Synthesis and Evaluation of Ph and Temperature Stimuli-Responsive Magnetic Nanohydrogels for Gene Delivery

Abstract

The offer of gene delivery technologies as a promising approach to treating a variety of diseases has revolutionized human medicine over the last two decades. So, the application of suitable vectors, particularly polymers with substrates with unique physicochemical properties for the transfer of targeted genes to logical sites for effective treatment, plays an indispensable role for more personalized medicine and improves the safety profile in response to continuing to use new medical technologies. For this purpose, we synthesized nanocarriers with a two-block cationic hydrogel, magnetic and non-magnetic, based on N-isopropyl acrylamide (NIPAM) and quaternary alkyl ammonium halide salts of DMAEMA (DMAEMAQ) with pH and temperature responsiveness via the free radical polymerization technique. The bulk properties of these co-polymers were characterized by using Fourier transform infrared spectroscopy, 1H NMR spectroscopy, zeta potential, lower critical solution temperature (LCST), and gel electrophoresis to show the loading of nanoparticles with the gene. In the results, magnetic P[NIPAM-DMAEMAQ] hydrogel showed controllable responsive properties determined by the nature of the cationic charge +24.7 mV incorporated, nanosize around 86.95 and 91.22 nm, and efficiency loaded with the gene more than 95%. As well, the synthesized nanohydrogel exhibited a sharp volume-phase transition in water at a LCST of ∼40 °C. So, the combination of both monomers yielded an interesting system with high transfection efficiency and compliant biocompatibility characteristics, which could effectively achieve gene loading. Also, the magnetic potential of nanohydrogel was determined as a vector to deliver genes to localized sites. Notably, the synthesized combination P[NIPAM-DMAEMAQ] nanohydrogel has been considered a transfection of the biodegradable and biocompatible magnetic nanoparticle sensitive to tunable pH and temperature responsiveness, demonstrating that it will hold a promising approach as a potential carrier to improve gene delivery therapeutic efficacy in cancer and different disease treatments.

Keywords

• Gene delivery
• Biodegradation
• Magnetic P(NIPAM-DMAEMAQ)
• pH and thermoresponsive hydrogels

References

1. Bi Q, Song X, Hu A, Luo T, Jin R, Ai H, Nie Y. 2020. Magnetofection: Magic magnetic nanoparticles for efficient gene delivery. Chin J Chem, 31: 3041-3046.
2. De Jesus‐Tullez MA, Sanchez‐Cerrillo DM, Quintana‐Owen P, Schubert US, Contreras‐Lopez D, Guerrero‐Sanchez C. 2020. Kinetic investigations of quaternization reactions of poly [2‐(dimethylamino) ethyl methacrylate] with diverse alkyl halides. Macromol Chem Phys, 221: 1900543.
3. Fussell SL, Bayliss K, Coops C, Matthews L, Li W, Briscoe WH, Faers M, Royall C, Van Duijneveldt JS. 2019. Reversible temperature-controlled gelation in mixtures of pNIPAM microgels and non-ionic polymer surfactant. Soft Matter, 15: 8578-8588.
4. Gutarowska B, Stawski D, Sknra J, Herczynska L, Pielech-Przybylska K, Połowinski S, Krucinska I. 2015. PLA nonwovens modified with poly (dimethylaminoethyl methacrylate) as antimicrobial filter materials for workplaces. Text Res J, 85: 1083-1094.
5. Hamimed S, Jabberi M, Chatti A. 2022. Nanotechnology in drug and gene delivery. Naunyn Schmiedebergs Arch Pharmacol, 395: 769-787.
6. He Y, Li D, Wu L, Yin X, Zhang X, Patterson LH , Zhang J. 2023. Metal‐Organic Frameworks for Gene Therapy and Detection. Adv Funct Mater, 33: 2212277.
7. Huang Y, Yong P, Chen Y, Gao Y, Xu W, Lv Y, Yang L, Reis RL, Pirraco RP, Chen J. 2017. Micellization and gelatinization in aqueous media of pH-and thermo-responsive amphiphilic ABC (PMMA 82-b-PDMAEMA 150-b-PNIPAM 65) triblock copolymer synthesized by consecutive RAFT polymerization. RSC Adv, 7: 28711-28722.
8. Jacob S, Kather FS, Morsy MA, Boddu SH, Attimarad M, Shah J, Shinu P, Nair AB. 2024. Advances in nanocarrier systems for overcoming formulation challenges of curcumin: Current İnsights. Nanomater, 14: 672.

9. Kim YK, Kim E-J, Lim JH, Cho HK, Hong WJ, Jeon HH, Chung BG. 2019. Dual stimuli-triggered nanogels in response to temperature and pH changes for controlled drug release. Nanoscale Res Lett, 14: 1-9.
10. Lanzalaco S, Armelin E. 2017. Poly (N-isopropylacrylamide) and copolymers: a review on recent progresses in biomedical applications. Gels, 3: 36.
11. Lin G, Revia RA, Zhang M. 2021. Inorganic nanomaterial‐mediated gene therapy in combination with other antitumor treatment modalities. Adv Func Mater, 31: 2007096.
12. Liu R, Cellesi F, Tirelli N, Saunders B. 2009. A study of thermoassociative gelation of aqueous cationic poly (N-isopropyl acrylamide) graft copolymer solutions. Polymer, 50: 1456-1462.
13. Manouras T, Platania V, Georgopoulou A, Chatzinikolaidou M, Vamvakaki M. 2021. Responsive quaternized PDMAEMA copolymers with antimicrobial action. Polymers, 13: 3051.
14. Materon EM, Miyazaki CM, Carr O, Joshi N, Picciani PH, Dalmaschio CJ, Davis F, Shimizu FM. 2021. Magnetic nanoparticles in biomedical applications: A review. Appl Surf Sci Adv, 6: 100163.
15. Moselhy J, Vira T, Liu FF, Wu XY. 2009. Characterization of complexation of poly (N-isopropylacrylamide-co-2-(dimethylamino) ethyl methacrylate) thermoresponsive cationic nanogels with salmon sperm DNA. Int J Nanomed, 2009: 153-164.
16. Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, Diaz-Torres LA, Grillo R, Swamy MK, Sharma S. 2018. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnol, 16: 1-33.
17. Rai R, Alwani S, Badea I. 2019. Polymeric nanoparticles in gene therapy: New avenues of design and optimization for delivery applications. Polymers, 11: 745.
18. Roy I. 2022. Therapeutic applications of magnetic nanoparticles: recent advances. Mater Adv, 3: 7425-7444.
19. Satalkar P, Elger BS, Shaw DM. 2016. Defining nano, nanotechnology and nanomedicine: why should it matter? Sci Eng Ethics, 22: 1255-1276.
20. Sayed N, Allawadhi P, Khurana A, Singh V, Navik U, Pasumarthi SK, Khurana I, Banothu AK, Weiskirchen R , Bharani KK. 2022. Gene therapy: Comprehensive overview and therapeutic applications. Life Sci, 294: 120375.
21. Shahryari A, Burtscher I, Nazari Z, Lickert H. 2021. Engineering gene therapy: advances and barriers. Adv Therap, 4: 2100040.
22. Shillitoe EJ. 2009. Gene therapy: the end of the rainbow?. Head Neck Oncol, 1: 1-5.
23. Sung YK, Kim S. 2019. Recent advances in the development of gene delivery systems. Biomater Res, 23: 8.
24. Thang NH, Chien TB, Cuong DX. 2023. Polymer-based hydrogels applied in drug delivery: An overview. Gels, 9: 523.
25. Valipour F, Esmhosseini M, Nejati K, Kianfar H, Pasdaran A, Davaran S. 2011. Synthesis and antibacterial activity of silver nanoparticles embedded in smart poly (N-isopropylacrylamide)-based hydrogel networks. J Nanotechnol Eng Med, 2: 041001.
26. Valipour F, Valipour F, Rahbarghazi R, Navali AM, Rashidi MR, Davaran S. 2021. Novel hybrid polyester-polyacrylate hydrogels enriched with platelet-derived growth factor for chondrogenic differentiation of adipose-derived mesenchymal stem cells in vitro. J Biol Eng, 15: 1-14.
27. Wulandari AD, Sutriyo S, Rahmasari R. 2022. Synthesis conditions and characterization of superparamagnetic iron oxide nanoparticles with oleic acid stabilizer. J Adv Pharm Technol Res, 13: 89-94.
28. Yang HY, Van Ee RJ, Timmer K, Craenmehr EG, Huang JH, Oner FC, Dhert WJ, Kragten AH, Willems N, Grinwis GC. 2015. A novel injectable thermoresponsive and cytocompatible gel of poly (N-isopropylacrylamide) with layered double hydroxides facilitates siRNA delivery into chondrocytes in 3D culture. Acta Biomater, 23: 214-228.
29. Yang R, Chen F, Guo J, Zhou D, Luan S. 2020. Recent advances in polymeric biomaterials-based gene delivery for cartilage repair. Bioact Mater, 5: 990-1003.
30. Zhang Q, Kuang G, Li W, Wang J, Ren H, Zhao Y. 2023. Stimuli-responsive gene delivery nanocarriers for cancer therapy. Nanomicro Lett, 15: 44.