- Open Access
PEGylated self-assembled enzyme-responsive nanoparticles for effective targeted therapy against lung tumors
© The Author(s) 2018
- Received: 13 March 2018
- Accepted: 6 July 2018
- Published: 16 July 2018
Matrix-metalloproteinases, which are overexpressed in many types of cancer, can be applied to improve the bioavailability of chemotherapeutic drugs and guide therapeutic targeting. Thus, we aimed to develop enzyme-responsive nanoparticles based on a functionalized copolymer (mPEG-Peptide-PCL), which was sensitive to matrix metalloproteinase, as smart drug vesicles for enhanced biological specificity and reduced side effects.
The rate of in vitro curcumin (Cur) release from Cur-P-NPs was not markedly accelerated in weakly acidic tumor microenvironment, indicating a stable intracellular concentration and a consistent therapeutic effect. Meanwhile, P-NPs and Cur-P-NPs displayed prominent biocompatibility, biostability, and inhibition efficiency in tumor cells. In addition, Cur-P-NPs showed higher fluorescence intensity than Cur-NPs in tumor cells, implying enhanced cell permeability and targeting ability. Moreover, the internalization and intracellular transport of Cur-P-NPs were mainly via macropinocytosis. Studies of pharmacodynamics and cellular uptake in vitro and biodistribution in vivo demonstrated that Cur-P-NPs had stronger target efficiency and therapeutic effect than Cur-DMSO and Cur-NPs in tumor tissue.
Results indicate that Cur-P-NPs can be employed for active targeted drug delivery in cancer treatment and other biomedical applications.
- Enzyme-responsive nanoparticles
- Cell-penetrating peptide
- Matrix metalloproteinase
- Cellular uptake
- Tumor extracellular environment
Lung cancer is currently one of the most prevalent cancers in the world with high morbidity and mortality [1–3]. In developing countries, in particular, the increasing incidence of lung cancer has not been effectively controlled [4, 5]. Histologically, lung cancer is classified as small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Due to the high prevalence of tobacco consumption, NSCLC is found to occur more commonly compared to SCLC [6, 7]. Several researchers have reported that neoangiogenesis is a significantly negative prognostic factor in lung cancer [8, 9]. Therefore, an effective anti-angiogenesis drug for NSCLC therapy is urgently required. Curcumin (Cur), an active substance extracted from turmeric, has been widely studied for its anti-inflammatory , anti-angiogenic , antioxidant , wound healing [13, 14], and anti-cancer effects . Furthermore, Cur can reverse chemo-resistance by inhibiting multiple signaling pathways. However, its poor water solubility, structural instability, low membrane permeability, and bioavailability has greatly inhibited the application of Cur in clinic.
In the last two decades, nanotechnology has been greatly developed in the arena of biomedicine, pharmaceuticals, and drug delivery [16, 17]. Nanoparticles, one of the representative nano delivery systems, are developed for use in oncotherapy due to specific properties, such as surface modification, good stability, and low toxicity . However, indistinctive tumor cell specific uptake and the rapid elimination of nanoparticles by the reticuloendothelial system (RES) are still barriers in efficient drug delivery in vivo . To address these challenges, functionalized nanoparticles such as magnetic nanoparticles [20–22], redox-sensitive nanoparticles , pH-response nanoparticles [24, 25], and enzyme-response nanoparticles [26–28] were designed. Because specific enzymes are overexpressed in tumor cells, enzyme-responsive nanoparticles can be an excellent candidate for designing a smart drug delivery system. Matrix metalloproteinases (MMPs) are over-expressed in many types of cancer. Therefore, they are logical targets for enzyme-triggered therapeutics. MMP targeting peptides have been successfully designed [29, 30]. In addition, increasing evidence demonstrates that cell penetrating peptides (CPPs) can help to enhance the ability of cell penetration in cargo delivery. Therefore, the combination of targeting peptides and CPPs could be a potential strategy for improving the effectiveness of cancer therapy.
In this study, we successfully synthesized a novel enzyme-responsive nanoparticle based on a tri-block biomaterial (mPEG-Peptide-PCL), which reconfigures in response to MMPs that are active and overexpressed in cancers, to guide therapeutic targeting. In mPEG-Peptide-PCL, PCL was used for drug loading; (ACP)-GPLGIAGQr9-(ACP) was selected as the targeting peptide. GPLGIAGQ was designed for degradation by MMP-2 , and the exposed cell penetrating peptide r9 would enhance the cellular uptake of nanoparticles ; PEGylation could improve the stability of the carrier, and prolong the retention time in vivo. Thereafter, the nanoparticle was prepared by the solvent evaporation method. In vitro, the accumulative releasing rate of the drug (Cur as the model drug) in different pH conditions was also evaluated. Furthermore, the toxicity and cellular uptake (including mechanism study) of the biomaterials were assessed in L929 mouse embryonic fibroblasts and NSCLC A549 cells. In vivo, due to a strong fluorescence effect of Cur, the selective targeting behavior and biodistribution of mPEG-Peptide-PCL nanoparticles were measured using an in vivo imaging system.
Cur was purchased from Hangzhou Guang Lin Biological Pharmaceutical Co. Ltd. (Hangzhou, China). (ACP)-GPLGIAGQr9-(ACP) was from ChinaPeptides Co. Ltd. (Shanghai, China). Poloxamer188 was obtained from BASF (Shanghai, China). Stannous 2-ethylhexanoate [Sn(Oct)2] was obtained from Sigma (St. Louis, MO, USA). Dialysis bags (MWCO = 14,000) were obtained from Gene Star Co. (Shanghai, China). L929 mouse embryonic fibroblasts and A549 cells were from the Cell Bank of the Chinese Academy of Sciences (Beijing, China). Kunming mice were obtained from Zhejiang Academy of Medical Sciences (Hangzhou, China). mPEG (Mn = 1900) and ε-caprolactone (ε-CL) were purchased from Aladdin Chemicals (Shanghai, China). Other reagents (analytical or chromatographic grade) were obtained from Aladdin Chemicals.
Synthesis of tri-block copolymer
Synthesis of PCL-NH2
2-(tert-Butoxycarbonylamino)-1-ethanol (922.1 mg, 5.72 mmol), ε-caprolactone (9.9987 g, 87.6 mmol), and Sn(Oct)2 (catalyst, 40 μL, 0.124 mmol) were mixed in a 100 mL three-necked flask. Then a polymerization reaction was performed at 120 °C under dry nitrogen for 24 h. PCL-NHtBoc was purified by precipitation in cold methanol to remove the unreacted monomer and oligomer, and the purified product was obtained after filtration and vacuum drying at 40 °C for 24 h.
PCL-NHtBoc (5 g) was dissolved into DCM (20 mL), and 4 mL trifluoroacetic acid was added to the solution; the solution was stirred for 8 h at 0 °C under dry nitrogen. After the reaction was completed, the crude copolymer (PCL-NH2) solution was washed with saturated NaHCO3 solution and distilled water; the extraction process was repeated three times. DCM solution was collected and added drop-wise to cold methanol (1:15, v/v). PCL-NH2 was purified by precipitation, and obtained after filtration and vacuum drying at 40 °C for 24 h. The number average molecular weight (Mn), the weight-average molecular weight (Mw), and polydispersity index (PDI) of PCL-NH2 were measured by Gel Permeation Chromatography (GPC) analysis .
Synthesis of mPEG-NHS
mPEG (Mw: 1900, 7.6 g, 4 mmol) and butanedioic anhydride (0.8 g, 8 mmol) were dissolved in pyridine (60 mL), then 4-dimethylaminopyridine (DMAP, 73.3 mg, 0.6 mmol) and triethylamine (404.8 mg, 4 mmol) were added, followed by mixing of the solutions. The mixture was stirred under dry nitrogen at room temperature for 24 h. After the reaction was completed, the crude product was dissolved in DCM (20 mL) and precipitated into cold ethyl ether (1:15, v/v). The precipitate (mPEG-COOH) was dried in vacuo at 25 °C for 48 h to remove the solvent.
mPEG-COOH (5.0 g, 2.5 mmol) and N-hydroxy succinimide (1.2 g, 10 mmol) were dissolved in acetonitrile (60 mL), followed by addition of N,N′-dicyclohexylcarbodiimide (DCC, 1.0316 g, 5 mmol). The reaction was carried out under N2 protection at room temperature for 24 h. The purification process used was the same as that used for mPEG-COOH.
Synthesis of mPEG-Peptide-PCL
The peptide (50 mg, 0.0213 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 27.3 mg, 0.142 mmol), and DMAP (17.4 mg, 0.142 mmol) were dissolved in acetonitrile–water solution (20/80, 10 mL), and the mixture was stirred under dry nitrogen at 0 °C for 2 h to activate the peptide. Thereafter, mPEG-NHS (49.9 mg, 0.0178 mmol) was mixed into the reaction solution, and transesterification was allowed to occur at room temperature for 24 h. The mPEG-Peptide solution was purified by dialysis (Mw: 3500) for 72 h, and lyophilized to the powder form. The Mn, Mw, and PDI were measured by GPC .
mPEG-Peptide (100 mg, 0.0194 mmol), DCC (40 mg, 0.1942 mmol), and N-hydroxy succinimide (23.7 mg, 0.1942 mmol) were dissolved in DCM (10 mL), followed by stirring of the mixture under dry nitrogen at 0 °C for 2 h. Later, PCL-NH2 (165 mg, 0.0291 mmol) was added to the mixture, and the mixture was further stirred at room temperature for 96 h. After the reaction was completed, the mPEG-Peptide-PCL solution was purified by dialysis (Mw: 7000) for 72 h, and lyophilized to powder. The structure of mPEG-Peptide-PCL was confirmed by Fourier transform infrared (FT-IR) spectroscopy (Nicolet 6700; Thermo Fisher Scientific, USA) and 1H-NMR spectroscopy, and the Mn, Mw, and PDI of mPEG-Peptide-PCL were measured by GPC . Meanwhile, mPEG-PCL as a contrast compound was aggregated by mPEG and ε-caprolactone as per the method described in “Synthesis of PCL-NH2” section.
Preparation of Cur-loaded NPs
Cur-P-NPs were prepared by the emulsion-solvent evaporation method. The optimal conditions for the preparation were as follows: Cur (2.4 mg) and mPEG-Peptide-PCL (24.0 mg) were co-dissolved in 2 mL acetone, and added drop-wise to 10 mL of an aqueous phase containing Poloxamer-188 (20.0 mg) under magnetic stirring. The mixture was stirred for 4 h to remove acetone. The NP suspension was then filtrated through 0.45 μm filter membrane to remove the unwrapped Cur and achieve a homogeneous suspension. At last, the nanoscaled suspensions were centrifuged at 19,000 rpm for 30 min. The precipitate was collected and washed twice with deionized water, and lyophilized. The fundamental characterization of particle size, polymer dispersity index (PDI), and Zeta potential were measured by a laser particle analyzer (Malvern Zetasizer Nano-ZS90; Malvern, UK).
Entrapment efficiency (EE) and drug loading (DL)
The morphology of the Cur-P-NPs was observed by transmission electron microscopy (TEM) on a JEOL JEM-1010 at 40,000× magnification.
X-ray diffraction (XRD)
For the study of the surface properties of Cur-P-NPs, X-ray diffraction (XRD) analysis was carried out with the following parameters: output voltage = 40 kV, output current = 40 mA, and wave length = 0.1546 nm.
In vitro stability of mPEG-Peptide-PCL and Cur-P-NPs
The mPEG-Peptide-PCL (100 mg) was dissolved in 10 mL tetrahydrofuran. Then, 2 mL of the mPEG-Peptide-PCL solution was diluted four-fold using 0.1 M PBS (pH 7.4), DMEM, and fetal bovine serum and incubated at 37 °C. At every given time point (0, 1, 4, 8, and 24 h), 1 mL of the sample solution was collected (for fetal bovine serum sample, excess acetonitrile was added to remove the protein, followed by centrifugation), and the Mn, Mw, and PDI of mPEG-Peptide-PCL were measured using GPC as described above.
Cur-P-NPs solution (2 mL) was diluted four-fold using 0.1 M PBS (pH 7.4), DMEM, and fetal bovine serum and incubated at 37 °C. At every given time point (0, 1, 4, 8 and 24 h), 1 mL of the sample solution was collected (for fetal bovine serum sample, excess acetonitrile was added to remove the protein, followed by centrifugation), and the particle diameter and PDI of Cur-P-NPs were measured.
In vitro drug release
In vitro drug release was studied by dialysis. Cur-DMSO (5 mL) and Cur-P-NPs (5 mL × 2) with the same Cur content (150 μg/mL) were prepared. Dialysis of Cur-DMSO, the control group, was carried out at pH 7.4, and that of Cur-P-NPs (5 mL × 2), the treatment group, was carried out at 7.4 and 6.5, simulating the conditions of systemic circulation and weakly acidic tumor environment,respectively. The solutions were poured into dialysis bags (Mw 14 kDa). Then, the bags were submerged in 50 mL PBS at the respective pH values, and placed in an incubator at 37.0 °C ± 0.5 °C with shaking at 100 rpm. At predetermined time points (0, 1, 2, 4, 6, 12, 24, 36, 48, 60, 72, and 96 h), 3.0 mL of external solution was removed and replaced with an equivalent volume of fresh dissolution medium. The Cur content was determined by ultraviolet spectrophotometry.
L929 mouse embryonic fibroblasts and A549 lung carcinoma cells were maintained in DMEM with 10% (v/v) fetal calf serum, penicillin (100 μg/mL), and streptomycin (100 μg/mL), and incubated in a humid atmosphere at 37 °C with 5% CO2.
In vitro cytotoxicity of NPs
The cytotoxicity of NPs was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using L929 mouse embryonic fibroblasts. Cells were seeded in 96-well plates at a density of 1 × 105 cells/well. After 24 h of appropriate growth, various doses of sterilized blank NP or medium only (negative control) were added, and the cells were incubated for 48 h. All samples were prepared in triplicate. A 20 μL volume of MTT labeling reagent was added, and cells were cultured for 4 h at 37 °C. The absorbance was measured at 570 nm, and cell viability (%) was represented as the ratio of the absorbance of the test and negative control solutions.
In vitro anticancer activity assay
The efficacy of Cur-P-NPs solution against lung cancer cell viability was assessed in A549 cell lines by MTT analysis. Cells were seeded in 96-well plates at a density of 1 × 105 cells/well, and incubated with 100 μL of the different dilutions of Cur-P-NPs or medium only (negative control) for 48 h. A 20-μL volume of MTT labeling reagent was added, and cells were co-cultured for 4 h at 37 °C. All samples were prepared in triplicate. The cell viability (%) was determined as per the method described in “In vitro cytotoxicity of NPs” section.
L929 (as non-target cells) and A549 cells (as target cells) were seeded in 96-well plates (105 cells/well), respectively. Thereafter, 100 μL of Cur-DMSO, blank NPs, Cur-NPs (prepared using mPEG-PCL without peptide modification), Cur-P-NPs, or DMSO only (negative control) with Cur content of 50 μg/mL were co-cultured at 37 °C for 4 h. The medium was then discarded, and the cells were washed with PBS thrice. Cellular uptake was evaluated by fluorescence microscopy at 200× magnification (Eclipse Ti-S; Nikon, Tokyo, Japan).
Endocytic mechanism of Cur-P-NPs
To further study the endocytic mechanism of Cur-P-NPs in A549 cells, chlorpromazine (an endocytosis inhibitor of clathrin-mediated endocytosis), cytochalasin D (an endocytosis inhibitor of macropinocytosis mediated endocytosis), or genistein (an endocytosis inhibitor of caveolae-mediated endocytosis) were used, with no treatment as control . Firstly, cells were seeded in 12-well plates (105 cells/well) and co-cultured at 37 °C for 1 h with 100 μL of the endocytosis inhibitors at concentrations of 1, 5, or 25 μM. The medium was removed and replaced with complete medium containing Cur-P-NPs (Cur:50 μg/mL) and different inhibitors for another 15 min. Thereafter, the medium was removed and the cells were washed twice with PBS solution. The cells were finally analyzed by flow cytometry (Beckman Coulter Cytoflex; Beckman, USA). All experiments were carried out in triplicate.
Pharmacokinetic distribution studies were performed in nude mice . About 5 × 107 A549 cells in 200 μL PBS were subcutaneously injected into the left hind flank of the mice. Once the tumors had reached ~ 100 mm3 in size (typically 2 weeks later), 0.2 mL of Cur-DMSO, and Cur-NPs and Cur-P-NPs with a Cur content of 50 μg/mL were injected in the tumor-bearing mice via the tail vein at a Cur dose of 1.5 mg/kg. For the imaging studies, mice were anesthetized at the prescribed time points (1 and 6 h), and the images were shot using a small animal imager (IVIS, Lumina XRMS III) with Ex = 488 nm and Em = 520 nm. All the samples were prepared in triplicate.
Results were expressed as mean ± standard error of the mean. Differences between groups were examined for statistical significance with the Student’s t-test, and P-values < 0.05 were considered statistically significant.
Tri-block polymer characterization
Mn, Mw, and PDI of the prepolymers
Characterization of NPs
Physicochemical characteristics of Cur-P-NPs
Particle size (nm)
Zeta potentials (mV)
159.7 ± 2.566
0.116 ± 0.017
5.74 ± 1.46
180.3 ± 2.227
0.131 ± 0.025
3.48 ± 0.408
In vitro stability of mPEG-Peptide-PCL and Cur-P-NPs
In vitro drug release
Cytotoxicity evaluation of blank P-NPs for different concentration
Cell viability (%)
2.05 (origin solution)
87.86 ± 1.232
89.72 ± 1.077
93.46 ± 0.839
97.22 ± 0.955
97.96 ± 0.826
97.73 ± 0.426
In vitro anticancer activity assay
To further evaluate the enzyme-targeted availability of Cur-P-NPs, the ability of cellular uptake was compared between L929 (non-target cells) and A549 (target cells) cells. As illustrated in Fig. 10E, F, more Cur-P-NPs were internalized by A549 than L929, demonstrating that the Cur-P-NPs are a site-specific drug delivery system targeting tumors.
Endocytic mechanism of Cur-P-NPs
In the current study, a novel mPEG-Peptide-PCL with enzyme sensitivity was successfully synthesized; the peptide can self-assemble to form nanoparticles as a biomimetic platform with tumor targeting ability. The cytotoxicity and stability analysis revealed that Cur-P-NPs exhibited excellent biocompatibility and biostability. The in vitro release profiles of Cur from the NPs were observed to be similar to those observed under systemic circulation and a weakly acidic tumor environment, indicating a stable intracellular concentration of Cur and a consistent therapeutic effect. The cellular uptake of drugs in tumor cells occurred mainly via macropinocytosis. Moreover, in nude mice, Cur-P-NPs displayed stronger fluorescence than Cur-DMSO and Cur-NPs, demonstrating more effective target efficiency and therapeutic effect. This result is in agreement with those reported by pharmacodynamics and cellular uptake studies in vitro. Therefore, Cur-P-NPs can be employed as an active targeting drug delivery system for lung cancer treatment.
FyG and GsY conceived and designed the experiments. FyG, JqW, WcW, and DxH performed the experiments. FyG, QyY, and QlY analyzed the data. FyG, YG, and GsY drafted and wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
All authors have provided consent for the manuscript to be published.
Ethics approval and consent to participate
All animal experiments were performed in compliance with the local ethics committee of the ZJUT.
This work was financial supported by the National Natural Science Foundation of China (No. 21376223).
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