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pH-responsive theranostic nanocomposites as synergistically enhancing positive and negative magnetic resonance imaging contrast agents
© The Author(s) 2018
Received: 12 December 2017
Accepted: 13 March 2018
Published: 27 March 2018
The rational design of theranostic nanoprobe to present responsive effect of therapeutic potency and enhanced diagnostic imaging in tumor milieu plays a vital role for efficient personalized cancer therapy and other biomedical applications. We aimed to afford a potential strategy to pose both T1- and T2-weighted MRI functions, and thereby realizing imaging guided drug delivery and targeted therapy.
Theranostic nanocomposites Mn-porphyrin&Fe3O4@SiO2@PAA-cRGD were fabricated and characterized, and the nanocomposites were effectively used in T1- and T2-weighted MRI and pH-responsive drug release. Fluorescent imaging also showed that the nanocomposites specifically accumulated in lung cancer cells by a receptor-mediated process, and were nontoxic to normal cells. The r2/r1 ratio was 20.6 in neutral pH 7.4, which decreased to 7.7 in acidic pH 5.0, suggesting the NCs could act as an ideal T1/T2 dual-mode contrast agent at acidic environments of tumor. For in vivo MRI, T1 and T2 relaxation was significantly accelerated to 55 and 37%, respectively, in the tumor after i.v. injection of nanocomposites.
The magnetic resonance imaging (MRI) technique has been introduced to clinic to provide multiplanar imaging for the soft tissues in the body without invasion. Because of its superb soft tissues imaging contrast, multidimensional imaging function, and absent of ionizing radiation, MRI is becoming increasingly available for clinical imaging . In 2016, there were about 39 million diagnostic MRI procedures carried out in the United States, which presents an average annual growth rate of around 4% during the past 5 years .
Globally, contrast agents (CAs) are widely employed in the MRI, for which over 200 million doses had been administered . The most frequently used reagents for contrast enhancement are gadolinium-based, such MRI contrast agents are representative T1 contrast agents that can effectively curtailing the T1 relaxation time of protons inside tissues by interactions with the neighboring contrast agent . All clinically approved Gd-CAs are small molecules. For the reduction of toxicity, Gd3+ ions are usually chelated using DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DTPA (diethylene triamine pentaacetic acid) molecules . Large amounts of Gd3+ ion chelates are injected during the clinical MRI procedure to yield millimolar concentrations required for the detection. On the other hand, nano-based CAs can be manufactured in small enough sizes to reach remote regions while simultaneously enabling surface functionalization that yields good biocompatibility, specific targeting, prolonged blood circulation time, and improved imaging effect as well as therapeutic efficacy [6–10].
Compared to traditional contrast agent, dual-mode T1/T2 MRI contrast agent can provide more accurate and detailed information associated with disease than single mode MRI contrast agent [11–20]. The dual-mode T1/T2 MRI contrast agent has gained much attention, since it can give more precise and reliable diagnostic information by the enhanced contrast effects in both T1 imaging with high tissue resolution and T2 imaging with high feasibility on detection of a lesion . Further, different from other multimodal imaging technologies (e.g., MR/optical, MR/PET) [21–23], dual-mode T1/T2 MRI can provide simultaneously imaging by adopting a single instrumental system, which could avoid the differences in penetration depths and spatial/time resolutions from multiple imaging devices .
However, the realization of dual-mode T1/T2 contrast agents has been challenging . When combining the T1 and T2 CAs together, the strong magnetic coupling between them could perturb the relaxation effect of the paramagnetic T1 contrast agent, resulting in undesirable quenching of magnetic resonance signal . To circumvent this problem, we have rationally constructed dual-mode T1/T2 CAs with releasable T1 contrast materials in the weak acidic tumor microenvironments. Therefore, the distance between T1 and T2 contrast materials could be increased after responsive releasing of T1 contrast materials to avoid the disturbance between them. As for the microenvironment in malignance, it is distinctly different from the normal tissues for several dimensions, which owes to the alterations in the metabolism of therioma . The accumulation of lactic acid and H+, which is related to the upregulated anaerobic glycolysis in tumorigenesis and the excessive transport of hydrogen ions from tumor cells to the outside, leads to the declined extracellular pH values and the acidic microenvironment in tumor tissue. The variation in the pH has been proved to be able to serve as an effective design for cancer diagnosis and treatment by many previous researches [26–29].
Poly(acrylic acid) (PAA, Mw = 2000), N-hydroxysuccinimide (NHS), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) were obtained from Aladdin. Tetraethyl orthosilicate (TEOS) and Igepal CO-520 were purchased from Sigma-Aldrich. 4-dimethylaminopyridine (DMAP), manganese (II) acetate, N-cetyltrimethylammonium chloride (CTAC) and triethanolamine (TEA) were purchased from Sinopharm Chemical Reagent Co., Ltd. c(RGDyK) peptides (cRGD) was purchased from GL Bioche. All other reagents were analytical grade and used without further purification.
1H and 13C NMR spectra for compounds were obtained in DMSO-d 6 , using a Bruker AMX-500 NMR spectrometer. Transmission electron microscopy (TEM) images were obtained on a HITACHI H-7000 FA transmission electron microscope. High-resolution mass spectrometry (HR MS–ESI) spectra were recorded on a Bruker micro TOF-Q instrument. The magnetic properties were measured at 300 K with a vibrating sample magnetometer (SQUID-VSM, Quantum Design, American). In vitro fluorescence images of cells were recorded on a confocal laser scanning microscope (CLSM, Nikon, Japan). The surface areas were measured by an ASAP-2020 physisorption apparatus (Micromeritics, American). The UV–Vis absorption spectra were determined by an Evolution 220 spectrophotometer (Thermofisher Scientific). The size distributions and zeta potentials were measured by a Malvern Zetasizer 90. The metal contents in cells and tissues were tested by ICP-MS (FLEXAR NEXLON300X).
Preparation of Mn-porphyrin&Fe3O4@SiO2@PAA-cRGD (Mn-IOSP)
Fe3O4 NPs were prepared by a thermal decomposition reaction with ferric oleate complex as precursor, oleic acid as reductant, and trioctylamine as solvent at a reaction temperature of 340 °C . 1.8 g of ferric oleate and 0.624 g of oleic acid were dissolved in the trioctylamine (10 mL). The mixture was heated gradually from room temperature to 340 °C and kept in this temperature for 1 h in N2 atmosphere. Fe3O4@nSiO2 was synthesized through a typical water-in-oil microemulsion method by using nonionic surfactant Igepal CO-520 . For the synthesis of Fe3O4@nSiO2@mSiO2 , Fe3O4@nSiO2 was added into aqueous solution containing CTAC and TEA and stirred to be well-mixed, then TEOS was added into the solution and the hydrolysis reaction was carried out. After the reaction, the nanoparticles were purified by repeated washing and reprecipitation. For preparation of Fe3O4@SiO2@PAA-cRGD, we first synthesized PAA-cRGD. Then the Fe3O4@SiO2@PAA-cRGD NPs were synthesized from the change of the interfacial energy between PAA, Fe3O4@SiO2 NPs and the solvent . Detailed experimental steps were presented in Additional file 1: S1.
The manganese porphyrin compounds 1 (Mn-porphyrin) was synthesized following the reported literature with some modifications . Tetrakis (4-carboxyphenyl) porphyrin (TCPP, 94 mg) was mixed with EDCI (143 mg) and NHS (90 mg) in DMF and then stirred under nitrogen. After 1 h, a DMF solution containing N-boc ethylenediamine (151 mg) and DMAP (118 mg) was added into the mixture above-mentioned and continued for 1-day stir. The mixture was dealt with 100 mL brine before filtering. The N-Boc protected porphyrin (5, 10, 15, 20-tetrakis 2-[(4-tert-butyl benzamido)] ethyl carbamate] porphyrin) was separated with impurities through column chromatography using a mobile phase of DCM: methanol 90:10. The product was mixed with excess manganese acetate in methanol and reacted at 70 °C for 12 h with stirring. The N-Boc protected Mn-BOC-porphyrin (manganese 5, 10, 15, 20-tetrakis 2-[(4-tert-butyl benzamido) ethyl carbamate] porphyrin) was also purified through column chromatography using a mobile phase of DCM:methanol 90:10. Then the N-Boc protected Mn-BOC-porphyrin (30 mg) was added into CH2Cl2 with stirring for 30 min under 0 °C. HCl (4 M, 0.5 mL in dioxin) was dripped into the mixture before a 12-h stir, and the solution kept 0 °C for the duration of dripping. Then the reaction product was poured into diethyl ether and filtered. The precipitate was washed by some diethyl ether before collecting. The 1H NMR, 13C NMR, MS, UV spectra and structures for porphyrin-compounds were showed in Additional file 1: S2, including the Figs. S1–S11.
For the preparation of Mn-IOSP, 5 mg of Fe3O4@SiO2@PAA NPs were dissolved in a mixed solution containing 5 mL water and 45 mL isopropanol. Mn-porphyrin aqueous solution (1 mL, 10 mg/mL) was mixed into the solution before being shaken for 24 h. Finally, the desired Mn-IOSPs were gained through centrifugation separation and purification with PBS buffer.
In vitro cytotoxicity test
The A549 non-small-cell lung cancer cells were seeded into 96-well plates for 5000 cells/well before 1-day culture. For the following 4-h incubation, the medium was changed to RPMI-1640 mediums dispersing Fe3O4@SiO2@PAA NCs, Mn-IOSP NCs or DOX loaded NCs with pre-established concentrations, respectively. The NCs solution was then sucked out and unabsorbed NCs were removed by rinsing with fresh PBS twice. For an additional 44-h culture, 100 μL of medium without NCs was added into every plate. The cell viabilities were tested by MTT assays with a plate reader (Molecular Devices, USA). The cell viabilities were calculated basing on the ratio of absorbance value of treatment group to that of control group. Detailed cell culture process was showed in Additional file 1: S3.
In vivo MRI
Transplantation tumor models of non-small-cell lung cancer were established on the 4- to 5-week-old BALB/c male nude mice through subcutaneous injection of A549 cells. The mice were reared for another 2 weeks after subcutaneous injection of 1 × 107 A549 cells per mouse in hind leg. T1- and T2-weighted MR images were performed on a 7.0 T animal MRI scanner (Bruker BioSpec 70/20 USR). Mn-IOSP NCs were intravenous injected into mice, and images were acquired both before and after injection. Specific parameters for images were showed in Additional file 1: S4.
In vitro MR contrast properties
A549 cells were used for validating the in vitro MRI capacity of the Mn-IOSP NCs. After 1-h incubation with the indicated concentrations of Mn-IOSP NCs, the NCs solution was then sucked out and unabsorbed NCs were removed by rinsing with fresh PBS. Then the cells were digested and then collected with 500 μL PBS. T1- and T2-weighted MR images were performed on a 9.4 T NMR spectrometer (Bruker Avance 400, Ettlingen, Germany) equipped with microimaging gradient coils. Specific parameters were showed in Additional file 1: S4.
To measure the longitudinal (r1) and transverse (r2) relaxation parameters of Mn-IOSP NCs, different concentration points of Mn-IOSP NCs were dispersed in different buffer solutions (pH 7.4, 6.5, 5.0). T1- and T2- relaxation times of the solutions were tested by the 7.0 T animal MRI scanner using the same sequences as in vivo MRI after 1-day incubation at 37 °C.
Results and discussion
Fabrication and characterization
In vitro fluorescence and UV–Vis analysis
The capacity of nanoparticles for loading drug and Mn-porphyrin has been evaluated. The loading efficiency and releasing rate of modal drug doxorubicin hydrochloride (DOX) for Fe3O4@SiO2@PAA-cRGD NPs was evaluated by fluorescence spectrophotometer at different time points emission at 590 nm and excitation at 495 nm. AAS and UV spectra were used for the quantification of Mn-porphyrin in the NCs. Detailed drug loading and release procedures were showed in Additional file 1: S6. After the loading process of the Mn-porphyrin and DOX with the nanoparticles, the desired NCs were gained through centrifugation separation and the concentrations of Mn-porphyrin and DOX in supernatant were determined. The loading efficiency of DOX could be up to 90% without adding Mn-porphyrin. The excellent efficiency was benefited from the synergistic loading function of both PAA-cRGD and mSiO2 shells. The loading efficiency of Mn-porphyrin in Mn-IOSP NCs calculated from UV spectra was 75%, which was approximately in accordance with the metal content ratio tested by AAS (7.4/1 for iron/manganese). The structure of Mn-porphyrin has 4 amino groups and would be easy to be positively charged in the pH from 5.0 to 7.4. The strong electrostatic attraction existed between the negatively charged PAA and silica pores and the Mn-porphyrin molecules. The possible interaction of π–π stacking between the Mn-porphyrin molecules and hydrogen bonds would make it also easy to exist in the PAA shells and silica channels. When Mn-porphyrin was added into the solution simultaneously with DOX, the loading efficiency changed to 57% for DOX and 52% for Mn-porphyrin. The loading efficiencies of both DOX and Mn-porphyrin decreased when Mn-porphyrin and DOX was added into the solution simultaneously, which indicated the competition between Mn-porphyrin and DOX in loading process for the similar mechanism in the loading process.
The confocal fluorescence imaging was also employed to analyse the NCs (Fig. 3c). In the A549 cells which were incubated with DOX&Mn-IOSP NCs, strong red fluorescence was displayed in the cytoplasm and strong blue fluorescence was obtained in the nucleus. The blue fluorescence occurred by staining with DAPI and excited with a 405 nm laser, and the red fluorescence excited with a 488 nm laser from DOX indicates the successful entrance into the cell and the release of the DOX of the DOX&Mn-IOSP NCs. To validate the red fluorescence in the cell was caused from the entrance of NPs rather than only the DOX previously released, A549 cells was incubated with free DOX and both red and blue fluorescence was displayed in the nucleus, which was different from cells incubated with NPs, declaring the two different ways for the DOX coming into cells.
Tumor targeting ability of the Mn-IOSP NCs was investigated by CLSM following the incubation of A549 cells and WI38 cells with the DOX&Mn-IOSP NCs. The red fluorescence (attributed to DOX) in A549 cells incubated with DOX&Mn-IOSP NCs was distinguishably higher than that of NCs without modified with c(RGDyK), and the fluorescence intensity in A549 cells was obviously higher compared with that in non targeted WI38 cells under same incubation condition (Fig. 3c), which verified the specific targeting ability of NCs. DOX fluorescence was observed mostly in the cytoplasm instead of the cell nuclei, suggesting that DOX-loaded NCs were internalized and release DOX into the cytoplasm after uptake by A549 cells.
For further demonstration of the T1 and T2-effect and cellular uptake of the Mn-IOSP NCs, in vitro T1-weighted and T2-weighted MR images of A549 cells were observed after incubated with NCs for 1 h. Quantitative analysis of Fe and Mn in the incubated cells has also been carried out by ICP-MS to help to quantify the cell uptake. The contents of metal in cells after incubation with NCs modified with PAA-cRGD or PAA were analyzed by ICP-MS. The concentrations of both manganese and iron were higher in the cells incubated with the NCs modified with c(RGDyK) than the NCs without c(RGDyK) (Fig. 4b). In addition, the higher of the NCs concentration incubated with cells, the higher the signal intensities of manganese and iron were tested by ICP-MS (Fig. 4c). The results were consilient with the experiments of in vitro cell MRI. As shown in Fig. 4d, the T1 and T2-weighted MRI contrast effect correlated with the concentration of the Mn-IOSP NCs. The Mn-IOSP NCs displayed an enhancement in the T1-weighted MR signal, and a reduction in T2-weighted MR signal with the increasing Mn concentration. This confirmed that the Mn-IOSP NCs could be utilized as efficient T1 and T2 dual-mode contrast agents for A549 tumor cells.
To further validate the ability of Mn-IOSP NCs as T1/T2 dual-mode MRI agents, we conducted the in vivo MRI of mice which transplanted subcutaneous A549 tumor before and after injecting the Mn-IOSP NCs (200 μL, [Mn] = 2 mM) via the tail vein. As shown in Fig. 4e, the T1 and T2 relaxation time in mice-transplanted tumor areas was obviously fasted after injection of Mn-IOSP NCs, and T1-weighted signal was enhanced whereas T2-weighted signal was reduced. Compared to the images without injection of NCs, the most powerful acceleration in tumor signal for T1 was 55%, and for T2 was 37%, both after 3 h injection of the NCs. T1-weighted images took on brighter effects in the region of A549 tumor after injection, whereas darker effects were exhibited in T2-weighted images. In addition, after 12 h injection, the signal intensity recovered to some extent. The biodistributions of NPs were evaluated in A549 tumor-bearing mice after 3 h intravenous injection of Mn-IOSP NCs (details in Additional file 1: S7). Both manganese and iron showed significant tumor accumulation (Additional file 1: Fig. S17), which were consistent with the MR images. The Mn-IOSP NCs with appropriate residence time and controlled release performance show the remarkable potential for in vivo MRI for tumor. The accumulation of Mn-IOSP NCs in tumor might realize through the EPR effect and the targeting effect of c(RGDyK).
These evidences showed that the synthesized Mn-IOSP NCs exhibited highly sensitive MRI contrast function no matter in solution, cells or in vivo, and comprehensive analysis from the information of both T1/T2 imaging could be conducted, which to some extent breaks the restrictions of ordinary one-mode contrast agents.
Hematoxylin and Eosin (H&E) staining method was used to assess the toxicity of the developed Mn-IOSP NCs in vivo. Mice treated with Mn-IOSP NCs or PBS (as control) were sacrificed post 48 h i.v. injection. Apparently, we can see from Fig. 5b, no obvious damage or abnormalities can be seen in the major tissue sections such as heart, liver, spleen, lung, and kidney after 48 h i.v. injection of the NCs, which suggests that the Mn-IOSP NCs have good organ compatibility.
In conclusion, we have developed a multifunctional nanocomposite of Mn-porphyrin&Fe3O4@SiO2@PAA-cRGD for dual-modal bioimaging and drug-loading capacity as a result of our studies. Compared to previous multifunctional contrast agents, the proposed nanocomposite integrates the advantages of synergistically enhancing positive and negative magnetic resonance imaging signals, no matter in solution, cells or in vivo. The r2/r1 ratio was 20.6 in neutral pH 7.4, which decreased to 7.7 in acidic pH 5.0, suggesting the NCs could act as an ideal T1/T2 dual-mode contrast agent at acidic environments of tumor. Conjugation with RGD enables the functional imaging probe for high A549 cellular uptake and targeted tumor imaging in vivo. The findings of this study illustrate that Mn-porphyrin&Fe3O4@SiO2@PAA-cRGD is a potentially useful tool for multimodal molecular imaging of cancer cells as well as a drug delivery platform for therapeutic agents.
XH, SC and XZ designed the experiments. XH and LL conducted the preparation and characterization. YY, WR and XH performed the relaxivity measurements and data analysis. XH performed the toxicity and fluorescence analysis. XH and SC wrote the paper. XZ and ML contributed reagents, materials and analysis tools. All authors read and approved the final manuscript.
X. Zhou thanks the National Program for Special Support of Eminent Professionals (National Program for Support of Top-notch Young Professionals).
The authors declare that they have no competing interests.
Availability of data and materials
All data supporting this study are included in this published article and its additional information files. All mouse experimental procedures were performed in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals approved by the State Council of People’s Republic of China.
Consent for publication
All authors agree to publish this manuscript.
Ethics approval and consent to participate
All mouse experimental procedures were performed in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals approved by the State Council of People’s Republic of China.
This work was supported by the National Natural Science Foundation of China (21575157, 81227902 and 81625011), and Key Research Program of Frontier Sciences, CAS, Grant NoQYZDY-SSW-SLH018.
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