10.57647/j.ijic.2025.1602.12

Design of Temperature-Sensitive Hydrogel Nanoparticles and Investigation of Their Application in the Development of a New Generation of Anti-Cancer Drugs with Optimization Conditions by Central Composite Design

  1. Department of Chemistry, NT.C., Islamic Azad University, Tehran, Iran
  2. Department of Chemistry, Central Tehran Branch, Islamic Azad University, Tehran, Iran
  3. Department of Chemistry, Varamin (Pishva) Branch, Islamic Azad University, Varamin, Iran

Received: 2025-03-10

Revised: 2025-05-09

Accepted: 2025-05-29

Published in Issue 2025-06-30

How to Cite

Tavassoty Kheiry, B., Tadayon, F., Panahi, H. A., & Moniri, E. (2025). Design of Temperature-Sensitive Hydrogel Nanoparticles and Investigation of Their Application in the Development of a New Generation of Anti-Cancer Drugs with Optimization Conditions by Central Composite Design . International Journal of Industrial Chemistry, 16(2). https://doi.org/10.57647/j.ijic.2025.1602.12

PDF views: 108

Abstract

Temperature-sensitive nanohydrogels present notable advantages in biomedical applications due to their high permeability, selectivity, water solubility, and minimal invasiveness, making them ideal carriers for controlled chemotherapy drug delivery. In this study, a novel polyphenylglycine-based nanohydrogel was synthesized via N-phenylglycine polymerization and subsequently functionalized with heat-responsive and allylamine groups to improve solubility and introduce additional active sites. The multi-target anticancer drug, sunitinib malate (Sun), was then incorporated into the nanohydrogel for targeted delivery. The structure of the nanohydrogel was confirmed via FTIR, XRD, FE-SEM, EDX, and TGA analyses. Drug loading parameters, including pH, contact time, and temperature, were optimized using response surface methodology, yielding optimal conditions at pH 7.4, 60 minutes, and 50 °C. Adsorption followed the Langmuir isotherm (19.81 mg/g monolayer capacity), and the kinetics were best described by a pseudosecond-order model. The nanohydrogel exhibits a lower critical solution temperature slightly above physiological temperature and demonstrates excellent photothermal stability. These properties highlight its potential as a promising platform for controlled and targeted delivery of anti-cancer therapeutics.  

Keywords

  • Nanohydrogels,
  • Temperature-Sensitive,
  • Photothermal Polymer,
  • Drug Delivery,
  • Sunitinib Malate,
  • Chemotherapy

References

  1. Hussain SMM, Ladha BZ, Khan MH. Nanotechnology: arevolution in modern industry. Molecules. 2023;28(2):661. doi:10.3390/molecules28020661
  2. Kanaoujiya R, Saroj SK, Rajput VD, Alimuddin, Srivastava S, Minkina T, et al. Emerging application of nanotechnology for mankind. Emergent Mater. 2023;6(2):439–52. doi:10.1007/s42247-023-00461-8
  3. Islam S, Ahmed MMS, Islam MA, Hossain N, Chowdhury MA. Advances in nanoparticles in targeted drug delivery: a review. Results Surf Interfaces. 2025;19:100529. doi:10.1016/j.rsurfi.2020.100529
  4. Cong X, Zhang Z, Li H, Yang YG, Zhang Y, Sun T. Nanocarriers for targeted drug delivery in the vascular system: focus on endothelium. J Nanobiotechnol. 2024;22:620. doi:10.1186/s12951-024-02892-9
  5. Zhao Z, Ukidve A, Kim J, Mitragotri S. Targeting strategies for tissue-specific drug delivery. Cell. 2020;181(1):151–67. doi:10.1016/j.cell.2020.02.001
  6. Kenchegowda M, Rahamathulla M, Hani U, Begum MY, Guruswamy S, Osmani RAM, et al. Smart nanocarriers as an emerging platform for cancer therapy: a review. Molecules. 2022;27(1):146. doi:10.3390/molecules27010146
  7. Torabi Fard N, Tadayon F, Ahmad Panahi H, Moniri E. Synthesis, characterization and application of a novel three-dimensional magnetic graphene oxide decorated with polyester dendrimers for detection of donepezil hydrochloride in pharmaceutical formulation and biological fluid. Journal of Molecular Liquids. 2022;365:118149. doi:10.1016/j.molliq.2021.118149
  8. Pires PC, Mascarenhas-Melo F, Pedrosa K, Lopes D, Lopes J, Macário-Soares A, et al. Polymer-based biomaterials for pharmaceutical and biomedical applications: a focus on topical drug administration. European Polymer Journal. 2023;187:111868. doi:10.1016/j.eurpolymj.2023.111868
  9. Liechty WB, Kryscio DR, Slaughter BV, Peppas NA. Polymers for drug delivery systems. Annu Rev Chem Biomol Eng. 2010;1:149–73. doi:10.1146/annurev-chembioeng-073009-100847
  10. Wang T, Wu C, Hu Y, Zhang Y, Ma J. Stimuli-responsive nanocarrier delivery systems for Pt-based antitumor complexes: a review. RSC Adv. 2023;13:16488–511. doi:10.1039/D3RA00866E
  11. Rahmaninia M, Tamaddon AM, Yazdani M, Sameni J. Cytotoxicity and in vitro evaluation of whey protein-based hydrogels. Int J Ind Chem. 2019;10(3):341–50. doi:10.1007/s40090-019-0181-3
  12. Ahmadian I, Kargar Razi M, Sadeghi B, Nakhaei M. Synthesis of photocatalytic material based on polyaniline supported PVC/NiAl₂O₃/AlF₃ nanocomposite. Int J Ind Chem. 2024;15(2):16. doi:10.57647/j.ijic.2024.1502.16
  13. Nosrati H, Heydari M, Khodaei M. Cerium oxide nanoparticles: synthesis methods and applications in wound healing. Mater Today Bio. 2023;23:100823. doi:10.1016/j.mtbio.2023.100823
  14. Rajaram S, Dharmalingam SR, Natarajan V, Ravi K, Shanmugam N. An extensive review on hydrogels in pharmaceutical drug delivery applications. Int J Pharm Investig. 2022;12(2):108–12. doi:10.5530/ijpi.2022.2.20
  15. Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;49(8):1993–2007. doi:10.1016/j.polymer.2008.01.027
  16. Liu C, Guo X, Ruan C, Hu H, Jiang BP, Liang H, et al. An injectable thermosensitive photothermal-network hydrogel for near-infrared-triggered drug delivery and synergistic photothermal-chemotherapy. Acta Biomater. 2019;96:281–94. doi:10.1016/j.actbio.2019.07.024
  17. Yu Y, Cheng Y, Tong J, Zhang L, Wei Y, Tian M. Recent advances in thermo-sensitive hydrogels for drug delivery. J Mater Chem B. 2021;9:2979–92. doi:10.1039/D0TB02877K
  18. Salehi S, Naghib SM, Garshasbi HR, Ghorbanzadeh S, Zhang W. Smart stimuli-responsive injectable gels and hydrogels for drug delivery and tissue engineering applications: a review. Front Bioeng Biotechnol. 2023;11:1104126. doi:10.3389/fbioe.2023.1104126
  19. Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016;1(12):16071. doi:10.1038/natrevmats.2016.71
  20. Torabi Fard N, Tadayon F, Ahmad Panahi H, Moniri E. The synthesis of functionalized graphene oxide by polyester dendrimer as a pH-sensitive nanocarrier for targeted delivery of venlafaxine hydrochloride: central composite design optimization. J Mol Liq. 2021;349:118149. doi:10.1016/j.synthmet.2022.117141
  21. Zhang XZ, Zhuo RX, Cui JZ, Zhang JT. A novel thermo-responsive drug delivery system with positive controlled release. J Pharmaceutics. 2002;235:43–50. doi:10.1016/S0378-5173(01)00976-0
  22. Bae YH, Okano T, Hsu R, Kim SW. Thermosensitive polymers as on–off switches for drug release. Chem Rapid Commun. 1987;8:481–5. doi:10.1002/marc.1987.030081002
  23. Rahimi Haji Abadi F, Tadayon F, Tehrani MS, Ahmad Panahi H. Synthesis and characterization of the photoresponsive and thermoresponsive molecularly imprinted polymer with a novel functional monomer for controlled release of 4-aminopyridine. Int J Polym Mater Polym Biomater. 2023;72(6):425–32. doi:10.1080/00914037.2021.2018318
  24. Shi X, Gong H, Li Y, Wang C, Cheng L, Liu Z. Graphene-based magnetic plasmonic nanocomposite for dual bioimaging and photothermal therapy. Biomaterials. 2013;34:4786–93. doi:10.1016/j.biomaterials.2013.03.046
  25. Cheng L, Yang K, Chen Q, Liu Z. Organic stealth nanoparticles for highly effective in vivo near-infrared photothermal therapy of cancer. ACS Nano. 2012;6:5605–13. doi:10.1021/nn302236d
  26. Jiang B-P, Zhang L, Guo X-L, Shen X-C, Wang Y, Zhu Y, Liang H. Poly(N-phenylglycine)-based nanoparticles as highly effective and targeted near-infrared photothermal therapy/photodynamic therapeutic agents for malignant melanoma. J Nanomicro Small. 2016;13(8):1602496. doi:10.1002/smll.201602496
  27. Nabid MR, Taheri SS, Sedghi R, Entezami AA. Chemical synthesis and characterization of water-soluble, conducting poly(N-phenylglycine). Iranian Polymer J. 2008;17(5):365–71
  28. Mubarak ANM, Naseem K, Tabassum H, Rizwan M, Najda A, Kashif M, et al. Recent advancement and development of chitin and chitosan-based nanocomposite for drug delivery: critical approach to clinical research. Arab J Chem. 2020;13:8935–64. doi:10.1016/j.arabjc.2020.10.003
  29. Kumari S, Singh RP, Chavan NN, Sahi SV, Sharma N. Characterization of a novel nanocomposite film based on functionalized chitosan–Pt–Fe₃O₄ hybrid nanoparticles. Nanomaterials. 2021;11:1275. doi:10.3390/nano11051275
  30. Fang G, Yang X, Chen S, Wang Q, Zhang A, Tang B. Cyclodextrin-based host–guest supramolecular hydrogels for local drug delivery. J Coord Chem Rev. 2022;454:214352. doi:10.1016/j.ccr.2022.214352
  31. Hamidi M, Azadi A, Rafiei P. Hydrogel nanoparticles in drug delivery. Adv Drug Deliv Rev. 2008;60:1638–49. doi:10.1016/j.addr.2008.08.002
  32. Amin S, Rajabnezhad S, Kohli K. Hydrogels as potential drug delivery systems. Sci Res Essay. 2009;3:1175–83
  33. Ichikawa H, Fukumori Y. Design of nanohydrogel-incorporated microcapsules for appropriate controlled-release of peptide drugs. Yakugaku Zasshi. 2007;127:813–23. doi:10.1248/yakushi.127.813
  34. Lee SM, Yoo ES, Ghim HD, Lee SJ. Alginate nanohydrogels prepared by emulsification-diffusion method. Macromol Res. 2009;17:168–73. doi:10.1007/BF03218674
  35. Jahanbekam S, Asare-Addo K, Alipour S, Nokhodchi A. Smart hydrogels and the promise of multi-responsive in-situ systems. J Drug Deliv Sci Technol. 2025;107:106758. doi:10.1016/j.jddst.2025.106758
  36. Stevanović N, Filipović N. A review of recent developments in biopolymer nano-based drug delivery systems with antioxidative properties: insights into the last five years. Pharmaceutics. 2024;16(5):670. doi:10.3390/pharmaceutics16050670
  37. Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MdP, Acosta-Torres LS, et al. Nano based drug delivery systems: recent developments and future prospects. Nanobiotechnol. 2018;16:71. doi:10.1186/s12951-018-0392-8
  38. Hoffman AS. The origins and evolution of controlled drug delivery systems. J Control Release. 2008;132(3):153–63. doi:10.1016/j.jconrel.2008.08.012
  39. Masood F. Polymeric nanoparticles for targeted drug delivery system for cancer therapy. Mater Sci Eng C. 2016;60:569–78. doi:10.1016/j.msec.2015.11.067
  40. Pinto Reis C, Neufeld RJ, Ribeiro AJ, Veiga F. Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine. 2006;2:8–21. doi:10.1016/j.nano.2005.12.003
  41. Anwar M, Afzal I, Abid H, Ullah I, Haq UU. Nanoparticles in drug delivery: a chemical engineering perspective on biocompatibility targeting and controlled release mechanisms. Kashf J Multidiscip Res. 2025;2(03):27–46. doi:10.71146/kjmr33
  42. Hosny S, Mohamed LZ, Ragab MS, Alomoush QK, Abdalla EM, Aly SA. Nanomaterials in biomedical applications: opportunities and challenges—a review. Chem Pap. 2025;79:2657–78. doi:10.1007/s11696-025-03937-5
  43. Abu-Thabit NY. Chemical oxidative polymerization of polyaniline: a practical approach for preparation of smart conductive textiles. J Chem Educ. 2017;93(9):94–101. doi:10.1021/acs.jchemed.6b00060
  44. Chen H, Liang W, Zhu Y, Guo Z, Jian J, Jiang B-P, et al. Supercharged fluorescent protein functionalized watersoluble poly(N-phenylglycine) nanoparticles for highly effective imaging-guided photothermal therapy. Chem Commun. 2018;54:73. doi:10.1039/C8CC05278F
  45. Pham DT, Nguyen DX, Nguyen NY, Nguyen TTL, Nguyen TQC, Vo TT, Nguyen NH, Thuy BTP. Development of pH-responsive Eudragit S100-functionalized silk fibroin nanoparticles as a prospective drug delivery system. PLoS ONE. 2024;19:e0303177. doi:10.1371/journal.pone.0303177
  46. Sayyar Z, Mohammadzadeh Pakdel P, Peighambardoust SJ. Oral delivery of sunitinib malate using carboxymethyl cellulose/poly(acrylic acid-itaconic acid)/Cloisite 30B nanocomposite hydrogel as a pH-responsive carrier. BMC Biotechnol. 2024;24:70. doi:10.1186/s12896-024-00883-0
  47. Scrivano L, Parisi OI, Iacopetta D, Ruffo M, Ceramella J, Sinicropi MS, Puoci F. Molecularly imprinted hydrogels for sustained release of sunitinib in breast cancer therapy. Polym Adv Technol. 2018;30(3):743–8. doi:10.1002/pat.4512
  48. Jafari H, Mahdavinia GR, Kazemi B, Ehrlich H, Joseph Y, Rahimi N, Nasrabadi. Highly efficient sunitinib release from pH-responsive mHPMC@Chitosan core-shell nanoparticles. Carbohydr Polym. 2021;258:117719. doi:10.1016/j.carbpol.2021.117719
  49. Tunç ID, Erol M, Günes F, Sütçü M. Growth of ZnO nanowires on carbon fibers for photocatalytic degradation of methylene blue aqueous solutions: An investigation on the optimization of processing parameters through response surface methodology/central composite design. Ceram Int. 2020;46:7459–74. doi:10.1016/j.ceramint.2019.11.244
  50. Zhang B, Han X, Gu P, Fang S, Bai J. Response surface methodology approach for optimization of ciprofloxacin adsorption using activated carbon derived from the residue of desilicated rice husk. J Mol Liq. 2017;238:316–25. doi:10.1016/j.molliq.2017.04.022
  51. Hao Z, Sadek I. Sunitinib: the anti-angiogenic effects and beyond. OncoTargets and Therapy. 2016;9:5495–5505. https://doi.org/10.2147/OTT.S112242
  52. Kim S., Ding W., Zhang L., et al. Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: a review of clinical trials. OncoTargets and Therapy. 2014;7:719–728. https://doi.org/10.2147/OTT.S61388