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Nano-encapsulated tanshinone IIA in PLGA-PEG-COOH inhibits apoptosis and inflammation in cerebral ischemia/reperfusion injury

  • Xin Zhang , Xutong Zhu , Lifa Huang , Zupeng Chen , Yuchen Wang EMAIL logo , Yajun Liu , Ruihan Pan and Ling Lv EMAIL logo
Published/Copyright: March 11, 2023
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Green Processing and Synthesis
From the journal Green Processing and Synthesis Volume 12 Issue 1

Abstract

Tanshinone IIA has a potential therapeutic effect on cerebral ischemia/reperfusion injury (CIRI). In this study, tanshinone IIA was encapsulated in poly(lactic-co-glycolic acid)-block-poly (ethylene glycol)-carboxylic acid (PLGA-PEG-COOH) nanoparticles, and its therapeutic efficacy on CIRI was investigated. Morphology and dynamic light scattering analyses were performed to identify and optimize nano-formulations. A drug release test was conducted using the dialysis method. The cytotoxic effect of tanshinone IIA on human neuroblastoma cells (SH-SY5Y) and brain endothelial capillary cells (hCMEC/D3) was measured using the MTT assay. The protective effect of PLGA-PEG-COOH-encapsulated tanshinone IIA against CIRI was evaluated in oxygen and glucose deprivation/reoxygenation-induced SH-SY5Y/IR cells and middle cerebral artery occlusion (MCAO) rats. Results showed that PLGA-PEG-COOH-encapsulated tanshinone IIA promoted viability and inhibited apoptosis of SH-SY5Y/IR cells (P < 0.01). Moreover, PLGA-PEG-COOH-encapsulated tanshinone IIA facilitated the invasion of SH-SY5Y/IR cells and repressed inflammation in MCAO rats (P < 0.01). Noteworthy, PLGA-PEG-COOH-encapsulated tanshinone IIA combined with angiopep-2 peptide presented a better inhibitory effect on CIRI than tanshinone IIA alone (P < 0.01). Angiopep-2 peptide contributes to traversing blood–brain barrier by recognizing lipoprotein-related protein expressed in the brain capillary endothelial cells. In conclusion, PLGA-PEG-COOH-encapsulated tanshinone IIA plus angiopep-2 peptide holds promising therapeutic potential toward CIRI.

Keywords: PLGA-PEG-COOH nanoparticles; tanshinone IIA; cerebral ischemia/reperfusion injury; angiopep-2 peptide; blood–brain barrier

1 Introduction

Cerebral ischemic, a common form of stroke, is mainly caused by blockage of a blood vessel due to a thrombus or embolus [1]. It affects all ages and is a leading cause of mortality and morbidity worldwide [2]. Several risk factors are associated with cerebral ischemic, including age, Fisher grade, tobacco smoking, systemic inflammatory response, diabetes, and obstructive hydrocephalus [2,3]. Tissue damage induced by cerebral ischemia is the main cause of fatal disease [4]. Early reperfusion is crucial for the recovery of blood flow in ischemic brain tissue but is not conducive to the recovery of brain function. In contrast, it further aggravates the dysfunction and structural damage caused by ischemia, known as cerebral ischemia/reperfusion injury (CIRI) [5,6,7]. The effects of neuronal necrosis, apoptosis, and poor prognosis after reperfusion during CIRI have been demonstrated [8,9,10]. It is of great significance to develop effective protection strategies and treatment methods for CIRI.

Oxidative stress and excessive inflammation are important pathophysiological mechanisms that cause neuronal apoptosis and brain injury after CIRI [11]. It has been proven that the clearance of excessive oxidative stress levels and regulation of the inflammatory microenvironment can slow down the process of neuronal death and improve prognosis [12,13]. Active components from traditional Chinese medicines possess favorable bioactivities including anti-oxidative stress, apoptosis, and inflammatory reactions [14,15]. Multi-component, multi-pathway, and multi-target features have unique therapeutic advantages and potential for CIRI with complex pathological mechanisms [16,17,18,19]. Tanshinones are lipophilic diterpenes isolated from the rhizome of Salvia miltiorrhiza, with favorable pharmacological activities against neurological diseases [20]. Tanshinone IIA is the mostly studied tanshinone, which reportedly mitigates blood–brain barrier (BBB) permeability in stroke [20]. It also reportedly exerts the therapeutic effect on CIRI. Song et al. suggested that tanshinone IIA modulates microglial polarization to confer anti-neuroinflammatory effects in CIRI [21]. Wang et al. demonstrated that sodium tanshinone IIA sulfonate protects against CIRI via inhibiting autophagy and inflammatory activity [22]. Tanshinone IIA also showed neuroprotective capabilities via anti-apoptotic pathway in rats with CIRI [23]. These previous studies confirmed the therapeutic efficacy of tanshinone IIA on CIRI.

Unfortunately, there are very few traditional Chinese medicine treatments that translate into clinical benefits [24,25,26]. The main reason may be that the rigidity of the BBB leads to ineffective drug delivery to the ischemic region, making it difficult to exert a therapeutic effect on the ischemic core [27,28,29]. As early as the 1970s, nanoparticles were first proposed as drug carriers and have been widely used in the field of biomedical transportation because of their biodegradability and sustained drug release [30,31,32]. Related studies have reported that puerarin-loaded poly(d,l-lactic-co-glycolic acid) nanoparticles increase and prolong puerarin concentration in the brain and promote functional recovery in ischemic regions [33]. We are aware of the BBB problem in the glioma area, and there have been many successful cases [34,35]. For example, studies on angiopep-2 peptide-functionalized nanoparticles demonstrated that compared with lactoferrin, transferrin, and avidin, the angiopep-2 peptide has a higher transport efficiency of BBB and glioma accumulation [36,37]. Moreover, it provides a proof of concept for lipoprotein receptor-related protein (LRP) receptor-mediated targeted administration in the cerebral ischemic region [38,39,40].

Poly(lactic-co-glycolic acid)-block-poly(ethylene glycol)-carboxylic acid (PLGA-PEG-COOH) constitutes the skeleton of the drug delivery nanoplatform [41]. Poly(lactic-co-glycolic acid) (PLGA) possesses good biodegradability and biocompatibility, which is a favorable shell for drug delivery [42]. Waters et al. suggested that tanshinone IIA-loaded PLGA nanoparticles mitigate neural injury in a translational pig ischemic stroke model [43]. Tanshinone IIA-loaded PEG-PLGA modified by borneol is a promising nose-to-brain delivery system that can enhance the prevention effect of tanshinone IIA on CIRI [44]. Herein, we designed multifunctional PLGA-PEG complex capsules with a water-soluble indocyanine green (ICG) fluorescent probe and ester-soluble tanshinone IIA by the water-in-oil-in-water (W/O/W) double emulsion method. Tanshinone IIA exhibits antiplatelet aggregation, antithrombotic activity, and improved microcirculation [45,46]. Angiopep-2 peptide modified by carboxyl on the surface of PLGA-PEG capsules can achieve the breakthrough of the BBB and targeted treatment of complex diseases (Scheme 1). The objective of the study was to achieve better targeted therapeutic effect of tanshinone IIA on CIRI by nanoparticle fabrication. This opens a new direction for the clinical treatment of CIRI and other oxidative stress-induced diseases.

Scheme 1 PLGA-PEG-COOH-IT was selected for the preparation conditions and follow-up experiments.
Scheme 1

PLGA-PEG-COOH-IT was selected for the preparation conditions and follow-up experiments.

2 Materials and methods

2.1 Materials

PLGA-PEG-COOH (MW = 10 K, PLGA: 75/25) was purchased from Ponsure Biotechnology Co., Ltd. (Shanghai, China). Poly(vinyl alcohol) (PVA) (88%, MW = 31,000) was obtained from Acros Organics (Geel, Belgium). Chloroform (AR) was purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Tanshinone IIA (high-performance liquid chromatography [HPLC] ≥98%) was purchased from Yuanye Bio-Technology Co., Ltd. (Shanghai, China). Angiopep-2 peptide (TFFYGGSRGKRNNFKTEEYC) was obtained from China Peptides Co., Ltd. (Shanghai, China). ICG-Sulfo-Osu was purchased from Annoron Biotechnology Co., Ltd. (Beijing, China). Finally, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (99.9%) and N-hydroxysuccinimide (NHS) (99%) were provided by Aladdin Bio-Chem Technology Co., Ltd. (Shanghai, China).

2.2 Preparation of PLGA-PEG-COOH-ICG-tanshinone IIA (PLGA-PEG-COOH-IT) nanoparticles and PLGA-PEG complex capsules

PLGA-PEG-COOH-IT nanoparticles were fabricated by a typical double emulsion process (W/O/W). With 50 μL of ICG aqueous solution (4 mg·mL−1) as the internal water phase, 1 mg tanshinone IIA and 50 mg PLGA-PEG-COOH were added to 1 mL chloroform. Colostrum was formed using an ultrasound probe for 30 s (80 W) in an ice bath. The colostrum was dripped into 3 mL of PVA (1% w/v, external water phase) and ultrasonicated with a probe for 2 min (80 W) in an ice bath to form a W/O/W double emulsion. Finally, the mixed solution was added to 50 mL of PVA (0.3% w/v, dispersed phase) and stirred overnight to volatilize the chloroform and solidify the nanosphere surface. Residual tanshinone IIA was removed by low-speed centrifugation (2,000 × g) for 7 min at 4°C. Then, ultrafiltration concentration and cleaning were performed at 4°C with a 100 kDa ultrafiltration tube to collect PLGA-PEG-COOH-IT nanoparticles. Finally, the collected PLGA-PEG-COOH-IT nanoparticles were stored at 4°C in pure water at a constant volume of 5 mL (10 mg·mL−1). Appropriate samples were dried and weighed to determine their concentration and solid content. The non-loaded PLGA-PEG-COOH nanoparticles (without ICG and tanshinone IIA) were prepared using the same method.

LRP-targeted PLGA-PEG complex capsules were produced by a similar process. Briefly, 0.5 mL of PLGA-PEG-COOH-IT (10 mg·mL−1) was dispersed in 1.5 mL of 4-morpholineethanesulfonic acid (MES) buffer (100 mM, pH 6.0; 100 μL MES buffer containing 10 mg EDC and 10 mg NHS) by shaking for 30 min at room temperature. Then, 5 mg angiopep-2 peptide (recognizing LRP) was poured into the reaction tube and shaken overnight. After coupling, the product was purified by ultrafiltration with pure water and stored in water. The ultrafiltered purified liquid was collected, and the coupling efficiency was determined.

2.3 Characterization of nanoparticles

The morphology of nanoparticles was examined by transmission electron microscopy (TEM) (JEM-2100, JEOL Ltd., Japan). The size and zeta potential of the nanoparticles were measured by dynamic light scattering (DLS) and Zetasizer Pro (Nano-ZS90, Malvern, UK). HPLC (Shimadzu, Japan) and UV-Vis absorption spectroscopy (UV-1780, Shimadzu, Japan) were used to determine drug release. The fluorescence spectrum and in vitro fluorescence imaging of nanoparticles were performed using a Fluoromax-4 spectrofluorometer (Horiba Scientific, Edison, NJ, USA) and an optical imaging system (IVIS Lumina LT, PerkinElmer, USA).

2.4 In vitro drug release

The release rate of tanshinone IIA from PLGA-PEG complex capsules in vitro was determined by a dialysis method. Briefly, 1 mL of PLGA-PEG complex capsule suspension was tightly placed into a centrifuge tube containing 5 mL of sustained-release medium ([0.02 M phosphate-buffered saline, PBS, containing 1% SDS, pH 7.4 or 5.5]:methanol = 60:40) and put into a separate dialysis bag (MWCO: 8,000–14,000 Da). The centrifuge tube was then placed in a constant temperature shaker (120 rpm) at 37°C for continuous oscillation. At regular intervals (0, 0.5, 1, 2, 4, 19, 24, 48, 72, 96, and 120 h), 1 mL of dialysate was collected and filtered with a 0.45 μm membrane. Simultaneously, the filtered dialysate was replenished with an equal amount of the sustained-release medium to maintain constant volume. The released concentrations of tanshinone IIA at different time points were determined using HPLC at a wavelength of 270 nm. The cumulative release percentages of tanshinone IIA from nanoparticles were calculated.

2.5 CIRI cell model

SH-SY5Y (human neuroblastoma, CRL-2266), HaCaT (human immortalized keratinocytes, PCS-200-201), and hCMEC/D3 (human brain capillary endothelial, SCC066) cell lines were purchased from the ATCC (Manassas, VA, USA) and MilliPore (Bedford, MA, USA). H-SY5Y and HaCaT cells were cultured in the Dulbecco’s modified Eagle’s medium (DMEM; Gibco, Grand Island, NY, USA) added with 10% fetal bovine serum (FBS) and 1% sterile antibiotic–antimycotic solution. hCMEC/D3 cells were cultured in an EBM-2 medium (Lonza, Switzerland) containing 5% FBS, 1% penicillin/streptomycin, bFGF, hydrocortisone, and ascorbic acid. All these cells were incubated in a humidified atmosphere at 37°C with 5% CO2. The SH-SY5Y cell model of CIRI (SH-SY5Y/IR) was established as previously reported by oxygen and glucose deprivation/reoxygenation (OGD/R) [47,48].

2.6 Cell viability and apoptosis assay

The effect of tanshinone IIA on the viability of SH-SY5Y and hCMEC/D3 cells was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cells were seeded in 96-well plates at 5 × 103 cells·well−1 and incubated for 24 h. Afterward, cells were incubated with tanshinone IIA (160 μg·mL−1) for 24 h at 37°C. An equal volume of PBS was utilized as the control. Then, 20 μL of MTT reagent (5 mg·mL−1; EMD Millipore, MA, USA) was added for further culture for 4 h, and dimethyl sulfoxide (100 μL·well−1) was added to dissolve crystals. Absorbances of cells were measured by a Microplate Reader (Victor X, PerkinElmer, USA) at 570 nm.

For the CIRI cell model, SH-SY5Y cells were seeded in 12-well plates at 5 × 103 cells·well-1 and were incubated for 24 h. After washing with PBS, the cells were treated with different samples of tanshinone IIA (160 μg·mL−1), PLGA-PEG-COOH (1.95 mg·mL−1), PLGA-PEG-COOH-IT, and PLGA-PEG complex capsules (containing 160 μg·mL−1 tanshinone IIA) at 37°C for 24 h, and the PBS control group was set. Subsequently, cells were treated with OGD/R to induce CIRI. Cell viability was measured by the MTT assay as mentioned above. For apoptosis detection, the co-cultured cells were harvested, washed with ice-cold PBS, stained with the Annexin V-FITC/PI (Solarbio, CA1020, Beijing, China) for 15 min, and analyzed using flow cytometry (FACSCalibur, USA).

2.7 Cellular uptake behavior evaluation

The intracellular uptake of PLGA-PEG-COOH-IT and PLGA-PEG complex capsules was detected using a fluorescence microscope (Carl Zeiss Microscope Systems, Jena, Germany) [49], with PBS as the control. Briefly, SH-SY5Y cells were seeded on 6-well plates (1 × 105 cells·well−1) the day before dosing and then incubated with complexes at 37°C for 6 h (OGD/R). Equivalent amounts of PBS buffer were used for comparison. The cells were washed and harvested. After fixation with 4% paraformaldehyde for 15 min, cell nuclei were labeled with 4′,6-diamidino-2-phenylindole (DAPI) for the same time. Finally, the fluorescence images were captured using a fluorescence microscope.

2.8 Hemocompatibility test

Fresh blood from healthy rats was stabilized with an anticoagulant (e.g., citrate dextrose), dispersed in PBS buffer (10%, v/v), and centrifuged for washing (1,500 rpm, 10 min) to obtain the supernatant. Diluted blood (0.2 mL) was added to each tube with different samples and incubated at 37°C for 1 h. Ultrapure water and PBS buffer were used as the positive (+Ref) and negative control groups (−Ref), respectively. After centrifugation, the supernatant was obtained by spectrophotometry (540 nm absorbance), and the hemolytic ratio (%) was calculated using the following formula [50]:

(1) H ( % ) = OD Sample − OD − Ref OD + Ref − OD − Ref × 100 %

2.9 Transwell invasion assay

To evaluate the potential of PLGA-PEG complex capsules penetrating the BBB, hCMEC/D3 cells were used to develop an in vitro model [51]. First, different drugs (PBS, tanshinone IIA, PLGA-PEG-COOH, PLGA-PEG-COOH-IT, and PLGA-PEG complex capsules) were added to the serum-free EBM-2 medium. The hCMEC/D3 cell (5 × 105 cells·mL−1) in the above medium was seeded onto the upper chamber of the transwell insert containing a porous polycarbonate membrane (3 µm, Corning Costar, MD, USA) pre-coated with type I collagen. The medium containing 10% FBS was used as a chemoattractant in the lower chamber. After co-culturing for 48 h, SH-SY5Y/IR cells in the lower chamber of transwell were collected and washed three times with PBS. To verify the proliferation ability of SH-SY5Y/IR cells after treatment, we adopted the classic detection procedure mentioned in the previous literature [52]. The cells were stained with 0.1% crystal violet, observed, and counted under the microscope.

2.10 Western blotting (WB)

WB was performed to investigate the relative protein expression levels of LRP in SH-SY5Y, hCMEC/D3, and HaCaT cells. Cells cultured overnight were washed in PBS and lysed in 100 μL RIPA lysis buffer supplemented with a protease inhibitor cocktail (Sigma, P8340, MO, USA) to extract total proteins. Total proteins were separated by SDS-PAGE and incubated with an anti-LRP primary antibody (ab92544, 1:50; Abcam, UK) or GAPDH (ab8245, internal; Abcam) overnight at 4°C. After washing three times with Tris buffer and Tween, the blots were incubated with a secondary antibody for 1 h. Finally, ImageQuant LAS4000 Mini (GE Healthcare Life Science, Beijing, China) was used to detect the protein expression.

2.11 CIRI rat model and treatment

Sprague Dawley rats (Leagene, Bio-Technology Co., Ltd, Shanghai, China) were randomly divided into five groups (Sham, tanshinone IIA [10 mg·kg−1], PLGA-PEG-COOH [100 mg·kg−1], PLGA-PEG-COOH-IT, and PLGA-PEG complex capsules). Rats in each group were intraperitoneally injected with drug and nanoparticles containing 10 mg·kg−1 tanshinone IIA for seven consecutive days as previously reported [53]. The CIRI rat model was established by the middle cerebral artery occlusion (MCAO) operation. The bilateral common carotid artery was blocked by intraperitoneal injection of 10% chloral hydrate anesthesia (0.36 mL per 100 g) in rats after ischemia for 30 min. The clamp was removed, and blood reperfusion was restored for 90 min. During the experiment, the rats were kept at normal body temperature under a 100 W silk lamp (Guangqian Lighting Co., Ltd, Zhongshan, China). At the end of the experiment, rats were sacrificed by cervical dislocation. Brain tissues were immediately harvested, rinsed with cold saline, and kept at −80°C until use [54].

2.12 Distribution of nanoparticles in the brain homogenate

After intraperitoneal injection of PLGA-PEG-COOH-IT and PLGA-PEG complex capsules (tanshinone IIA: 10 mg·kg−1) for 3 h, rats were euthanized, and brain tissues were collected for embedding, sectioning, and DAPI staining. The distribution of nanoparticles in brain tissues was observed under an inverted fluorescence microscope (Axio Observer.A1, ZEISS, Germany; excitation wavelength ICG = 780 nm and emission wavelength ICG = 845 nm).

2.13 Detection of inflammatory factor levels

Cortex tissues were placed in an ice-cold homogeneous buffer and centrifuged at 3,000 rpm to collect the supernatant. Levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) were determined using the corresponding enzyme-linked immunosorbent assay (ELISA) kits (FineTest, Wuhan, China).

2.14 Statistical analysis

Data in this study are represented as mean ± standard deviation. Student’s t-test was performed to determine differences between two groups. Statistical significance was set at P < 0.05.

3 Results

3.1 Fabrication and characterization of nanoparticles

Nanoparticles were synthesized using the W/O/W double emulsion method. The size, zeta potential, fluorescence, and drug-loading characteristics of the nanoparticles at different preparation parameters are displayed in Table 1. Based on these parameters, PLGA-PEG-COOH-IT was selected as Scheme 1 for the preparation conditions and follow-up experiments. The morphology, particle size, and zeta potential of PLGA-PEG-COOH, PLGA-PEG-COOH-IT, and PLGA-PEG complex capsules were analyzed by TEM and Zetasizer Pro (Figure 1a–f). By comparing the TEM images in Figure 1a and c, it was found that the morphology of PLGA-PEG polymer nanoparticles changed significantly after drug loading, but the size changed less (approximately 100–150 nm). The surface potential changes of PLGA-PEG-COOH and PLGA-PEG-COOH-IT also confirmed the successful drug loading (Figure 1b and d). This was partly due to the negative charge on the ICG surface [55]. Based on the surface carboxyl-conjugated angiopep-2 peptide, the PLGA-PEG complex capsule spheres retained intact monodisperse nanospheres, showing a clear double-shell structure (Figure 1e). The particle size (∼268.3 nm, PDI: 0.391) and zeta potential (∼9.29 mV) were significantly different from those previously reported (Figure 1f). To some extent, the weakly positive surface charge reflects the anti-protein adsorption performance of the nanosystem during in vivo circulation [56].

Table 1

Size, zeta-potential, fluorescence, and drug loading characteristics of the nanoparticles at different preparation parameters

Parameters Nanoparticles
PLGA-PEG-COOH PLGA-PEG-COOH-IT
1 2 3 4
Drug/ester ratio (mg·mg−1) / 1:50 1:50 1:50 1:50
Oil/external water phase (mL·mL−1) 1:3 1:3 1:10 1:20 1:10
PLGA-PEG-COOH (mg·mL−1) 50 50 50 50 25
ICG (mg) / 0.2 0.2 0.2 0.2
Tanshinone IIA (mg) / 1 1 1 1.5
Z-Average (nm) 150.2 157 236.3 198.1 191.2
PDI 0.098 0.218 0.541 0.197 0.334
Zeta (mV) −27.6 −30.5 −13.1 −14.2 −16.7
Fluorescence / Strong Strong Extremely weak Weak
Encapsulation rate (%) / 8.2 21.2 17.8 9.7
Drug loading (%) / 0.23 0.38 0.29 0.45
Figure 1 Characterization of PLGA-PEG complex capsules. TEM image, hydrodynamic size distribution, and zeta potential of PLGA-PEG-COOH (a and b), PLGA-PEG-COOH-IT (c and d), and PLGA-PEG complex capsules (e and f). (g) Fluorescence spectrum and fluorescence imaging (ICG excitation wavelength: 764 nm) of suspension samples. (h) HPLC chromatogram and in vitro release curve (pH 7.4 and 5.5) of tanshinone IIA.
Figure 1

Characterization of PLGA-PEG complex capsules. TEM image, hydrodynamic size distribution, and zeta potential of PLGA-PEG-COOH (a and b), PLGA-PEG-COOH-IT (c and d), and PLGA-PEG complex capsules (e and f). (g) Fluorescence spectrum and fluorescence imaging (ICG excitation wavelength: 764 nm) of suspension samples. (h) HPLC chromatogram and in vitro release curve (pH 7.4 and 5.5) of tanshinone IIA.

3.2 In vitro fluorescence performance and drug release characteristics of nanoparticles

Nano-encapsulation water affinity of ICG as a near-infrared dye, with NIR-II fluorescence imaging performance, acts as a tracer in the body [57,58,59]. Therefore, it is necessary to verify the fluorescence properties of composite capsules in vitro. Compared with blank PLGA-PEG-COOH, the fluorescence spectra of PLGA-PEG-COOH-IT and PLGA-PEG complex capsules showed a prominent fluorescent signal between 820 and 850 nm (Figure 1g). This also confirmed that ICG was effectively encapsulated by nanoparticles. Fluorescence images in the illustration also revealed that the complex capsules still possessed high fluorescence ability and were unaffected by the modification.

To study the drug release characteristics, the tanshinone IIA release concentration in PLGA-PEG complex capsules was determined by HPLC (Figure 1h). As a biodegradable PLGA-PEG polymer material, tanshinone IIA is released slowly with its degradation [60,61]. From the release curve, tanshinone IIA has an obvious slow-release effect owing to its encapsulation in complex capsules. Only approximately 20% of drug release rate was achieved at pH 7.4, after 120 h. However, at pH 5.5, the release behavior was significantly different, reaching nearly 40% after 120 h. At the same time, the mass ratio (angiopep-2 peptide/tanshinone IIA) determined by HPLC was approximately 0.189.

3.3 LRP expression and in vitro cytotoxicity analysis of nanoparticles

To select suitable cell lines for subsequent in vitro function tests, we first measured the relative expression levels of LRP in SH-SY5Y, hCMEC/D3, and HaCaT cells by WB. WB analysis (Figure 2a) revealed that LRP was expressed in SH-SY5Y cells but not in hCMEC/D3 and HaCaT cells. To some extent, it was confirmed that modification of the angiopep-2 peptide based on the LRP target could improve the specific internalization behavior of target cells to nano-drugs, thus enhancing cell lethality.

Figure 2 WB, cell viability, and apoptosis test in vitro. (a) LRP expressions in SH-SY5Y, hCMEC/D3, and HaCaT cells. (b) Effect of PLGA-PEG complex capsules with different dosages on SH-SY5Y and hCMEC/D3 cell viability (n = 4, mean ± SD, *P < 0.05, **P < 0.01). (c) Effects of different treatment groups on SH-SY5Y/IR cell viability co-incubated with nanoparticles before OGD/R treatment (n = 4, mean ± SD, **P < 0.01). (d and e) Representative scatter plots and statistical histogram showing apoptosis in SH-SY5Y/IR cells by flow cytometry (n = 3, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001).
Figure 2

WB, cell viability, and apoptosis test in vitro. (a) LRP expressions in SH-SY5Y, hCMEC/D3, and HaCaT cells. (b) Effect of PLGA-PEG complex capsules with different dosages on SH-SY5Y and hCMEC/D3 cell viability (n = 4, mean ± SD, *P < 0.05, **P < 0.01). (c) Effects of different treatment groups on SH-SY5Y/IR cell viability co-incubated with nanoparticles before OGD/R treatment (n = 4, mean ± SD, **P < 0.01). (d and e) Representative scatter plots and statistical histogram showing apoptosis in SH-SY5Y/IR cells by flow cytometry (n = 3, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001).

The in vitro biocompatibility and CIRI therapeutic potential of PLGA-PEG complex capsules were studied in SH-SY5Y cells and SH-SY5Y/IR cells because they are easy to culture and have a common in vitro neuron model [48,62]. First, the effects of PLGA-PEG complex capsules on SH-SY5Y and hCMEC/D3 cell viability were evaluated (Figure 2b). The MTT assay demonstrated a dose-dependent decrease in cell viability (P < 0.05), but PLGA-PEG complex capsules did not induce any obvious cytotoxicity at tanshinone IIA concentrations up to 160 μg·mL−1. In this study, the effects of PBS, tanshinone IIA, PLGA-PEG-COOH, PLGA-PEG-COOH-IT, and PLGA-PEG complex capsules on the viabilities of SH-SY5Y/IR cells were further evaluated (Figure 2c). Compared with the control group, other groups containing tanshinone IIA had higher cell viability (P < 0.01). As expected, the nano-polymer capsules protected against IR-induced cell damage. In addition, flow cytometry showed that tanshinone IIA significantly inhibited the ratio of cell apoptosis induced by IR injury (P < 0.05; Figure 2d and e). An approximately 10.6% increase in apoptosis was observed in the PLGA-PEG-COOH group compared with that in the control group (P < 0.01). The proportion of apoptotic cells in the PLGA-PEG-COOH-IT and PLGA-PEG complex capsule groups decreased significantly (8.16 ± 0.33% and 2.43 ± 0.31%, respectively; P < 0.001). These results suggest that tanshinone IIA might alleviate IR injury by inhibiting apoptosis.

3.4 In vitro intracellular distribution and the transportation of nanoparticles across BBB

The internalization behavior of cells to nanomedicine was further verified at the cellular level. In this study, the uptake of PLGA-PEG-COOH-IT and PLGA-PEG complex capsules by SH-SY5Y/IR cells was observed by fluorescence microscopy (Figure 3). Compared with the control group, a certain amount of ICG green fluorescence appeared in cells treated by PLGA-PEG-COOH-IT, indicating that some nanoparticles were successfully ingested by cells. Comparatively, the green fluorescence intensity in the PLGA-PEG complex capsules group was the most significant, indicating that angiopep-2 peptide as a specific ligand of LRPs might promote the uptake of nanoparticles [63].

Figure 3 In vitro cellular internalization evaluation of PLGA-PEG-COOH-IT and PLGA-PEG complex capsules incubated with SH-SY5Y/IR cells for 6 h by fluorescence microscope (blue: cell nuclei; green: ICG; scale: 25 μm, n = 3).
Figure 3

In vitro cellular internalization evaluation of PLGA-PEG-COOH-IT and PLGA-PEG complex capsules incubated with SH-SY5Y/IR cells for 6 h by fluorescence microscope (blue: cell nuclei; green: ICG; scale: 25 μm, n = 3).

Additional evidence to support this hypothesis was based on the transwell BBB model test in vitro. The BBB model was first established using monolayers of hCMEC/D3 cells cultured on a transwell insert with an aperture of 3 μm (Figure 4a and b). The activity of SH-SY5Y/IR cells in the lower chamber was detected to evaluate the ability of nanocomposite capsules to break through the BBB. Compared with other groups, PLGA-PEG complex capsule treatment significantly improved the ability of SH-SY5Y/IR cells to break through the BBB (P < 0.001). Compared with the control group, the PLGA-PEG complex capsule group showed perfect cell proliferation ability (P < 0.001), similar to that in Figure 2c. However, the efficacy of free tanshinone IIA is not only offset by passive diffusion and drug efflux in SH-SY5Y/IR cells but also by drug efflux mechanisms operating in hCMEC/D3 cells [51,64]. Our results confirmed the potential of PLGA-PEG complex capsules to deliver therapeutic drugs across the BBB in vitro.

Figure 4 Evaluation of biological barrier-breaking and hemolytic activity in vitro. (a and b) Schematic of the in vitro BBB model formed by hCMEC/D3 cells over transwell insert with 3 μm pores. Proliferation was assessed at the 48-h treatment of stained SH-SY5Y/IR cells with crystal violet and viewing under an optical microscope, as well as evaluation of SH-SY5Y/IR cell number in the lower chamber of transwell BBB model after 48-h incubation (n = 3, mean ± SD, **P < 0.01, ***P < 0.001). (c) Photographs of rat red blood cells after 60-min treatment with different samples: PBS (−Ref, 1), water (+Ref, 2), tanshinone IIA (3), PLGA-PEG-COOH (4), PLGA-PEG-COOH-IT (5), and PLGA-PEG complex capsules (6). (d) Graph summarizing the hemolytic activity of the corresponding groups (n = 3, mean ± SD, **P < 0.01, ***P < 0.001).
Figure 4

Evaluation of biological barrier-breaking and hemolytic activity in vitro. (a and b) Schematic of the in vitro BBB model formed by hCMEC/D3 cells over transwell insert with 3 μm pores. Proliferation was assessed at the 48-h treatment of stained SH-SY5Y/IR cells with crystal violet and viewing under an optical microscope, as well as evaluation of SH-SY5Y/IR cell number in the lower chamber of transwell BBB model after 48-h incubation (n = 3, mean ± SD, **P < 0.01, ***P < 0.001). (c) Photographs of rat red blood cells after 60-min treatment with different samples: PBS (−Ref, 1), water (+Ref, 2), tanshinone IIA (3), PLGA-PEG-COOH (4), PLGA-PEG-COOH-IT (5), and PLGA-PEG complex capsules (6). (d) Graph summarizing the hemolytic activity of the corresponding groups (n = 3, mean ± SD, **P < 0.01, ***P < 0.001).

3.5 Hemocompatibility of nanoparticles

Hemocompatibility detection in drug development research is used to observe whether the tested drug causes hemolysis and red blood cell coagulation [50]. Therefore, the biocompatibility of different nanoparticles was evaluated by a hemolysis assay after incubation for 60 min (Figure 4c and d). The pure tanshinone IIA group had a higher hemolysis rate (P < 0.001). The hemolysis rate decreased after the polymer nanoparticles were coated, and PLGA-PEG complex capsules were lower than PLGA-PEG-COOH-IT (P < 0.01). These results met the requirements for medical applications of biomaterials and indicated that the PLGA-PEG complex capsules had good biocompatibility.

3.6 Ex vivo distribution, inflammatory factor levels, and anti-ischemia–reperfusion efficacy in the MCAO rats

To evaluate the active targeting capability of angiopep-2 peptide-modified polymer nanoparticles toward the ischemic site in the rat brain, the MCAO rat model was developed as the research object [65]. PLGA-PEG-COOH-IT and PLGA-PEG complex capsules were injected intraperitoneally into MCAO rats. Ex vivo fluorescent imaging was performed on the ischemic cerebral homogenates of each group. The ICG green fluorescence intensity observed in the PLGA-PEG complex capsule groups was stronger than that of the sham and PLGA-PEG-COOH-IT groups (P < 0.01; Figure 5a and b). This indicates that the modification of the angiopep-2 peptide was conducive to the long circulation of nanoparticles and the accumulation of therapeutic drugs in the ischemic brain area. In general, the above results confirmed that the angiopep-2 peptide could actively enhance the targeting ability of nanoparticles to cerebral ischemia neurons. Also, the mechanism of angiopep-2 peptide homing to ischemic sites may be related to the overexpression of LRP in ischemic injury sites.

Figure 5 Distribution of nanoparticles and inflammatory response in brain tissues of the MCAO model. (a and b) Fluorescence distribution and intensity statistics (n = 3, *P < 0.05, **P < 0.01) of composite nanocapsules in the ischemic brain sections (DAPI blue fluorescence: cell nuclei; FITC green fluorescence: nanoparticle; scale: 20 μm). (c) The levels of TNF-α, IL-6, and CRP in the ischemic brain sections were detected by ELISA (n = 3).
Figure 5

Distribution of nanoparticles and inflammatory response in brain tissues of the MCAO model. (a and b) Fluorescence distribution and intensity statistics (n = 3, *P < 0.05, **P < 0.01) of composite nanocapsules in the ischemic brain sections (DAPI blue fluorescence: cell nuclei; FITC green fluorescence: nanoparticle; scale: 20 μm). (c) The levels of TNF-α, IL-6, and CRP in the ischemic brain sections were detected by ELISA (n = 3).

Meanwhile, the inflammatory responses at cerebral infarction sites in each group were explored. The ELISA test results in Figure 5c show that compared with other drug treatments in the MCAO model group, the treatment with PLGA-PEG complex capsules significantly decreased the levels of TNF-α, IL-6, and CRP (P < 0.01), indicating that the treatment could inhibit the inflammatory response of MCAO model mice. This result was consistent with the previous literature, reporting that tanshinone IIA could effectively alleviate cerebral ischemic injury [21]. More importantly, the treatment with PLGA-PEG-COOH-IT and PLGA-PEG complex capsules distinctly improved the neurological deficits induced by IR, indicating that tanshinone IIA exhibited greater neuroprotection than the other groups by nanoparticle encapsulation and angiopep-2 peptide functionalization. This study provided a novel approach to modify tanshinone IIA nanoparticles to elevate the ability of drug to cross the BBB [44].

4 Discussion

Over the past few decades, the branch of therapeutics based on complementary and alternative medicine has attracted considerable attention worldwide. The pharmacological efficacy of various traditional medicinal plants and their derivatives has been increasingly explored [66]. Tanshinone IIA, a fat-soluble diterpenoid isolated from Salvia miltiorrhiza Bunge, reportedly attenuates cerebral ischemic injury [21]. However, the low solubility and poor bioavailability of tanshinone IIA limit its clinical application. Nanoscale drug delivery systems are expected to produce synergistic anticancer effects, maximize therapeutic effects, and overcome multiple drug resistance [67]. The strategy of loading tanshinone IIA in nanoparticles may effectively improve the therapeutic efficacy of tanshinone IIA on CIRI. PLGA-PEG polymers have demonstrated their ability to improve traditional Chinese medicine preparations including tanshinone IIA [68,69]. However, it remains a challenge to increase the specific accumulation of drugs at injured sites and realize the controlled release of drugs in cells. In this study, tanshinone IIA was encapsulated in PLGA-PEG-COOH nanoparticles that were conjugated with ICG and angiopep-2 peptide. ICG is a water-soluble anionic tricarbocyanine dye mainly used for bioimaging applications [70]. Angiopep-2 peptide is a 19-mer peptide that can trigger transcytosis and traverse the BBB by recognizing LRP-1 expressed on the brain capillary endothelial cells [71]. After the characterization of the designed nanoparticles, the effects of tanshinone IIA-loaded PLGA-PEG-COOH nanoparticles were investigated on SH-SY5Y/IR cells and MCAO rats. Our results demonstrated that PLGA-PEG complex capsules loaded by tanshinone IIA, ICG, and angiopep-2 peptide can enhance the cellular uptake and attenuate CIRI in vitro and in vivo.

PLGA-PEG polymer nanoparticles can provide longer circulation times, thus enhancing drug localization at the treatment site and selective targeting to improve the therapeutic index. However, the optimal properties also depend on the route of administration and the particle size of the nanocarrier. Nanoparticles with larger sizes show more retention upon local injection, and smaller sizes are more optimal for passive targeting [72]. Therefore, in this study, a series of attempts were made to prepare polyethylene–polyethylene glycol polymer nanoparticles with various excellent properties (Table 1). The prepared nanoparticles were characterized by TEM (nanoparticle shape) and DLS (hydrodynamic diameter and zeta potential) methods. Previous studies reported that nanoparticles have favorable physicochemical properties, contributing to cellular uptake and in vivo drug distribution [73,74]. In this study, the size and zeta potential of PLGA-PEG complex capsules were approximately 268.3 nm and 9.29 mV, respectively. Also, the PLGA-PEG polymer nanoparticles had a weak positive surface charge and spherical morphology, which to some extent reflects the anti-protein adsorption performance of the nanosystem during in vivo circulation [56]. In addition, the drug release of PLGA-PEG complex capsules was evaluated at pH 7.4 and pH 5.5. PLGA-PEG complex capsules showed a sustained-release pattern at pH 7.4, and just approximately 20% of drug release rate was achieved after 120 h. Such a sustained drug release may pertain to the electrostatic interaction between tanshinone IIA and nanoparticles. At pH 5.5, the drug release from PLGA-PEG complex capsules reached approximately 40% after 120 h, which may be owing to the loss of negative charge of nanoparticles.

Reliable diagnosis and effective targeted therapy are important; therefore, multifunctional nanotherapeutic agents show great potential for therapeutic and diagnostic applications in various diseases [75]. Interestingly, the fluorescence properties of drug delivery systems enable the simultaneous tracking and monitoring of drugs, which is very promising for drug delivery and targeted therapy [76]. Near-infrared (NIR)-responsive drug delivery systems have received enormous attention owing to their good biocompatibility and high biological penetration [77]. Among them, ICG has the dual function of in vivo fluorescence imaging and photoacoustic imaging, as well as the characteristic of single light-triggered nanoparticle-based phototherapies, which has an important potential for the future combined treatment of diseases [78]. Nano-encapsulation water affinity of ICG as a near-infrared dye, with NIR-II fluorescence imaging performance, acts as a tracer in the body [57,58,59]. Therefore, it is necessary to verify the fluorescence properties of the composite capsules in vitro and in vivo. The results showed that the synthesized PLGA-PEG polymer nanoparticles possessed excellent fluorescence and tracking properties in vitro.

Poor drug delivery for CIRI is a critical challenge in the treatment of ischemic stroke. Inspired by the intriguing BBB-penetrating ability of cancer cells upon their brain metastasis, promising biomimetic nanoplatforms targeting CIRI have been designed [27,79]. Israel synthesized a biodegradable nontoxic β-poly(l-malic acid) as a scaffold to chemically bind the BBB-crossing peptides such as angiopep-2 and MiniAp-4, and the transferrin receptor ligands such as cTfRL and B6 [80]. Angiopep-2-modified PLGA-PEG-based nanoparticles showed higher endocytosis and parenchymal accumulation, fully demonstrating targeted selectivity for receptor-mediated drugs in the brain [81]. This study further confirmed that PLGA-PEG complex capsules can be effectively taken up by SH-SY5Y/IR cells and break through the BBB.

Resistance and low drug efficacy have prompted the investigation of new therapeutic strategies that have high efficacy and low toxicity, especially for diseases with poor prognosis [82]. The MTT assay demonstrated that the PLGA-PEG complex capsules increased the viability of SH-SY5Y/IR cells and showed good biocompatibility. At the same time, PLGA-PEG complex capsules could effectively reverse CIRI, improve cell viability, and alleviate brain injury in animals at the cellular and animal levels. Of note, PLGA-PEG complex capsules presented better mitigative effect on CIRI than free tanshinone IIA or PLGA-PEG-COOH-IT.

5 Conclusion

This study successfully designed a promising tanshinone IIA-loaded PLGA-PEG polymer nanoparticle by combining the advantages of the nano-delivery system with the BBB-penetrating properties of the angiopep-2 peptide. We demonstrated that PLGA-PEG complex capsules can penetrate the BBB, deliver tanshinone IIA to the ischemic penumbra, and enhance its antioxidant and anti-inflammatory effects in vivo. The in vitro evaluation suggested that PLGA-PEG complex capsules might have the potential to provide greater protection against SH-SY5Y cytotoxicity in an IR-based model. In general, tanshinone IIA was encapsulated into PLGA-PEG-COOH nanoparticles loaded with ICG and angiopep-2 peptide, which contributes to traversing BBB and better drug release. Thus, tanshinone IIA could exert better therapeutic effect on CIRI. Consequently, PLGA-PEG complex capsules may be utilized as a potential delivery platform for tanshinone IIA to enhance the clinical treatment of CIRI. However, further investigations are required to confirm the therapeutic efficacy of PLGA-PEG complex capsules on CIRI by animal and clinical experiments. Also, the specific cytotoxicity of PLGA-PEG complex capsules is needed to be evaluated.

# These authors have contributed equally to this work.

  1. Funding information: This work was supported by the National Natural Science Foundation of China (Grant number 81873186), and “Naoliuping” inhibits EMT and invasion and metastasis of glioblastoma through miRNAs-ZIC2 pathway mediated by DANCR and its mechanism (Grant number 2021ZZ011).

  2. Author contributions: Xin Zhang: conceptualization, funding acquisition, writing – original draft; Xutong Zhu: conceptualization, writing – original draft; Lifa Huang: data curation, formal analysis; Zupeng Chen: data curation, methodology; Yuchen Wang: data curation, supervision; Yajun Liu: data curation, visualization; Ruihan Pan: data curation, validation; Ling Lv: conceptualization, writing – review and editing.

  3. Conflict of interest: The authors state no conflict of interest.

  4. Ethics statement: The study was reviewed and approved by the Animal Experiment Ethics Committee of The First Affiliated Hospital of Zhejiang Chinese Medical University.

  5. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Received: 2022-12-27
Revised: 2023-02-06
Accepted: 2023-02-07
Published Online: 2023-03-11

© 2023 the author(s), published by De Gruyter

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

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  5. Removal efficiency of dibenzofuran using CuZn-zeolitic imidazole frameworks as a catalyst and adsorbent
  6. Rapid and efficient microwave-assisted extraction of Caesalpinia sappan Linn. heartwood and subsequent synthesis of gold nanoparticles
  7. The catalytic characteristics of 2-methylnaphthalene acylation with AlCl3 immobilized on Hβ as Lewis acid catalyst
  8. Biodegradation of synthetic PVP biofilms using natural materials and nanoparticles
  9. Rutin-loaded selenium nanoparticles modulated the redox status, inflammatory, and apoptotic pathways associated with pentylenetetrazole-induced epilepsy in mice
  10. Optimization of apigenin nanoparticles prepared by planetary ball milling: In vitro and in vivo studies
  11. Synthesis and characterization of silver nanoparticles using Origanum onites leaves: Cytotoxic, apoptotic, and necrotic effects on Capan-1, L929, and Caco-2 cell lines
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  126. Erratum
  127. Erratum to “Synthesis, characterization, and evaluation of nanoparticles of clodinofop propargyl and fenoxaprop-P-ethyl on weed control, growth, and yield of wheat (Triticum aestivum L.)”
https://doi.org/10.1515/gps-2022-8156
Keywords for this article
PLGA-PEG-COOH nanoparticles; tanshinone IIA; cerebral ischemia/reperfusion injury; angiopep-2 peptide; blood–brain barrier
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Value-added utilization of coal fly ash and recycled polyvinyl chloride in door or window sub-frame composites
  3. High removal efficiency of volatile phenol from coking wastewater using coal gasification slag via optimized adsorption and multi-grade batch process
  4. Evolution of surface morphology and properties of diamond films by hydrogen plasma etching
  5. Removal efficiency of dibenzofuran using CuZn-zeolitic imidazole frameworks as a catalyst and adsorbent
  6. Rapid and efficient microwave-assisted extraction of Caesalpinia sappan Linn. heartwood and subsequent synthesis of gold nanoparticles
  7. The catalytic characteristics of 2-methylnaphthalene acylation with AlCl3 immobilized on Hβ as Lewis acid catalyst
  8. Biodegradation of synthetic PVP biofilms using natural materials and nanoparticles
  9. Rutin-loaded selenium nanoparticles modulated the redox status, inflammatory, and apoptotic pathways associated with pentylenetetrazole-induced epilepsy in mice
  10. Optimization of apigenin nanoparticles prepared by planetary ball milling: In vitro and in vivo studies
  11. Synthesis and characterization of silver nanoparticles using Origanum onites leaves: Cytotoxic, apoptotic, and necrotic effects on Capan-1, L929, and Caco-2 cell lines
  12. Exergy analysis of a conceptual CO2 capture process with an amine-based DES
  13. Construction of fluorescence system of felodipine–tetracyanovinyl–2,2′-bipyridine complex
  14. Excellent photocatalytic degradation of rhodamine B over Bi2O3 supported on Zn-MOF nanocomposites under visible light
  15. Optimization-based control strategy for a large-scale polyhydroxyalkanoates production in a fed-batch bioreactor using a coupled PDE–ODE system
  16. Effectiveness of pH and amount of Artemia urumiana extract on physical, chemical, and biological attributes of UV-fabricated biogold nanoparticles
  17. Geranium leaf-mediated synthesis of silver nanoparticles and their transcriptomic effects on Candida albicans
  18. Synthesis, characterization, anticancer, anti-inflammatory activities, and docking studies of 3,5-disubstituted thiadiazine-2-thiones
  19. Synthesis and stability of phospholipid-encapsulated nano-selenium
  20. Putative anti-proliferative effect of Indian mustard (Brassica juncea) seed and its nano-formulation
  21. Enrichment of low-grade phosphorites by the selective leaching method
  22. Electrochemical analysis of the dissolution of gold in a copper–ethylenediamine–thiosulfate system
  23. Characterisation of carbonate lake sediments as a potential filler for polymer composites
  24. Evaluation of nano-selenium biofortification characteristics of alfalfa (Medicago sativa L.)
  25. Quality of oil extracted by cold press from Nigella sativa seeds incorporated with rosemary extracts and pretreated by microwaves
  26. Heteropolyacid-loaded MOF-derived mesoporous zirconia catalyst for chemical degradation of rhodamine B
  27. Recovery of critical metals from carbonatite-type mineral wastes: Geochemical modeling investigation of (bio)hydrometallurgical leaching of REEs
  28. Photocatalytic properties of ZnFe-mixed oxides synthesized via a simple route for water remediation
  29. Attenuation of di(2-ethylhexyl)phthalate-induced hepatic and renal toxicity by naringin nanoparticles in a rat model
  30. Novel in situ synthesis of quaternary core–shell metallic sulfide nanocomposites for degradation of organic dyes and hydrogen production
  31. Microfluidic steam-based synthesis of luminescent carbon quantum dots as sensing probes for nitrite detection
  32. Transformation of eggshell waste to egg white protein solution, calcium chloride dihydrate, and eggshell membrane powder
  33. Preparation of Zr-MOFs for the adsorption of doxycycline hydrochloride from wastewater
  34. Green nanoarchitectonics of the silver nanocrystal potential for treating malaria and their cytotoxic effects on the kidney Vero cell line
  35. Carbon emissions analysis of producing modified asphalt with natural asphalt
  36. An efficient and green synthesis of 2-phenylquinazolin-4(3H)-ones via t-BuONa-mediated oxidative condensation of 2-aminobenzamides and benzyl alcohols under solvent- and transition metal-free conditions
  37. Chitosan nanoparticles loaded with mesosulfuron methyl and mesosulfuron methyl + florasulam + MCPA isooctyl to manage weeds of wheat (Triticum aestivum L.)
  38. Synergism between lignite and high-sulfur petroleum coke in CO2 gasification
  39. Facile aqueous synthesis of ZnCuInS/ZnS–ZnS QDs with enhanced photoluminescence lifetime for selective detection of Cu(ii) ions
  40. Rapid synthesis of copper nanoparticles using Nepeta cataria leaves: An eco-friendly management of disease-causing vectors and bacterial pathogens
  41. Study on the photoelectrocatalytic activity of reduced TiO2 nanotube films for removal of methyl orange
  42. Development of a fuzzy logic model for the prediction of spark-ignition engine performance and emission for gasoline–ethanol blends
  43. Micro-impact-induced mechano-chemical synthesis of organic precursors from FeC/FeN and carbonates/nitrates in water and its extension to nucleobases
  44. Green synthesis of strontium-doped tin dioxide (SrSnO2) nanoparticles using the Mahonia bealei leaf extract and evaluation of their anticancer and antimicrobial activities
  45. A study on the larvicidal and adulticidal potential of Cladostepus spongiosus macroalgae and green-fabricated silver nanoparticles against mosquito vectors
  46. Catalysts based on nickel salt heteropolytungstates for selective oxidation of diphenyl sulfide
  47. Powerful antibacterial nanocomposites from Corallina officinalis-mediated nanometals and chitosan nanoparticles against fish-borne pathogens
  48. Removal behavior of Zn and alkalis from blast furnace dust in pre-reduction sinter process
  49. Environmentally friendly synthesis and computational studies of novel class of acridinedione integrated spirothiopyrrolizidines/indolizidines
  50. The mechanisms of inhibition and lubrication of clean fracturing flowback fluids in water-based drilling fluids
  51. Adsorption/desorption performance of cellulose membrane for Pb(ii)
  52. A one-pot, multicomponent tandem synthesis of fused polycyclic pyrrolo[3,2-c]quinolinone/pyrrolizino[2,3-c]quinolinone hybrid heterocycles via environmentally benign solid state melt reaction
  53. Green synthesis of silver nanoparticles using durian rind extract and optical characteristics of surface plasmon resonance-based optical sensor for the detection of hydrogen peroxide
  54. Electrochemical analysis of copper-EDTA-ammonia-gold thiosulfate dissolution system
  55. Characterization of bio-oil production by microwave pyrolysis from cashew nut shells and Cassia fistula pods
  56. Green synthesis methods and characterization of bacterial cellulose/silver nanoparticle composites
  57. Photocatalytic research performance of zinc oxide/graphite phase carbon nitride catalyst and its application in environment
  58. Effect of phytogenic iron nanoparticles on the bio-fortification of wheat varieties
  59. In vitro anti-cancer and antimicrobial effects of manganese oxide nanoparticles synthesized using the Glycyrrhiza uralensis leaf extract on breast cancer cell lines
  60. Preparation of Pd/Ce(F)-MCM-48 catalysts and their catalytic performance of n-heptane isomerization
  61. Green “one-pot” fluorescent bis-indolizine synthesis with whole-cell plant biocatalysis
  62. Silica-titania mesoporous silicas of MCM-41 type as effective catalysts and photocatalysts for selective oxidation of diphenyl sulfide by H2O2
  63. Biosynthesis of zinc oxide nanoparticles from molted feathers of Pavo cristatus and their antibiofilm and anticancer activities
  64. Clean preparation of rutile from Ti-containing mixed molten slag by CO2 oxidation
  65. Synthesis and characterization of Pluronic F-127-coated titanium dioxide nanoparticles synthesized from extracts of Atractylodes macrocephala leaf for antioxidant, antimicrobial, and anticancer properties
  66. Effect of pretreatment with alkali on the anaerobic digestion characteristics of kitchen waste and analysis of microbial diversity
  67. Ameliorated antimicrobial, antioxidant, and anticancer properties by Plectranthus vettiveroides root extract-mediated green synthesis of chitosan nanoparticles
  68. Microwave-accelerated pretreatment technique in green extraction of oil and bioactive compounds from camelina seeds: Effectiveness and characterization
  69. Studies on the extraction performance of phorate by aptamer-functionalized magnetic nanoparticles in plasma samples
  70. Investigation of structural properties and antibacterial activity of AgO nanoparticle extract from Solanum nigrum/Mentha leaf extracts by green synthesis method
  71. Green fabrication of chitosan from marine crustaceans and mushroom waste: Toward sustainable resource utilization
  72. Synthesis, characterization, and evaluation of nanoparticles of clodinofop propargyl and fenoxaprop-P-ethyl on weed control, growth, and yield of wheat (Triticum aestivum L.)
  73. The enhanced adsorption properties of phosphorus from aqueous solutions using lanthanum modified synthetic zeolites
  74. Separation of graphene oxides of different sizes by multi-layer dialysis and anti-friction and lubrication performance
  75. Visible-light-assisted base-catalyzed, one-pot synthesis of highly functionalized cinnolines
  76. The experimental study on the air oxidation of 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid with Co–Mn–Br system
  77. Highly efficient removal of tetracycline and methyl violet 2B from aqueous solution using the bimetallic FeZn-ZIFs catalyst
  78. A thermo-tolerant cellulase enzyme produced by Bacillus amyloliquefaciens M7, an insight into synthesis, optimization, characterization, and bio-polishing activity
  79. Exploration of ketone derivatives of succinimide for their antidiabetic potential: In vitro and in vivo approaches
  80. Ultrasound-assisted green synthesis and in silico study of 6-(4-(butylamino)-6-(diethylamino)-1,3,5-triazin-2-yl)oxypyridazine derivatives
  81. A study of the anticancer potential of Pluronic F-127 encapsulated Fe2O3 nanoparticles derived from Berberis vulgaris extract
  82. Biogenic synthesis of silver nanoparticles using Consolida orientalis flowers: Identification, catalytic degradation, and biological effect
  83. Initial assessment of the presence of plastic waste in some coastal mangrove forests in Vietnam
  84. Adsorption synergy electrocatalytic degradation of phenol by active oxygen-containing species generated in Co-coal based cathode and graphite anode
  85. Antibacterial, antifungal, antioxidant, and cytotoxicity activities of the aqueous extract of Syzygium aromaticum-mediated synthesized novel silver nanoparticles
  86. Synthesis of a silica matrix with ZnO nanoparticles for the fabrication of a recyclable photodegradation system to eliminate methylene blue dye
  87. Natural polymer fillers instead of dye and pigments: Pumice and scoria in PDMS fluid and elastomer composites
  88. Study on the preparation of glycerylphosphorylcholine by transesterification under supported sodium methoxide
  89. Wireless network handheld terminal-based green ecological sustainable design evaluation system: Improved data communication and reduced packet loss rate
  90. The optimization of hydrogel strength from cassava starch using oxidized sucrose as a crosslinking agent
  91. Green synthesis of silver nanoparticles using Saccharum officinarum leaf extract for antiviral paint
  92. Study on the reliability of nano-silver-coated tin solder joints for flip chips
  93. Environmentally sustainable analytical quality by design aided RP-HPLC method for the estimation of brilliant blue in commercial food samples employing a green-ultrasound-assisted extraction technique
  94. Anticancer and antimicrobial potential of zinc/sodium alginate/polyethylene glycol/d-pinitol nanocomposites against osteosarcoma MG-63 cells
  95. Nanoporous carbon@CoFe2O4 nanocomposite as a green absorbent for the adsorptive removal of Hg(ii) from aqueous solutions
  96. Characterization of silver sulfide nanoparticles from actinobacterial strain (M10A62) and its toxicity against lepidopteran and dipterans insect species
  97. Phyto-fabrication and characterization of silver nanoparticles using Withania somnifera: Investigating antioxidant potential
  98. Effect of e-waste nanofillers on the mechanical, thermal, and wear properties of epoxy-blend sisal woven fiber-reinforced composites
  99. Magnesium nanohydroxide (2D brucite) as a host matrix for thymol and carvacrol: Synthesis, characterization, and inhibition of foodborne pathogens
  100. Synergistic inhibitive effect of a hybrid zinc oxide-benzalkonium chloride composite on the corrosion of carbon steel in a sulfuric acidic solution
  101. Review Articles
  102. Role and the importance of green approach in biosynthesis of nanopropolis and effectiveness of propolis in the treatment of COVID-19 pandemic
  103. Gum tragacanth-mediated synthesis of metal nanoparticles, characterization, and their applications as a bactericide, catalyst, antioxidant, and peroxidase mimic
  104. Green-processed nano-biocomposite (ZnO–TiO2): Potential candidates for biomedical applications
  105. Reaction mechanisms in microwave-assisted lignin depolymerisation in hydrogen-donating solvents
  106. Recent progress on non-noble metal catalysts for the deoxydehydration of biomass-derived oxygenates
  107. Rapid Communication
  108. Phosphorus removal by iron–carbon microelectrolysis: A new way to achieve phosphorus recovery
  109. Special Issue: Biomolecules-derived synthesis of nanomaterials for environmental and biological applications (Guest Editors: Arpita Roy and Fernanda Maria Policarpo Tonelli)
  110. Biomolecules-derived synthesis of nanomaterials for environmental and biological applications
  111. Nano-encapsulated tanshinone IIA in PLGA-PEG-COOH inhibits apoptosis and inflammation in cerebral ischemia/reperfusion injury
  112. Green fabrication of silver nanoparticles using Melia azedarach ripened fruit extract, their characterization, and biological properties
  113. Green-synthesized nanoparticles and their therapeutic applications: A review
  114. Antioxidant, antibacterial, and cytotoxicity potential of synthesized silver nanoparticles from the Cassia alata leaf aqueous extract
  115. Green synthesis of silver nanoparticles using Callisia fragrans leaf extract and its anticancer activity against MCF-7, HepG2, KB, LU-1, and MKN-7 cell lines
  116. Algae-based green AgNPs, AuNPs, and FeNPs as potential nanoremediators
  117. Green synthesis of Kickxia elatine-induced silver nanoparticles and their role as anti-acetylcholinesterase in the treatment of Alzheimer’s disease
  118. Phytocrystallization of silver nanoparticles using Cassia alata flower extract for effective control of fungal skin pathogens
  119. Antibacterial wound dressing with hydrogel from chitosan and polyvinyl alcohol from the red cabbage extract loaded with silver nanoparticles
  120. Leveraging of mycogenic copper oxide nanostructures for disease management of Alternaria blight of Brassica juncea
  121. Nanoscale molecular reactions in microbiological medicines in modern medical applications
  122. Synthesis and characterization of ZnO/β-cyclodextrin/nicotinic acid nanocomposite and its biological and environmental application
  123. Green synthesis of silver nanoparticles via Taxus wallichiana Zucc. plant-derived Taxol: Novel utilization as anticancer, antioxidation, anti-inflammation, and antiurolithic potential
  124. Recyclability and catalytic characteristics of copper oxide nanoparticles derived from bougainvillea plant flower extract for biomedical application
  125. Phytofabrication, characterization, and evaluation of novel bioinspired selenium–iron (Se–Fe) nanocomposites using Allium sativum extract for bio-potential applications
  126. Erratum
  127. Erratum to “Synthesis, characterization, and evaluation of nanoparticles of clodinofop propargyl and fenoxaprop-P-ethyl on weed control, growth, and yield of wheat (Triticum aestivum L.)”
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