinical necessity. However, the issue of targeted accumulation of GNPs in tumor tissues hindered the transference to in vivo applications. In this study, hybrid nano-sized cyclic Arg-Gly-Asp-conjugated GNPs (cRGD-GNPs) integrated with radioactive iodine-125 was fabricated as tumor-targeted radiosensitizer. Therapeutic effects, including acute apoptosis (2 days post treatment) and long-term influence (up to 21 days), were investigated on NCI-H446 tumor-bearing mice via Tc-99 m-Annexin V SPECT and volume measurements, respectively. Apoptosis and volume loss were consistent in showing that tumor growth was effectively suppressed via the treatment of 125I-cRGD-GNP sensitized radiotherapy (RT), a more significantly radiosensitive effect than the treatment of non-targeted GNPs with RT, RT treatment alone, and no treatment. SPECT/CT images showed that the uptake of cRGD-GNPs by tumor tissues reached the peak target/non-target value of 4.76 at around 2 h post injection, and dynamic radioactivity monitoring showed that 125I-cRGD-GNPs maintained about 2.5% of injected dosage at 55 h post injection. For long-term influence, a significant radiosensitized RT-induced volume loss was observed. Hence, cyclic RGD conjugation makes the GNP-based radiosensitizer tumor targeting, offering a new modality for enhancing radiotherapeutic efficacy. Additionally, the introduction of I-125 serves as both a therapeutic factor and a radiotracer for in vivo tracking of GNPs.
- cRGD-gold nanoparticles
Surface plasmon resonance and the ability to bind thiol and amine group enabled the biological and medical applications of gold nanoparticles (GNPs) , such as photodynamic therapy , therapeutic delivery agents , diagnostic agents [4,5], and radiosensitizer [6,7]. Remarkably, research on radiosensitive properties of gold nanoparticles and corresponding mechanism has got a lot of progress. In general, dose enhancement factor (DEF) related to radiosensitive effect ranges from 1.01 to 2.11 , depending on various items, such as the dosage of radiation, concentration, size, morphology, surface coating, and charging of radiosensitizer. For radiation energy, kV radiotherapy (RT) carries higher DEF than MV energy  but is limited to superficial tumors because of the weak penetrability. For tumor targeting, GNPs may passively accumulate in tumor tissues due to enhanced permeability and retention (EPR) effect of immature blood vessels, but target molecules, such as antibodies, could promote active targeting process, where an interaction of cell membrane and target molecules on the surface existed. On the other side, size and morphology influence the cellular uptake and cytotoxicity. As a general rule, a diameter of less than 30 nm is deemed as necessary for adequate cellular import , but smaller GNPs bring bigger toxicity [11,12]. The uptake of shorter rod-shaped GNPs is higher than that of longer ones, but both are lower than spherical ones . On the contrary, rod-shaped GNPs were exocytosed faster than spherical ones because of the relatively less conjugated binding factors . For in vivo applications, besides EPR effect, reticuloendothelial system (RES) also heavily influences the in vivo distribution of nano-sized radiosensitizer. Smaller size is helpful in avoiding the RES uptake . Moreover, polyethylene glycol (PEG) coating is effective to reduce the RES uptake and increase circulation times, leading to a significant growth of GNP amount in tumor (10- to 100-folds, compared to nude GNPs) [16,17] and less spleen and liver damage . Hence, compromises among these items above are considerable for practical applications.
Radiosensitive property, reflected as drug efficacy, is heavily influenced by targeting efficiency. The αβ serial integrins in regulation of angiogenesis is one of the most promising and best studied targets in oncology research . Correspondingly, Arg-Gly-Asp (RGD)-based strategy to target αvβ3 integrin, which mediates various cancer stages, such as malignant transformation, tumor growth and progression, invasion, and metastasis, is most researched in cancer diagnosis and therapy. Conjugation of RGD peptides enables drugs to recognize αvβ3 integrin, abundantly expressed on tumor blood vessels but not on vessels of normal tissues . Therefore, lots of RGD-based αvβ3-targeted drugs, including hybrid nanoparticles, have been designed as therapy drug, drug delivery system, imaging agent, and complex functionalized drugs. Chemotherapeutics, such as doxorubicin, has been loaded by RGD-based nanoparticles ; moreover, the more complex ‘all-in-one’ RGD-based magnetic nanoparticles, which contained iron oxides as contrast agent, siRNA as therapeutic agent, and a fluorescent dye for fluorescent microscopy, were designed and evaluated in vitro . Particularly, RGD-conjugated gold nanoparticles were reported and tested for targeting efficiency and radiosensitization as well, but in vitro evaluation was rarely reported . Overall, the targeting of RGD-grafted nanoparticles to tumoral endothelium was more effective than non-targeted nanoparticles [24,25]. Additionally, safety profiles and no-dose-limiting toxicity proved in patients are more advantaged than antibody strategies [26,27]. Hence, RGD-based strategy provides a promising and efficient approach in guiding the GNPs.
Herein, we chose the 20-nm GNPs as the platform for constructing the multifunctional agent. Cyclic RGDyC peptides were chosen considering the rigidity and variety of chemical modification. In order to evaluate the in vivo targeting efficiency and RT effect of the targeting radiosensitizer, human small-cell lung cancer model, NCI-H446 tumor cell-bearing mice model, was utilized due to the relatively moderate sensitivity to RT and the clinical needs. For the assessment of RT effect, Tc-99 m-Annexin V SPECT was utilized in early evaluation of apoptosis induced by radiosensitized RT for the first time and cooperated with tumor volume measurements, guaranteeing the consistency of acute apoptosis assessment and long-term observation of therapeutic effect. In this study, radionuclide was also introduced in fabrication of radiosensitizer. Iodine-125 was labeled to the cRGD-GNPs and delivered an effective radiation dose to tumor cells with minimal damage to normal tissues . As a clinically used therapeutic radionuclide, I-125 contributes to the radiotherapy effect; even more importantly, I-125 provides an approach of in vivo dynamic monitoring to figure out biodistributions of cRGD-GNPs.
Materials and instruments
The following instruments were used: cobalt-60 radioactive point source, NanoSPECT/CT (Bioscan, Washington, DC, USA); radioactivity meter (CRC-25R, Capintec Inc., Ramsey, NJ, USA); centrifuge (80–1, Zhengzhou Boke Instrument Equipment Co., Ltd., Henan, China); transmission electron microscope (TEM; 2100 F, JEOL Ltd., Tokyo, Japan); and zetasizer Nano (ZSP, Malvern Instruments Ltd., Worcestershire, UK).
The following materials and reagents were used: 1,3,4,6-tetrachloro-3a,6a-diphenylglucoluril (Iodogen) and 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid 3-sulfo-N-hydroxysuccinimide ester sodium salt (Sulfo-SMCC) were purchased from Sigma-Aldrich, St. Louis, MI, USA. Additional materials include Annexin V (human recombinant, Abcam, Cambridge, MA, USA), cyclic RGDyC peptide (cyclo (Arg-Gly-Asp-Tyr-Cys), GL Biochem Ltd., Shanghai, China); Na99mTcO4 and Na125I (China Isotope & Radiation Corporation, Beijing, China); Whatman 3MM chromatography paper (GE Healthcare UK Limited, Buckinghamshire, UK), and BD Matrigel™ Basement Membrane Matrix. Diethylene triamine pentacetate acid (DTPA), amine-PEG-thiol (M W = 3 kDa, 1,500 equivalents), analytical phosphate-buffered saline (PBS; 0.2 M), SnCl2 · 2H2O, and acetone were purchased from China National Pharmaceutical Group Corporation, Beijing, China. 99mTc-DTPA-Annexin V was prepared in-house following the reported method with radiochemical purity >95% .
All animal experiments were approved by the Tianjin Medical University Cancer Institute and Hospital Animal Care Committee and were in accordance with the ethical guidelines of the National Institutes of Health. All efforts were made to minimize animal suffering and the number of animals that were used. Twenty BALB/C mice (male, 10 weeks, weight of 20 ± 1 g each) were provided by the Institute of Laboratory Animal Science, CAMS. Mice were raised in a SPF class experimental animal room. 5 × 106 cells (in 30 μL Matrigel) were subcutaneously injected into the right hind leg to prepare the NCI-H466 tumor model mice. Tumor-bearing mice were ready for treatment when tumor volume reached 80 to 100 mm3 (10 to 14 days needed).
Synthesis and characterization of 125I-cRGD-GNPs
The morphology and size of GNPs were characterized using TEM at an acceleration voltage of 200 kV; UV absorbance of nude GNPs was measured to detect maximum absorption peak, and UV spectrums of liquid supernatant of cRGD conjugation reaction system were obtained before and after the reaction to confirm the conjugation of cRGD. The size distribution of PEG-coated GNPs was measured by dynamic light scattering (DLS); measurement of surface ζ potential was performed by zetasizer to evaluate the PEG covering and cRGD coupling. The in vitro stability of 125I-cRGD-GNPs was tested by incubating 125I-cRGD-GNPs in 0.05 M PBS or 10% fetal bovine serum (FBS) for 3 days at 37°C. Radiolabeling efficiency and radio-chemical purity were monitored by thin-layer chromatography silica-gel-based thin-layer chromatography with 0.9% NaCl as developing solvent: R f of 125I-cRGD-GNPs is 0 and R f of I-125 is 1.
Investigation of biodistribution
I-125-labeled cRGD-GNPs (37 MBq, containing 1-mg GNPs) were injected intravenously. At 1, 2, and 4 h post injection, mice were anesthetized via 2% isoflurane inhalation. SPECT was performed with the following parameters: four high-resolution, conical collimators with nine-pinhole plates; energy peak, 28 keV; window width, 10%; resolution, 1 mm/pixel; matrix, 256 × 256; and scan time, 60 s/projection with 24 projections in all. Three-dimensional ordered subset expectation maximization images were reconstructed using HiSPECT (Bioscan, Washington D.C., USA). CT was then performed with the following scan parameters: frame resolution, 256 × 512; tube voltage, 45 kVp; current, 0.15 mA; and exposure time, 500 ms/frame. Real-time 3D reconstructions of the collected images were performed using the Nucline software (v 1.02, Mediso, Hungary). A fused SPECT/CT image was generated for investigation of biodistribution.
Drug residual was inspected by the radioactivity meter, and the radioactivity of excreta was recorded by the γ counter as well to detect the metabolic pathways. A value lower than 2.5% of the injected dosage was deemed as roughly cleared. Samples of blood, urine, and feces were collected immediately after injection and at 0.5, 1, 2, 4, and 10 h and 1, 2, and 3 days post injection and then measured by the γ counter to investigate the %ID/g. All the recorded data of radioactivity was corrected to the original injected radioactivity dosage.
Radiotherapy of tumor-bearing mice
Twenty NCI-H466 tumor-bearing mice were divided into five groups for treatments: 125I-cRGD-GNPs with radiotherapy, cRGD-GNPs with radiotherapy, GNPs with radiotherapy, radiotherapy alone, and control group (no treatment). Injections were sterilized by 0.22-μm filter membrane. For the radiosensitized radiotherapy, 100 μL (containing 1-mg Au) 125I-cRGD-GNPs, cRGD-GNPs, or GNPs were injected intravenously. At the definite time, mice were anesthetized via intraperitoneal injection of 150 μL 4% chloral hydrate. Tumor tissues were exposed to 5-Gy γ rays emitted by the Co-60 source. The injected doses were normalized to about 50-μg GNPs every gram body weight.
Investigation of therapeutic effect
Two days after treatment, 99mTc-Annexin V (18.5 MBq/mouse) was administered intravenously for apoptosis evaluation. At 2 h after the injection, mice were anesthetized via 2% isoflurane inhalation. SPECT was performed using the following parameters: four high-resolution, conical collimators with nine-pinhole plates; energy peak, 140 keV; window width, 10%; resolution, 1 mm/pixel; matrix, 256 × 256; and scan time, 60 s/projection with 24 projections in all. Target/non-target (T/NT) analysis focused on the treated tumor tissues and corresponding comparison to the tissues on the left leg.
For assessments of long-term influence, tumor sizes were measured every 3 days (during early stage) or every 6 days (during later stage) and calculated as follows: Volume = (Tumor length) × (Tumor width)2/2. The body weight of every mouse was recorded as well. Mice were sacrificed at the 21st day after treatment, and the weight of excised tumors was recorded.
Data of volume and weight were expressed as mean ± standard deviation (SD). One-way (treatment method) analysis of variance (ANOVA) followed by post hoc test was used to analyze the differences between groups. Statistics were performed in SPSS 19.0.
Synthesis of 125I-cRGD-GNPs
The as-synthesized GNPs were of a uniform size of 21.7 ± 2.1 nm, and the maximum UV absorption peak was at 537 nm. DLS hydrodynamic diameter of PEG-covered GNPs was 45.2 ± 2.6 nm. cRGD was successfully conjugated to GNPs based on the changes of surface ζ potential and RGD concentration changes of reaction supernate reflected by the UV spectrum. The surface ζ potentials of 125I-cRGD-GNP synthesis after every step are marked in Figure 1.
In vivo biodistribution
For tumor-targeted agents, an ideal delivery of nanoparticles to tumor tissues will preferentially increase tumor cytotoxicity and minimize damage to healthy tissues simultaneously. A lot of efforts have been made to facilitate the targeted accumulation of gold nanoparticles, such as the introduction of anti-EGFR antibody [31,32]. Based on a similar mechanism, RGD conjugation approach utilized active angiogenesis targeting as well; furthermore, the rigidity of cyclic RGDyC and unique expression of αvβ3 integrin in blood tumor vessels guarantee the persistence, specificity, and high efficiency of radiosensitizer. On the other side, particle size and surface covering is an important role in determining the clearance. Smaller size and biocompatible materials, such as glutathione , are contributing factors in enhancing EPR effect. In this research, functionalized PEG was used and exhibited an appreciating stability and clearance, avoiding abundant uptake by RES. Besides these, the versatility of functionalized PEG provides multiple potential for modification of particles.
Radiosensitized therapeutic effect
Apoptosis and necrosis are the primary approach of radiotherapy-induced cell death, which related to a series of complex mechanisms, including double-strand break of DNA and mitochondrial damage [34,35]. Apoptosis imaging is an innovative strategy in the pathogenesis detection and early therapeutic effect evaluation, such as tumor response to chemotherapy and radiotherapy . In this research, 99mTc-Annexin V SPECT after radiotherapy, but the commonly used in vitro test, such as TUNEL staining and γ-H2AX assay of DNA double-strand break, were utilized, avoiding the separate characterization of apoptosis and long-term therapeutic effect. When considering apoptosis and long-term volume change together, we found that there are a kind of connection and a predicting significance of apoptosis for long-term therapeutic effect. Hence, 99mTc-Annexin V SPECT provides an approach of early evaluation of radiosensitized radiotherapy.
For a better understanding of radiosensitizing effect of GNPs, such as the detailed biodistribution, some efforts have been made emphasizing on the in vivo tracking. Different with the introduction of MRI-detectable gadolinium chelates , the introduction of I-125 provided a signal closely correlated with the concentration of cRGD-GNPs. Therapeutic effect of I-125 was shown, but not a statistically significant improvement when compared with cRGD-GNP group. Therapeutic effect of radionuclide may be heavily enhanced if a more effective radionuclide, such as I-131, was chosen. On the other hand, based on the point of view that ‘exposure of tumors to irradiation causes transient upregulation of αvβ3 on tumor blood vessel endothelium’ [38,39], cRGD targeting may be enhanced by upregulation of αvβ3 resulting from the introduction of iodine-125 . So, radionuclide plays roles as a radiotracer, a therapeutic factor, as well as a contributing factor for targeting.
In this research, I-125-labeled cRGD-GNPs were successfully synthesized for targeting tumor tissues. Tumor uptake of cRGD-GNPs reached the peak T/NT value at 2 h post injection. For therapeutic effect, 125I-cRGD-GNPs were of a high radiotherapy efficiency due to the radiosensitive property of gold nanoparticles, as well as the introduction of αvβ3-targeted molecule and radionuclide. This study demonstrated that 50-μg GNPs every gram body weight in combination with 5-Gy γ ray radiotherapy at 4 h post injection resulted in effective suppression of tumor growth. These results have important implications in developing radionuclide-labeled radiosensitizer for enhanced radiotherapy.
The authors would like to thank Mr. Li for the guidance of synthesis of radiopharmaceuticals. We would also like to thank the department for the financial support and our colleagues for the technical support.
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