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Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models

  • Lishan Tan , Xiulong Deng , Xuandi Lai , Tao Zeng , Aiqing Li EMAIL logo , Jianqiang Hu EMAIL logo and Zuying Xiong EMAIL logo
Published/Copyright: September 26, 2020
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Open Chemistry
From the journal Open Chemistry Volume 18 Issue 1

Abstract

The aim of this study is to explore the kidney-targeting capability of mesoscale nanoparticles (MNPs)-emodin (Em-MNPs) and its potential antifibrosis in the animal model. First, MNPs and Em-MNPs were synthesized via nanoprecipitation method, and their diameters were both ∼400 nm with the uniform size. The entrapment efficiency of MNPs was 45.1% when adding emodin at the concentration of 12 mg/mL. Moreover, cytotoxicity assay showed that Em-MNPs presented excellent biocompatibility in rat proximal tubular cells. Cellular uptake assay demonstrated that Em-MNPs had high-efficiency uptake, especially in the cytoplasm. Ex vivo organ fluorescence imaging revealed that Em-MNPs possessed specific kidney-targeting ability with relative long retention time in the kidney (∼24 h). In the renal unilateral ureteral obstruction model, Em-MNPs treatment could significantly alleviate kidney tubule injury and reduce extracellular matrix deposition compared with free MNPs. Herein, Em-MNPs with specific kidney-targeting and preferable antifibrosis effects in animal model may pave an avenue for treating renal diseases.

Keywords: mesoscale nanoparticles; emodin; kidney-targeting; anti-fibrosis; UUO model

1 Introduction

Multifunctional nanomaterials have been widely studied in the biomedical field because of their unique and adjustable physicochemical properties [1]. Researches focused on their application in biosensor, bioimaging and diagnosis, drug delivery, and disease treatment, and tissue regeneration engineering have attracted widespread attention [2,3,4,5]. The biological functions and applications of nanomaterials are usually closely related to their structure, size, and surface chemistry (such as surface modification) [6,7]. Thus, appropriate construction and modification of nanomaterials are of significance to broaden their application. It is well known that shortcomings such as insufficient water solubility, no renal targeting, and high toxicity of some small molecule drugs often restricted the therapy efficiency in a variety of diseases. Therefore, it is urgent to develop nontoxic and specific targeting drug delivery system.

Chronic kidney disease (CKD) have attracted increasing worldwide attention because of its high morbidity (10.8%), and it often progresses to end-stage kidney disease (ESKD), which required renal replacement therapy [8]. The key procedure of CKD to ESKD is renal fibrosis [9], so finding the drugs to reverse or halt the progression of fibrosis is incredibly essential for CKD patients. Although the therapies of chronic fibrosis increased, there are several adverse effects in their clinical practice. Several ingredients of Chinese herbs (emodin and triptolide) that were verified have been useful in treating chronic kidney fibrosis [10,11,12]. However, they also have some disadvantages such as low aqueous solubility, low kidney targeting, and short retention that may limit their application [13]. Recently, several studies focus on the medical application of nanomaterials, such as gold nanoparticles (NPs), polymer NPs, and other NPs with different sizes [14,15]. Qiao et al. synthesized catechol-derived chitosan complex (HCA-Chi) to improve the water solubility and renal-targeting ability of emodin and to further alleviate chronic kidney injury, which was an effective way to increase the effects of Chinese herbs [16]. However, the retention time of HCA-Chi in the kidneys was relatively short (∼12 h), and it would be preferable to prolong the kidney distribution time with good biocompatibility. Recently, it was demonstrated that mesoscale nanoparticles (MNPs), with a diameter of ∼400 nm, showed excellent kidney targeting ability, high stability, and high efficiency for the treatment of acute kidney injury after loading triptolide [17]. Therefore, MNPs would be a potential nanoplatform for emodin delivery to the kidney and finally to improve chronic kidney fibrosis.

In this study, we constructed monodispersed MNPs and loaded with emodin (Em-MNPs, ∼400 nm) for treating kidney fibrosis. Em-MNPs with good biocompatibility, kidney-targeting ability, and high uptake efficiency of kidney cells were synthesized for further pharmacodynamics study. Finally, we revealed that Em-MNPs had good therapeutic effects in the renal fibrosis animal model.

2 Materials and methods

2.1 Chemicals

Poly(d,l-lactate-co-glycolic acid) (PLGA; terminal carboxylation, molecular weight 38–54 kDa), EDC, methoxypolyethylene glycol amine (mPEG-NH2, 5 kDa), and FBS were purchased from Sigma (USA). Emodin (Em), poloxam 188, acetonitrile, methanol, and ethyl acetate were purchased from Aladdin (Shanghai). Cy7 was purchased from Lumiprode (USA). Other chemical reagents were purchased from Sinopharm Group Chemical Reagent Co. LTD. Ultrapure water was used throughout the experiments (18.2 MΩ cm).

2.2 Fabrication of PLGA-b-mPEG

The synthesis of PLGA-b-mPEG was based on the method reported in the previous study [18], that is, it was synthesized by the amide reaction between the amino group of mPEG-NH2 terminal and the carboxyl group of PLGA terminal. First, PLGA (1 g), mPEG-NH2 (250 mg), and EDC (75 mg) were dissolved in 5 mL anhydrous chloroform and stirred vigorously at room temperature for 12 h. After the reaction, 15 mL ethyl ether/methanol mixture (V/V, 1:1, 0°C) was added to precipitate the product. Centrifugation (10,000 rpm, 15 min) was performed to collect the bottom residue, and the upper liquid was rotated to evaporate and then the solvent was removed. Then, all residuals were dissolved with a small amount of acetonitrile and precipitated by ether/methanol (v/v, 1:5, 0°C). The products were collected by centrifugation (10,000 rpm, 15 min), and this procedure of purification (dissolved and precipitated) was repeated for three times. Finally, the product was vacuum dried to constant weight at 35°C, and brown solid was obtained, which was stored at −20°C for later use.

2.3 Preparation of MNPs, Em-MNPs, and Cy7-Em-MNPs

Under vigorous string, 2 mL PLGA-b-mPEG solution (acetonitrile/tetrahydrofuran (THF) = 1:1, 100 mg/mL) was added to 2 mL proloxam 188 aqueous solution (50 mg/mL) at the rate of 0.5 mL/min. After acetonitrile was completely volatilized, MNPs were collected by centrifugation (6,600 rpm, 10 min) and washed with water for three times. When Em-MNPs and Cy7-Em-MNPs were prepared, Em or Cy7 was dissolved with PLGA-b-mPEG in acetonitrile/tetrahydrofuran (v/v = 1:1, 100 mg/mL), and then, Em or Cy7-Em-MNPs were prepared according to the preparation and the purification method of MNPs. Finally, MNPs, Em-MNPs, or Cy7-Em-MNPs were dispersed in saline or water and stored at 4°C for later use.

2.4 Determination of encapsulation efficiency (EE)

The content of Em in Em-MNPs was determined by the UV/visible spectrophotometer. First, lyophilized Em-MNPs (1 mg) were dissolved in the mixture of acetonitrile (LC-MS, 50 µL) and methanol (LC-MS, 500 µL). PLGA precipitation and Em were dissolved in methanol and centrifuged (13,000 rpm, 10 min). The centrifugation of residue was repeated (dissolved – precipitated – centrifuged) for three times. Then, the upper liquid was concentrated in a new centrifuge tube (7 mL) and blow dried with nitrogen. Methanol (LC-MS) was added to dissolve the residue, with a constant volume of 50 mL. Finally, 2.0 mL Em methanol solution was removed with a 0.22 nm filter head, and the Em concentration was determined by the UV-vis spectrometer (Thermo Fisher Multiskan, Finland). Meanwhile, the EE and drug loading efficiency (DLE) of Em were calculated according to the following formulas:

(1)EE(%)=EmamountinEm−MNPsEmaddingamount×100%.
(2)DLE(%)=EmamountinEm−MNPsQuantityofMNPs×100%.

2.5 In vitro stability and drug release of Em-MNPs

First, Em-MNPs were dispersed in phosphate buffered solution (PBS) (10 mM, pH 7.4), 10% FBS, and saline and placed in a constant temperature metal bath (37°C, 1,000 rpm). Then, 100 µL dispersion was extracted at different times (1, 3, 6, 12, 24, 48, 72, 120, and 168 h) for the determination of hydrodynamic diameter (HD) of Em-MNPs. Before HD of Em-MNPs was determined, the PBS and saline dispersions of Em-MNPs were diluted with 2 mL water, and the FBS dispersions of Em-MNPs were centrifuged (6,600 rpm, 15 min) to remove FBS, and then 2 mL water was added for dispersion. HD was characterized by quantity value.

The in vitro release of Em-MNPs was determined by dialysis [19]. Fetal bovine serum (FBS; 10%), renal tissue homogenate (10%), PBS (10 mM, pH 7.4), and saline were selected as dispersion and dialysate. The preparation method of renal tissue homogenate was as follows: twice the volume of saline (g/mL) was added to the kidney of C57BL/6 mice, and the kidney was homogenized with cell pulverizer. First, the concentration of Em-MNPs was made to be 2 mg/mL. 2 mL of Em-MNPS dispersions were placed in a dialysis bag (30 kDa) and placed in the corresponding dialytic solution (100 mL), which was stirred slowly at 37°C. Then, 1 mL dialysate was taken out at different time points (0.5, 1, 2, 4, 8, 12, and 24 h), 3 mL ethyl acetate (LC-MS) was added for extraction by rotating for 5 min, the mixture was centrifuged at 10,000 rpm for 5 min, and the upper organic extract was collected, which was repeated for three times. All the extraction liquid was blow dried with nitrogen, and the residue was added to methanol for dissolution and constant volume to 10 mL. Finally, 2.0 mL methanol solution was used to remove the large particles with a 0.22 µm filter head. The concentration of Em was determined by the UV-vis spectrometer, and the cumulative release rate of Em was calculated.

2.6 Cell uptake assay

MNPs were labeled with Cy7 to track the specificity of intracellular distribution. Normal rat kidney proximal tubular epithelial cells (NRK-52E, American Type Culture Collection, USA) were planted into coverslip at 37°C overnight and then incubated with Cy7 and Cy7-Em-MNPs (equivalent to 50 µg/mL emodin) for 2 h, respectively. Then, the medium was removed, and ice-cold PBS was added to wash the Cy7 and Cy7-Em-MNPs for three times. Then, the cell nuclear was stained with 4′,6-diamidino-2-phenylindole for 5 min in the dark. Epifluorescence microscope was used to analyze the cellular distribution of Em-MNPs.

2.7 Cytotoxicity assay

NRK-52E cells were cultured with Dulbecco’s Modified Eagles’s Medium containing 10% FBS, 100 U/mL penicillin, and 100 µg/mL streptomycin. Different concentrations of emodin and Em-MNPs solution from 5 to 50 µg/mL were added to 96-well plates for 12 and 24 h. Finally, the cell viability was evaluated using a cell counting CCK-8 kit and measured by Thermo Fisher Multiskan GO UV/visible spectrophotometer (Shimadzu, Japan) [20].

2.8 Kidney targeting evaluation

The animal protocol was approved by the Animal Ethics Committee of Nanfang Hospital. Balb/c mice were administrated with Cy7 and Cy7-Em-MNPs (equivalent to 1.0 mg/kg emodin) for 12 and 24 h, respectively. All mice were sacrificed at corresponding time, and then their major organs, namely, heart, liver, spleen, lung, kidneys, thymus, muscle, small intestine, and brain, were collected. Before fluorescence imaging, major organs were washed with ice-cold PBS for three times to remove the surface fluorescence. After washing, fresh organs were placed on the glass plate to image with excitation at 710 nm and emission at 790 nm by the imaging system (Burker Imaging System, USA).

2.9 Pharmacodynamics study on renal unilateral ureteral obstruction (UUO) model

UUO models were performed based on the procedure demonstrated in the previous study [21]. 6–8 weeks mice were anesthetized using pentobarbital sodium (3%, 1.5 mL/kg, i.p.). All mice were randomly divided into four groups (n = 6 per group): (1) Sham group, (2) UUO + vehicle (PBS) group, (3) UUO + MNPs group, (4) UUO + Em-MNPs (equivalent to 1.0 mg/kg emodin). The mice were injected with corresponding drugs on the first day after operation and for 3 days. Then, all mice were sacrificed, and kidneys were collected for the following measurements.

After fixing with 10% neutral formaldehyde at 4°C overnight, kidneys were dehydrated, hyalinized, and embed for histology staining. 4 µm kidney slices were cut and stained with hematoxylin and eosin (H&E) staining to analyze the effect of Em-MNPs in the UUO mice model.

2.10 Statistical analysis

All experiments were performed for at least three times, and the data were collected. The statistical comparisons between groups were performed by t test using SPSS software (version 23.0). P < 0.05 was considered as statistically significant.

3 Results and discussion

3.1 Characterization of PLGA-b-mPEG and Em-MNPs

The structures of PLGA-b-mPEG and the encapsulation of Em were confirmed by 1H nuclear magnetic resonance spectra, Fourier transform infrared (FTIR) and UV-vis spectra. As shown in Figure 1a, the chemical shift peaks at 2.1, 6.5–7.5 and 11.0–12.1 ppm of Em-MNPs were consistent with that of Em, and the peaks at 1.5, 3.5 and 4.9–5.3 ppm were consistent with that of PLGA-b-mPEG. Relative to FTIR spectra of Em-MNPs, there appeared obvious vibration peaks at 1,750 and 1,627 cm−1, which were carboxyl characteristic vibration of PLGA-b-mPEG. Besides, the visible stretching vibration peaks of benzene in Em-MNPs indicated that the Em had been encapsulated in NPs successfully (Figure 1b). This was further confirmed by UV-vis spectra (Figure 1c). These three methods were favorable measurements to verify the linkage of Em with MNPs, which was also used in other studies [22,23].

Figure 1 Characterization of MNPs and Em-MNPs. (a) 1H NMP spectra of Em, MNPs, and Em-MNPs. (b) FTIR of the Em, MNPs, and Em-MNPs. (c) UV-vis spectra of MNPs, free Em, and Em-MNPs.
Figure 1

Characterization of MNPs and Em-MNPs. (a) 1H NMP spectra of Em, MNPs, and Em-MNPs. (b) FTIR of the Em, MNPs, and Em-MNPs. (c) UV-vis spectra of MNPs, free Em, and Em-MNPs.

3.2 Optimization of the Em-MNPs fabrication

Em-MNPs were prepared by a simple nanometer precipitation method, in which Poloxam 188 was used as a surfactant to stabilize Em-MNPs. The size and the homogeneity of Em-MNPs can be adjusted by changing PLGA-b-mPEG concentration, poloxam 188 concentration, and aqueous/solvent phase volume ratio. Figure 2a shows the hydrodynamic size (HD) and polydispersity index (PDI) of Em-MNPs prepared under different organic solvent ratio. Along with the decreasing of THF, the particle size gradually increased, while the PDI for each sample kept steady. However, with the increase of PLGA-b-mPEG concentration, the HD and PDI of Em-MNPs increased significantly, which reached the high concentration of PLGA-b-mPEG went against to the monodispersion of NPs (Figure 2b). The effect of poloxam 188 on particle size and dispersion was negligible (Figure 2c), while the proportion of organic solvent showed great influence on the particle size (Figure 2d). Therefore, the optimal condition for the preparation of Em-MNPs was as follows: 100 mg/mL PLGA-b-mPEG, 50 mg/mL Proloxam 188, and the volume ratio of aqueous/solvent phase 1.0.

Figure 2 Optimization of the Em-MNPs. Hydrodynamic size of Em-MNPs prepared under different (a) volume ratios of THF to CH3CN, (b) PLAG-b-mPEG concentration, (c) poloxamer concentration, and (d) volume ration of water to CH3CN.
Figure 2

Optimization of the Em-MNPs. Hydrodynamic size of Em-MNPs prepared under different (a) volume ratios of THF to CH3CN, (b) PLAG-b-mPEG concentration, (c) poloxamer concentration, and (d) volume ration of water to CH3CN.

Then, the morphology of MNPs and Em-MNPs was observed by scan electronic microscope (SEM). As shown in Figure 3, the as-prepared NPs were uniform spheres. The diameter observed from SEM images of Em-MNPs (394.0 ± 71.4 nm) was slightly larger than that of MNPs (361.3 ± 74.9 nm), and the HD for Em-MNPs was also greater than MNPs, indicating that the Em encapsulation enlarged the size of MNPs and the hydration layer on the surface of NPs enhanced this trend. It is worth noting that the EE and DLE were closely related to the amount of Em added. As shown in Figure 4, the EE decreased along with the increased Em concentration, while the DLE was proportionate to the Em concentration. When the Em concentration was 6 mg/mL, the EE and DLE reached a balance of 66.9% and 4.0%, respectively. The cross point of EE and DLE indicated that the concentration of Em added has reached an optimal value with relatively high drug loading amount and efficiency.

Figure 3 Morphology of MNPs and Em-MNPs. SEM images of MNPs (a) and Em-MNPs (b). Diameter distributions of MNPs (c) and Em-MNPs (d) counted in SEM images.
Figure 3

Morphology of MNPs and Em-MNPs. SEM images of MNPs (a) and Em-MNPs (b). Diameter distributions of MNPs (c) and Em-MNPs (d) counted in SEM images.

Figure 4 Encapsulation efficiency (EE) and drug loading efficiency (DLE). EE and DLE after adding different concentrations of Em (1–12 mg/mL).
Figure 4

Encapsulation efficiency (EE) and drug loading efficiency (DLE). EE and DLE after adding different concentrations of Em (1–12 mg/mL).

3.3 Stability and in vitro release assays

To further investigate the stability of Em-MNPs in different media, HDs of Em-MNPs were measured after incubation with PBS (10 mM, pH 7.4), saline, and 10% FBS at different time points. As shown in Figure 5a, the HDs of Em-MNPs were stable up to 7 days when Em-MNPs were incubated with PBS and saline. After treated with FBS, a medium enriched with proteins, the HD of Em-MNPs was nearly same to that of the initial condition at 5 days. As reported in the recent study, the HD of Em-MNPs remained stable for 2.5 times longer than MNPs [24]. In vitro release assay was conducted in 10% FBS and kidney homogenate at 37°C. With the increasing time, Em exhibited a high release profile from the Em-MNPs in those two media (Figure 5b). The cumulative release rate reached 80.2% and 86.6% in the FBS and kidney homogenate for 24 h, respectively. Compared to covalent modification, Em-MNPs showed higher drug release rate [25], thereby releasing Em from Em-MNPs and improving drug efficacy.

Figure 5 Stability and in vitro release assays of Em-MNPs in different media. The stability of Em-MNPs (a) measured by HD in PBS (pH 7.4), 10% FBS, and saline (NS) at 37°C. In vitro release assay of Em released from Em-MNPs (b) in 10% FBS and kidney homogenate at 37°C.
Figure 5

Stability and in vitro release assays of Em-MNPs in different media. The stability of Em-MNPs (a) measured by HD in PBS (pH 7.4), 10% FBS, and saline (NS) at 37°C. In vitro release assay of Em released from Em-MNPs (b) in 10% FBS and kidney homogenate at 37°C.

3.4 Cellular uptake study

Cy7 and Cy7-Em-MNPs were used to observe the intracellular uptake efficiency. Figure 6 shows the fluorescence imaging distribution of NRK-52E cells treated with PBS, Cy7, and Cy7-Em-MNPs, respectively. After incubation for 2 h, the fluorescence signal of Cy7-Em-MNPs was significantly stronger than that of free Cy7. It was suggested that the accumulation of Cy7-Em-MNPs was much higher than that of Cy7. The Cy7-Em-MNPs were mainly distributed around nucleus, thereby suggesting that Cy7-Em-MNPs were mainly located and released drugs in the cytoplasm rather than nucleus. Accordingly, these data indicated that Em-MNPs had higher uptake efficiency in vitro and might be suitable for kidney diseases. The possible endocytic mechanism was the protonation of the surface of Em-MNPs, coinciding with triptolide-encapsulated MNPs [17], which resulted in endosome rupture and then realized lysosome escape [26]. Besides, Williams et al. also demonstrated that free MNPs performed good cellular uptake and biocompatibility [24].

Figure 6 Cytotoxicity assay. Cell viability of rat proximal tubular cells treated with emodin (0–50 µg/mL) and Em-MNPs (equivalent to 0–50 µg/mL emodin) for 12 h (a) and 24 h (b), respectively. *p < 0.05 versus the Em-MNPs group.
Figure 6

Cytotoxicity assay. Cell viability of rat proximal tubular cells treated with emodin (0–50 µg/mL) and Em-MNPs (equivalent to 0–50 µg/mL emodin) for 12 h (a) and 24 h (b), respectively. *p < 0.05 versus the Em-MNPs group.

3.5 Cytotoxicity assay

To compare the cytotoxicity of emodin and Em-MNPs, NRK-52E cells were treated with emodin and Em-MNPs in different concentration gradients (5–50 µg/mL) for 12 and 24 h, respectively (Figure 7). The viability of cells was measured by CCK-8, which is a classical method to evaluate cell toxicity of nanomaterials [27]. When cells incubated with free emodin at the concentration of 10 µg/mL, cell viability presented significant suppression. With the increasing concentration of emodin, the toxicity of emodin grow sharply after incubation for 24 h. However, the viability of cells treated with Em-MNPs were maintained in relative high levels (>85%). This result suggested that loading emodin with MNPs could significantly decrease the cytotoxicity of emodin. Moreover, our previous study found that MNPs reduced the toxicity of triptolide in other three cell lines [17] and further demonstrated that MNPs could serve as promising drug carriers with good biocompatibility.

Figure 7 Cellular uptake images. NRK-52E cells incubated with Cy7 and Cy7-Em-MNPs for 2 h. Images were captured in 400× magnification.
Figure 7

Cellular uptake images. NRK-52E cells incubated with Cy7 and Cy7-Em-MNPs for 2 h. Images were captured in 400× magnification.

3.6 Kidney targeting capacity

To further examine the kidney targeting capacity of Cy7-Em-MNPs, an ex vivo tissue localization was performed at 12 h and 24 h in Balb/c mice (Figure 8). As a result, Cy7-Em-MNPs was mostly accumulated in kidneys rather than other organs (heart, liver, spleen, and lung) after injection for 12 h. With the increasing time, the fluorescence density was increased in kidneys of Cy7-Em-MNPs. However, free Cy7 treated kidneys had no apparent fluorescence retention during the period, indicating that Cy7-Em-MNPs had favorable renal retention ability. The slit diaphragm of podocytes (the molecular barrier of the nephron, ∼40 nm) are too small for Em-MNPs to pass through [28,29]. So, the kidney-targeting mechanism of MNPs might be attributed to the endothelial cells of the peritubular in the kidneys, which also verified that excellent kidney-targeting capability of free MNPs [24]. The pressure in the nephron and the reabsorption ability of peritubular capillaries induced endocytosis of Cy7-Em-MNPs in kidney tubular cells. Therefore, Cy7-Em-MNPs was an excellent option for the following pharmacodynamics analysis in the animal model.

Figure 8 Ex vivo fluorescence imaging. Balb/c mice injected with PBS (control), and Cy7 and Cy7-Em-MNPs for 12 h and 24 h, respectively and major organs were collected for imaging. 1, heart; 2, liver; 3, spleen; 4, lung; 5, kidney; 6, thymus; 7, small intestine; 8, muscle; 9, brain.
Figure 8

Ex vivo fluorescence imaging. Balb/c mice injected with PBS (control), and Cy7 and Cy7-Em-MNPs for 12 h and 24 h, respectively and major organs were collected for imaging. 1, heart; 2, liver; 3, spleen; 4, lung; 5, kidney; 6, thymus; 7, small intestine; 8, muscle; 9, brain.

3.7 Pharmacodynamics study

UUO mice were a well-recognized and classical animal model of chronic kidney fibrosis [30]. So, the therapeutic effect of Em-MNPs was performed in the UUO model. Figure 9 depicts histology characteristics in different treatment groups for H&E staining. The ligated kidney in UUO mice showed apparent tubular dilation, lumen disappear, fibrosis, and increased inflammatory cells [31]. After treating with Em-MNPs, the manifestation of ligated kidney was significantly alleviated, which characterized as decreased inflammation cells and less matrix accumulation in the tubulointerstitium. These results revealed that Em-MNPs could specifically treat kidney injury, which might be ascribed to the targeting ability and long retention of Em-MNPs in kidneys. Furthermore, UUO mice treated with free MNPs could not perform the therapeutic effects, suggesting that the effects of Em-MNPs mainly was derived from emodin.

Figure 9 Histology analysis of kidneys. H&E staining images of kidneys from sham-operated, UUO + Vehicle (PBS), UUO + MNPs, and UUO + Em-MNPs mice.
Figure 9

Histology analysis of kidneys. H&E staining images of kidneys from sham-operated, UUO + Vehicle (PBS), UUO + MNPs, and UUO + Em-MNPs mice.

4 Conclusion

In summary, we successfully designed monodispersed MNPs and loaded with emodin (Em-MNPs). Em-MNPs possessed low toxicity, high cell uptake efficiency, kidney-targeting ability, and long retention time in the kidneys. In the UUO model, Em-MNPs presented excellent antifibrosis effects and may represent a potential strategy for the treatment of renal diseases.

Acknowledgments

This study was supported by the China Postdoctoral Science General Foundation (Nos.2018M643138, 2018M643135), “San-ming” Project of Medicine in Shenzhen (No. SZSM201812097), the National Natural Science Foundation of China (Grants 81770727, 21673081), GDUPS (2017), Key Project of Guangzhou Science Technology and Innovation Commission (201804020054), Key Project of Guangdong Natural Science Foundation (2018B030311002), and Key Project Science and Technology Planning Project of Guangdong Province (2017A010103041).

  1. Conflict of interest: The authors declare no conflict of interest.

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Received: 2020-07-05
Revised: 2020-08-06
Accepted: 2020-08-17
Published Online: 2020-09-26

© 2020 Lishan Tan et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
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  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
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  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
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https://doi.org/10.1515/chem-2020-0163
Keywords for this article
mesoscale nanoparticles; emodin; kidney-targeting; anti-fibrosis; UUO model
Creative Commons
BY 4.0

Articles in the same Issue

  1. Regular Articles
  2. Electrochemical antioxidant screening and evaluation based on guanine and chitosan immobilized MoS2 nanosheet modified glassy carbon electrode (guanine/CS/MoS2/GCE)
  3. Kinetic models of the extraction of vanillic acid from pumpkin seeds
  4. On the maximum ABC index of bipartite graphs without pendent vertices
  5. Estimation of the total antioxidant potential in the meat samples using thin-layer chromatography
  6. Molecular dynamics simulation of sI methane hydrate under compression and tension
  7. Spatial distribution and potential ecological risk assessment of some trace elements in sediments and grey mangrove (Avicennia marina) along the Arabian Gulf coast, Saudi Arabia
  8. Amino-functionalized graphene oxide for Cr(VI), Cu(II), Pb(II) and Cd(II) removal from industrial wastewater
  9. Chemical composition and in vitro activity of Origanum vulgare L., Satureja hortensis L., Thymus serpyllum L. and Thymus vulgaris L. essential oils towards oral isolates of Candida albicans and Candida glabrata
  10. Effect of excess Fluoride consumption on Urine-Serum Fluorides, Dental state and Thyroid Hormones among children in “Talab Sarai” Punjab Pakistan
  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
  33. Diorganotin(iv) benzyldithiocarbamate complexes: synthesis, characterization, and thermal and cytotoxicity study
  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
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  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
  50. Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique
  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
  52. Cadmium (Cd) chloride affects the nutrient uptake and Cd-resistant bacterium reduces the adsorption of Cd in muskmelon plants
  53. Removal of H2S by vermicompost biofilter and analysis on bacterial community
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  55. A self-breaking supramolecular plugging system as lost circulation material in oilfield
  56. Synthesis, characterization, and pharmacological evaluation of thiourea derivatives
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  58. Synthesis and characterization of a novel chitosan-grafted-polyorthoethylaniline biocomposite and utilization for dye removal from water
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  60. DFT investigations on arylsulphonyl pyrazole derivatives as potential ligands of selected kinases
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  62. New derivatives of a natural nordentatin
  63. Fluorescence biomarkers of malignant melanoma detectable in urine
  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
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  68. Synthesis of magnesium carbonate hydrate from natural talc
  69. Stability-indicating HPLC-DAD assay for simultaneous quantification of hydrocortisone 21 acetate, dexamethasone, and fluocinolone acetonide in cosmetics
  70. A novel lactose biosensor based on electrochemically synthesized 3,4-ethylenedioxythiophene/thiophene (EDOT/Th) copolymer
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  72. Development and validation of a high performance liquid chromatography/diode array detection method for estrogen determination: Application to residual analysis in meat products
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  77. A Zn(ii)–organic cage with semirigid ligand for solvent-free cyanosilylation and inhibitory effect on ovarian cancer cell migration and invasion ability via regulating mi-RNA16 expression
  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
  85. Antioxidant activity as a response to cadmium pollution in three durum wheat genotypes differing in salt-tolerance
  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
  87. Synthesis and efficacy of herbicidal ionic liquids with chlorsulfuron as the anion
  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
  114. Study on online soft sensor method of total sugar content in chlorotetracycline fermentation tank
  115. Studies on the Anti-Gouty Arthritis and Anti-hyperuricemia Properties of Astilbin in Animal Models
  116. Effects of organic fertilizer on water use, photosynthetic characteristics, and fruit quality of pear jujube in northern Shaanxi
  117. Characteristics of the root exudate release system of typical plants in plateau lakeside wetland under phosphorus stress conditions
  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
  122. Special issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  123. Insight into the cadmium and zinc binding potential of humic acids derived from composts by EEM spectra combined with PARAFAC analysis
  124. Source apportionment of soil contamination based on multivariate receptor and robust geostatistics in a typical rural–urban area, Wuhan city, middle China
  125. Special Issue on 13th JCC 2018
  126. The Role of H2C2O4 and Na2CO3 as Precipitating Agents on The Physichochemical Properties and Photocatalytic Activity of Bismuth Oxide
  127. Preparation of magnetite-silica–cetyltrimethylammonium for phenol removal based on adsolubilization
  128. Topical Issue on Agriculture
  129. Size-dependent growth kinetics of struvite crystals in wastewater with calcium ions
  130. The effect of silica-calcite sedimentary rock contained in the chicken broiler diet on the overall quality of chicken muscles
  131. Physicochemical properties of selected herbicidal products containing nicosulfuron as an active ingredient
  132. Lycopene in tomatoes and tomato products
  133. Fluorescence in the assessment of the share of a key component in the mixing of feed
  134. Sulfur application alleviates chromium stress in maize and wheat
  135. Effectiveness of removal of sulphur compounds from the air after 3 years of biofiltration with a mixture of compost soil, peat, coconut fibre and oak bark
  136. Special Issue on the 4th Green Chemistry 2018
  137. Study and fire test of banana fibre reinforced composites with flame retardance properties
  138. Special Issue on the International conference CosCI 2018
  139. Disintegration, In vitro Dissolution, and Drug Release Kinetics Profiles of k-Carrageenan-based Nutraceutical Hard-shell Capsules Containing Salicylamide
  140. Synthesis of amorphous aluminosilicate from impure Indonesian kaolin
  141. Special Issue on the International Conf on Science, Applied Science, Teaching and Education 2019
  142. Functionalization of Congo red dye as a light harvester on solar cell
  143. The effect of nitrite food preservatives added to se’i meat on the expression of wild-type p53 protein
  144. Biocompatibility and osteoconductivity of scaffold porous composite collagen–hydroxyapatite based coral for bone regeneration
  145. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  146. Effect of natural boron mineral use on the essential oil ratio and components of Musk Sage (Salvia sclarea L.)
  147. A theoretical and experimental study of the adsorptive removal of hexavalent chromium ions using graphene oxide as an adsorbent
  148. A study on the bacterial adhesion of Streptococcus mutans in various dental ceramics: In vitro study
  149. Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study
  150. Special Issue on Chemistry Today for Tomorrow 2019
  151. Diabetes mellitus type 2: Exploratory data analysis based on clinical reading
  152. Multivariate analysis for the classification of copper–lead and copper–zinc glasses
  153. Special Issue on Advances in Chemistry and Polymers
  154. The spatial and temporal distribution of cationic and anionic radicals in early embryo implantation
  155. Special Issue on 3rd IC3PE 2020
  156. Magnetic iron oxide/clay nanocomposites for adsorption and catalytic oxidation in water treatment applications
  157. Special Issue on IC3PE 2018/2019 Conference
  158. Exergy analysis of conventional and hydrothermal liquefaction–esterification processes of microalgae for biodiesel production
  159. Advancing biodiesel production from microalgae Spirulina sp. by a simultaneous extraction–transesterification process using palm oil as a co-solvent of methanol
  160. Topical Issue on Applications of Mathematics in Chemistry
  161. Omega and the related counting polynomials of some chemical structures
  162. M-polynomial and topological indices of zigzag edge coronoid fused by starphene
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