Construction of Hybrid Alginate Nanogels Loaded with Manganese

Jan 5, 2018 - Development of sensitive contrast agents for positive magnetic resonance (MR) imaging of biosystems still remains a great challenge. Her...
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Letter Cite This: ACS Macro Lett. 2018, 7, 137−142

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Construction of Hybrid Alginate Nanogels Loaded with Manganese Oxide Nanoparticles for Enhanced Tumor Magnetic Resonance Imaging Wenjie Sun,†,∥ Jiulong Zhang,‡,∥ Changchang Zhang,†,∥ Peng Wang,† Chen Peng,*,‡ Mingwu Shen,*,† and Xiangyang Shi*,†,§ †

State Key Laboratory for Modification of Chemical Fiber and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People’s Republic of China ‡ Department of Radiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China § CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal S Supporting Information *

ABSTRACT: Development of sensitive contrast agents for positive magnetic resonance (MR) imaging of biosystems still remains a great challenge. Herein, we report a facile process to construct hybrid alginate (AG) nanogels (NGs) loaded with manganese oxide (Mn3O4) nanoparticles (NPs) for enhanced tumor MR imaging. The obtained AG/PEI-Mn3O4 NGs with a mean size of 141.6 nm display excellent colloidal stability in aqueous solution and good cytocompatibility in the studied concentration range. Moreover, the hybrid NGs have a high r1 relaxivity of 26.12 mM−1 s−1, which is about 19.5 times higher than that of PEI-Mn3O4 NPs with PEI surface amine acetylated (PEI.Ac−Mn3O4 NPs). Furthermore, the AG/PEI-Mn3O4 NGs presented longer blood circulation time and better tumor MR imaging performances in vivo than PEI.Ac−Mn3O4 NPs. With the good biosafety confirmed by histological examinations, the developed AG/PEI-Mn3O4 NGs may be potentially used as an efficient contrast agent for enhanced MR imaging of different biosystems.

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of mere cytotoxicity is one of the important parameters of MR contrast agents used for in vivo applications.2 In our previous work, a simple method was reported to synthesize polyethylenimine (PEI)-coated Mn3O4 NPs with good water dispersibility and biocompatibility for T1-weighted tumor MR imaging.18 However, the r1 relaxivity of the Mn3O4 NPs (0.56−0.59 mM−1 s−1) is much lower than that of clinical Gd complexes (3.5−4.5 mM−1 s−1).2 Therefore, it still remains a challenge to prepare manganese oxide-based contrast agents having a high r1 relaxivity for enhanced T1-weighted MR imaging applications. Nanogels (NGs), physically or chemically cross-linked colloidal polymer networks, are hydrogels having a size in nanoscale and having combined properties of both NPs and bulk hydrogels.19,20 Their attractive properties such as good water-retaining property and quick responses to external stimuli such as ions, pH, and temperature can be endowed during the synthesis process by varying the monomers, cross-linkers, and initiators. These properties afford their uses in a wide variety of

agnetic resonance (MR) imaging is one of the efficient molecular imaging techniques for the diagnosis of diseases in clinic practices.1,2 It can noninvasively visualize and provide excellent anatomical information on soft tissues with high spatial resolution.3 MR contrast agents used could be divided into two types including T1 positive and T2 negative contrast agents.4,5 Due to the difficulty in distinguishing hypointense pathogenic conditions, the development of T2 negative contrast agents based on superparamagnetic iron oxide nanoparticles (SPIO NPs) has been limited.5−7 The commonly used T1 positive contrast agents are gadolinium (Gd) complexes with small molecular weights. However, the small molecular Gd complexes could be rapidly excreted through the renal route with a short half-life.2 Moreover, the uses of Gd complexes are quite restricted due to their toxicity at higher doses and the possible occurrence of nephrogenic systemic fibrosis (NSF) in the patients with renal malfunctions.8,9 Therefore, many researchers have attempted to develop macromolecular Gd complexes10,11 and inorganic NPs as T1 positive contrast agents, such as manganese oxide (MnO or Mn3O4)12−14 and gadolinium oxide NPs15,16 that can be modified with different polymers to overcome the drawback of short blood circulation time.2,17 Additionally, biosafety instead © XXXX American Chemical Society

Received: December 23, 2017 Accepted: January 2, 2018

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DOI: 10.1021/acsmacrolett.7b00999 ACS Macro Lett. 2018, 7, 137−142

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ACS Macro Letters Scheme 1. Schematic Illustration of the Preparation of PEI-Mn3O4 NPs (a) and AG/PEI-Mn3O4 NGs (b)

Figure 1. TEM image (a) and size distribution histogram (b) of AG/PEI-Mn3O4 NGs; hydrodynamic size (c) of the AG/PEI-Mn3O4 NGs in aqueous solution at various storage time periods; the TGA curves (d) of the PEI-Mn3O4 NPs and AG/PEI-Mn3O4 NGs.

biomedical fields,21 in particular molecular imaging.22−24 For instance, Yuan et al.25 reported the design of polyethylene glycol (PEG)-grafted poly(maleic anhydride-alt-1-octadecene) (PMAO-g-PEG) NGs encapsulated with Gd2O3 NPs for T1weighted MR imaging. The formed Gd2O3-loaded PMAO-gPEG NGs displayed a higher r1 value (7.9 mM−1 s−1) than that of Gd2O3 NPs (1.5 mM−1 s−1). Poly(N-vinylcaprolactam) NGs loaded with Gd complexes displayed a higher r1 relaxivity and better in vivo MR imaging performance than the clinical Gd chelates.10 Alginate (AG) NGs immobilized with SPIO NPs exhibited an increased r2 relaxivity of 170.9 mM−1 s−1 compared to the individual SPIO NPs (137.1 mM−1 s−1).26 These studies highlight the importance of using NGs as a carrier to load contrast agents for enhanced MR imaging.

In this current study, we proposed to develop a convenient polymer NG-based approach to load Mn3O4 NPs within AG NGs for enhanced MR imaging of tumors. PEI-modified Mn3O4 NPs (PEI-Mn3O4 NPs) were first synthesized according to our previous work.18 The PEI-Mn3O4 NPs were then used as a cross-linker to cross-link AG NGs with AG carboxyl groups activated by 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) preformed via a double emulsion process. The thus formed AG/ PEI-Mn3O4 NGs were systematically characterized in terms of the morphology, size, composition, structure, colloidal stability, T1 MR relaxometry, and cytocompatibility. Moreover, the performances of the AG/PEI-Mn3O4 NGs for MR imaging of cancer cells in vitro and a xenografted tumor model in vivo after 138

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Figure 2. T1-weighted MR images (a) and linear fitting of 1/T1 (b) of the AG/PEI-Mn3O4 NGs at various Mn concentrations; T1-weighted MR images (c, d) and MR SNR (e) of U87MG cells treated with PEI.Ac−Mn3O4 NPs (c) and AG/PEI-Mn3O4 NGs (d) at various Mn concentrations for 4 h, respectively.

Meanwhile, the AG/PEI-Mn3O4 NGs with a smaller mass ratio (1:2 or 1:3) display a smaller size than that of NGs formed with a larger mass ratio (1:0.5 or 1:1). This means that at a higher cross-linking density (smaller mass ratio of AG/PEIMn3O4) a more tightened gel structure can be formed. Additionally, Figure S1 (Supporting Information) shows the hydrodynamic size distributions of NGs with different compositions, demonstrating that NGs with smaller AG/PEIMn3O4 NP mass ratios have a relatively narrow size distribution. Taking into consideration the above analysis, hybrid NGs with a AG/PEI-Mn3O4 NP mass ratio of 1:3 were chosen for further characterization and the following MR imaging applications. Transmission electron microscopy (TEM) was employed to observe the morphology of the hybrid NGs. As shown in Figure 1a, the synthesized AG/PEI-Mn3O4 NGs display a typical spherical shape with a mean size of 141.6 ± 34.0 nm (Figure 1b). It should be noted that it is hard to see the Mn3O4 NPs within the NGs. This is likely due to the fact that the content of inorganic Mn3O4 NPs within the AG/PEI-Mn3O4 NGs is very low (18.28%) based on the thermal gravimetric analysis (TGA) data (see below) and the used low accelerating voltage (120 kV). Since the cross-linking reaction between the AG carboxyl groups and the PEI amines could occur in the interior water phase of the NGs, the PEI-Mn3O4 NPs should be located within the interior of the NGs. To assess the colloidal stability

intravenous injection to highlight tumor sites were assessed. To the best of our knowledge, there are no previous reports related to the use of AG NGs loaded with manganese oxide NPs for enhanced tumor T1 MR imaging. AG, a kind of natural occurring polysaccharide, possessing good biocompatibility and biodegradability has been widely used in a variety of biomedical fields.27,28 Here we used AG NGs to load Mn3O4 NPs for MR imaging applications due to the advantages of NGs that have good fluidity, softness, and enhanced cellular uptake and tumor penetration ability.10,22,24,26 Prior to the synthesis of the AG/PEI-Mn3O4 NGs, PEIMn3O4 NPs were prepared and characterized (Scheme 1a) according to protocols reported in our previous work (Table S1, Figures S1−S4, Supporting Information).18 The carboxyl groups of AG were activated by EDC/NHS, and the AG NGs were formed by a double emulsion process.24,26 Finally, the AG/PEI-Mn3O4 NGs were formed through the chemical crosslinking between surface amine groups of PEI-Mn3O4 NPs and the activated carboxyl groups of AG, which occurred at the first water phase (Scheme 1b). In order to optimize the formation of AG/PEI-Mn3O4 NGs, different mass ratios of AG/PEI-Mn3O4 NPs were set during the synthesis process. As shown in Table S1 (Supporting Information), all the AG/PEI-Mn3O4 NGs show a negative surface potential when compared with PEI-Mn3O4 NPs. 139

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Figure 3. In vivo color T1-weighted MR images (a, c) and tumor MR SNR (b, d) of xenografted U87MG tumor-bearing mice before and at different time points postintravenous injection of the AG/PEI-Mn3O4 NGs (a, b) and the PEI.Ac−Mn3O4 NPs (c, d) (5 × 10−3 mmol-Mn/kg, 100 μL in PBS solution). Arrows indicate the tumor regions.

of the NGs, the hydrodynamic size of the AG/PEI-Mn3O4 NGs was monitored during 2 weeks storage (Figure 1c). Clearly, the hydrodynamic size does not have any appreciable changes, validating their good colloidal stability. TGA curves were used to quantify the composition of the NGs (Figure 1d). It can be seen that the weight percentages of the PEI-Mn3O4 NPs and hybrid NGs at 700 °C are 31.29% and 18.28%, respectively. Therefore, the weight percentage of AG in the final NGs can be calculated to be 13.01%. In addition, the chemical structure of the NGs was also confirmed by Fourier transform infrared (FTIR) spectroscopy (Figure S4, Supporting Information). T1 MR phantom studies were performed to evaluate the T1 MR imaging performance of the AG/PEI-Mn3O4 NGs (Figure 2). Clearly, the MR image intensity gradually increases with the Mn concentration of the NGs, demonstrating the potential to use them for MR imaging applications (Figure 2a). The T1 relaxation times of the AG/PEI-Mn3O4 NGs at different Mn concentrations were measured, and the r1 value was calculated by a linear fitting of 1/T1 as a function of Mn concentration (Figure 2b). Meanwhile, the MR phantom studies of the PEI.Ac−Mn3O4 NPs were also carried out for comparison (Figure S8, Supporting Information). The r1 value of AG/PEIMn3O4 NGs was calculated to be 26.12 mM−1 s−1, which is about 19.5-fold higher than that of the PEI.Ac−Mn3O4 NPs (1.34 mM−1 s−1).18 The increased r1 value may be ascribed to the enlarged molecular dimension of the clustered PEI-Mn3O4

NPs within the NGs (hydrodynamic size = 219.1 nm) compared to PEI-Mn3O4 NPs in a free form (hydrodynamic size = 120.7 nm). During the relaxation process, the enlarged molecular dimension could lengthen the rotational correlation time (τc), thus leading to the increased r1 value.2,25,29−32 It is interesting to note that the size of the developed NGs may be reduced by varying the cross-linking reaction conditions (e.g., concentration of cross-linker, pH, and temperature, etc.) during the synthesis while retaining the T1 relaxation performance.33,34 We next confirmed the cytocompatibility of the AG/PEIMn3O4 NGs by cell viability assay and cell morphology observation (Figures S5−7, Supporting Information). After that, the potential to use the developed AG/PEI-Mn3O4 NGs for MR imaging of cancer cells in vitro was assessed. The synthesized acetylated PEI-Mn3O4 NPs (PEI.Ac−Mn3O4 NPs, details can be seen in Supporting Information) were employed to make comparison under the same treatments at the same Mn concentrations. Figures 2c and 2d show the T1-weighted MR images of U87MG cells treated with the NPs and NGs at different Mn concentrations for 4 h, respectively. We can find that the NG group (Figure 2d) displays a much stronger MR contrast enhancement than the NP group at a high concentration ([Mn] = 1 μM). Additionally, the quantitative analysis of MR signal-to-noise (SNR) indicates that the MR SNR of U87MG cells increases after the treatment of PEI.Ac− Mn3O4 NPs (from 13.8 to 18.4) and AG/PEI-Mn3O4 NGs 140

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(from 14.4 to 21.1) with the Mn concentration (Figure 2e). Moreover, at a Mn concentration of 1 μM, the MR SNR displays a significant difference (***p < 0.001) between the NP and NG groups. Therefore, our results imply that the AG/PEIMn3O4 NGs hold an excellent T1 MR relaxation performance with a high r1 value of 26.12 mM−1 s−1 and could be used as a positive contrast agent for enhanced MR imaging of cancer cells in vitro. Next, the AG/PEI-Mn3O4 NGs were used for enhanced MR imaging of a subcutaneous tumor model in vivo. As shown in Figure 3a (also Figure S9, Supporting Information), obvious changes of MR signal intensities in the tumor region (as indicated by arrows) could be observed after the treatment of AG/PEI-Mn3O4 NGs. The tumor MR signal intensity first keeps an increasing tendency within 40 min postinjection and then begins to recover at 50 min postinjection probably due to the metabolism process of the NGs in the tumor site. Quantitative analysis of the tumor MR SNR as a function of time postinjection further confirms this variation tendency (Figure 3b). Specifically, the tumor MR SNR increases from 20.4 (preinjection) to 30.7 at 40 min postinjection and remains at a value of 24.5 even at 90 min postinjection, which is higher than that of preinjection. For comparison, the tumor MR images and MR SNR change after injection of the PEI.Ac−Mn3O4 NPs are shown in Figure 3c and 3d. We can observe a slight change of the MR signal intensity during the given scanning time range. The highest MR SNR value was also obtained at 40 min postinjection, rising from 22.2 (preinjection) to 25.1. Then the MR SNR decreased to the level of preinjection at 60 min postinjection. The AG/ PEI-Mn3O4 NGs exhibited more significant MR contrast enhancement when compared to the PEI.Ac−Mn3O4 NPs under the same low injection dose. Compared to the PEI.Ac− Mn3O4 NPs, AG/PEI-Mn3O4 NGs displayed enhanced MR imaging ability and prolonged imaging time, which can be attributed to the high r1 relaxivity, the prolonged blood circulation time, and the enhanced tumor retention effect of the hybrid NG-based contrast agent with good softness and fluidity.10,24,26 Therefore, the developed AG/PEI-Mn3O4 NGs could be employed as a promising contrast agent for enhanced tumor MR imaging. In addition, the pharmacokinetics, in vivo biodistribution, and histological examinations of mice after intravenous injection of the AG/PEI-Mn3O4 NGs demonstrate that the AG/PEI-Mn3O4 NGs possess prolonged blood circulation time, can be slowly cleared out from the body, and display good biosafety to mice after injection of 30 days (details can be seen in the Supporting Information). In conclusion, we designed and constructed a hybrid AG/ PEI-Mn3O4 NG platform by means of a double emulsion method combined with EDC cross-linking chemistry for enhanced MR imaging of tumors. The characterizations show that the AG/PEI-Mn3O4 NGs with a mean size (dTEM) of about 141.6 nm are quite colloidally stable and have a good cytocompatibility in the studied concentration range. T1 MR phantom studies indicate that the AG/PEI-Mn3O4 NGs have a higher r1 value of 26.12 mM−1 s−1 than that of free PEI.AcMn3O4 NPs, which endows the NGs with an ability for enhanced MR imaging of cancer cells in vitro and a subcutaneous tumor model in vivo. The developed AG/PEIMn3O4 NGs with good biosafety may hold a promising potential for enhanced MR imaging of different biosystems.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.7b00999. Experimental details and data of hydrodynamic sizes, zeta potentials, TEM image and size distribution histogram, EDX spectra, FTIR spectra, cell viability, cell morphology observation, T1-weighted MR phantom measurements, in vivo gray scale T1-weighted MR images, pharmacokinetics, in vivo biodistribution, and H&E staining (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (X. Shi). *E-mail: [email protected] (C. Peng). *E-mail: [email protected] (M. Shen). ORCID

Xiangyang Shi: 0000-0001-6785-6645 Author Contributions ∥

W.S., J.Z. and C.Z. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was financially supported by National Science Foundation of China (81761148028 and 81401458), the Science and Technology Commission of Shanghai Municipality (17540712000 and 15520711400), and the Fundamental Research Funds for the Central Universities (for W. Sun, C. Peng, M. Shen, and X. Shi). X. Shi also acknowledges the support by FCT-Fundaçaõ para a Ciência e a Tecnologia (project PEst-OE/QUI/UI0674/2013, CQM, Portuguese Government funds) and by ARDITI-Agência Regional para o Desenvolvimento da Investigaçaõ Tecnologia e Inovaçaõ through the project M1420-01-0145-FEDER-000005-Centro ́ de Quimica da Madeira-CQM+ (Madeira 14-20).

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