Fully biodegradable self-healing hydrogel prepared based on poly(aspartic acid) and pectin for drug delivery and anti-tumor therapy

doi:10.21203/rs.3.rs-2964046/v1

Download PDF

Research Article

Fully biodegradable self-healing hydrogel prepared based on poly(aspartic acid) and pectin for drug delivery and anti-tumor therapy

https://doi.org/10.21203/rs.3.rs-2964046/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 28 Nov, 2023

Read the published version in Journal of Polymer Research →

You are reading this latest preprint version

With biocompatibility and biodegradability, self-healing hydrogels prepared from biopolymers show great advantages in bioengineering and bioscience as drug delivery carrier. In this research, the biodegradable hydrogel was constructed based on poly(amino acid) of poly(aspartic acid) (PAsp) and pectin for in vivo antitumor applications as DOX release carrier. The PAsp with hydrazide groups and isopropyl groups (PAPH) was synthesized by ring opening of the polysuccinimide (PSI) by isopropylamine and hydrazine, and used to fabricate fully biodegradable hydrogel with oxidized pectin (OPec) through dynamic covalent bonds cross-linking. The regulatable mechanical strength of the hydrogel could adapt its bioapplication, and the excellent biocompatibility ensured biosafety in biomedical areas. Furthermore, the pectin backbone and the PAsp endowed the hydrogel with biodegradability both by enzyme and in vivo. The PAPH/Opec hydrogel as DOX carrier reduced the in vivo toxicity of the DOX while the antitumor efficacy of the drug was well preserved. As a result, this biodegradable PAPH/Opec hydrogel could find show great potential as sustained drug delivery vehicle in biomedical areas.

poly(aspartic acid)

pectin

hydrogel

drug release

antitumor therapy

Colon cancer is a kind of malignant tumor commonly occurs in the digestive tract [1, 2]. The incidence and fatality rate of colon cancer are growing worldwide in recent years, which threat people's health and life expectancy seriously [3–6]. As a popular method to treatment of colon cancer [7, 8], the chemotherapeutic drugs also have certain toxicity to the body and even aggravate the patient's condition [6, 9]. As a result, promoting the chemotherapy efficacy of colon cancer still faces great challenges, and more effective strategies that can enhance the chemotherapeutic performance of the colon cancer are urgently needed in clinical application.

The controlled drug release can improve the therapeutic efficacy of cancer by designing drug carriers [10–12], while the injectable hydrogels are effective biocompatible drug release vehicles [13–16]. The tissue mimic hydrogels with water swollen in three-dimensional network can provide good biocompatibility [17–20], and the injectable property can localize the chemotherapeutic drugs around the tumor site to promote the antitumor performance and reduce the by-effect of the drug to normal tissues [21–27]. At the same time, biodegradability of hydrogels can remove the hydrogel to avoid the possible by-effects as foreign matters [28–30]. In recent years, self-healing hydrogels which can provide stable properties have begun to show advantages in biological applications [31–34]. In order to achieve the above expectations, biodegradable self-healing hydrogels prepared from chitosan, CMC, sodium alginate, HA and other biomass as raw materials have been reported [35–38]. Recently, another water-soluble bio-based polymer, pectin, begun to attract attentions [19, 39, 40]. As a well-known natural anionic polysaccharide extracted from the cell walls of natural fruits, pectin bears large amount of carboxyl groups (-COOH), hydroxyl groups (-OH) and vicinal diol groups which can be modified conveniently [41–43]. Thus, the pectin could be endowed with important applications as drug loading and release vehicle [41, 44]. Among these modification methods, oxidation of vicinal diols of pectin into aldehyde group and react with hydrazide functionalized polymers to fabricate hydrazone bond cross-linked self-healing hydrogel is the most popular [45, 46]. Moreover, further modification of carboxyl and ester groups on pectin can introduce more functional groups [44, 45, 47]. Therefore, pectin has greater potential in biodegradable hydrogels preparation and deserves intensive study.

The dynamic hydrazone bond is an important reversible chemical bond to fabricate self-healing hydrogels. The oxidized pectin (OPec) as aldehyde functionalized biopolymer, is expected to fabricate fully biodegradable self-healing hydrogels with biodegradable hydrazide functionalized polymer cross-linking [48, 49]. The poly(amino acid)s bearing hydrazide groups can be used to cross-link the aldehyde group bearing polymers to fabricate biodegradable hydrogels [50–53], among which the PAsp derivatives is the most accessible one since the poly(aspartic hydrazide) (PAH) could be synthesized through polyssuccinimide (PSI) hydrazinolysis directly. Moreover, the PSI could also react with various amines and hydrazide successively to regulate the hydrazide group density. As a result, hydroxyethyl groups were introduced to PAH to regulate the property of the hydrogel in our previous publication [54]. Based on the above method, more PAH with various modification can be designed to fabricate fully biodegradable hydrogels.

In this research, isopropylamine was imported to PAH to regulate the hydrazide group density and expected to mimic the structure of PNIPAM with thermal response (Fig. S1) [55–57]. The obtained isopropyl amine grafted PAH (PAPH) were reacted with Opec to fabricate injectable hydrogel by hydrazone bond cross-linking. The properties of the hydrogel were investigated and the hydrogel was used as DOX carrier to treat the colon tumor in vivo [58]. Although the PAPH/OPec hydrogel did not show thermos-response as expected, the hydrogel showed well expected biodegradability along with excellent biocompatibility, and the DOX loaded PAPH/OPec hydrogel showed improved antitumor performance with toxicity reduced. Therefore, this study demonstrates that the PAPH/OPec hydrogels have great application potential as DOX carriers for colon cancer treatment.

Materials

Pectin (D-Galacturonic acid ≥ 74%, esterification degree: ~35%) and NaIO4 were purchased from Aladdin Chem. Co. (Shanghai, China). L-aspartic acid (99%) and Doxorubicin hydrochloride (DOX ∙HCl) were purchased from Macklin Inc. (Shanghai, China). Other chemical reagents and solvents were supplied by Kermal Chemical Reagent Co. Ltd. (Tianjin, China).

Polycondensation of PSI and synthesis of PAPH

The PSI synthesized from L-aspartic acid through polycondensation [54] was used to prepare PAPH. The PSI (4.95 g, 0.05 mol) was dissolved in DMSO (15 mL) in a flask first, then the isopropylamine (0.025 mol) was dropped slowly and reacted for 24 h. Then the flask was cooled in ice water and excess of hydrazine hydrate was added dropwise to open the left PSI ring for another 24 h. The product named as PAPH was precipitated in acetone and dried under vacuum for hydrogel preparation.

Preparation of and morphology of the hydrogels

The oxidation of pectin was prepared following the previous study [59] and used to react with PAPH to fabricate biodegradable hydrogel. The oxidized pectin (OPec) and PAPH were dissolved into water solutions with 7%-10% concentrations. Then the two solutions were mixed into homogeneous hydrogel solution with same volume and concentrations to form hydrogel discs for characterizations.

The hydrogels with different gelator concentrations were lyophilized and coated with Au for SEM observation. The JSM-7500 scanning electron microscope (SEM, JEOL, Japan) was used for the observation and the images were recorded with a CCD.

Mechanical strength and self-healing behavior of PAPH/OPec hydrogel

The rheology study of the PAPH/OPec hydrogels was performed with frequency sweep (0.1 rad‧s^− 1 to 100 rad‧s^− 1). The strain sweep with increasing strain was conducted to investigate the flexibility of the hydrogels and the critical strain was defined as the G′′ exceed G′. Furthermore, the strain of the hydrogel was increased to 100% and 200% below and above critical strain to observe the crack formation and repairing of the hydrogel. The hydrogel discs with different colors were cut and contacted under saturated moisture, and the integration of the hydrogel disc also confirmed the self-healing result.

Cell compatibility determined through CCK-8 assay

The influences the PAPH, OPec and hydrogel solutions on LO-2 cells were investigated. After the cells were cultured in the solutions for 24 h, 48 h and 72 h, CCK-8 solution was added and the absorbance of the cells was scanned at 450 nm to determine the cell viability.

In vitro hemolysis ratio test of the PAPH/OPec hydrogel

The red blood cells (RBCs) were collected from white rabbit. The PAPH solution, OPec solution and hydrogel solution in PBS were contacted with RBC and centrifuged to compare the differences between the samples and the control. The optical appearance of the samples was recorded and the hemolysis ratios was quantified based on absorbance at 450 nm.

DOX release of the PAPH/OPec hydrogel

The PAPH/OPec hydrogel was used to load the DOX and the release profile was investigated. The PAPH/OPec hydrogel with 3.0 mg/mL DOX loading was subjected to the release and accumulative release ratio was determined with a UV-Vis spectrometer at 485 nm.

In vitro and in vivo degradation of the hydrogel

The PAPH/OPec hydrogels (1 mL) were prepared in glass vials, then 100 µL pectinase solution (1%) was added to one vial and the vials were sealed to avoid the water evaporation. The state of the PAPH/OPec hydrogels was compared and photographed.

The in vivo degradation of PAPH/OPec hydrogel was carried out on Kunming mice (8 weeks old, 20–25 g weight). The hydrogel (8%) was injected under the skin of the mice back (200 µL) through mixing needle and the mice were sacrificed at 0th, 5th and 15th day to observe the hydrogel size under the skin. The epidermal tissue around the hydrogel injection site was incised for H&E staining observation.

In vivo antitumor experiment of PAPH/OPec hydrogel loaded DOX

The colon cancer model was created on the backs of Kunming mice approved by Animal Welfare and Ethical Committee of Hebei University. The mice were divided into (1) control group, (2) hydrogel group, (3) DOX group (25 mg/kg), and (4) DOX/hydrogel group (25 mg/kg) after the tumor volume grew to 130–150 mm³. Each group of the mice was treated with corresponding injection around the tumor and the tumor volume (length×width²/2) was measured every five days. At last, the mice were sacrificed, the tissues and tumor of the mice were collected and cut into 5 µm sections for pathological observation after H&E staining (40×10 magnification). The experimental results are expressed as mean ± SD. The p < 0.05 was considered as statistically significant.

Synthesis of PAPH and oxidation of pectin

The PSI was reacted with isopropylamine and hydrazine successively to prepare PAPH (Fig. 1a). The importation of the hydrazide groups was designed for cross-linking, while the isopropyl groups was aimed to regulate the hydrophilicity of the polymer to mimic the PNIPAM structure (Scheme S1) and expected to obtain thermo-sensitive poly(amino acid). The structure of PAPH at various stages was determined by FT-IR, there is a strong absorbance at 1718 cm^− 1 and a shoulder at 1797 cm^− 1 on the FT-IR spectrum of PSI, which are characteristic absorbances of the five-numbered PSI rings (Fig. 1b). When the PSI was reacted with 50% ratio of isopropylamine, the characteristic absorbance of PSI decreased and only a small shoulder left at 1797 cm^− 1, at the same time, the ¹H NMR spectra showed a new peak at 3.80 ppm proved the isopropylamine was imported onto the PSI (Fig. S1). The absorbance at 1718 cm^− 1 and 1797 cm^− 1 disappeared completely after reacted with the hydrazine and moved to 1650 cm^− 1 indicated all PSI rings were consumed completely. At the same time, the peak represented PSI ring (5.0 ppm) disappeared from the ¹H NMR spectrum also proved the complete consumption of the PSI and the hydrazide groups were imported. The resultant poly(aspartic acid) derivative did not show thermos-responsivity and the product PAPH with 50% hydrazide group ratios was used for following investigations.

The NaIO₄ oxidation was used to transform vicinal diols on pectin into aldehyde groups [59] (Fig. 1c). The FT-IR spectra of the product (OPec) showed an increased absorbance at 1730 cm^− 1, proved aldehyde groups were generated and ready to react with PAPH to fabricate biodegradable hydrogels.

Fabrication of the PAPH/OPec hydrogel and mechanical property investigation

The PAPH solution and the OPec solution with same concentrations were mixed together and put into the round molds or glass vials for gelation (Fig. 2a). It was observed the hydrogels formed pretty fast and the gelation time decreased with increasing concentration. However, all hydrogel from 7%-10% formed within 3 min, fast enough for injection applications. As a result, when the mixture solution was loaded in a syringe and injected into a petri dish, hydrogel formed shortly after the injection (Fig. S2).

The hydrogels were investigated by rheology study on TA AR2000ex rheometer with 25 mm plates. The hydrogels with concentration from 7–10% showed higher storage modulus (G′) compared to loss modulus (G″) (Fig. S3), and the mechanical strength (G′) decreased with decreasing concentration. The G′ of the hydrogels increased from ~ 350 Pa to ~ 2400 Pa with concentration increased from 7–10% because of increased cross-linking density (Fig. 2b), at the same time, the flexibility decreased accordingly. The G′ of 10% hydrogel with highest mechanical strength began to decrease around 20% strain and the G′′ exceeded G′ to show liquid characteristic at 109% strain (Fig. S3). The critical strain 9% and 8% hydrogels increased to 147% and 208% (Fig. 2c, d) and the 7% hydrogel showed an even higher critical strain of 260%.

Morphology and self-healing of the hydrogels

The hydrogels with microporous structure could supply spaces and channels for drug loading and diffusion. The SEM images of PAPH/OPec hydrogels exhibited interconnected microstructures with the pore diameters increased with deceasing gelator concentrations (Fig. 3a). All hydrogel showed microporous structure fit for drug loading and delivery, which endowed the PAPH/OPec hydrogel with potential application in biomedications. Based on moderate mechanical strength and good flexibility, the 8% hydrogel was selected for intensive studies as DOX release carrier in following experiments.

The alternate strain sweep can be used to determine the self-healing of PAPH/OPec hydrogel. As shown in Fig. 3(b), the G′ of the 8% hydrogel decreased when the strain increased from 5% to100%, but the G′ recovered to its original value right after the G′ was returned to 5%, indicated the formed cracks were repaired. The hydrogel could also heal the large cracks after the strain was regulated to 200% for 3 min. As a result, when the hydrogel halves were contacted for 24 h, the hydrogel integrated into a whole disc and could hold its weight by tweezers (Fig. 3c). The contact interface became almost invisible indicated the large cracks could be repaired slowly to show consistent property during its bioapplications.

Cytotoxicity of the PAPH/OPec hydrogel

The biocompatibility of PAPH/OPec hydrogel was evaluated through a variety of methods. The CCK-8 experiment showed over 90% cell viability when the LO-2 cells were incubated with PAPH/OPec hydrogel solutions for 24 h or 48 h and 72 h with the hydrogel solution up to 10 mg/mL (Fig. 4a). Moreover, the absorbance increased with increasing incubation time indicated the hydrogel did not influence the cell prefoliation (Fig. 4b). The good biocompatibility of PAPH proved the coupling of isopropylamine did not influence the application of PAsp in bioapplications. As a result, the PAPH/OPec hydrogel has good biocompatibility, which ensured biosafety as in vivo drug release vehicle in future biomedical applications.

Hemocompatibility of the PAPH/OPec hydrogel

The hydrogel used in vivo need to contact with blood and the hemolysis could cause serious consequences. The hemolysis test was used to evaluate the in vitro blood compatibility of PAPH/OPec hydrogel [60]. After the red blood cells (RBC) were incubated in the hydrogel solutions for 1 h and centrifuged for 15 min, the color of samples was observed and the absorbance of the up-layer solution was scanned by microreader. The RBC in all hydrogel groups aggregated at the bottom of the tube and the up layers were light yellow comparable to that of PBS rather than bright red color of the positive control (Fig. 5a). The quantitative determination showed the hemolysis ratio of all precursors and hydrogels were lower than 5%. The hemolysis ratio was below 2% for precursors and hydrogel no matter the concentration, which indicated good blood compatibility during blood contact.

DOX loading and sustained release the PAPH/OPec hydrogel

The biocompatible hydrogel was expected to be used as DOX release vehicle for antitumor therapy. The DOX released fast in first a few hours and the release rate decreased after 24 h (Fig. 5b). In pH 7.4 buffer, the DOX released 46.4% in 24 h, but the release ratio increased to 54.5% in pH 6.5 buffer and 63.9% in 5.4 buffer. It is well known the DOX released fast in acidic conditions because the DOX dissolves better in low pH since it contains amine group. Furthermore, the acid could catalyze the reversible reaction of the dynamic covalent hydrazone bond. As a result, the DOX would be more released to the tumor site based on low pH caused by fast metabolization of the tumors.

In vitro biodegradation of PAPH/OPec hydrogel

The PAPH has biodegradable PAsp backbone and the pectin is a biobased polymer, as a result, the PAPH/OPec hydrogel could be degraded by enzymes. Although the PAsp backbone could also be degraded under natural conditions, the hydrogel was still solid in 7 days. On the other hand, the pectinase degraded the PAPH/OPec hydrogel into viscous solution by 7th days because the pectinase could cleave the pectin backbone (Fig. 6a).

In situ PAPH/OPec hydrogel formation and in vivo biodegradation

The PAPH/OPec mixture solutions turned into hydrogels fast, which facilitates location of the loaded drugs to the injection position. When the PAPH solution and OPec solution were mixed in the mixing needle and injected into the back of Kunming mice, a hump appeared on each mouse. The hydrogel under the skin could be observed and could be peeled off. The size of the hydrogel became smaller and smaller by degradation and the size decreased ~ 50% after 5 days (Fig. 6b). At this time, the color of the hydrogel changed because of the fluid exchange, which is an important process for drug release. After 9 days, the hydrogel disappeared completely with no residue figured out. Moreover, there is no inflammation observed around the hydrogel during the whole in vivo degradation process based on excellent biocompatibility. The H&E images was observed to further confirm this point, and the tissues around the hydrogel showed same morphology compared to normal tissues (Fig. 6c).

In vivo colon cancer treatment of PAPH/OPec hydrogel loaded DOX

The PAPH/OPec hydrogel was used to load DOX for colon cancer therapy to evaluate the performance of hydrogel in improving antitumor efficacy and reducing in vivo toxicity. The process of the antitumor investigation is shown in Fig. 7(a), the DOX loaded hydrogel was injected into the tumor position and the tumor size was measured regularly. The tumors grew fast in the hydrogel group comparable to the control group. On the contrary, the DOX group showed significant antitumor efficacy, which is consistent with antitumor property of the DOX. The hydrogel loaded DOX showed comparable antitumor performance with direct DOX injection, proved the PAPH/OPec hydrogel could take full advantage of the DOX, as show in Fig. 7(b). The tumor volume in the control group increased about 10 times at the end of the experiment, while the tumor in the DOX/hydrogel group only increased ~ 25%. However, the DOX also showed serious in vivo toxicity and the mice in this group died successively. All mice in DOX group died within 15 days, while all mice in other groups survived to the end indicated the PAPH/OPec hydrogel could reduce the in vivo toxicity of DOX (Fig. S4). However, the body weight of the mice in the DOX/hydrogel group also decreased with treating times. At the end of the experiment, the average body weight of the mice in the control group and the hydrogel group increased ~ 40%, but the body weight of the mice in the DOX/hydrogel group decreased ~ 25% (Fig. 7c). Above result showed although the adverse effect of the DOX was still existed, the hydrogel could reduce the toxicity of the drug to the living body.

After the last time tumor size and body weight measurement, the tumors and organs of the mice were collected. As shown in Fig. 7(d), compared to large tumors in the control group and the hydrogel group, the tumors in the DOX/hydrogel group were much smaller. All the mice dead in DOX group and no tumor illustrated as a result. Combined with the biocompatibility experiment, the PAPH/OPec hydrogel loaded DOX could preserve good antitumor efficacy of the DOX and at the same time reduce the toxicity of the drug.

H&E staining observation of the tumors and other tissues

The H&E images are always used to determine the adverse effect of the antitumor drugs. As shown in Fig. 8, The tumor in the hydrogel group did not show significant difference compared to control group, however, the tumor in DOX/hydrogel group showed large part of the cell death similar to DOX group and consisted with the antitumor performance of the DOX. The DOX group also showed obvious spleen and lung toxicity, along with the well-known heart and kidney harm. As for the DOX/hydrogel group, the adverse effect decreased since the release of the DOX from the PAPH/OPec hydrogel reduced the drug concentration in these tissues. However, there were still toxicity to the tissues and resulted body weight decrease possibly because the DOX doses were still too high for this poor targeted drug. To further confirm the localization performance of the PAPH/OPec hydrogel in cancer therapy, tumor targeting drug delivery is under investigation. As a result, the DOX/hydrogel system could reduce the toxicity of loaded drug and could be used as antitumor drug carrier for tumor treatment applications.

The PAPH with PAsp backbone and hydrazide groups was designed as multihydrazide polymer, the coupled isopropylamine was imported onto the PAPH structure to regulate the hydrazide group density and mimic the PNIPAM structure. The OPec as multialdehyde bearing biopolymer was used to react with PAPH to fabricate biodegradable hydrogels. The PAPH/OPec hydrogels showed microporous structure similar to other reported hydrogels and could supply sustained DOX release profile as biodegradable antitumor drug release carrier. Also the PAPH/OPec hydrogel showed biodegradability along with excellent hemocompatibility and cell compatibility. As a result, the PAPH/OPec hydrogel have the potential to be used as DOX delivery carrier to reduce the in vivo toxicity of the DOX in antitumor therapy.

Competing Interests: The author declares that there is no conflict of interest.

Acknowledgements

This research was kindly supported by the National Natural Science Foundation of China (No. 82072327) and Medical Science Foundation of Hebei University (2021A01, 2021X01).

Supplementary Information

Supplementary data to this article can be found online.

Hao Y, Chung CK, Gu Z, Schomann T, Dong X, Veld R, Camps MGM, Ten Dijke P, Ossendorp FA, Cruz LJ (2022) Combinatorial therapeutic approaches of photodynamic therapy and immune checkpoint blockade for colon cancer treatment. Mol Biomed 3: 26.
Gao M, Yang C, Wu C, Chen Y, Zhuang H, Wang J, Cao Z (2022) Hydrogel-metal-organic-framework hybrids mediated efficient oral delivery of siRNA for the treatment of ulcerative colitis. J Nanobiotechnology 20: 404.
Abedi F, Davaran S, Hekmati M, Akbarzadeh A, Baradaran B, Moghaddam SV (2021) An improved method in fabrication of smart dual-responsive nanogels for controlled release of doxorubicin and curcumin in HT-29 colon cancer cells. J Nanobiotechnology 19: 18.
Del Piccolo N, Shirure VS, Bi Y, Goedegebuure SP, Gholami S, Hughes CCW, Fields RC, George SC (2021) Tumor-on-chip modeling of organ-specific cancer and metastasis. Adv Drug Deliv Rev 175: 113798.
Hassani I Anbiah B, Kuhlers P, Habbit NL, Ahmed B, Heslin MJ, Mobley JA, Greene MW, Lipke E A (2022) Engineered colorectal cancer tissue recapitulates key attributes of a patient-derived xenograft tumor line. Biofabrication 14: 045001.
Leonard NA, Reidy E, Thompson K, McDermott E, Peerani E, Tomas Bort E, Balkwill FR, Loessner D, Ryan AE (2021) Stromal Cells Promote Matrix Deposition, Remodelling and an Immunosuppressive Tumour Microenvironment in a 3D Model of Colon Cancer. Cancers. (Basel) 13: 5998
Shao J, Ruan C, Xie H, Li Z, Wang H, Chu PK, Yu XF (2018) Black-Phosphorus-Incorporated Hydrogel as a Sprayable and Biodegradable Photothermal Platform for Postsurgical Treatment of Cancer. Adv Sci (Weinh) 5, 1700848.
Zhu P, Chen Y, Shi J (2020) Piezocatalytic Tumor Therapy by Ultrasound-Triggered and BaTiO3 -Mediated Piezoelectricity. Adv Mater 32: e2001976.
Zhang H, Zhang J, Liu Y, Jiang Y, Li Z (2021) Molecular Targeted Agent and Immune Checkpoint Inhibitor Co-Loaded Thermosensitive Hydrogel for Synergistic Therapy of Rectal Cancer. Front Pharmacol 12: 671611.
Chen M, Tian J, Liu Y, Cao H, Li R, Wang J, Wu J, Zhang Q (2019) Dynamic covalent constructed self-healing hydrogel for sequential delivery of antibacterial agent and growth factor in wound healing. Chem Eng J 373: 413–424.
Naahidi S, Jafari M, Logan M, Wang Y, Yuan Y, Bae H, Dixon B, Chen P (2017) Biocompatibility of hydrogel-based scaffolds for tissue engineering applications. Biotechnol Adv 35: 530–544.
Wang T, Wang D, Yu H, Feng B, Zhou F, Zhang H, Zhou L, Jiao S, Li Y (2018) A cancer vaccine-mediated postoperative immunotherapy for recurrent and metastatic tumors. Nat Commun 9: 1532.
Jing X, Mi HY, Lin YJ, Enriquez E, Peng XF, Turng LS (2018) Highly Stretchable and Biocompatible Strain Sensors Based on Mussel-Inspired Super-Adhesive Self-Healing Hydrogels for Human Motion Monitoring. ACS Appl Mater Interfaces 10: 20897–20909.
Ma N, Yan Z (2021) Research Progress of Thermosensitive Hydrogel in Tumor Therapeutic. Nanoscale Res Lett 16: 42.
Zhang H, Sun X, Wang J, Zhang Y, Dong M, Bu T, Li L, Liu Y, Wang L (2021) Multifunctional Injectable Hydrogel Dressings for Effectively Accelerating Wound Healing: Enhancing Biomineralization Strategy. Adv Funct Mater 31:2100093
Chen D, Chen C, Huang C, Chen T, Liu Z (2020) Injectable Hydrogel for NIR-II Photo-Thermal Tumor Therapy and Dihydroartemisinin-Mediated Chemodynamic Therapy. Front Chem 8: 251.
Zhang X, Sun Y, Yang R, Liu B, Liu Y, Yang J, Liu W (2022) An injectable mitochondria-targeted nanodrug loaded-hydrogel for restoring mitochondrial function and hierarchically attenuating oxidative stress to reduce myocardial ischemia-reperfusion injury. Biomaterials 287: 121656.
Zhao D, Feng M, Zhang L, He B, Chen X, Sun J (2021) Facile synthesis of self-healing and layered sodium alginate/polyacrylamide hydrogel promoted by dynamic hydrogen bond. Carbohydr Polym 256: 117580.
Trombino S, Servidio C, Curcio F, Cassano R (2019) Strategies for Hyaluronic Acid-Based Hydrogel Design in Drug Delivery. Pharmaceutics 11: 407
Sun Z, Song C, Wang C, Hu Y, Wu J (2020) Hydrogel-Based Controlled Drug Delivery for Cancer Treatment: A Review. Mol Pharm 17: 373–391.
Du YN, Wei Q, Zhao LJ, Fan CQ, Guo LR, Ye JF, Li Y (2022) Hydrogel-based co-delivery of CIK cells and oncolytic adenovirus armed with IL12 and IL15 for cancer immunotherapy. Biomed Pharmacother 151: 113110.
Qiu M, Wang D, Liang W, Liu L, Zhang Y, Chen X, Sang DK, Xing C, Li Z, Dong B, Xing F, Fan D, Bao S, Zhang H, Cao Y (2018) Novel concept of the smart NIR-light-controlled drug release of black phosphorus nanostructure for cancer therapy. Proc Natl Acad Sci 115: 501–506.
Wang F, Su H, Xu D, Dai W, Zhang W, Wang Z, Anderson C F, Zheng M, Oh R, Wan F, Cui H (2020) Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel. Nat Biomed Eng 4: 1090–1101.
Ye X, Liang X, Chen Q, Miao Q, Chen X, Zhang X, Mei L (2019) Surgical Tumor-Derived Personalized Photothermal Vaccine Formulation for Cancer Immunotherapy. ACS Nano 13: 2956–2968.
Zhang J, Chen C, Li A, Jing W, Sun P, Huang X, Liu Y, Zhang S, Du W, Zhang R, Liu Y, Gong A, Wu J, Jiang X (2021) Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection. Nat Nanotechnol 16: 538–548.
Carreno G, Pereira A, Avila-Salas F, Marican A, Andrade F, Roca-Melendres MM, Valdes O, Vijayakumar S, Schwartz S, Jr, Abasolo I, Rafael D, Duran-Lara EF (2021) Development of "on-demand" thermo-responsive hydrogels for anti-cancer drugs sustained release: Rational design, in silico prediction and in vitro validation in colon cancer models. Mater Sci Eng C Mater Biol Appl 131: 112483.
Zhou Y, Ye T, Ye C, Wan C, Yuan S, Liu Y, Li T, Jiang F, Lovell JF, Jin H, Chen J (2022) Secretions from hypochlorous acid-treated tumor cells delivered in a melittin hydrogel potentiate cancer immunotherapy. Bioact Mater 9: 541–553.
Ren X, Wang N, Zhou Y, Song A, Jin G, Li Z, Luan Y (2021) An injectable hydrogel using an immunomodulating gelator for amplified tumor immunotherapy by blocking the arginase pathway. Acta Biomater 124: 179–190.
Wu Y, Li Q, Shim G, Oh YK (2021) Melanin-loaded CpG DNA hydrogel for modulation of tumor immune microenvironment. J Control Release 330: 540–553.
Norouzi M, Nazari B, Miller DW (2016) Injectable hydrogel-based drug delivery systems for local cancer therapy, Drug Discov Today 21: 1835–1849.
Wei Z, Yang JH, Liu ZQ, Xu F, Zhou JX, Zrínyi M, Osada Y, Chen YM (2015) Novel Biocompatible Polysaccharide-Based Self-Healing Hydrogel. Adva Funct Mater 25: 1352–1359.
Zhou R, Zhou Y, Cheng J, Cao J, Li M, Yu H, Wei D, Li B, Wang Y, Zhou Y (2022) Surface configuration of microarc oxidized Ti with regionally loaded chitosan hydrogel containing ciprofloxacin for improving biological performance. Mater Today Bio 16: 100380.
Zhou L, Chen F, Hou Z, Chen Y, Luo X (2021) Injectable self-healing CuS nanoparticle complex hydrogels with antibacterial, anti-cancer, and wound healing properties. Chem Eng J 409: 128224.
An H, Yang Y, Bo Y, Ma X, Wang Y, Liu L, Wang H, He Y, Qin J (2021) Fabrication of self-healing hydrogel from quaternized N-[3(dimethylamino)propyl]methacrylamide copolymer for antimicrobial and drug release applications. J Biomed Mater Res A 109: 42–53.
Hwang J, An EK, Zhang W, Kim HJ, Eom Y, Jin JO (2022) Dual-functional alginate and collagen-based injectable hydrogel for the treatment of cancer and its metastasis, J Nanobiotechnology 20: 245.
Liang Y, Xu H, Li Z, Zhangji A, Guo B (2022) Bioinspired Injectable Self-Healing Hydrogel Sealant with Fault-Tolerant and Repeated Thermo-Responsive Adhesion for Sutureless Post-Wound-Closure and Wound Healing. Nanomicro Lett 14: 185.
Liang Y, Zhao X, Hu T, Chen B, Yin Z, Ma PX, Guo B (2019) Adhesive Hemostatic Conducting Injectable Composite Hydrogels with Sustained Drug Release and Photothermal Antibacterial Activity to Promote Full-Thickness Skin Regeneration During Wound Healing, Small 15: e1900046.
Xu H, Luo R, Dong L, Pu X, Chen Q, Ye N, Qi S, Han X, Nie W, Fu C, Hu Y, Zhang J, Gao F (2022) pH/ROS dual-sensitive and chondroitin sulfate wrapped poly (beta-amino ester)-SA-PAPE copolymer nanoparticles for macrophage-targeted oral therapy for ulcerative colitis. Nanomedicine 39: 102461.
Kokulnathan T, Ramaraj S, Chen SM, Han-Yu Y (2018) Eco-Friendly Synthesis of Biocompatible Pectin Stabilized Graphene Nanosheets Hydrogel and Their Application for the Simultaneous Electrochemical Determination of Dopamine and Paracetamol in Real Samples, J Electrochemical Society 165: B240-B249.
Chen W, Yuan S, Shen J, Chen Y, Xiao Y (2020) A Composite Hydrogel Based on Pectin/Cellulose via Chemical Cross-Linking for Hemorrhage. Front Bioeng Biotechnol 8: 627351.
Popović N, Stanišić M, Ilić Đurđić K, Prodanović O, Polović N, Prodanović R (2021) Dopamine-modified pectin for a Streptomyces cyaneus laccase induced microbeads formation, immobilization, and textile dyes decolorization Environ Techn Innov 22:101399.
Xiao M (2021) Advances and rational design of chitosan-based autonomic self-healing hydrogels for biomedical applications. J Polym Res 28: 321.
Chen D, Chang L, Zhou Z, Bo Y, Wang Y, He Y, Qin J (2021) Pectin-based self-healing hydrogel with NaHCO3 degradability for drug loading and release. J Polym Res 28: 59.
Hu S, Martinez-Garcia FD, Moeun BN, Burgess JK, Harmsen MC, Hoesli C, de Vos P (2021) An immune regulatory 3D-printed alginate-pectin construct for immunoisolation of insulin producing beta-cells. Mater Sci Eng C Mater Biol Appl 123: 112009.
Mala T, Anal AK (2021) Protection and Controlled Gastrointestinal Release of Bromelain by Encapsulating in Pectin-Resistant Starch Based Hydrogel Beads. Front Bioeng Biotechnol 9: 757176.
McCrorie P, Mistry J, Taresco V, Lovato T, Fay M, Ward I, Ritchie AA, Clarke PA, Smith SJ, Marlow M, Rahman R (2020) Etoposide and olaparib polymer-coated nanoparticles within a bioadhesive sprayable hydrogel for post-surgical localised delivery to brain tumours. Eur J Pharm Biopharm 157: 108–120.
Amirian J, Zeng Y, Shekh MI, Sharma G, Stadler FJ, Song J, Du B, Zhu Y (2021) In-situ crosslinked hydrogel based on amidated pectin/oxidized chitosan as potential wound dressing for skin repairing. Carbohydr Polym 251: 117005.
Mamidi N, Delgadillo RMV (2021) Design, fabrication and drug release potential of dual stimuli-responsive composite hydrogel nanoparticle interfaces. Colloids and Surfaces B: Biointerfaces 204: 111819.
Liang Y, Zhao X, Ma PX, Guo B, Du Y, Han X (2019) pH-responsive injectable hydrogels with mucosal adhesiveness based on chitosan-grafted-dihydrocaffeic acid and oxidized pullulan for localized drug delivery. J Colloid Interface Sci 536: 224–234.
Hu Q, Li H, Archibong E, Chen Q, Ruan H, Ahn S, Dukhovlinova E, Kang Y, Wen D, Dotti G, Gu Z (2021) Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets. Nat Biomed Eng 5: 1038–1047.
Wezgowiec J, Tsirigotis-Maniecka M, Saczko J, Wieckiewicz M, Wilk KA (2021) Microparticles vs. Macroparticles as Curcumin Delivery Vehicles: Structural Studies and Cytotoxic Effect in Human Adenocarcinoma Cell Line. Molecules 26:6056.
Xu, Z., Liu, G., Huang, J., and Wu, J. (2022) Novel Glucose-Responsive Antioxidant Hybrid Hydrogel for Enhanced Diabetic Wound Repair, ACS Appl Mater Interfaces 14, 7680–7689.
Yesilyurt V, Webber MJ, Appel EA, Godwin C, Langer R, Anderson DG (2016) Injectable Self-Healing Glucose-Responsive Hydrogels with pH-Regulated Mechanical Properties, Adv Mater 28: 86–91.
An H, Zhu L, Shen J, Li W, Wang Y, Qin J (2020) Self-healing PEG-poly(aspartic acid) hydrogel with rapid shape recovery and drug release. Colloids Surf B Biointerfaces 185: 110601.
Gan D, Xu T, Xing W, Ge X, Fang L, Wang K, Ren F, Lu X (2019) Mussel-Inspired Contact-Active Antibacterial Hydrogel with High Cell Affinity, Toughness, and Recoverability. Adv Funct Mater 29:1805964.
Hou F, Xi B, Wang X, Yang Y, Zhao H, Li W, Qin J, He Y (2019) Self-healing hydrogel with cross-linking induced thermo-response regulated light emission property. Colloids Surf B Biointerfaces 183: 110441.
Zhao H, An H, Xi B, Yang Y, Qin J, Wang Y, He Y, Wang X (2019) Self-Healing Hydrogels with both LCST and UCST through Cross-Linking Induced Thermo-Response. Polymers 11: 490.
Feng C, Ouyang J, Tang Z, Kong N, Liu Y, Fu L, Ji X, Xie T, Farokhzad OC, Tao W (2020) Germanene-Based Theranostic Materials for Surgical Adjuvant Treatment: Inhibiting Tumor Recurrence and Wound Infection. Matter 3: 127–144.
An H,Yang Y, Zhou Z, BoY, Wang Y, He Y, Wang D, Qin J (2021) Pectin-based injectable and biodegradable self-healing hydrogels for enhanced synergistic anticancer therapy. Acta Biomaterial 131: 149–161.
Zhang D, Xu Z, Li H, Fan C, Cui C, Wu T, Xiao M, Yang Y, Yang J, Liu W (2020) Fabrication of strong hydrogen-bonding induced coacervate adhesive hydrogels with antibacterial and hemostatic activities. Biomater Sci 8: 1455–1463.

SupplementaryMaterial.docx

Download PDF

Journal Publication

published 28 Nov, 2023

Read the published version in Journal of Polymer Research →

Reviewers agreed at journal
06 Jun, 2023
Reviewers invited by journal
01 Jun, 2023
Editor invited by journal
28 May, 2023
Editor assigned by journal
24 May, 2023
First submitted to journal
21 May, 2023

You are reading this latest preprint version

Fully biodegradable self-healing hydrogel prepared based on poly(aspartic acid) and pectin for drug delivery and anti-tumor therapy

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Materials and methods

Materials

Polycondensation of PSI and synthesis of PAPH

Preparation of and morphology of the hydrogels

Mechanical strength and self-healing behavior of PAPH/OPec hydrogel

Cell compatibility determined through CCK-8 assay

DOX release of the PAPH/OPec hydrogel

Result and discussion

Synthesis of PAPH and oxidation of pectin

Fabrication of the PAPH/OPec hydrogel and mechanical property investigation

Morphology and self-healing of the hydrogels

Cytotoxicity of the PAPH/OPec hydrogel

Hemocompatibility of the PAPH/OPec hydrogel

DOX loading and sustained release the PAPH/OPec hydrogel

H&E staining observation of the tumors and other tissues

Conclusion

Declarations

References

Supplementary Files

Status:

Journal Publication

Version 1