Citation: Qing-Ri Jin, Tian-Jiao Zhou, Ya-Ting Yao, Hai-Qing Yu, Hao-Bin Che, Meng-Meng Zhang, Chun-Hui Cui, Yi Wang, Cheng-Jun Li, Lei Xing, Hu-Lin Jiang. Icaritin-incorporated dual-sensitizing hydrogel for osteosarcoma doxorubicin treatment and bone regeneration[J]. Chinese Chemical Letters, ;2026, 37(6): 111539. doi: 10.1016/j.cclet.2025.111539 shu

Icaritin-incorporated dual-sensitizing hydrogel for osteosarcoma doxorubicin treatment and bone regeneration

Qing-Ri Jin ^{a, 1} ,
Tian-Jiao Zhou ^{b, 1} ,
Ya-Ting Yao ^{b, 1} ,
Hai-Qing Yu ^b ,
Hao-Bin Che ^b ,
Meng-Meng Zhang ^b ,
Chun-Hui Cui ^b ,
Yi Wang ^b ,
Cheng-Jun Li ^{c, *,} ,
Lei Xing ^{b, *,} ,
Hu-Lin Jiang ^{b, d, e, *,}

a.
School of Pharmacy, Hangzhou Medical College, Hangzhou 311399, China
b.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
c.
Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China
d.
College of Pharmacy, Yanbian University, Yanji 133002, China
e.
Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, South Korea

48933897@qq.com

xinglei6xl@163.com

jianghulin3@163.com

Received Date: 11 February 2025
Revised Date: 1 July 2025
Accepted Date: 2 July 2025
Available Online: 3 July 2025

Figures(6)

Osteosarcoma (OS) is the most common primary bone malignancy. However, treatment remains challenging due to multidrug resistance, toxic side effects from high-dose and frequent chemotherapy, and surgery-induced bone defects. Herein, we report a double-sensitizing chemotherapeutic hydrogel for efficient OS treatment and bone regeneration, which is constructed by loading doxorubicin hydrochloride (DOX) and icaritin (ICT) into Pluronic F127 (F127) and Pluronic F68 (F68) hydrogel matrix (DOX/ICT-gel). Both ICT and Pluronics can sensitize cancer cells to DOX treatment and enhance intracellular DOX accumulation, thereby boosting the cytotoxic activity of DOX. The addition of ICT can not only downregulate the required dose of DOX and reduce the toxic side effects of DOX, but also induce osteoblast differentiation, contributing to bone regeneration. In the in-situ anti-OS study, the DOX/ICT-gel was shown to stay locally for 7 days, and effectively inhibits OS tumor growth and metastasis, providing robust anticancer efficacy with low toxicity from a single injection for long-lasting treatment. This research provides a novel dual-sensitive DOX strategy for localized OS therapy, potentially advancing the clinical management of this challenging disease.
- Osteosarcoma,
- Thermosensitive hydrogel,
- Doxorubicin hydrochloride,
- Icaritin,
- Pluronics
1. [1]
  J. Ritter, S.S. Bielack, Ann. Oncol. 21 (2010) vii320–vii325. doi: 10.1093/annonc/mdq276
2. [2]
  L.C. Sayles, M.R. Breese, A.L. Koehne, et al., Cancer Discov. 9 (2019) 46–63. doi: 10.1158/2159-8290.cd-17-1152
3. [3]
  H.C. Beird, S.S. Bielack, A.M. Flanagan, et al., Nat. Rev. Dis. Primers. 8 (2022) 77. doi: 10.1038/s41572-022-00409-y
4. [4]
  R.L. Siegel, K.D. Miller, A. Jemal, CA Cancer J. Clin. 70 (2020) 7–30. doi: 10.3322/caac.21590
5. [5]
  C.K. Lettieri, N. Appel, N. Labban, et al., Immunotherapy 8 (2016) 1233–1244. doi: 10.2217/imt-2016-0048
6. [6]
  R. Rathore, B.A. Van Tine, J. Clin. Med. 10 (2021) 1182. doi: 10.3390/jcm10061182
7. [7]
  J. Gill, R. Gorlick, Nat. Rev. Clin. Oncol. 18 (2021) 609–624. doi: 10.1038/s41571-021-00519-8
8. [8]
  M. Gu, W. Yu, S.T. Stefanello, et al., J. Control. Release 377 (2025) 174–185. doi: 10.1016/j.jconrel.2024.11.012
9. [9]
  K. Igarashi, K. Kawaguchi, S. Li, et al., Cancer Lett. 417 (2018) 168–173. doi: 10.1016/j.canlet.2017.12.028
10. [10]
  C.M. Hattinger, M. Fanelli, E. Tavanti, et al., Expert Opin. Emerg. Drugs 20 (2015) 495–514. doi: 10.1517/14728214.2015.1051965
11. [11]
  S.E. Lipshultz, R. Karnik, P. Sambatakos, et al., Curr. Opin. Cardiol. 29 (2014) 103–112. doi: 10.1097/HCO.0000000000000034
12. [12]
  Y. Cao, X. Ge, Y. Wei, et al., Chin. Chem. Lett. 35 (2024) 108672. doi: 10.1016/j.cclet.2023.108672
13. [13]
  S. Zhang, X. Liu, T. Bawa-Khalfe, et al., Nat. Med. 18 (2012) 1639–1642. doi: 10.1038/nm.2919
14. [14]
  S.S. Bielack, B. Kempf-Bielack, G. Delling, et al., J. Clin. Oncol. 20 (2002) 776–790. doi: 10.1200/JCO.2002.20.3.776
15. [15]
  L. Kager, A. Zoubek, U. Pötschger, et al., J. Clin. Oncol. 21 (2003) 2011–2018. doi: 10.1200/JCO.2003.08.132
16. [16]
  S. Wang, K. Yu, Z. Yu, et al., Chin. Chem. Lett. 34 (2023) 108184. doi: 10.1016/j.cclet.2023.108184
17. [17]
  F. Shen, W.S. Cai, J.L. Li, et al., Onco Targets. Ther. 7 (2014) 305–314.
18. [18]
  J. Chen, W. Wang, H. Wang, et al., Drug Discov. Ther. 8 (2014) 33–41. doi: 10.5582/ddt.8.33
19. [19]
  C. Zhang, J. Niu, J. Li, et al., Chin. Chem. Lett. 35 (2024) 108556. doi: 10.1016/j.cclet.2023.108556
20. [20]
  J. Li, S. Shen, Z. Liu, et al., J. Nat. Prod. 86 (2023) 290–306. doi: 10.1021/acs.jnatprod.2c00908
21. [21]
  M. Seiti, P.S. Ginestra, R.M. Ferraro, et al., Int. J. Bioprint. 8 (2022) 504. doi: 10.18063/ijb.v8i1.504
22. [22]
  Z. Yu, J. Guo, M. Hu, et al., ACS Nano 14 (2020) 4816–4828. doi: 10.1021/acsnano.0c00708
23. [23]
  L. Huang, X. Wang, H. Cao, et al., Biomaterials 182 (2018) 58–71. doi: 10.1016/j.biomaterials.2018.07.046
24. [24]
  Q. Wang, Q. Liang, J. Dou, et al., Nat. Nano 19 (2024) 95–105. doi: 10.1038/s41565-023-01498-w
25. [25]
  Z. Li, W. Xu, J. Yang, et al., Adv. Mater. 34 (2022) e2200449. doi: 10.1002/adma.202200449
26. [26]
  T.J. Zhou, L. Xing, Y.T. Fan, et al., J. Control. Release 307 (2019) 44–54. doi: 10.1016/j.jconrel.2019.06.016
27. [27]
  Y. Feng, Z. Zhang, W. Tang, Y. Dai, Exploration 3 (2023) 20220173. doi: 10.1002/EXP.20220173r.2021.02.002
28. [28]
  R. Tian, X. Qiu, W. Mu, et al., Chin. Chem. Lett. 35 (2024) 108343. doi: 10.1016/j.cclet.2023.108343
29. [29]
  Y. Feng, Z. Zhang, W. Tang, et al., Exploration 3 (2023) 20220173. doi: 10.1002/EXP.20220173r.2021.02.002
30. [30]
  J. Li, D.J. Mooney, Nat. Rev. Mater. 1 (2016) 16071. doi: 10.1038/natrevmats.2016.71
31. [31]
  Q. Luo, J. Sun, Z. Li, et al., Chin. Chem. Lett. 36 (2025) 110433. doi: 10.1016/j.cclet.2024.110433
32. [32]
  N.U. Khaliq, J. Lee, S. Kim, et al., Pharmaceutics 15 (2023) 2102. doi: 10.3390/pharmaceutics15082102
33. [33]
  T.J. Zhou, L. Xing, Y.T. Fan, et al., J. Control. Release 309 (2019) 82–93. doi: 10.1016/j.jconrel.2019.07.028
34. [34]
  L.S. Yap, M.C. Yang, Colloids Surf. B 185 (2020) 110606. doi: 10.1016/j.colsurfb.2019.110606
35. [35]
  M.M. Al-Rajabi, Y.H. Teow, Sustain. Chem. Pharm. 31 (2023) 100939. doi: 10.1016/j.scp.2022.100939
36. [36]
  A.V. Kabanov, E.V. Batrakova, V.Y. Alakhov, Adv. Drug Deliv. Rev. 54 (2002) 759–779. doi: 10.1016/S0169-409X(02)00047-9
37. [37]
  C. Pérez-Arnaiz, N. Busto, J.M. Leal, et al., J. Phys. Chem. B 118 (2014) 1288–1295. doi: 10.1021/jp411429g
38. [38]
  M. Lashkari, A. Fatemi, H.M. Valandani, et al., Sci. Rep. 12 (2022) 12657. doi: 10.1038/s41598-022-16943-4
39. [39]
  T.J. Zhou, M.M. Zhang, D.M. Liu, et al., Biomaterials 305 (2024) 122447. doi: 10.1016/j.biomaterials.2023.122447
40. [40]
  Y. Jin, G. Han, Y. Gao, et al., Nat. Commun. 16 (2025) 2022. doi: 10.1038/s41467-025-57278-8
41. [41]
  L. Zhang, Y.X. Liu, Y.T. Yao, et al., Int. J. Pharm. 634 (2023) 122637.
42. [42]
  D.D. Ilchovska, D.M. Barrow, Autoimmun. Rev. 20 (2021) 102741. doi: 10.1016/j.autrev.2020.102741
43. [43]
  X. Wu, Z. Cai, L. Lou, Y. Zhu, Cancer Epidemiol. 36 (2012) 212–216. doi: 10.1016/j.canep.2011.08.002
44. [44]
  T. Nedelcu, B. Kubista, A. Koller, et al., J. Cancer Res. Clin. 134 (2008) 237–244.
45. [45]
  C.J. Ho, H.J. Ko, T.S. Liao, et al., Cell Death. Discov. 7 (2021) 275. doi: 10.1038/s41420-021-00658-y
46. [46]
  C.J. Lee, T.Y. Jang, S.E. Jeon, et al., Nat. Commun. 15 (2024) 10422. doi: 10.1038/s41467-024-54920-9
47. [47]
  J. Wang, Q. Shi, T. Yuan, et al., Clin. Chim. Acta 433 (2014) 225–231. doi: 10.1016/j.cca.2014.03.023
48. [48]
  H. Li, K. Zhang, L. Liu, et al., Tumor Biol. 35 (2014) 5487–5491. doi: 10.1007/s13277-014-1717-3
49. [49]
  E.V. Batrakova, S. Li, A.M. Brynskikh, A.K. Sharma, et al., J. Control. Release 143 (2010) 290–301. doi: 10.1016/j.jconrel.2010.01.004
50. [50]
  T. Minko, E.V. Batrakova, S. Li, et al., J. Control. Release 105 (2005) 269–278. doi: 10.1016/j.jconrel.2005.03.019
51. [51]
  V. Alakhov, E. Klinski, S. Li, et al., Colloids Surf. B 16 (1999) 113–134. doi: 10.1016/S0927-7765(99)00064-8
52. [52]
  Z. Lin, Z. Chen, Y. Chen, et al., Exploration 3 (2023) 20220149. doi: 10.1002/EXP.20220149
53. [53]
  Y. Luo, Y. Gao, Nano Biomed. Eng. 16 (2024) 188–202. doi: 10.26599/nbe.2024.9290055
54. [54]
  J. Chang, F. Zhao, X. Sun, et al., J. Vis. Exp. (2021) e63072.
55. [55]
  T.J. Zhou, Y. Xu, L. Xing, et al., Adv. Mater. 33 (2021) e2100114. doi: 10.1002/adma.202100114
56. [56]
  T.J. Zhou, X. Wan, M.M. Zhang, Biomaterials 300 (2023) 122205. doi: 10.1016/j.biomaterials.2023.122205
1. [1]
  Xin Liu , Haoran Zhu , Yi Wang , Haili Zhang , Yujie Li , Hongcheng Gao , Yi Han , Dejin Wang , Yunsheng Xia . Carbon dots-embedded hydrogel ratiometric fluorescent platform for portable determination of doxorubicin in clinical samples. Chinese Chemical Letters, 2026, 37(2): 111891-. doi: 10.1016/j.cclet.2025.111891
2. [2]
  Xuebing Jiang , Siyi Wang , Li Zhang , Xian Jiang , Maling Gou . Lidocaine hydrochloride loaded isomaltulose microneedles for efficient local anesthesia of the skin. Chinese Chemical Letters, 2024, 35(4): 108686-. doi: 10.1016/j.cclet.2023.108686
3. [3]
  Hongyi Huang , Siyao Che , Wenjie Zhou , Yunchu Zhang , Weiling Zhuo , Xijing Yang , Songping Zheng , Jiagang Liu , Xiang Gao . Apatinib potentiates doxorubicin with cRGD-functionalized pH-sensitive micelles against glioma. Chinese Chemical Letters, 2025, 36(5): 110084-. doi: 10.1016/j.cclet.2024.110084
4. [4]
  Liangbo Zhang , Jun Cheng , Yahui Shi , Kunjie Hou , Qi An , Jingyi Li , Baohui Cui , Fei Chen . Efficient removal of tetracycline hydrochloride by ZnO/HNTs composites under visible light: Kinetics, degradation pathways and mechanism. Chinese Chemical Letters, 2025, 36(7): 110400-. doi: 10.1016/j.cclet.2024.110400
5. [5]
  Ya-Jie Zhu , Zhi-Min Lv , Hao-Feng Zhu , Qi-Yan Qi , Shang-Bo Yu , Jia Tian , Wei Zhou , Zhan-Ting Li . Self-assembly of disassemblable supramolecular organic frameworks for doxorubicin delivery, photofrin posttreatment phototoxicity inhibition and heparin neutralization. Chinese Chemical Letters, 2026, 37(1): 111353-. doi: 10.1016/j.cclet.2025.111353
6. [6]
  Jia Wang , Yunxiu Fan , Shilin Xu , Zhouxue Wu , Tian Hu , Yun Lu , Yue Li , Kang Xiong , Hongjun Deng , Jingrong Huang , Bo Yang , Shaozhi Fu . Self-propelled biomotors co-deliver doxorubicin liposomes and aPD-1 antibody to fight breast cancer. Chinese Chemical Letters, 2026, 37(2): 111607-. doi: 10.1016/j.cclet.2025.111607
7. [7]
  Yu Wang , Changjiang Lu , Danhua Jiao , Fei Wang , Xiaojian Gong , Tianhua Yu , Anping Wang , Chong-Chen Wang . Efficient degradation of tetracycline hydrochloride via high-redox S-scheme MOF-on-MOF heterojunction catalyst. Chinese Chemical Letters, 2026, 37(6): 111979-. doi: 10.1016/j.cclet.2025.111979
8. [8]
  Xi Chen , Xue Zhang , Shuai Yang , Jie Wang , Tian Tang , Maling Gou . An adhesive hydrogel for the treatment of oral ulcers. Chinese Chemical Letters, 2025, 36(3): 110021-. doi: 10.1016/j.cclet.2024.110021
9. [9]
  Shanshan Yan , Sihai Sun , Zhiwu Chen , Xin Wang . Improved photocatalytic activity of SrBi2Nb2O9 for the degradation of ciprofloxacin hydrochloride via piezoelectric-enhanced charge transfer. Chinese Journal of Structural Chemistry, 2025, 44(5): 100569-100569. doi: 10.1016/j.cjsc.2025.100569
10. [10]
  Xiaopeng Han , Jiayin Li , Fei Li , Zhongyue Yuan , Hao Li , Lei Yang , Yan-Ming Xia , Chao Teng , Chao Qin , Lifang Yin . ROS-sensitive dihydroartemisinin prodrug amplify chemo-immunotherapy efficacy of doxorubicin by coordinating robust tumor cell immunogenic cell death and PD-L1 blockade. Chinese Chemical Letters, 2026, 37(2): 111335-. doi: 10.1016/j.cclet.2025.111335
11. [11]
  Yangyang Sun , Tianyu Huang , Houqiang Ji , Tian Tian , Xingwang Zhu , Wenlin Xu , Huan Pang . Efficient charge separation by Ti₃C₂ MXene modified nano MIL-125(Ti) Schottky photocatalysts for N₂ reduction and tetracycline hydrochloride removal. Chinese Chemical Letters, 2026, 37(3): 111391-. doi: 10.1016/j.cclet.2025.111391
12. [12]
  Xiaoliu Liang , Chunliu Huang , Hui Liu , Hu Chen , Jiabao Shou , Hongwei Cheng , Gang Liu . Natural hydrogel dressings in wound care: Design, advances, and perspectives. Chinese Chemical Letters, 2024, 35(10): 109442-. doi: 10.1016/j.cclet.2023.109442
13. [13]
  Guilong Li , Wenbo Ma , Jialing Zhou , Caiqin Wu , Chenling Yao , Huan Zeng , Jian Wang . A composite hydrogel with porous and homogeneous structure for efficient osmotic energy conversion. Chinese Chemical Letters, 2025, 36(2): 110449-. doi: 10.1016/j.cclet.2024.110449
14. [14]
  Hongyi Li , Huiyun Wen , He Zhang , Jin Li , Xiang Cao , Jiaqing Zhang , Yutao Zheng , Saipeng Huang , Weiming Xue , Xiaojun Cai . Polymeric micelle-hydrogel composites design for biomedical applications. Chinese Chemical Letters, 2025, 36(5): 110072-. doi: 10.1016/j.cclet.2024.110072
15. [15]
  Zhuan Chen , Bo Yang , Jun Li , Kun Du , Jiangchen Fu , Xiao Wu , Jiazhen Cao , Mingyang Xing . Environmentally safe storage and sustained release of hydrogen peroxide utilizing commercial hydrogel. Chinese Chemical Letters, 2025, 36(6): 110320-. doi: 10.1016/j.cclet.2024.110320
16. [16]
  Zeyang Yao , Xinru You , Xudong Wang , Yunze Kang , Liying Wang , Ziji Zhang . Stem cell-based hydrogel for the repair and regeneration of cartilage. Chinese Chemical Letters, 2025, 36(8): 110607-. doi: 10.1016/j.cclet.2024.110607
17. [17]
  Yingqiang Liang , Shilun Li , Yixiao Pan , Weiyu Zhang , Shupeng Liu , Yiwen Chen , Jiangfeng Hu , Xueliang Zhang , Jun Zhao , Zhigang Zheng . Exosome-hybridized hydrogel acts as a foamy protective coat for the liver. Chinese Chemical Letters, 2025, 36(11): 110841-. doi: 10.1016/j.cclet.2025.110841
18. [18]
  Yongzhi Wu , Rong He , Bowen Tan , Longjiang Li , Jinfeng Liao . An injectable hydrogel for chemodynamic therapy-induced ferroptosis in malignant melanoma. Chinese Chemical Letters, 2026, 37(3): 111339-. doi: 10.1016/j.cclet.2025.111339
19. [19]
  Yun Wang , Huage Lin , Jiaxiang Zong , Mengjiao Yu , Guangyu Wu , Weinan Xing . Interface design of S-scheme Co9S8/flower-like g-C3N4 van der Waals heterojunction with enhanced photocatalytic hydrogen production and tetracycline hydrochloride degradation. Chinese Journal of Structural Chemistry, 2026, 45(2): 100798-100798. doi: 10.1016/j.cjsc.2025.100798
20. [20]
  Jianye Kang , Xinyu Yang , Xuhao Yang , Jiahui Sun , Yuhang Liu , Shutao Wang , Wenlong Song . Carbon dots-enhanced pH-responsive lubricating hydrogel based on reversible dynamic covalent bondings. Chinese Chemical Letters, 2024, 35(5): 109297-. doi: 10.1016/j.cclet.2023.109297

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(15)
HTML views(2)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142