POLY(N-ISOPROPYLACRYLAMIDE) HYDROGEL INCORPORATING SQUARAINE: SYNTHESIS, DRUG DELIVERY AND PHOTODYNAMIC PROPERTIES

Öz

In the present work, we describe the fabrication of a thermosensitive hydrogel. To fabricate the hydrogel (Sq1@PNIPAAm), we opted to use biocompatible poly(N-isopropylacrylamide) (PNIPAM) and squaraine dye (Sq1) as the polymer and the crosslinker, respectively. It is noteworthy that Sq1@PNIPAAm can be loaded with fluorescein, and we evaluated the fluorescein release behavior of Sq1@PNIPAAm hydrogel. We noted that on demand sustainable release of fluorescein was feasible upon gradual heating of Sq1@PNIPAAm hydrogel. Furthermore, Sq1@PNIPAAm hydrogels can be used as photosensitizers pertinent to photodynamic therapy (PDT). Our results show that hydrogel possesses favorable biological safety for use in in vitro anticancer studies. In vitro experiments confirmed that Sq1@PNIPAAm hydrogels could kill over 40% of cancer cells. Overall, we have successfully shown that Sq1@PNIPAAm enabled photodynamic therapy. Moreover, fluorescein loading into Sq1@PNIPAAm was possible, and it could be used to successfully accomplish temperature-controlled on-demand release. Given the abundance of low-cost, commercially accessible monomers available for use in hydrogel synthesis, this method offers access to a wide range of functional hydrogels for use in biomedical applications.

Anahtar Kelimeler

• Poly(N-isopropylacrylamide)
• Hydrogel
• Drug release
• Photodynamic therapy
• In vitro

SKUARİN İÇEREN POLİ(N-İZOPROPİLAKRİLAMİD) HİDROJEL: SENTEZ, İLAÇ SALIMI VE FOTODİNAMİK ÖZELLİKLER

Öz

Bu çalışmada, termo-duyarlı bir hidrojel sentezi açıklanmaktadır. Hidrojeli (Sq1@PNIPAAm) elde etmek için biyouyumlu poli(N-izopropilakrilamid) (PNIPAM) ve skuarain boyasını (Sq1) sırasıyla polimer ve çapraz bağlayıcı olarak kullanmayı tercih ettik. Sq1@PNIPAAm'ın floresin ile yüklenebileceğini ve floresin salım davranışını inceledik. Sq1@PNIPAAm hidrojelinin kademeli olarak ısıtılmasıyla istenildiğinde sürdürülebilir floresin salımının mümkün olduğunu gözlemledik. Ayrıca, Sq1@PNIPAAm hidrojelleri, fotodinamik tedavide kullanılabilecek fotoduyarlaştırıcı özellik göstermektedir. Sonuçlarımız, hidrojelin in vitro antikanser çalışmalarında kullanım için uygun biyo güvenliğe sahip olduğunu göstermektedir. In vitro deneyler, Sq1@PNIPAAm hidrojellerinin kanser hücrelerinin %40'ından fazlasını öldürebileceğini doğruladı. Genel olarak, Sq1@PNIPAAm'ın fotodinamik tedaviyi mümkün kıldığını başarıyla gösterdik. Dahası, Sq1@PNIPAAm'a ilaç yüklemek mümkündür ve sıcaklık kontrollü ilaç salımı başarıyla gerçekleştirilebilmiştir. Hidrojel sentezi için kullanılabilecek ucuz ve ticari olarak erişilebilir monomerlerin bol miktarda bulunması göz önüne alındığında, bu yöntem biyomedikal uygulamalarda kullanılmak üzere geniş bir yelpazede işlevsel hidrojellere erişim sağlar.

Anahtar Kelimeler

• Poli(N-izopropilakrilamid)
• Hidrojel
• İlaç salımı
• Fotodinamik tedavi
• In vitro

Kaynakça

1. Simões JCS, Sarpaki S, Papadimitroulas P, Therrien B, Loudos G. Conjugated photosensitizers for imaging and PDT in cancer research. J Med Chem 2020;63:14119–50.
2. Shi H, Sadler PJ. How promising is phototherapy for cancer? Br J Cancer 2020;123:871–3.
3. Escudero A, Carrillo-Carrión C, Castillejos MC, Romero-Ben E, Rosales-Barrios C, Khiar N. Photodynamic therapy: photosensitizers and nanostructures. Mater Chem Front 2021;5:3788–812.
4. Beharry AA. Next-generation photodynamic therapy: new probes for cancer imaging and treatment. Biochemistry 2018;57:173–4.
5. Callaghan S, Senge MO. The good, the bad, and the ugly–controlling singlet oxygen through design of photosensitizers and delivery systems for photodynamic therapy. Photochemical & Photobiological Sciences 2018;17:1490–514.
6. Zhao X, Liu J, Fan J, Chao H, Peng X. Recent progress in photosensitizers for overcoming the challenges of photodynamic therapy: from molecular design to application. Chem Soc Rev 2021;50:4185–219.
7. Pamuk Algi M, Sarıgöl R. Squaraine-containing polymeric nanoparticles enable photodynamic and photothermal therapy of cancer cells. Dyes and Pigments 2024:112138.
8. Tuncaboylu DC, Argun A, Algi MP, Okay O. Autonomic self-healing in covalently crosslinked hydrogels containing hydrophobic domains. Polymer (Guildf) 2013;54:6381–8.

9. Chambre L, Saw WS, Ekineker G, Kiew LV, Chong WY, Lee HB, et al. Surfactant-free direct access to porphyrin-cross-linked nanogels for photodynamic and photothermal therapy. Bioconjug Chem 2018;29:4149–59.
10. Argun A, Algi MP, Tuncaboylu DC, Okay O. Surfactant-induced healing of tough hydrogels formed via hydrophobic interactions. Colloid Polym Sci 2014;292:511–7.
11. Algi MP, Okay O. Highly stretchable self-healing poly (N, N-dimethylacrylamide) hydrogels. Eur Polym J 2014;59:113–21.
12. Bashir S, Hina M, Iqbal J, Rajpar AH, Mujtaba MA, Alghamdi NA, et al. Fundamental concepts of hydrogels: Synthesis, properties, and their applications. Polymers (Basel) 2020;12:2702.
13. Cha GD, Lee WH, Sunwoo S-H, Kang D, Kang T, Cho KW, et al. Multifunctional injectable hydrogel for in vivo diagnostic and therapeutic applications. ACS Nano 2022;16:554–67.
14. Li D, Chen K, Tang H, Hu S, Xin L, Jing X, et al. A Logic‐Based Diagnostic and Therapeutic Hydrogel with Multistimuli Responsiveness to Orchestrate Diabetic Bone Regeneration. Advanced Materials 2022;34:2108430.
15. Joo C, Kai D, Lee C-LK. Synergistic antibacterial action of lignin-squaraine hybrid photodynamic therapy: advancing towards effective treatment of antibiotic-resistant bacteria. J Mater Chem B 2023;11:5748–51.
16. Yao S, Jin X, Wang C, Cao A, Hu J, Chen B, et al. ICG/5-Fu coencapsulated temperature stimulus response nanogel drug delivery platform for chemo-photothermal/photodynamic synergetic therapy. J Biomater Appl 2021;36:565–78.
17. Meesaragandla B, Sarkar D, Mahalingam V. Methylene blue-loaded upconverting hydrogel nanocomposite: potential material for near-infrared light-triggered photodynamic therapy application. ACS Omega 2019;4:3169–77.
18. Belali S, Karimi AR, Hadizadeh M. Novel nanostructured smart, photodynamic hydrogels based on poly (N-isopropylacrylamide) bearing porphyrin units in their crosslink chains: A potential sensitizer system in cancer therapy. Polymer (Guildf) 2017;109:93–105.
19. Belali S, Savoie H, O’Brien JM, Cafolla AA, O’Connell B, Karimi AR, et al. Synthesis and characterization of temperature-sensitive and chemically cross-linked poly (N-isopropylacrylamide)/photosensitizer hydrogels for applications in photodynamic therapy. Biomacromolecules 2018;19:1592–601.
20. Gulyuz U, Okay O. Self-healing poly (N-isopropylacrylamide) hydrogels. Eur Polym J 2015;72:12–22.
21. Choi JH, Lee JS, Yang DH, Nah H, Min SJ, Lee SY, et al. Development of a Temperature-Responsive Hydrogel Incorporating PVA into NIPAAm for Controllable Drug Release in Skin Regeneration. ACS Omega 2023;8:44076–85. https://doi.org/10.1021/acsomega.3c06291.
22. Raghuwanshi VS, Joram Mendoza D, Browne C, Ayurini M, Gervinskas G, Hooper JF, et al. Effect of temperature on the conformation and functionality of poly(N-isopropylacrylamide) (PNIPAM)-grafted nanocellulose hydrogels. J Colloid Interface Sci 2023;652:1609–19.
23. Wang Y, Kan X. LuMA-Functionalized Thermosensitive Hydrogel: A Versatile and Robust Dopamine-Triggered Platform for Diverse Biomolecules Sensing. ACS Appl Bio Mater 2023;6:5097–104.
24. Maddahzadeh-Darini N, Ghorbanloo M. Supra-Amphiphilic Porphyrin Based on Thermoresponsive Poly (N-Isopropylacrylamide-co-2-Acrylamido-2-Methylpropane Sulfonic Acid Sodium) Hydrogels: Synthesis, Characterization and Catalytic Applications. Catal Letters 2023;153:3342–56.
25. Toksoy A, Sonkaya Ö, Erkan DS, Gulen RB, Algi MP, Algi F. Norsquaraine endowed with anticancer and antibacterial activities. Photodiagnosis Photodyn Ther 2022;40:103110.
26. Ayyala RS, S. Suner S, Bhethanabotla VR, Sahiner N. Fungal Keratitis Treatment Using Drug-Loaded Hyaluronic Acid Microgels. ACS Appl Bio Mater 2022;5:3806–15.
27. Huang K-T, Hsieh P-S, Dai L-G, Huang C-J. Complete zwitterionic double network hydrogels with great toughness and resistance against foreign body reaction and thrombus. J Mater Chem B 2020;8:7390–402.
28. Degirmenci A, Sonkaya O, Soylukan C, Karaduman T, Algi F. BODIPY and 2, 3-dihydrophthalazine-1, 4-dione conjugates as heavy atom-free chemiluminogenic photosensitizers. ACS Appl Bio Mater 2021;4:5090–8.
29. Hu QJ, Lu YC, Yang CX, Yan XP. Synthesis of covalently bonded boron-dipyrromethene–diarylethene for building a stable photosensitizer with photo-controlled reversibility. Chemical Communications 2016;52:5470–3.
30. Usui Y. Determination of quantum yield of singlet oxygen formation by photosensitization. Chem Lett 1973;2:743–4.
31. Giacoletto N, Ibrahim-Ouali M, Dumur F. Recent advances on squaraine-based photoinitiators of polymerization. Eur Polym J 2021;150:110427.
32. Yadav Y, Owens E, Nomura S, Fukuda T, Baek Y, Kashiwagi S, et al. Ultrabright and Serum-Stable Squaraine Dyes. J Med Chem 2020;63:9436–45.
33. Beverina L, Sassi M. Twists and turns around a square: the many faces of squaraine chemistry. Synlett 2014;25:477–90.
34. Hu L, Yan Z, Xu H. Advances in synthesis and application of near-infrared absorbing squaraine dyes. RSC Adv 2013;3:7667–76.
35. Khopkar S, Shankarling G. Synthesis, photophysical properties and applications of NIR absorbing unsymmetrical squaraines: A review. Dyes and Pigments 2019;170:107645.
36. Sarıgöl R, Algi MP. Cross-linker engineering of hydrogel enables photothermal therapy and controlled drug release. J Drug Deliv Sci Technol 2023:104993.
37. Bhat MA, Rangreez TA, Yaseen Z, Rather RA, Shalla AH. Smart polyacrylamide− cholic acid hybrid composite hydrogel: Development, characterization, and encapsulation study of methylene blue dye. Mater Today Commun 2022;33:104515.
38. Dave PN, Macwan PM, Kamaliya B. Drug release and thermal properties of magnetic cobalt ferrite (CoFe2O4) nanocomposite hydrogels based on poly (acrylic acid-gN-isopropyl acrylamide) grafted onto gum ghatti. Int J Biol Macromol 2023;224:358–69.
39. Farahani BV, Ghasemzaheh H, Afraz S. Intelligent semi-IPN chitosan–PEG–PAAm hydrogel for closed-loop insulin delivery and kinetic modeling. RSC Adv 2016;6:26590–8.
40. Hu X, Feng L, Xie A, Wei W, Wang S, Zhang J, et al. Synthesis and characterization of a novel hydrogel: salecan/polyacrylamide semi-IPN hydrogel with a desirable pore structure. J Mater Chem B 2014;2:3646–58.
41. Purnomo AS, Bahruji H, Allouss D, El Alaoui-Elbalrhiti I, Subagyo R, Rohmah AA, et al. Hectorite-CTAB–alginate composite beads for water treatment: kinetic, isothermal and thermodynamic studies. RSC Adv 2023;13:790–801.
42. Kraljić I, Mohsni S El. A new method for the detection of singlet oxygen in aqueous solutions. Photochem Photobiol 1978;28:577–81.
43. Fu G, Soboyejo WO. Swelling and diffusion characteristics of modified poly (N-isopropylacrylamide) hydrogels. Materials Science and Engineering: C 2010;30:8–13.