One-pot synthesis of tunable fluorescent polyethylene glycol (PEG) polymer for antimicrobial and anticancer theranostics

Abstract

Poly (ethylene glycol) (PEG), is a well-known biocompatible and biodegradable polymer with a wide range of applications such as surface coating of nano/micro materials for improving their biocompatibility, immunological inertness, and systemic circulation. However, PEG is a nonfluorescent material limiting its application in bioimaging. So herein, a novel fluorescent PEG polymer was synthesized using a facile method. For this, in-house water-soluble compound [4,5-bis-{(N- carboxy methyl benzimidazolium) methyl} acridine] dibromide}] (b-ACA) was synthesized and used to modify nonfluorescent PEG polymer into a novel fluorescent PEG polymer (PEG-b-ACA) by one-pot method. PEG-b-ACA displayed a range of fluorescence from green to red with respect to the concentration of b-ACA being used. The synthesized PEG-b-ACA mixture was evaluated for its antimicrobial and antiviral efficacy against E. coli, S. aureus, C. albicans, and Bacteriophage Lambda, and it showed significant inhibition of microbial and viral growth. The mixture was also evaluated for its cellular uptake and anticancer efficacy using 4T1 breast cancer cells, and it showed significant results in both. The results demonstrated that the PEG-b-ACA mixture is a potent antimicrobial, antiviral, and anticancer agent when compared with PEG and b-ACA alone. Therefore, the synthesized PEG-b-ACA mixture could be an effective material for various biomedical applications.

Keywords

anticancer / antimicrobial / biomaterial / fluorescent polymers / theranostics

References

[1] BakerRE, MahmudAS, MillerIF, et al. Infectious disease in an era of global change. Nat Rev Microbiol. 2022;20(4):193-205.

[2] DoronS, Gorbach S. Bacterial infections: overview. Bacteriol Amsterdam, Amsterdam, Netherlands. 2020;3:273.

[3] FernebroJ. Fighting bacterial infections - future treatment options. Drug Resist Updates. 2011;14(2):125-139.

[4] BierneH, HamonM, CossartP. Epigenetics and bacterial infections. Cold Spring Harbor Perspect Med. 2012;2(12):a010272.

[5] Qasim AlmajidiY, Althomali RH, GandlaK, et al. Multifunctional immunosensors based on mesoporous silica nanomaterials as efficient sensing platforms in biomedical and food safety analysis: a review of current status and emerging applications. Microchem J. 2023;191:108901.

[6] IsonMG, Heldman M. Bacterial infections. Hepatic Crit Care. 2018;647(1 997):191-200.

[7] DebtaP, SwainSK, SoyabMT, Sahu MC, LenkaS. Microbial infectious disease: a mini review. Indian J Forensic Med Toxicol. 2020;14(4):8389-8393.

[8] ZhangK, LiX, YuC, WangY. Promising therapeutic strategies against microbial biofilm challenges. Front Cell Infect Microbiol. 2020;10:1-16.

[9] GarberG. An overview of fungal infections. Drugs. 2001;61(suppl 1):1-12.

[10] LockhartSR, Guarner J. Emerging and reemerging fungal infections. Semin Diagn Pathol. 2019;36(3):177-181.

[11] HayRJ. Fungal infections. Clin Dermatol. 2006;24(3):201-212.

[12] GuarnerJ, BrandtME. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev. 2011;24(2):247-280.

[13] SankaranarayananSA, Yadav DN, YadavS, et al. Tailoring phage nanosomes for enhanced theranostic properties of near infrared dyes. Langmuir. 2024;40:16743-16756.

[14] AppidiT, Ravichandran G, MudigundaSV, et al. Highly fluorescent polyethylene glycol-ascorbic acid complex for imaging and antimicrobial therapeutics. Mater Today Commun. 2021;29:102987.

[15] ChenX, LiaoB, ChengL, et al. The microbial coinfection in COVID-19. Appl Microbiol Biotechnol. 2020;104(18):7777-7785.

[16] ZhangG, LiW, ChenS, Zhou W, ChenJ. Problems of conventional disinfection and new sterilization methods for antibiotic resistance control. Chemosphere. 2020;254:126831.

[17] TseBN, AdaljaAA, HouchensC, Larsen J, InglesbyTV, HatchettR. Challenges and opportunities of nontraditional approaches to treating bacterial infections. Clin Infect Dis. 2017;65(3):495-500.

[18] MubeenB, AnsarAN, RasoolR, et al. Nanotechnology as a novel approach in combating microbes providing an alternative to antibiotics. Antibiotics. 2021;10(12):1473.

[19] PancuDF, ScurtuA, MacasoiIG, et al. Antibiotics: conventional therapy and natural compounds with antibacterial activity-a pharmaco-toxicological screening. Antibiotics. 2021;10(4):401.

[20] MurugaiyanJ, Anand Kumar P, RaoGS, et al. Progress in alternative strategies to combat antimicrobial resistance: focus on antibiotics. Antibiotics. 2022;11(2):1-37.

[21] BrayF, Laversanne M, SungH, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.

[22] SiegelRL, MillerKD, WagleNS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.

[23] BailleuxC, EberstL, BachelotT. Treatment strategies for breast cancer brain metastases. Br J Cancer. 2021;124(1):142-155.

[24] YadavDN, Sankaranarayanan SA, ThanekarAM, RenganAK. Bioinspired gold coated phage nanosomes for anti-microbial and anti-cancer theranostics. Mater Today Nano. 2023;23:100348.

[25] AbbasMN, KhanSA, SadozaiSK, et al. Nanoparticles loaded thermoresponsive in situ gel for ocular antibiotic delivery against bacterial keratitis. Polymers. 2022;14(6):1135.

[26] Aliakbar AhovanZ, Esmaeili Z, EftekhariBS, et al. Antibacterial smart hydrogels: new hope for infectious wound management. Mater Today Bio. 2022;17:100499.

[27] PranantyoD, ZhangK, SiZ, HouZ, Chan-ParkMB. Smart multifunctional polymer systems as alternatives or supplements of antibiotics to overcome bacterial resistance. Biomacromolecules. 2021;23:1873-1891.

[28] PatarroyoJL, Cifuentes J, MuñozLN, CruzJC, ReyesLH. Novel antibacterial hydrogels based on gelatin/polyvinyl-alcohol and graphene oxide/silver nanoconjugates: formulation, characterization, and preliminary biocompatibility evaluation. Heliyon. 2022;8(3):e09145.

[29] YadavD, Dewangan HK. PEGYLATION: an important approach for novel drug delivery system. J Biomater Sci Polym Ed. 2021;32(2):266-280.

[30] YadavDN, AliMS, ThanekarAM, Pogu SV, RenganAK. Recent advancements in the design of nanodelivery systems of siRNA for cancer therapy. Mol Pharm. 2022;19:4506-4526.

[31] RahmanMA, JuiMS, BamM, et al. Facial Amphiphilicity-induced polymer nanostructures for antimicrobial applications. ACS Appl Mater Interfaces. 2020;12(19):21221-21230.

[32] Dandan DoganciM, Doganci E, BalciH, CetinM. Antibacterial and cytotoxic performance of methenamine-based poly(lactic acid)/poly(ethylene glycol) (PLA/PEG) composite films. J Appl Polym Sci. 2024;141(21):1-13.

[33] NalawadeT, BhatK, SogiSP. Bactericidal activity of propylene glycol, glycerine, polyethylene glycol 400, and polyethylene glycol 1000 against selected microorganisms. J Int Soc Prevent Commun Dentistry. 2015;5(2):114.

[34] ChirifeJ, Herszage L, JosephA, BozziniJP, Leardini N, KohnES. In vitro antibacterial activity of concentrated polyethylene glycol 400 solutions. Antimicrob Agents Chemother. 1983;24(3):409-412.

[35] ConcilioM, Garcia Maset R, LemoncheLP, et al. Mechanism of action of oxazoline-based antimicrobial polymers against staphylococcus aureus: in vivo antimicrobial activity evaluation. Adv Healthc Mater. 2023;12(29):1-13.

[36] ZouY, TaoS, LiJ, WuM, ZhouX. Applications of nanomaterials as treatments and diagnostic biosensors in microbial infections. MedComm – Biomater Appl. 2023;2:4.

[37] JobD, MattaJ, DangCT, et al. Comparison of antimicrobial properties of inorganic peroxide polymer composites. MedComm – Biomater Appl. 2024;3(1):1-13.

[38] ThomasA, AppidiT, JogdandAB, et al. Facile synthesis of fluorescent polymer encapsulated metal (PoeM) nanoparticles for imaging and therapeutic applications. ACS Appl Polym Mater. 2020;2(3):1388-1397.

[39] SinghS, PandeyY, PandeyVK. A novel route to the synthesis of acridine derivatives and assay of their antiviral activity. Der Pharma Chemica. 2021;13:1-3.

[40] RuparJ, Dobričić V, AleksićM, BrborićJ, Čudina O. A review of published data on acridine derivatives with different biological activities. Kragujevac J Sci. 2018;40(40):83-101.

[41] ChenR, HuoL, JaiswalY, et al. Design, synthesis, antimicrobial, and anticancer activities of acridine thiosemicarbazides derivatives. Molecules. 2019;24(11):2065.

[42] GabrielI. “Acridines” as new horizons in antifungal treatment. Molecules. 2020;25:1480.

[43] KarimiN, PordelM, DavoodniaA, Sadeghian H, MousavianM. Synthesis, characterization and biological evaluations of new imidazo[4, 5-a]acridines as potential antibacterial agents. Pharm Chem J. 2019;53(1):52-56.

[44] WaringMJ. DNA-binding characteristics of acridinylmethanesulphonanilide drugs: comparison with antitumour properties. Eur J Cancer (1965). 1976;12(12):995-1001.

[45] ChenYY, LukkaPB, JosephWR, et al. Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent. Cancer Chemother Pharmacol. 2014;74(1):25-35.

[46] MurzaA, Sánchez-Cortés S, García-RamosJV, GuisanJM, Alfonso C, RivasG. Interaction of the antitumor drug 9-aminoacridine with guanidinobenzoatase studied by spectroscopic methods: a possible tumor marker probe based on the fluorescence exciplex emission. Biochemistry. 2000;39(34):10557-10565.

[47] BraunsEB, MurphyCJ, BergMA. Local dynamics in DNA by temperature-dependent stokes shifts of an intercalated dye. J Am Chem Soc. 1998;120(10):2449-2456.

[48] PetitJM, Denis-Gay M, RatinaudMH. Assessment of fluorochromes for cellular structure and function studies by flow cytometry. Biol Cell. 1993;78(1-2):1-13.

[49] Gensicka-KowalewskaM, Cholewiński G, DzierzbickaK. Recent developments in the synthesis and biological activity of acridine/acridone analogues. RSC Adv. 2017;7(26):15776-15804.

[50] SunH, AnsariMF, FangB, Zhou CH. Natural Berberine-Hybridized benzimidazoles as novel unique bactericides against Staphylococcus aureus. J Agricult Food Chem. 2021;69(28):7831-7840.

[51] RajuG, Vishwanath S, PrasadA, PatelBK, Prabusankar G. Imidazolium tagged acridines: synthesis, characterization and applications in DNA binding and anti-microbial activities. J Mol Struct. 2016;1107:291-299.

[52] FaramarziM, PordelM, MorsaliA. Synthesis, antiviral, antibacterial, and cytotoxicity assessment of some 3H-benzo[a]imidazo[4, 5-j]acridines and 3H-benzo[a]pyrazolo[3, 4-j]acridines. Russ J Org Chem. 2020;56(8):1438-1445.

[53] ZhangD, JiangX, YangH, et al. Acridine-based macrocyclic fluorescent sensors: self-assembly behavior characterized by crystal structures and a tunable bathochromic-shift in emission induced by H2PO4-via adjusting the ring size and rigidity. Org Biomol Chem. 2013;11(20):3375-3381.

[54] ZhangZ, DengZ, ZhuL, et al. Aggregation-induced emission biomaterials for anti-pathogen medical applications: detecting, imaging and killing. Regen Biomater. 2023;10:rbad044.

[55] ZhangX, ZhangX, TaoL, ChiZ, XuJ, WeiY. Aggregation induced emission-based fluorescent nanoparticles: fabrication methodologies and biomedical applications. J Mater Chem B. 2014;2(28):4398-4414.

[56] ZhuC, KwokRTK, LamJWY, Tang BZ. Aggregation-induced emission: a trailblazing journey to the field of biomedicine. ACS Appl Bio Mater. 2018;1(6):1768-1786.

[57] ReboredoC, González-Navarro CJ, Martínez-OharrizC, Martínez-LópezAL, IracheJM. Preparation and evaluation of PEG-coated zein nanoparticles for oral drug delivery purposes. Int J Pharm. 2021:597.

[58] MallakpourS, AzadiE, HussainCM. Recent breakthroughs of antibacterial and antiviral protective polymeric materials during COVID-19 pandemic and after pandemic: coating, packaging, and textile applications. Curr Opin Colloid Interface Sci. 2021;55:101480.

[59] WancuraM, Nkansah A, RobinsonA, et al. PEG-Based hydrogel coatings: design tools for biomedical applications. Ann Biomed Eng. 2024;52(7):1804-1815.

[60] PrasadA, RajuG, SivalingamV, et al. An acridine derivative, [4, 5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models. Sci Rep. 2016;6:39490.

[61] GirdharA, Bharathi V, TiwariVR, et al. Computational insights into mechanism of AIM4-mediated inhibition of aggregation of TDP-43 protein implicated in ALS and evidence for in vitro inhibition of liquid-liquid phase separation (LLPS) of TDP-432C-A315T by AIM4. Int J Biiol Macromol. 2020;147:117-130.

[62] IidaA, Yamaguchi S. Intense solid-state blue emission with a small Stokes’ shift: π-stacking protection of the diphenylanthracene skeleton. Chem Commun. 2009;7345(21):3002-3004.

[63] MengZ, FuK, ZhaoY, et al. Aggregation-induced red-shifted emission and fluorescent patterning of poly(aryleneethynylene) with a lateral AIEgen substituent. J Mater Chem C. 2020;8(3):1010-1016.

[64] LiY, LinH, LuoC, et al. Aggregation induced red shift emission of phosphorus doped carbon dots. RSC Adv. 2017;7(51):32225-32228.

[65] MudigundaSV, Ravichandran G, AppidiT, RenganAK. Ascorbic acid assisted synthesis of fluorescent PEG for bioimaging application. Mater Today: Proc. 2022;62:5189-5193.

[66] AppidiT, Ravichandran G, MudigundaSV, et al. Highly fluorescent polyethylene glycol-ascorbic acid complex for imaging and antimicrobial therapeutics. Mater Today Commun. 2021;29:102987.

[67] AlviSB, Rajalakshmi PS, JogdandA, et al. Iontophoresis mediated localized delivery of liposomal gold nanoparticles for photothermal and photodynamic therapy of acne. Biomater Sci. 2021;9(4):1421-1430.

[68] PoguSV, YadavDN, SankaranarayananSA, SrivastavaR, Thatikonda S, RenganAK. Copper iodide microhexagons: a potential therapeutic agent for surface microbial infection and melanoma. Materials Advances. 2023;4:2853-2867.

[69] Dharul SalamF, Nadar Vinita M, PujaP, PrakashS, Yuvakkumar R, KumarP. Anti-bacterial and anti-biofilm efficacies of bioinspired gold nanoparticles. Mater Lett. 2020;261:126998.

[70] SharmaS, Acharya J, BanjaraMR, GhimireP, SinghA. Comparison of acridine orange fluorescent microscopy and gram stain light microscopy for the rapid detection of bacteria in cerebrospinal fluid. BMC Res Notes. 2020;13(1):29.

[71] XuY, LuH, ZhuS, et al. Multifactorial mechanisms of tolerance to ketoconazole in candida albicans. Microbiol Spectrum. 2021;9(1):1-10.

[72] AjdidiA, Sheehan G, Abu ElteenK, KavanaghK. Assessment of the in vitro and in vivo activity of atorvastatin against Candida albicans. J Med Microbiol. 2019;68(10):1497-1506.

[73] AlekhyaP, Aruna Sunder CP. A comparative study of potassium hydroxide wet mount, calcofluor White staining and culture for the diagnosis of keratomycosis. Avicenna J Clin Microbiol Infection. 2020;7(4):124-128.

[74] PoguSV, YadavDN, SankaranarayananSA, RenganAK. Barium sulfate nanocomposites for bioimaging and chemo-photothermal therapy of physiologically aggravated lung adenocarcinoma cells. ACS Appl Bio Mater. 2024;7:6213-6228.

[75] AppidiT, P.S R, ChinchulkarSA, et al. A plasmon-enhanced fluorescent gold coated novel lipo-polymeric hybrid nanosystem: synthesis, characterization and application for imaging and photothermal therapy of breast cancer. Nanoscale. 2022;14(25):9112-9123.

[76] P.S R, AlviSB, BegumN, Veeresh B, RenganAK. Self-assembled fluorosome–polydopamine complex for efficient tumor targeting and commingled photodynamic/photothermal therapy of triple-negative breast cancer. Biomacromolecules. 2021;22(9):3926-3940.

[77] AppidiT, Pemmaraju DB, KhanRA, et al. Light-triggered selective ROS-dependent autophagy by bioactive nanoliposomes for efficient cancer theranostics. Nanoscale. 2020;12(3):2028-2039.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm - Biomaterials and Applications published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).