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Construction of esterase-responsive hyperbranched polyprodrug micelles and their antitumor activity in vitro

  • Jianxia Qiao , Shufen Li , Haoyu Yuan , Yujie Wang , Jianhong Li , Peilong Wang and Xiao Duan EMAIL logo
Published/Copyright: May 23, 2022
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e-Polymers
From the journal e-Polymers Volume 22 Issue 1

Abstract

This research constructs an esterase-responsive hyperbranched polyprodrug nano pharmaceutical and investigates their antitumor activity. Polyprodrug micelle was prepared by one-pot method based on glutathione (GSH), doxorubicin (DOX), and polyethylene glycol (PEG) under the catalyst of N,N-dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), and 1-hydroxybenzotriazole (HOBt). The polyprodrug was characterized by nuclear magnetic resonance (NMR), Fourier transform infrared spectrometer (FT-IR), ultraviolet-visible spectrophotometer (UV-Vis), dynamic light scattering (DLS), and transmission electron microscope (TEM), respectively. The antitumor activity of polyprodrug micelle was evaluated by Hela cell and the distributions of micelles in cells were observed by fluorescent microscope. The NMR and FT-IR confirmed that the DOX-GSH-PEG polyprodrug was successfully synthesized. The drug loading rate is 10.21% and particle size is 106.4 ± 1 nm with a narrowed polydispersity (PDI = 0.145). The DLS showed that the micelles were stable during 7 days at 25°C. The drug release results showed that the micelles could be esterase-responsive disrupted, and the drug release rate could reach 43% during 72 h. Cell uptake and cell viability demonstrated that the micelles could distribute to cell nuclei during 8 h and induce cell apoptosis during 48 h. Overall, these hyperbranched polyprodrug micelles prepared by one-pot method could be esterase-responsive disrupted and release the antitumor drugs in a high esterase environment for cancer therapy in vitro. These results confirm that DOX-GSH-PEG is an effective nanomedicine in vitro and the endogenous-based strategy with one-pot synthesis to construct esterase-responsive polyprodrug would probably be a preferred choice in the future.

Keywords: doxorubicin; polyprodrug micelles; esterase-responsiveness; drug controlled-release; antitumor

1 Introduction

Chemotherapeutic is the most important and common method for cancer therapy in clinical application. However, the severe side effects on normal tissues are the major reason for the failure of cancer therapy (1,2,3). Many different smart-responsive drug delivery systems (DDS) were reviewed by researchers (4) and these smart-responsive DDS, including pH (5), temperature (6), enzymes (7), redox-reduction (8), etc., can significantly decrease the side effects of chemotherapeutics to normal tissues (9,10,11). Meanwhile, there are still many challenges of nanomedicines for clinical translation (12,13). One of the most important factors is the massive number of un-approved biocompatible materials in DDS (14,15,16,17) for developing the novel nanomedicines for clinical use (18). Although many biocompatible materials, like polylactic acid (19), poly(lactic-co-glycolic acid) (20), and polycaprolactone (6), showed good biocompatibility in vitro and in vivo, the endogenous-based biomaterials (21,22,23,24,25,26) are the perfect carriers to construct novel nanomedicine for the possible clinical application. Some endogenous organic or inorganic materials (27,28) were successfully used in constructing novel nanomedicines with higher biocompatibility.

Glutathione (GSH) is an endogenous molecule in the human body. The GSH molecule could be detected in tumor cells and normal cells, especially the tumor cells. The concentration range of GSH in different tumor cells is 2–20 mM (29,30). GSH-based prodrug nanomedicine is probably the better choice for addressing the problem of carriers’ safety in vivo. Fortunately, the carboxyl groups in GSH could be reacted with hydroxyl in DOX by easternization reaction for constructing esterase-responsive polyprodrug. The formation and disruption of the ester bond could be triggered under the catalyst of enzymes (7,31), supporting the application of esterase-responsive drug-releasing in drug delivery field.

Given the main consideration of carriers’ safety in clinical application, the hyperbranched polyprodrug micelle was fabricated with Food and Drug Administration (FDA)-approved material of polyethylene glycol, an endogenous molecule of GSH and the anticancer drug of doxorubicin (DOX) by one-pot method. The hydroxyl and amino groups in DOX could be reacted with carboxyl groups in GSH to form enzyme-responsive ester bonds and amido bonds. The ultimate product of hyperbranched polyprodrug (DOX-GSH-PEG) could be assembled into nano micelle in water or PBS and disrupted with a high concentration of esterase. This endogenous-based strategy with one-pot synthesis to construct esterase-responsive polyprodrug would probably be a preferred choice in the future.

2 Materials and methods

2.1 Materials

Doxorubicin hydrochloride (DOX·HCl, purity 98%), dicyclohexylcarbodiimide (DCC, purity 98%), 4-dimethylaminopyridine (DMAP, purity 99%), 1-hydroxybenzotrizole (HOBt, purity 97%), and GSH (purity 98%) were purchased from Macklin biocompany (Shanghai, China). Amino-polyethylene-glycol monomethyl ether (mPEG-NH2, purity 95%) was purchased from Yarebio company (Shanghai, China). Esterase (lyophilized powder, ≥15 units‧mg−1 solid) was obtained from Xianding biotech company (Shanghai, China). Cell counting Kit-8 (CCK-8), Hoechst 33258 Staining Kit, and trypsin cell digestion solution (0.25%) were purchased from Beyotime Biotechnology Company (China). Fetal bovine serum was purchased from Tianhang biotech company (Zhejiang, China). All other organic solvents were obtained from Fuchen chemical company (Tianjin, China).

2.2 Instruments

Vacuum freeze drier (FD-2), Ultraviolet-visible spectrophotometer (UV-Vis; TU-1901), fluoro spectrophotometer (RF-6000), Fourier transform infrared spectrometer (FT-IR) (Tensor 27, Bruker), dynamic light scattering (DLS) (Malvern, Zetasizer Nano ZSE), clean bench (SW-CJ-2FD), CO2 incubator (CQ-80L), fluorescent inverted microscope (IX53, Olympus), multifunctional enzyme marker (Infinite 200Pro, Tecan), nuclear magnetic resonance (NMR) (Bruker Avance 400 MHz), transmission electron microscope (TEM) (FEI Tecnai F20).

2.3 Preparation of hyperbranched polyprodrug micelle (DOX-GSH-PEG)

The GSH (127.5 mg) and DCC (186.7 mg) were added to a round flask with 10 mL dried DMF at temperature. One hour later, the DOX·HCl (100 mg) and DMAP (25.3 mg) were added to the same flask for reacting for 12 h in the darkroom. After that, the mPEG-NH2 (172.8 mg) and HOBt (9.3 mg) were added to the flask for continuously reacting for 5 days. The reaction solution was put into centrifuge tubes and centrifuged at high speed. Then, the supernatant was transferred to a dialysis bag (MWCO 3500) and immersed in a beaker with 200 mL of fresh DMF (change fresh DMF 3 times during 3 days). After that, the dialysis bag was immersed in water (change fresh water multiple times). The reaction solution in the dialysis bag was centrifuged at high speed and the supernatant was filtered by a 0.45 mm membrane. The filtered solution was freeze-dried, and the red powder was obtained. The structure of DOX-GSH-PEG was confirmed by FT-IR and NMR (yield: 40%).

2.4 Measurement of polyprodrug micelle’ particle and stability

One milligram red powder of DOX-GSH-PEG was dissolved in 3 mL of pure water under sonic conditions. Then, the DOX-GSH-PEG solution was filtered using a 0.45 mm membrane and prepared for particle measurement. The 1 mg red powder of DOX-GSH-PEG was dissolved in 12 mL of pure water. Then, 1 mL of micelle solution was put into a vial and 1 mg esterase was put into the same vial to measure the micelle particles’ change. Another vial with micelle was prepared without adding esterase as the control group. The micelle particles’ stability was evaluated using DLS at different time points.

2.5 Measurement of drug loading and drug release

The standard curve of DOX was measured by UV-Vis at 481 nm. The standard curve equation is A = 0.0186 C. The UV-Vis curves at 481 nm did not significantly change between free DOX and DOX-GSH-PEG. Based on the curves of free DOX and DOX-GSH-PEG at 481 nm, the approximate drug loading could be determined by the standard curve equation.

Three groups of DOX-GSH-PEG (6 mg) were dissolved into PBS, PBS with 2.5 U‧mL−1 esterase and PBS with 15 U‧mL−1 esterase, respectively, and put into corresponding dialysis bags (MWCO 3500). Then, the dialysis bags were put into the flasks and immersed in corresponding media. After that, the fixed volumes (3 mL) were taken out from flasks and added corresponding fresh media (PBS with 2.5 U‧mL−1 esterase and PBS with 15 U‧mL−1 esterase) to the flasks at fixed time points for 72 h. The absorbance of fixed volumes was measured by UV-Vis and the drug release rate could be calculated and determined depending on the standard curves of DOX. The drug release experiments were conducted twice.

2.6 Cell uptake experiment

Hela cells were seeded in a 24-well plate with a density of 1 × 105 cells per well. Twelve hours later, the media is discarded. Then, the prepared media of free DOX, DOX with 7.5 U‧mL−1 esterase, DOX-GSH-PEG, and DOX-GSH-PEG with 7.5 U‧mL−1 esterase were added to 24-well plate for continuously cultivating 30 min, 4 h, and 8 h, respectively. The concentration of DOX in DOX-GSH-PEG and free DOX was set up for 20 μg·mL−1. The media with the drug were discarded and the dye solution of Hoechst 33258 was added to 24-well for 30 min. After that, the cells were rinsed with fresh PBS three times. Finally, the distributions in cells of DOX and DOX-GSH-PEG were observed under inverted fluorescence microscope.

2.7 Cell viability experiment

The Hela cell viabilities were evaluated by CCK-8 kit treated by DOX and DOX-GSH-PEG micelle. The detailed process: Hela cells were seeded in a 96-well plate with a density of 8 × 103 cells per well. Twelve hours later, the media is discarded. Then, the DOX and DOX-GSH-PEG were dissolved into media with 2% fetal bovine serum and added to 96-well plate. The concentration of DOX in DOX-GSH-PEG is set up as 10, 20, and 40 μg·mL−1, respectively. The DOX-GSH-PEG group with 7.5 U‧mL−1 esterase and without esterase and its control groups were set up. After the Hela cells were treated with DOX and DOX-GSH-PEG for 24 and 48 h, the media were discarded and the fresh PBS (100 μL) with 5 μL CCK-8 was added to the 96-well plate for continuously cultivating for 1 h. Finally, the 96-well plate was measured by Microplate Reader at 450 nm.

3 Results and discussion

3.1 Synthesis and characterization of hyperbranched polyprodrug

The synthesis route of GSH-based hyperbranched polydoxorubicin prodrug is shown in Figure 1a. In Figure 1b, the characteristic peaks of ether bond (1,200 cm−1) in mPEG-NH2 and DOX-GSH-PEG are observed. The C═O peaks in DOX, GSH, and DOX-GSH-PEG are shown in Figure 1b. The carboxyl groups in GSH could be reacted with hydroxyl and amino groups in DOX to form a polymer of DOX-GSH with massive ester bonds and amido bonds. The excess carboxyl groups could be on the surface of DOX-GSH for further conjugating with mPEG-NH2 to form the amphiphilic hyperbranched polyprodrug (DOX-GSH-PEG). The NMR and FT-IR confirmed the structure of DOX-GSH-PEG. We can observe the characteristic peak of the benzene ring (7.5–8.0 ppm) in DOX-GSH-PEG (Figure 1c) and free DOX (Figure 1d), meaning that the DOX was conjugated with GSH in DOX-GSH-PEG. The characteristic peak of –CH2CH2O– (3.6 ppm) in PEG can be observed in Figure 1c compared with free DOX in Figure 1d. These NMR and FT-IR results fully demonstrated that the DOX-GSH-PEG was successfully synthesized.

Figure 1 (a) Synthesis route of hyperbranched polyprodrug; (b) FT-IR spectra of DOX, GSH, PEG, and DOX-GSH-PEG; NMR spectra of (c) DOX-GSH-PEG and (d) free DOX in DMSO-d6.
Figure 1

(a) Synthesis route of hyperbranched polyprodrug; (b) FT-IR spectra of DOX, GSH, PEG, and DOX-GSH-PEG; NMR spectra of (c) DOX-GSH-PEG and (d) free DOX in DMSO-d6.

3.2 The particle size and stability of hyperbranched polyprodrug

The polyprodrug of DOX-GSH-PEG could be assembled into nano micelle in PBS or water. Assembled nano micelle of DOX-GSH-PEG displayed a distinguished Tyndall phenomenon in pure water (Figure 2a). The particle size was 107.2 nm measured by DLS (Figure 2a) and 15 nm measured by TEM (Figure 2b). The significant differences in particle results between DLS and TEM are attributed to the status of hydrophilic PEG. The long chain of PEG could be swollen in water, resulting in the bigger particles measured by DLS. Otherwise, the PEG would be shown in shrinkable status on dried copper-mesh measured by TEM. These results were consistent with the previous paper (32).

Figure 2 The particle size of DOX-GSH-PEG micelle measured by (a) DLS and (b) TEM; (c) the stability of DOX-GSH-PEG micelle in PBS during 1 week and (d) the esterase-responsive un-stability of DOX-GSH-PEG micelle in esterase environment.
Figure 2

The particle size of DOX-GSH-PEG micelle measured by (a) DLS and (b) TEM; (c) the stability of DOX-GSH-PEG micelle in PBS during 1 week and (d) the esterase-responsive un-stability of DOX-GSH-PEG micelle in esterase environment.

The stability of DOX-GSH-PEG micelle was evaluated by DLS. Polyprodrug micelles were measured 7 times by DLS during 1 week in PBS without esterase, showing that the stability of DOX-GSH-PEG micelle was pretty good in non-esterase circumstances (Figure 2c). The statistical particles’ data of DOX-GSH-PEG is 106.4 ± 1 nm (size) and 0.145 ± 0.020 (PDI). Conversely, the DOX-GSH-PEG micelles were responsive-disrupted in PBS with esterase circumstances and the average particles’ size significantly increased from 108.8 to 262.1 nm with more extensive polydisperse index during 24 h (Table 1). The increased particle size and more extensive polydisperse index indicated that the partial ester bonds in hyperbranched polyprodrug were disrupted in esterase circumstances. These results were consistent with the drug release experiment in Figure 3b.

Table 1

The particle size of DOX-GSH-PEG micelle in esterase circumstance

Time (h) Z-average size (d.nm) PDI Temperature (°C)
0 108.8 ± 44.9 0.141 25.0
1 187.2 ± 162.7 0.393 25.0
3 187.6 ± 205.7 0.379 25.0
12 224.7 ± 230.9 0.478 25.0
24 262.1 ± 1006.0 0.451 25.0
Figure 3 (a) The UV-Vis curves of esterase, DOX·HCl, and DOX-GSH-PEG in PBS and (b) the accumulative drug release rate of DOX from DOX-GSH-PEG in PBS (pH = 6.0) with esterase environment.
Figure 3

(a) The UV-Vis curves of esterase, DOX·HCl, and DOX-GSH-PEG in PBS and (b) the accumulative drug release rate of DOX from DOX-GSH-PEG in PBS (pH = 6.0) with esterase environment.

3.3 The drug loading and release properties of hyperbranched polyprodrug

To measure the drug loading of DOX in hyperbranched polyprodrug, we measured the UV-Vis curves of esterase, DOX, and DOX-GSH-PEG in PBS, discovering that the absorbance peaks at 481 nm were observed and not significantly changed in the curves of DOX and DOX-GSH-PEG (Figure 3a). Based on these results, the drug loading of DOX in DOX-GSH-PEG could be determined according to the standard curve of DOX (C = A/0.0186, R 2 = 0.9999). The drug loading of DOX in DOX-GSH-PEG is 10.21%. To further precisely determine the drug release rate in vitro, we set up three groups of no esterase, low concentration of esterase (2.5 U‧mL−1), and high concentration of esterase (15 U‧mL−1) to evaluate the esterase-responsive drug release property. Esterase is an overexpressed enzyme with high concentration and activity in tumor cells compared with normal cells (33,34). The DOX-GSH-PEG micelle with massive ester bonds could be disrupted in the circumstance of a high concentration of esterase according to previous enzyme-responsive drug delivery systems (DDS) (7,35,36). In Figure 3b, we discovered that the DOXs were slightly released from DOX-GSH-PEG micelle under the environment of pH 6.0 during 72 h without esterase and the drug release rate only reached 11%. The experiment group showed that the drug release rate reached 43% under the high concentration of esterase environment (15 U‧mL−1) with pH 6.0 for 72 h and the low concentration of esterase environment (2.5 U‧mL−1) group showed that the 20% DOX was released from DOX-GSH-PEG. These results further indicated that the DOX-GSH-PEG micelle indeed could be disrupted in the high concentration of an esterase environment. Combining with the cell viability results of the DOX-GSH-PEG group (without esterase) at 24 and 48 h (Figure 5a), we can speculate that DOXs were esterase-responsive triggered and released from DOX-GSH-PEG in tumor cells with overexpressed esterase, resulting in the Hela cells apoptosis.

3.4 The distribution of DOX-GSH-PEG in Hela cells

The DOX-GSH-PEG micelle (red fluoresce) could be swallowed by cells via endocytosis and located by inverted fluorescence microscope. The nuclei were dyed by Hoechst 33258 (blue fluoresce). The free DOX and DOX-GSH-PEG micelle were co-cultured with Hela cells for 0.5, 4, and 8 h in culture media with esterase or without esterase. We discovered that the distribution of free DOX has no distinguishable differences between the with esterase group and the without esterase group during 8 h (Figure 4a and b). Meanwhile, the distribution of DOX-GSH-PEG micelle groups with esterase or without esterase showed significant differences. In the merged channel images of DOX-GSH-PEG at the time point of 4 h, we can clearly notice that the blue fluoresce (cell nuclei) was surrounded by red fluoresce (DOX-GSH-PEG) in the group of without esterase, meaning that most of the DOX-GSH-PEG did not distribute to cell nuclei during 4 h (Figure 4c). In the corresponding group (4 h) of DOX-GSH-PEG with esterase, the partial red fluoresce overlapped with blue fluoresce, indicating that the partial DOXs were released from DOX-GSH-PEG micelle in esterase circumstance in culture media and more quickly distributed into cells’ nuclei. In the time point of 8 h groups, the partial blue fluoresce cannot be overlapped with red fluoresce in the DOX-GSH-PEG group without esterase and the almost blue fluoresce was overlapped with red fluoresce in DOX-GSH-PEG group with esterase (Figure 4d), demonstrating that the massive ester bonds in DOX-GSH-PEG could be disrupted in esterase circumstance and the released free DOX from disrupted DOX-GSH-PEG distributed more quickly into cell nuclei. These results further confirmed that the DOX-GSH-PEG could be disrupted in a higher esterase environment and strongly supported the esterase-responsive drug release properties in vitro (Figure 3b).

Figure 4 The distributions of (a) free DOX, (b) free DOX with esterase, (c) DOX-GSH-PEG and (d) DOX-GSH-PEG with esterase in culture media at 0.5, 4, and 8 h (blue fluoresce means Hoechst 33258, red fluoresce means DOX).
Figure 4

The distributions of (a) free DOX, (b) free DOX with esterase, (c) DOX-GSH-PEG and (d) DOX-GSH-PEG with esterase in culture media at 0.5, 4, and 8 h (blue fluoresce means Hoechst 33258, red fluoresce means DOX).

3.5 Cell viability experiment

To evaluate the drug efficacy in vitro of esterase-responsive DOX-GSH-PEG, we added the esterase to media for co-culturing with Hela cells. The cell viabilities of DOX-GSH-PEG at 24 h have no significant differences between esterase group and without esterase group. The probable reasons are the drug release rate of DOX from DOX-GSH-PEG is 30% and the released DOXs were distributed into cells’ nuclei after 8 h, turning out that cell apoptosis cannot be instantly triggered by released and nuclei-distributed DOX. While the vast cell viability differences of DOX-GSH-PEG between esterase group and without esterase group are shown in Figure 5 at the DOX concentration of 10 mg‧mL−1. This result strongly indicated that the DOXs were released in an esterase environment (extra addition of esterase) from DOX-GSH-PEG at 48 h in vitro, resulting in lower cell viability compared with without esterase group. The higher concentration of DOX in DOX-GSH-PEG (20 and 40 mg‧mL−1) between esterase and without esterase group showed no significant difference at 48 h. This result should probably be attributed to itself, i.e., toxicity of the DOX-GSH-PEG in higher concentrations. The cell viability of DOX-GSH-PEG (including 10 mg‧mL−1 DOX) without esterase group at 48 h was 38%. The lower cell viability of DOX-GSH-PEG (including 10 mg‧mL−1 DOX) without esterase group at 48 h (38%) compared with DOX-GSH-PEG (including 40 mg‧mL−1 DOX) without esterase group at 24 h (69%) is probably attributed to that DOXs were released from DOX-GHS-PEG in Hela cells with overexpressed esterase for inducing the cell apoptosis (Figure 5a). To observe the cells’ status, the images were obtained by microscopy. We can observe that the cells were almost killed by free DOX at the concentration of 5 and 10 mg‧mL−1 at 48 h. Meanwhile, the massive cells showed a pretty good status at the DOX concentration of 10 mg‧mL−1 in the DOX-GSH-PEG group without esterase. Conversely, the shapes of the cells changed when treated by DOX-GSH-PEG with esterase, indicating that the esterase in culture media could speed up the disruption of DOX-GSH-PEG and the released DOXs can result in the death of massive Hela cells compared with the group of DOX-GSH-PEG without esterase in culture media (Figure 5b).

Figure 5 (a) The Hela cell viabilities treated with DOX-GSH-PEG during 24 and 48 h and (b) the cells’ status imaged by different concentrations of DOX and DOX-GSH-PEG with or without esterase at 48 h (scale: 20×).
Figure 5

(a) The Hela cell viabilities treated with DOX-GSH-PEG during 24 and 48 h and (b) the cells’ status imaged by different concentrations of DOX and DOX-GSH-PEG with or without esterase at 48 h (scale: 20×).

4 Conclusion

In this article, an endogenous-based hyperbranched polyprodrug was developed using the anticancer drug of DOX, endogenous molecule of GSH, and FDA-approved material of PEG by one-pot method. This polyprodrug micelle could be assembled into micelles with 106.4 ± 1 nm in PBS, which can be stable for 1 week. The massive ester bonds in polyprodrug could be responsively disrupted in a high concentration of esterase circumstances. The drug release experiment showed that the DOX can be released from polyprodrug micelle and reach 43% during 72 h. Cell viability results demonstrated that the group of DOX-GSH-PEG with esterase could significantly inhibit the growth of the cells compared with no esterase group in 48 h and the cell uptake experiment showed that the DOX-GSH-PEG could be swallowed by cells and the released DOX from DOX-GSH-PEG in esterase environment can be distributed to cell nuclei in 8 h. These in vitro results indicated that this hyperbranched polyprodrug can be esterase-responsive disrupted in higher esterase environment. This endogenous-based strategy is a better choice for developing novel nanomedicines.

# These authors contributed equally to this work.

Acknowledgment

We thank the Central Experiment Platform and Laboratory of Molecular Drug Design and New Pharmaceutical Preparation in Changzhi Medical College and a teacher called Wenjuan Li in Department of Pharmacy.

  1. Funding information: This work was supported by “1331” Project in Shanxi Province, Natural Science Foundation for Young Scientists of Shanxi Province, China (no. 201901D211473), Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi Province, China (no. 2021L349), Academic leader project of Changzhi Medical College (no. XSQ202102), and National College Student’ Innovation and Entrepreneurship Training Plan Program, China (no. 20210540 and 20210527).

  2. Author contributions: Jianxia Qiao and Shufen Li: writing – original draft; Haoyu Yuan: conducted the experiment; Yujie Wang, Jianhong Li, and Peilong Wang: formal analysis; Xiao Duan: writing – review and editing, supervision, project administration, and resources.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: All data generated or analysed during this study are included in this published article.

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Received: 2022-02-21
Revised: 2022-04-29
Accepted: 2022-05-06
Published Online: 2022-05-23

© 2022 Jianxia Qiao et al., published by De Gruyter

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

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  2. The effect of isothermal crystallization on mechanical properties of poly(ethylene 2,5-furandicarboxylate)
  3. The effect of different structural designs on impact resistance to carbon fiber foam sandwich structures
  4. Hyper-crosslinked polymers with controlled multiscale porosity for effective removal of benzene from cigarette smoke
  5. The HDPE composites reinforced with waste hybrid PET/cotton fibers modified with the synthesized modifier
  6. Effect of polyurethane/polyvinyl alcohol coating on mechanical properties of polyester harness cord
  7. Fabrication of flexible conductive silk fibroin/polythiophene membrane and its properties
  8. Development, characterization, and in vitro evaluation of adhesive fibrous mat for mucosal propranolol delivery
  9. Fused deposition modeling of polypropylene-aluminium silicate dihydrate microcomposites
  10. Preparation of highly water-resistant wood adhesives using ECH as a crosslinking agent
  11. Chitosan-based antioxidant films incorporated with root extract of Aralia continentalis Kitagawa for active food packaging applications
  12. Molecular dynamics simulation of nonisothermal crystallization of a single polyethylene chain and short polyethylene chains based on OPLS force field
  13. Synthesis and properties of polyurethane acrylate oligomer based on polycaprolactone diol
  14. Preparation and electroactuation of water-based polyurethane-based polyaniline conductive composites
  15. Rapeseed oil gallate-amide-urethane coating material: Synthesis and evaluation of coating properties
  16. Synthesis and properties of tetrazole-containing polyelectrolytes based on chitosan, starch, and arabinogalactan
  17. Preparation and properties of natural rubber composite with CoFe2O4-immobilized biomass carbon
  18. A lightweight polyurethane-carbon microsphere composite foam for electromagnetic shielding
  19. Effects of chitosan and Tween 80 addition on the properties of nanofiber mat through the electrospinning
  20. Effects of grafting and long-chain branching structures on rheological behavior, crystallization properties, foaming performance, and mechanical properties of polyamide 6
  21. Study on the interfacial interaction between ammonium perchlorate and hydroxyl-terminated polybutadiene in solid propellants by molecular dynamics simulation
  22. Study on the self-assembly of aromatic antimicrobial peptides based on different PAF26 peptide sequences
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  25. A machine learning investigation of low-density polylactide batch foams
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  29. Preparation and applications of hydrophilic quaternary ammonium salt type polymeric antistatic agents
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  83. Influence of filler material on properties of fiber-reinforced polymer composites: A review
  84. Rapid Communications
  85. Pressure-induced flow processing behind the superior mechanical properties and heat-resistance performance of poly(butylene succinate)
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  88. Topical Issue: Recent advances in smart polymers and their composites: Fundamentals and applications (Guest Editors: Shaohua Jiang and Chunxin Ma)
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https://doi.org/10.1515/epoly-2022-0047
Keywords for this article
doxorubicin; polyprodrug micelles; esterase-responsiveness; drug controlled-release; antitumor
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. The effect of isothermal crystallization on mechanical properties of poly(ethylene 2,5-furandicarboxylate)
  3. The effect of different structural designs on impact resistance to carbon fiber foam sandwich structures
  4. Hyper-crosslinked polymers with controlled multiscale porosity for effective removal of benzene from cigarette smoke
  5. The HDPE composites reinforced with waste hybrid PET/cotton fibers modified with the synthesized modifier
  6. Effect of polyurethane/polyvinyl alcohol coating on mechanical properties of polyester harness cord
  7. Fabrication of flexible conductive silk fibroin/polythiophene membrane and its properties
  8. Development, characterization, and in vitro evaluation of adhesive fibrous mat for mucosal propranolol delivery
  9. Fused deposition modeling of polypropylene-aluminium silicate dihydrate microcomposites
  10. Preparation of highly water-resistant wood adhesives using ECH as a crosslinking agent
  11. Chitosan-based antioxidant films incorporated with root extract of Aralia continentalis Kitagawa for active food packaging applications
  12. Molecular dynamics simulation of nonisothermal crystallization of a single polyethylene chain and short polyethylene chains based on OPLS force field
  13. Synthesis and properties of polyurethane acrylate oligomer based on polycaprolactone diol
  14. Preparation and electroactuation of water-based polyurethane-based polyaniline conductive composites
  15. Rapeseed oil gallate-amide-urethane coating material: Synthesis and evaluation of coating properties
  16. Synthesis and properties of tetrazole-containing polyelectrolytes based on chitosan, starch, and arabinogalactan
  17. Preparation and properties of natural rubber composite with CoFe2O4-immobilized biomass carbon
  18. A lightweight polyurethane-carbon microsphere composite foam for electromagnetic shielding
  19. Effects of chitosan and Tween 80 addition on the properties of nanofiber mat through the electrospinning
  20. Effects of grafting and long-chain branching structures on rheological behavior, crystallization properties, foaming performance, and mechanical properties of polyamide 6
  21. Study on the interfacial interaction between ammonium perchlorate and hydroxyl-terminated polybutadiene in solid propellants by molecular dynamics simulation
  22. Study on the self-assembly of aromatic antimicrobial peptides based on different PAF26 peptide sequences
  23. Effects of high polyamic acid content and curing process on properties of epoxy resins
  24. Experiment and analysis of mechanical properties of carbon fiber composite laminates under impact compression
  25. A machine learning investigation of low-density polylactide batch foams
  26. A comparison study of hyaluronic acid hydrogel exquisite micropatterns with photolithography and light-cured inkjet printing methods
  27. Multifunctional nanoparticles for targeted delivery of apoptin plasmid in cancer treatment
  28. Thermal stability, mechanical, and optical properties of novel RTV silicone rubbers using octa(dimethylethoxysiloxy)-POSS as a cross-linker
  29. Preparation and applications of hydrophilic quaternary ammonium salt type polymeric antistatic agents
  30. Coefficient of thermal expansion and mechanical properties of modified fiber-reinforced boron phenolic composites
  31. Synergistic effects of PEG middle-blocks and talcum on crystallizability and thermomechanical properties of flexible PLLA-b-PEG-b-PLLA bioplastic
  32. A poly(amidoxime)-modified MOF macroporous membrane for high-efficient uranium extraction from seawater
  33. Simultaneously enhance the fire safety and mechanical properties of PLA by incorporating a cyclophosphazene-based flame retardant
  34. Fabrication of two multifunctional phosphorus–nitrogen flame retardants toward improving the fire safety of epoxy resin
  35. The role of natural rubber endogenous proteins in promoting the formation of vulcanization networks
  36. The impact of viscoelastic nanofluids on the oil droplet remobilization in porous media: An experimental approach
  37. A wood-mimetic porous MXene/gelatin hydrogel for electric field/sunlight bi-enhanced uranium adsorption
  38. Fabrication of functional polyester fibers by sputter deposition with stainless steel
  39. Facile synthesis of core–shell structured magnetic Fe3O4@SiO2@Au molecularly imprinted polymers for high effective extraction and determination of 4-methylmethcathinone in human urine samples
  40. Interfacial structure and properties of isotactic polybutene-1/polyethylene blends
  41. Toward long-live ceramic on ceramic hip joints: In vitro investigation of squeaking of coated hip joint with layer-by-layer reinforced PVA coatings
  42. Effect of post-compaction heating on characteristics of microcrystalline cellulose compacts
  43. Polyurethane-based retanning agents with antimicrobial properties
  44. Preparation of polyamide 12 powder for additive manufacturing applications via thermally induced phase separation
  45. Polyvinyl alcohol/gum Arabic hydrogel preparation and cytotoxicity for wound healing improvement
  46. Synthesis and properties of PI composite films using carbon quantum dots as fillers
  47. Effect of phenyltrimethoxysilane coupling agent (A153) on simultaneously improving mechanical, electrical, and processing properties of ultra-high-filled polypropylene composites
  48. High-temperature behavior of silicone rubber composite with boron oxide/calcium silicate
  49. Lipid nanodiscs of poly(styrene-alt-maleic acid) to enhance plant antioxidant extraction
  50. Study on composting and seawater degradation properties of diethylene glycol-modified poly(butylene succinate) copolyesters
  51. A ternary hybrid nucleating agent for isotropic polypropylene: Preparation, characterization, and application
  52. Facile synthesis of a triazine-based porous organic polymer containing thiophene units for effective loading and releasing of temozolomide
  53. Preparation and performance of retention and drainage aid made of cationic spherical polyelectrolyte brushes
  54. Preparation and properties of nano-TiO2-modified photosensitive materials for 3D printing
  55. Mechanical properties and thermal analysis of graphene nanoplatelets reinforced polyimine composites
  56. Preparation and in vitro biocompatibility of PBAT and chitosan composites for novel biodegradable cardiac occluders
  57. Fabrication of biodegradable nanofibers via melt extrusion of immiscible blends
  58. Epoxy/melamine polyphosphate modified silicon carbide composites: Thermal conductivity and flame retardancy analyses
  59. Effect of dispersibility of graphene nanoplatelets on the properties of natural rubber latex composites using sodium dodecyl sulfate
  60. Preparation of PEEK-NH2/graphene network structured nanocomposites with high electrical conductivity
  61. Preparation and evaluation of high-performance modified alkyd resins based on 1,3,5-tris-(2-hydroxyethyl)cyanuric acid and study of their anticorrosive properties for surface coating applications
  62. A novel defect generation model based on two-stage GAN
  63. Thermally conductive h-BN/EHTPB/epoxy composites with enhanced toughness for on-board traction transformers
  64. Conformations and dynamic behaviors of confined wormlike chains in a pressure-driven flow
  65. Mechanical properties of epoxy resin toughened with cornstarch
  66. Optoelectronic investigation and spectroscopic characteristics of polyamide-66 polymer
  67. Novel bridged polysilsesquioxane aerogels with great mechanical properties and hydrophobicity
  68. Zeolitic imidazolate frameworks dispersed in waterborne epoxy resin to improve the anticorrosion performance of the coatings
  69. Fabrication of silver ions aramid fibers and polyethylene composites with excellent antibacterial and mechanical properties
  70. Thermal stability and optical properties of radiation-induced grafting of methyl methacrylate onto low-density polyethylene in a solvent system containing pyridine
  71. Preparation and permeation recognition mechanism of Cr(vi) ion-imprinted composite membranes
  72. Oxidized hyaluronic acid/adipic acid dihydrazide hydrogel as cell microcarriers for tissue regeneration applications
  73. Study of the phase-transition behavior of (AB)3 type star polystyrene-block-poly(n-butylacrylate) copolymers by the combination of rheology and SAXS
  74. A new insight into the reaction mechanism in preparation of poly(phenylene sulfide)
  75. Modified kaolin hydrogel for Cu2+ adsorption
  76. Thyme/garlic essential oils loaded chitosan–alginate nanocomposite: Characterization and antibacterial activities
  77. Thermal and mechanical properties of poly(lactic acid)/poly(butylene adipate-co-terephthalate)/calcium carbonate composite with single continuous morphology
  78. Review Articles
  79. The use of chitosan as a skin-regeneration agent in burns injuries: A review
  80. State of the art of geopolymers: A review
  81. Mechanical, thermal, and tribological characterization of bio-polymeric composites: A comprehensive review
  82. The influence of ionic liquid pretreatment on the physicomechanical properties of polymer biocomposites: A mini-review
  83. Influence of filler material on properties of fiber-reinforced polymer composites: A review
  84. Rapid Communications
  85. Pressure-induced flow processing behind the superior mechanical properties and heat-resistance performance of poly(butylene succinate)
  86. RAFT polymerization-induced self-assembly of semifluorinated liquid-crystalline block copolymers
  87. RAFT polymerization-induced self-assembly of poly(ionic liquids) in ethanol
  88. Topical Issue: Recent advances in smart polymers and their composites: Fundamentals and applications (Guest Editors: Shaohua Jiang and Chunxin Ma)
  89. Fabrication of PANI-modified PVDF nanofibrous yarn for pH sensor
  90. Shape memory polymer/graphene nanocomposites: State-of-the-art
  91. Recent advances in dynamic covalent bond-based shape memory polymers
  92. Construction of esterase-responsive hyperbranched polyprodrug micelles and their antitumor activity in vitro
  93. Regenerable bacterial killing–releasing ultrathin smart hydrogel surfaces modified with zwitterionic polymer brushes
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