{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T06:50:38Z","timestamp":1763621438948,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T00:00:00Z","timestamp":1689811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zhejiang Provincial Key R&amp;D Program of China","award":["2021C02049","LTY22E030002","22nya04"],"award-info":[{"award-number":["2021C02049","LTY22E030002","22nya04"]}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["2021C02049","LTY22E030002","22nya04"],"award-info":[{"award-number":["2021C02049","LTY22E030002","22nya04"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taizhou Science and Technology Plan Project in 2022","award":["2021C02049","LTY22E030002","22nya04"],"award-info":[{"award-number":["2021C02049","LTY22E030002","22nya04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>Diabetes mellitus type 2 (T2DM) is a disease caused by genetic and environmental factors, and the main clinical manifestation is hyperglycemia. Currently, insulin injections are still the first-line treatment for diabetes. However, repeated injections may cause insulin resistance, hypoglycemia, and other serious side effects. Thus, it is imperative to develop new diabetes treatments. Protein-based diabetes drugs, such as fibroblast growth factor-21 (FGF-21), have a longer-lasting glycemic modulating effect with high biosafety. However, the instability of these protein drugs limits their applications. In this study, we extract protein hypoglycemic drugs with oral and injectable functions. The FGF-21 analog (NA-FGF) was loaded into the chitosan derivative-based nanomaterials, N-2-Hydroxypropyl trimethyl ammonium chloride chitosan\/carboxymethyl chitosan (N-2-HACC\/CMCS), to prepare NA-FGF-loaded N-2-HACC\/CMCS microspheres (NA-FGF-N-2-HACC\/CMCS MPs). It was well demonstrated that NA-FGF-N-2-HACC\/CMCS MPs have great biocompatibility, biostability, and durable drug-release ability. In addition to injectable drug delivery, our prepared microspheres were highly advantageous for oral administration. The in vitro and in vivo experimental results suggested that NA-FGF-N-2-HACC\/CMCS MPs could be used as a promising candidate and universal nano-delivery system for both oral and injectable hypoglycemic regulation.<\/jats:p>","DOI":"10.3390\/polym15143099","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T05:42:01Z","timestamp":1689831721000},"page":"3099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Chitosan Derivative-Based Microspheres Loaded with Fibroblast Growth Factor for the Treatment of Diabetes"],"prefix":"10.3390","volume":"15","author":[{"given":"Jue","family":"Wu","sequence":"first","affiliation":[{"name":"College of Chemistry and Material Sciences, School of Life Science, Heilongjiang University, Harbin 150080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Chemistry and Material Sciences, School of Life Science, Heilongjiang University, Harbin 150080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3360-8082","authenticated-orcid":false,"given":"Wenfei","family":"Wang","sequence":"additional","affiliation":[{"name":"Bio-Pharmaceutical Lab, College of Life Sciences, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhong","family":"Lin","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Plant Evolutionary Ecology and Conservation, Taizhou Key Laboratory of Biomedicine and Advanced Dosage Forms, School of Life Sciences, Taizhou University, Taizhou 318000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Chemistry and Material Sciences, School of Life Science, Heilongjiang University, Harbin 150080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Chemistry and Material Sciences, School of Life Science, Heilongjiang University, Harbin 150080, China"},{"name":"Zhejiang Provincial Key Laboratory of Plant Evolutionary Ecology and Conservation, Taizhou Key Laboratory of Biomedicine and Advanced Dosage Forms, School of Life Sciences, Taizhou University, Taizhou 318000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6139-1912","authenticated-orcid":false,"given":"Kai","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Chemistry and Material Sciences, School of Life Science, Heilongjiang University, Harbin 150080, China"},{"name":"Zhejiang Provincial Key Laboratory of Plant Evolutionary Ecology and Conservation, Taizhou Key Laboratory of Biomedicine and Advanced Dosage Forms, School of Life Sciences, Taizhou University, Taizhou 318000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.addr.2018.06.022","article-title":"Molecular Imaging of \u03b2-Cells: Diabetes and Beyond","volume":"139","author":"Wei","year":"2019","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"389","DOI":"10.14341\/probl9960","article-title":"Perspectives of Application of Intranasally Administered Insulin for Correction of Metabolic and Hormonal Disorders in Diabetes Mellitus and Metabolic Syndrome","volume":"65","author":"Shpakov","year":"2019","journal-title":"Probl. Endokrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1097\/CM9.0000000000000680","article-title":"Macrophage migration inhibitory factor may contribute to hypertrophy of lumbar ligamentum flavum in type 2 diabetes mellitus","volume":"133","author":"Lu","year":"2020","journal-title":"Chin. Med. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1177\/1054773820951933","article-title":"The Association between Diabetes Complications, Diabetes Distress, and Depressive Symptoms in Patients with Type 2 Diabetes Mellitus","volume":"30","author":"Yang","year":"2021","journal-title":"Clin. Nurs. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ajog.2017.06.003","article-title":"Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and The Promotion of Longevity","volume":"217","author":"Romero","year":"2017","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1111\/1753-0407.13013","article-title":"Increasing Insulin Resistance Predicts Adverse Pregnancy Outcomes in Women with Gestational Diabetes Mellitus","volume":"12","author":"Sun","year":"2020","journal-title":"J. Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5461","DOI":"10.1021\/jacs.1c13426","article-title":"Acid-Resistant and Physiological pH-Responsive DNA Hydrogel Composed of A-Motif and i-Motif toward Oral Insulin Delivery","volume":"144","author":"Hu","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"112821","DOI":"10.1016\/j.jep.2020.112821","article-title":"Trigonella Stellata Reduced the Deleterious Effects of Diabetes Mellitus through Alleviation of Oxidative Stress, Antioxidant- and Drug-Metabolizing Enzymes Activities","volume":"256","author":"Sheweita","year":"2020","journal-title":"J. Ethnopharmacol."},{"doi-asserted-by":"crossref","unstructured":"Szkudelski, T., Konieczna, K., and Szkudelska, K. (2022). Regulatory Effects of Metformin, An Antidiabetic Biguanide Drug, on the Metabolism of Primary Rat Adipocytes. Molecules, 27.","key":"ref_9","DOI":"10.3390\/molecules27165250"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.psychres.2017.12.058","article-title":"Association Between Depression and Persistence with Oral Antihyperglycemic Drugs in Type 2 Diabetes Mellitus Patients in Germany","volume":"261","author":"Kostev","year":"2018","journal-title":"Psychiatry Res."},{"key":"ref_11","first-page":"363","article-title":"Diabetes Mellitus Associated with Immune Checkpoint Inhibitors Treatment: A Clinical Case by Atezolizumab","volume":"68","author":"Gomez","year":"2021","journal-title":"Endocrinol. Diabetes Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e000940","DOI":"10.1136\/bmjdrc-2019-000940","article-title":"Independent Effects of 15 Commonly Prescribed Drugs on All-Cause Mortality Among US Elderly Patients with Type 2 Diabetes Mellitus","volume":"8","author":"Baik","year":"2020","journal-title":"BMJ Open Diabetes Res. Care"},{"doi-asserted-by":"crossref","unstructured":"Coppage, A.L., Heard, K.R., Dimare, M.T., Liu, Y., Wu, W., Lai, J.H., and Bachovchin, W.W. (2017). Human FGF-21 Is A Substrate of Fibroblast Activation Protein. PLoS ONE, 11.","key":"ref_13","DOI":"10.1371\/journal.pone.0151269"},{"doi-asserted-by":"crossref","unstructured":"Pereira, R.I., Hecht, R., Li, Y.S., Sun, J., Belouski, E., Hall, M., Hager, T., Yie, J., Wang, W., and Winters, D. (2012). Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes. PLoS ONE, 7.","key":"ref_14","DOI":"10.1371\/journal.pone.0049345"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E128","DOI":"10.1017\/S0029665115001433","article-title":"The Association Between the Biguanide Drug Metformin and Vitamin B12 Deficiency in Diabetic Patients: A Systematic Review","volume":"74","author":"Chapman","year":"2015","journal-title":"Proc. Nutr. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1210\/clinem\/dgaa178","article-title":"Effects of Basal Insulin on Lipid Profile Compared to Other Classes of Antihyperglycemic Agents in Type 2 Diabetic Patients","volume":"105","author":"Rigato","year":"2020","journal-title":"J. Clin. Endocr. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/jep.13171","article-title":"Comparison of Effectiveness and Drug Cost Between Dipeptidyl Peptidase-4 Inhibitor and Biguanide as The First-Line Anti-Hyperglycaemic Medication Among Japanese Working Generation with Type 2 Diabetes","volume":"26","author":"Sugiyama","year":"2020","journal-title":"J. Eval. Clin. Pract."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"601448","DOI":"10.3389\/fphar.2020.601448","article-title":"A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF\/HFr Diet Mice","volume":"11","author":"Lee","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_19","first-page":"243","article-title":"Application of Chitosan and Its Derivatives in Nanocarrier Based Pulmonary Drug Delivery Systems","volume":"5","author":"Dua","year":"2017","journal-title":"Pharm. Nanotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"894667","DOI":"10.3389\/fbioe.2022.894667","article-title":"Applications of Chitosan and Its Derivatives in Skin and Soft Tissue Diseases","volume":"10","author":"Xia","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"doi-asserted-by":"crossref","unstructured":"Lisuzzo, L., Cavallaro, G., Milioto, S., and Lazzara, G. (2020). Halloysite Nanotubes Coated by Chitosan for the Controlled Release of Khellin. Polymers, 12.","key":"ref_21","DOI":"10.3390\/polym12081766"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"110689","DOI":"10.1016\/j.msec.2020.110689","article-title":"Preparation and properties of a highly dispersed nano-hydroxyapatite colloid used as a reinforcing filler for chitosan","volume":"110","author":"Ying","year":"2020","journal-title":"Mater. Sci. Eng. C"},{"doi-asserted-by":"crossref","unstructured":"Abu El-Soad, A.M., Lazzara, G., Abd El-Magied, M.O., Cavallaro, G., Al-Otaibi, J.S., Sayyed, M.I., and Kovaleva, E.G. (2022). Chitosan Functionalized with Carboxyl Groups as a Recyclable Biomaterial for the Adsorption of Cu (II) and Zn (II) Ions in Aqueous Media. Int. J. Mol. Sci., 23.","key":"ref_23","DOI":"10.3390\/ijms23042396"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.ijbiomac.2021.07.023","article-title":"A Review on Chitosan and Chitosan-Based Bionanocomposites: Promising Material for Combatting Global Issues and Its Applications","volume":"185","author":"Azmana","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1016\/j.nano.2018.08.007","article-title":"GRGDS-Functionalized Chitosan Nanoparticles as A Potential Intravenous Hemostat for Traumatic Hemorrhage Control in an Animal Model","volume":"14","author":"Zhang","year":"2018","journal-title":"Nanomedicine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.jconrel.2020.10.047","article-title":"Oral Delivery of Metformin by Chitosan Nanoparticles for Polycystic Kidney Disease","volume":"329","author":"Wang","year":"2021","journal-title":"J. Control. Release"},{"doi-asserted-by":"crossref","unstructured":"Shim, S., and Yoo, H.S. (2020). The Application of Mucoadhesive Chitosan Nanoparticles in Nasal Drug Delivery. Mar. Drugs, 18.","key":"ref_27","DOI":"10.3390\/md18120605"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9980","DOI":"10.1021\/acsami.8b01522","article-title":"Highly Biocompatible Chlorin e6-Loaded Chitosan Nanoparticles for Improved Photodynamic Cancer Therapy","volume":"10","author":"Ding","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6491","DOI":"10.1021\/acsnano.8b09679","article-title":"Delivery of MicroRNAs by Chitosan Nanoparticles to Functionally Alter Macrophage Cholesterol Efflux in Vitro and in Vivo","volume":"13","author":"Nguyen","year":"2019","journal-title":"ACS Nano"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"119174","DOI":"10.1016\/j.carbpol.2022.119174","article-title":"Mannose-anchored quaternized chitosan\/thiolated carboxymethyl chitosan composite NPs as mucoadhesive carrier for drug delivery","volume":"283","author":"Jin","year":"2022","journal-title":"Carbohydr. Polym."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.colsurfb.2011.08.007","article-title":"Submicroparticles Composed of Amphiphilic Chitosan Derivative for Oral Insulin and Curcumin Release Applications","volume":"88","author":"Shelma","year":"2011","journal-title":"Colloids Surf. B"},{"doi-asserted-by":"crossref","unstructured":"Wang, W.Q., Meng, Q.Y., Li, Q., Liu, J.B., Zhou, M., Jin, Z., and Zhao, K. (2020). Chitosan Derivatives and Their Application in Biomedicine. Int. J. Mol. Sci., 21.","key":"ref_32","DOI":"10.3390\/ijms21020487"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.carbpol.2016.04.085","article-title":"Biological Evaluation of N-2-Hydroxypropyl Trimethyl Ammonium Chloride Chitosan as a Carrier for the Delivery of Live Newcastle Disease Vaccine","volume":"149","author":"Zhao","year":"2016","journal-title":"Carbohydr. Polym."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1708172","DOI":"10.1155\/2018\/1708172","article-title":"Competitive Biological Activities of Chitosan and Its Derivatives: Antimicrobial, Antioxidant, Anticancer, and Anti-Inflammatory Activities","volume":"2018","author":"Kim","year":"2018","journal-title":"Int. J. Polym. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.2174\/0929867326666190405151538","article-title":"Recent Advances of Chitosan and Its Derivatives in Biomedical Applications","volume":"27","author":"Ding","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41076","DOI":"10.1021\/acsami.8b14526","article-title":"On-Demand Dissolvable Self-Healing Hydrogel Based on Carboxymethyl Chitosan and Cellulose Nanocrystal for Deep Partial Thickness Burn Wound Healing","volume":"10","author":"Huang","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.cej.2013.02.011","article-title":"Antimicrobial Activity and Cytotoxicity of N-2-HACC and Characterization of Nanoparticles with N-2-HACC and CMC as a Vaccine Carrier","volume":"221","author":"Jin","year":"2013","journal-title":"Chem. Eng. J."},{"doi-asserted-by":"crossref","unstructured":"Trucillo, P. (2022). Discrete and Continuous Glucose Monitoring Systems: The Point of View of a Patient Affected by Type-1 Diabetes. Processes, 10.","key":"ref_38","DOI":"10.3390\/pr10122706"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.carbpol.2016.05.049","article-title":"A Review of Chitosan and Its Derivatives in Bone Tissue Engineering","volume":"151","author":"Dhivya","year":"2016","journal-title":"Carbohydr. Polym."},{"doi-asserted-by":"crossref","unstructured":"Wang, M., Wang, C., Ren, S., Pan, J., Wang, Y., Shen, Y., Zeng, Z., Cui, H., and Zhao, X. (2022). Versatile Oral Insulin Delivery Nanosystems: From Materials to Nanostructures. Int. J. Mol. Sci., 23.","key":"ref_40","DOI":"10.3390\/ijms23063362"},{"doi-asserted-by":"crossref","unstructured":"Zhao, Y., Jiang, Z.S., Zhao, T.B., Ye, M.L., Hu, C.J., Zhou, H.M., Yin, Z.H., Chen, Y., Zhang, Y., and Wang, S.F. (2013). Targeting Insulin Resistance in Type 2 Diabetes via Immune Modulation of Cord Blood-Derived Multipotent Stem Cells (CB-SCs) in Stem Cell Educator Therapy: Phase I\/II Clinical Trial. BMC Med., 11.","key":"ref_41","DOI":"10.1186\/1741-7015-11-160"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"661","DOI":"10.2165\/00128071-200304100-00001","article-title":"Skin-Related Complications of Insulin Therapy","volume":"4","author":"Richardson","year":"2003","journal-title":"Am. J. Clin. Dermatol."}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/15\/14\/3099\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:15:38Z","timestamp":1760127338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/15\/14\/3099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,20]]},"references-count":42,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["polym15143099"],"URL":"https:\/\/doi.org\/10.3390\/polym15143099","relation":{},"ISSN":["2073-4360"],"issn-type":[{"type":"electronic","value":"2073-4360"}],"subject":[],"published":{"date-parts":[[2023,7,20]]}}}