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Evaluation of superparamagnetic iron oxide-polymer composite microcapsules for magnetic resonance-guided high-intensity focused ultrasound cancer surgery
© Sun et al.; licensee BioMed Central Ltd. 2014
Received: 11 April 2014
Accepted: 24 October 2014
Published: 3 November 2014
Superparamagnetic poly (lactic-co-glycolic acid) (PLGA)-coated Fe3O4 microcapsules are receiving increased attention as potential diagnostic and therapeutic modalities in the field of oncology. In this study, PLGA-coated Fe3O4 microcapsules were combined with a magnetic resonance imaging-guided high-intensity focused ultrasound (MR-guided HIFU) platform, with the objective of investigating the effects of these composite microcapsules regarding MR-guided HIFU liver cancer surgery in vivo.
PLGA-coated Fe3O4 microcapsules consisting of a liquid core and a PLGA-Fe3O4 shell were fabricated using a modified double emulsion evaporation method. Their acute biosafety was confirmed in vitro using MDA cells and in vivo using rabbits. To perform MR-guided HIFU surgery, the microcapsules were intravenously injected into a rabbit liver tumor model before MR-guided HIFU. T2-weighted images and MR signal intensity in normal liver parenchyma and tumor tissue were acquired before and after injection, to assess the MR imaging ability of the microcapsules. After MR-guided HIFU ablation tissue temperature mapping, the coagulative volume and histopathology of the tumor tissue were analyzed to investigate the ablation effects of MR-guided HIFUs.
Scanning and transmission electron microscopy showed that the microcapsules displayed a spherical morphology and a shell-core structure (mean diameter, 587 nm). The hysteresis curve displayed the typical superparamagnetic properties of the microcapsules, which are critical to their application in MR-guided HIFU surgery. In MR-guided HIFU surgery, these microcapsules functioned as an MRI contrast agent, induced significant hyperthermal enhancement (P < 0.05) and significantly enhanced the volume of coagulative necrosis (P < 0.05).
The administration of PLGA-coated Fe3O4 microcapsules is a potentially synergistic technique regarding the enhancement of MR-guided HIFU cancer surgery.
The clinical application of ultrasound is no longer limited to diagnosis. High-intensity focused ultrasound (HIFU) is a newly developed technique that applies ultrasonic energy to a focused region for the hyperthermal treatment of solid tumors [1, 2]. Compared with conventional surgical, chemotherapeutic and radiotherapeutic approaches, HIFU is a logical and attractive treatment modality that can selectively and non-invasively destroy multiple foci of origin [3, 4]. Moreover, HIFU provides additional therapeutic options in cases where conventional therapies have failed [5–7].
HIFU performance critically relies on imaging quality for an accurate determination of tumor location to facilitate the optimal deposition of ultrasonic energy in the tumor. The integration of magnetic resonance imaging (MRI) and HIFU forms an MR-guided HIFU system that offers superior soft tissue MRI resolution combined with non-invasive real-time tissue temperature mapping (T-Map) capabilities [8–10]. Consequently, MR-guided HIFU is being increasingly used in the clinic [11–14]. Despite its growing clinical acceptance, MR-guided HIFU has two key limitations. First, MRI as used in MR-guided HIFU can fail to visualize small early stage or MRI-insensitive tumors [15–17]. Second, the ultrasonic energy emitted by the MR-guided HIFU transducer is considerably attenuated when shifting from an in vitro environment to in vivo tissue; this attenuation adversely affects MR-guided HIFU ablation efficiency because the ability of HIFU to successfully ablate tumors depends on its capacity to deposit energy in tissue [18–21]. Therefore, limitations in tumor visualization and in vivo energy deposition adversely affect the treatment efficacy of MR-guided HIFU.
Superparamagnetic iron-oxide nanoparticles (SPIONs) possess unique magnetic properties that make them attractive advanced biomaterial candidates [22–25]. In cancer diagnosis and therapy, SPIONs can serve as MRI contrast agents [26, 27], miniaturized heaters capable of destroying malignant cells and colloidal carriers for targeted drug delivery [28–30]. Since SPION-enhanced MR imaging can be used to monitor the tumor prior to ablation therapy, SPIONs are particularly suitable for MR-guided HIFU applications. Moreover, as a functional medium, SPIONs can also change the acoustic tissue microenvironment in the targeted region, thereby enhancing the tumor-ablative effects of MR-guided HIFUs.
The objective of the present study was to combine the merits of SPIONs and polymers by constructing a composite particle, namely the superparamagnetic poly (lactic-co-glycolic acid) (PLGA)-coated Fe3O4 microcapsule. We investigated the in vitro properties of these superparamagnetic PLGA-coated Fe3O4 microcapsules and the in vivo application of these microcapsules in MR-guided HIFU liver cancer surgery using a rabbit model.
Synthesis of PLGA-coated Fe3O4microcapsules
Preparation and storage of the microcapsules were performed in the dark. Briefly, a 200-ml solution (3.1% w/v) of nano-sized Fe3O4 particles (31 mg/ml; size, 10 nm; Ocean NanoTech, USA) was added to 2 ml of CH3Cl dissolved in 100 mg of PLGA (50:50; MW = 20000; Daigang, China). For cell incubation, the fluorescent dye DiI was incorporated into the composite microcapsules. The above mixture was emulsified (Sonics & Materials Inc., USA) for 45 s. After adding 200 ml of deionized water, the solution was homogenized (FJ300-SH, Shanghai, China) for 5 min with a 10-ml poly(vinyl alcohol) (PVA; MW = 25000; Sigma) solution (5% w/v). Then, the CH3Cl solution was removed by mechanical mixing for 2 h. The mixture was subsequently centrifuged at 800 rpm for 10 min. After centrifugation, the precipitate containing large microcapsules was discarded, and the functionalized PLGA-coated Fe3O4 microcapsules were generated by a second centrifugation of the remaining microcapsule suspension at 5000 rpm for 5 min. In addition, pure PLGA microcapsules were prepared without the addition of Fe3O4 particles and used as a control agent.
Characterizing PLGA-coated Fe3O4microcapsules
The average size of the PLGA-coated Fe3O4 microcapsules was characterized using the Laser Particle Size Analyzer System (Zeta SIZER 3000HS: Malvern, PA, USA). The morphological and structural characteristics of the microcapsules were estimated using scanning electron microscopy (SEM) (S-3400 N: Hitachi, Japan) and transmission electron microscopy (TEM) (H-7500: Hitachi, Japan). DiI-labeled PLGA microcapsules were observed using inverted fluorescence microscopy (Olympus IX71: Canada). The magnetic properties of the microcapsules were investigated using the Physical Property Measurement System (PPMS, Model 6000: Quantum Design).
MDA cell culture and PLGA-coated Fe3O4microcapsule uptake by MDA cells
MDA cells obtained from the American Type Culture Collection (ATCC, USA) were cultured in RPMI-1640 medium supplemented with 10% FBS (both from Hycline) at 37°C with 5% CO2 in a humidified atmosphere and passaged every 2–3 days. DiI-labeled PLGA-coated Fe3O4 microcapsules were irradiated using a Co60 gamma ray source for sterilization prior to incubation with MDA cells.
MDA cells (2 × 105 per well) were placed on six-well tissue-culture clusters 24 h before incubation with PLGA-coated Fe3O4 microcapsules. Immediately before initiating incubation, the medium was removed from each well and the cells were washed three times with PBS. They were then incubated with the DiI-labeled PLGA-coated Fe3O4 microcapsules as described below. The microcapsules were diluted to a final Fe3O4 concentration of 0.15 mg/ml with culture medium and subsequently added to each well. Cells in culture medium without agents were used as the control group. The cells with PLGA-coated Fe3O4 were individually cultured for 4, 12 and 24 h, while the control group was cultured for 24 h. Thereafter, the medium was removed from each well, and the cells were washed three times with PBS and fixed in 10% formalin solution for 10 min. The cells were then stained using FITC for 45 min and Hoechst for 30 min before observation under an inverted fluorescence microscope.
Cell viability was determined using the MTT test. MDA cells (1 × 104 per well) were seeded into 96-well plates. After incubation for 24 h, the medium was removed and replaced with fresh culture medium containing PLGA-coated Fe3O4 microcapsules at Fe3O4 concentrations of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/ml. Cells in culture medium without agents were used as the control group. Following 24 h incubation, cell viability was measured by the addition of 20 μl 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT; 5 mg/ml) solution for 4 h. Then, 150 μl of DMSO was added to dissolve the formazan crystals. To assess cell viability, optical density (OD) was measured at 490 nm with an enzyme-linked immunosorbent assay (ELISA) plate reader.
Acute biosafety of PLGA-coated Fe3O4microcapsules
Thirty-six New Zealand white rabbits (weight, 2.0–2.5 kg; age, 2–3 months) were purchased and maintained in the Animal Center of Chongqing Medical University under standard conditions in accordance with the university’s environmental guidelines. All animal experiments were approved by the Animal Ethics Committee of Chongqing Medical University. All animal experiments and procedures were performed under complete anesthesia.
Prior to tumor implantation, 18 rabbits were divided into three groups to determine a safe dosage of PLGA-coated Fe3O4 microcapsules. Each group received a 2-ml injection of a different concentration of PLGA-coated Fe3O4 microcapsules via the ear vein, at Fe3O4 concentrations of 1, 4 and 8 mg/ml. Serum was sampled from the rabbits to detect biochemical indicators of liver, kidney and cardiac function before injection and at 1, 3 and 7 days after injection of the PLGA-coated Fe3O4 microcapsules. These biochemical indicators included alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), blood urea nitrogen (BUN), creatinine (SCr), creatine kinase (CK) and lactate dehydrogenase (LDH).
Animal model and experimental equipment
Rabbits with a VX2 tumor located in the thigh were obtained from the Ultrasound Engineering Institute of Chongqing Medical University (Chongqing Medical University). The liver tumor model was developed according to a previously described method .
The 18 recipient rabbits with detectable liver cancer (21 days after VX2 tumor implantation) underwent MR-guided HIFU treatment using Symphony A Tim 1.5 T MR-guided HIFU tumor ablation equipment (therapeutic transducer focal length, 145 mm; diameter, 220 mm; operating frequency, 0.94 MHz; Chongqing Haifu Technology, Chongqing, China). This system uses a focused ultrasonic transducer that emits high-intensity ultrasonic energy to target and destroy the tissue-of-interest, while the diagnostic MR scanner images the tumor and monitors the targeted tissue temperature during the therapeutic process.
MR-guided HIFU surgery for rabbits bearing the VX2 liver tumor
The 18 recipient rabbits with VX2 liver tumors were placed on the MR-guided HIFU treatment bed in the prone position after being completely anesthetized. Their abdomens were entirely immersed in degassed water. The rabbits were randomly divided into three groups: (i) MR-guided HIFU treatment without microcapsules (group I; n = 6); (ii) MR-guided HIFU treatment with a 2-ml intravenous injection of pure PLGA microcapsules at a PLGA concentration of 50 mg/ml (group II; n = 6); and (iii) MR-guided HIFU treatment with a 2-ml intravenous injection of PLGA-coated Fe3O4 microcapsules at a Fe3O4 concentration of 3.1 mg/ml (group III; n = 6). Prior to MR-guided HIFU ablation, T2-weighted images were acquired before and at 5 min after ear vein injection of pure PLGA microcapsules (group II) and PLGA-coated Fe3O4 microcapsules (group III). No injection of microcapsules was administered to rabbits in group I; thus, in group I, the second image was acquired at 5 min after the acquisition of the first image. Additionally, the MR signal intensity (SI) within the region of interest (including both normal liver parenchyma and liver tumor) was measured before and at 2 and 5 min after injection of the various agents to assess the enhanced MR imaging ability. After MR scanning, MR-guided HIFU ablation was performed using the “ablated-dot” mode, in which each tumor was destroyed in a single exposure. In all three MR-guided HIFU groups (groups I, II and III), MR-guided HIFU ablation parameters were kept constant with a 250-W acoustic power and a 5-s exposure duration. During MR-guided HIFU ablation, T-Map was imaged in the targeted region to investigate the effects of MR-guided HIFU ablation. To acquire T2-weighted images, turbo spin echo (TSE) sequences were run at TR values of 4100 ms (TE, 113 ms; FOV, 300 mm × 300 mm; slice thickness, 4.0 mm).
Animals were sacrificed after MR-guided HIFU ablation, and the livers were immediately removed for macroscopic observation. The tumor along with the surrounding normal liver tissue was sectioned into 2-mm slices, and the maximal section of necrotic tumor tissue was selected for observation of the area of coagulative necrosis. Then, the length, width and depth of the necrotic tissue were compiled from each tissue slice to calculate the volume of coagulative necrosis. The volume of coagulated tissues in the liver tumor was calculated using the following equation: V = π/6 × L × W × D (L, length; W, width; D, depth) . In addition, TEM was performed on the ablated tissue from each tumor to detect ultrastructural changes in the cancerous tissue.
All data are expressed as the mean ± standard deviation. Various groups were compared for differences using one-way analysis of variance (one-way ANOVA). All analyses were performed using SPSS Statistics 19.0. A difference with a P-value of <0.05 was deemed statistically significant.
Results and discussion
Characterization of PLGA-coated Fe3O4microcapsules
According to the microcapsule size distribution (Additional file 1), the mean diameter of the prepared PLGA-coated Fe3O4 microcapsules was 587 ± 60 nm. The characteristic pore cutoff size ranged from 380 to 780 nm and has been demonstrated in a variety of tumors, although some tumors show pore sizes of ≤2 μm [33–35]. In our study, the smallest particles (approximately 10–20% of the total particles) in the distribution could enter the tumor tissue by means of the enhanced permeability and retention (EPR) effect, which allows extravasation of nanoparticles through large inter-endothelial gaps in the effective tumor microvasculature for the induction of the MR signal and HIFU synergistic therapy.
Uptake of PLGA-coated Fe3O4microcapsules by MDA cells
Acute biosafety of PLGA-coated Fe3O4microcapsules
Serum biochemical indicators after the injection of PLGA-coated Fe 3 O 4 microcapsules (1 mg/ml)
64.33 ± 18.34
56.67 ± 15.01
51.00 ± 13.89
54.00 ± 16.09
41.33 ± 1.53
42.33 ± 2.52
40.67 ± 4.16
45.33 ± 2.08
3.47 ± 0.40
3.53 ± 0.15
3.27 ± 0.12
3.20 ± 0.26
7.55 ± 0.38
8.42 ± 0.39
7.81 ± 0.77
7.50 ± 0.62
68.77 ± 7.60
73.70 ± 4.40
62.37 ± 4.10
75.30 ± 9.04
3242.67 ± 71.14
3420.00 ± 172.50
3457.67 ± 132.50
3362.33 ± 116.11
839.67 ± 10.02
850.67 ± 19.86
834.00 ± 18.00
857.00 ± 12.77
Serum biochemical indicators after the injection of PLGA-coated Fe 3 O 4 microcapsules (4 mg/ml)
50.80 ± 14.23
57.17 ± 14.06
63.53 ± 17.35
53.70 ± 15.11
43.33 ± 1.56
41.35 ± 2.46
41.63 ± 3.56
43.83 ± 2.15
3.45 ± 0.39
3.54 ± 0.17
3.29 ± 0.14
3.21 ± 0.33
7.79 ± 0.67
8.45 ± 0.37
7.65 ± 0.48
7.66 ± 0.58
66.57 ± 6.70
72.73 ± 4.37
64.26 ± 4.11
74.80 ± 8.05
3354.39 ± 96.61
3422.00 ± 112.53
3446.62 ± 122.30
3277.65 ± 69.40
841.67 ± 11.02
848.63 ± 17.83
823.14 ± 16.73
856.37 ± 13.42
Serum biochemical indicators after the injection of PLGA-coated Fe 3 O 4 microcapsules (8 mg/ml)
59.23 ± 13.77
56.15 ± 14.55
51.30 ± 13.87
61.23 ± 16.55
42.88 ± 1.45
41.09 ± 1.65
41.64 ± 2.00
43.56 ± 3.15
3.49 ± 0.38
3.48 ± 0.23
3.37 ± 0.34
3.23 ± 0.32
7.58 ± 0.32
8.44 ± 0.43
7.76 ± 0.53
7.59 ± 0.63
69.65 ± 5.74
71.88 ± 4.43
66.30 ± 5.31
75.79 ± 7.98
3280.98 ± 66.33
3445.09 ± 98.71
3453.98 ± 112.27
3325.0 ± 111.20
853.34 ± 10.71
847.72 ± 15.30
838.99 ± 17.90
850.08 ± 16.98
PLGA-coated Fe3O4microcapsules as contrast agents for MR-guided HIFU surgery
PLGA-coated Fe3O4microcapsules show synergy with MR-guided HIFU surgery
We also investigated the properties of PLGA-coated Fe3O4 microcapsules as synergistic agents for MR-guided HIFU liver cancer surgery. Dibaji et al. assessed the utility of using magnetic nanoparticles to enhance heating during HIFU procedures in vitro; their findings demonstrated that the introduction of magnetic nanoparticles could locally increase the temperature . In the present study, PLGA-coated Fe3O4 microcapsules were intravenously administrated via the ear vein into rabbits with VX2 liver tumors. The microcapsules penetrated the liver tumor tissue as a result of the EPR effect and enhanced MR-guided HIFU ablation.
PLGA-coated Fe3O4 microcapsules combine the merits of the unique magnetic properties of SPIONs and the excellent biocompatibility of PLGA particles that make them attractive biomaterial candidates for MR-guided HIFU cancer ablation. These paramagnetic microcapsules exhibited contrast-enhanced imaging capability regarding MR imaging after intravenous injection; they effectively improved the accuracy of MR-guided HIFU liver cancer surgery. In addition, the introduction of PLGA-coated Fe3O4 microcapsules enhanced ultrasonic wave absorption and energy deposition in the targeted tissue, boosting hyperthermia in the targeted tissue and improving thermal ablation using MR-guided HIFU in the focused region. Furthermore, the PLGA-coated Fe3O4 microcapsules exhibited an excellent acute biosafety profile both in vitro and in vivo. However, the size of the superparamagnetic microcapsules used in the current study was slightly larger than those previously used. This was a limitation of our study and should be addressed in future investigations. In short, the administration of PLGA-coated Fe3O4 microcapsules provides an alternative strategy for MR-guided non-invasive HIFU synergistic therapy of cancer.
This work was partly supported by the National Nature Science of China (Grant Numbers 81471713, 81371579, 81401423 and 81161120548), the National Research Program of China (973 Program, Grant Number 2011CB707905) and Chongqing University Innovation Team Plans (KJTD201303). The authors are grateful to Yang Zhou, Ph.D., and Hongxia Shen for their assistance with the animal experiments. We also thank Wei Wu, Yingjiang Liu, Qi Wang and Chongyan Li for their support and technical expertise.
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