Yeni Jenerasyon TREN ve Jeffamine® D230 Çekirdekli PEG Sonlu PAMAM Dendrimerler: Sentezi, Karakterizasyonu, Sulfametoksazol (SMZ) İçin Kompleks ve İn Vitro Salımı Çalışması

Year 2018, Volume: 8 Issue: 1, 189 - 197, 31.03.2018

Mustafa Ulvi Gürbüz , Ali Serol Ertürk Metin Tülü

https://doi.org/10.21597/jist.407872

Abstract

Sulfametoksazol (SMZ) bir antibiyotiktir ve trimetoprim ile bakteriyostatik ve idrar yolu enfeksiyonlarının tedavisinde yaygın olarak kullanılır. SMZ ile ilgili sorun, zayıf su çözünürlüğü, dolayısıyla klinik uygulamalarda düşük biyoyararlanımıdır. Bu çalışmada, yeni jenerasyon TREN (T) ve Jeffamine® D230 (D) çekirdekli PEG bisamin sonlu (T5.PEG COOH ve D5.PEG COOH) PAMAM dendrimer sentezlendi. Sentezlenen dendrimerler, 1H NMR ve ATR-FTIR ile karakterize edilerek SMZ’nin ilaç taşıyıcı ve in vitro salımı çalışması araştırıldı. PAMAM dendrimerin SMZ’nin çözünürlüğünü arttırmada ki rol’ü 0.002 M dendrimer varlığında 54 kat ve T5.PEG COOH> D5.PEG COOH azalan sıralamada belirlendi. İn vitro salımı çalışması gösteriyor ki, 2 saat sonra SMZ’den en yavaş salımı SMZ-T5.PEG COOH (% 12.3) ilaç-dendrimer çözeltisinde gözlendi.

Keywords

İlaç taşıyıcı sistem, pegilasyon, poly(amidoamin) pamam, sulfametoksazol

New-Generation TREN and Jeffamine® D230 Core PEG Terminated PAMAM Dendrimers: Synthesis, Characterization, Complexation

Abstract

Sulfamethoxazole (SMZ) is an antibiotic and used widely in the treatment of bacteriostatic and urinary tract infections with trimethoprim. The problem with SMZ is its poor water solubility, therefore, low bioavailability in clinical applications. In this study, we synthesized new-generation TREN and Jeffamine® D230 core PEG bisamine terminated (T5.PEG COOH and D5.PEG COOH) PAMAM dendrimers. Synthesized dendrimers were characterized by 1H NMR, and ATR-FTIR investigated as drug carriers of SMZ and in vitro release studies. The role of PAMAM dendrimer in the solubility enhancement of SMZ was in the decreasing order of T5.PEG COOH> D5.PEG COOH, and 54-fold in the presence of 0.002 M dendrimer. In vitro release studies showed that after 2h, the slowest release of SMZ was observed from the drug-dendrimer solution of SMZ-T5.PEG COOH (% 12.3).

Keywords

Drug delivery system, pegylation, poly(amidoamine) pamam, sulfamethoxazole

References

• Agrawal P, Gupta U, Jain NK, 2007. Glycoconjugated peptide dendrimers-based nanoparticulate system for the delivery of chloroquine phosphate. Biomaterials, 28: 3349-3359.
• Caminade AM, Turrin CO, 2014. Dendrimers for drug delivery. Journal of Materials Chemistry B, 2: 4055-4066.
• Ertürk AS, Gürbüz MU, Tülü M, 2017a. The effect of PAMAM dendrimer concentration, generation size and surface functional group on the aqueous solubility of candesartan cilexetil. Pharmaceutical Development and Technology, 22: 111-121.
• Ertürk AS, Gürbüz MU, Tülü M, 2017b. New-generation Jeffamine® D230 core amine, TRIS and carboxyl-terminated PAMAM dendrimers: Synthesis, characterization and the solubility application for a model NSAID drug Ibuprofen. Marmara Pharmaceutical Journal, 21: 385-399.
• Gürbüz MU, Ertürk AS, Tülü M, 2017. Synthesis of surface-modified TREN-cored PAMAM dendrimers and their effects on the solubility of sulfamethoxazole (SMZ) as an analog antibiotic drug. Pharmaceutical Development and Technology, 22: 678-689.
• Gürbüz MU, Öztürk K, Ertürk AS, Yoyen-Ermis D, Esendagli G, Çalış S, Tülü M, 2016. Cytotoxicity and biodistribution studies on PEGylated EDA and PEG cored PAMAM dendrimers. Journal of Biomaterials Science, Polymer Edition, 27: 1645-1658.
• Jain V, Bharatam PV, 2014. Pharmacoinformatic approaches to understand complexation of dendrimeric nanoparticles with drugs. Nanoscale, 6: 2476-2501.
• Jevprasesphant R, Penny J, Jalal R, Attwood D, McKeown NB, D’Emanuele A, 2003. The influence of surface modification on the cytotoxicity of PAMAM dendrimers. International Journal of Pharmaceutics, 252: 263-266.
• Kesharwani P, Jain K, Jain NK, 2014. Dendrimer as nanocarrier for drug delivery. Progress in Polymer Science, 39: 268-307.
• Luo D, Haverstick K, Belcheva N, Han E, Saltzman WM, 2002. Poly(ethylene glycol)-conjugated PAMAM dendrimer for biocompatible, high-efficiency DNA delivery. Macromolecules, 35: 3456-3462.
• Maeda H, 2012. Macromolecular therapeutics in cancer treatment: The EPR effect and beyond. Journal of Controlled Release, 164: 138-144.
• Medina SH, El-Sayed ME, 2009. Dendrimers as carriers for delivery of chemotherapeutic agents. Chemical Reviews, 109: 3141-3157.
• Morgan MT, Nakanishi Y, Kroll DJ, Griset AP, Carnahan MA, Wathier M, Oberlies NH, Manikumar G, Wani MC, Grinstaff MW, 2006. Dendrimer-encapsulated camptothecins: increased solubility, cellular uptake, and cellular retention affords enhanced anticancer activity in vitro. Cancer Research, 66: 11913-11921.
• Oerlemans C, Bult W, Bos M, Storm G, Nijsen JFW, Hennink WE, 2010. Polymeric micelles in anticancer therapy: targeting, imaging and triggered release. Pharmaceutical Research, 27: 2569-2589.
• Ohyama A, Higashi T, Motoyama K, Arima H, 2016. In vitro and in vivo tumor-targeting siRNA delivery using folate-PEG-appended dendrimer (G4)/α-cyclodextrin conjugates. Bioconjugate Chemistry, 27: 521-532.
• Okuda T, Kawakami S, Akimoto N, Niidome T, Yamashita F, Hashida M, 2006. PEGylated lysine dendrimers for tumor-selective targeting after intravenous injection in tumor-bearing mice. Journal of Controlled Release, 116: 330-336.
• Öztürk K, Esendağlı G, Gürbüz MU, Tülü M, Çalış S, 2017. Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers. International Journal of Pharmaceutics, 517: 157-167.
• Thanki K, Gangwal RP, Sangamwar AT, Jain S, 2013. Oral delivery of anticancer drugs: challenges and opportunities. Journal of Controlled Release, 170: 15-40.
• Zhang Y, Sun Y, Xu X, Zhang X, Zhu H, Huang L, Qi Y, Shen YM, 2010. Synthesis, biodistribution, and microsingle photon emission computed tomography (SPECT) imaging study of technetium-99m labeled PEGylated dendrimer poly(amidoamine) (PAMAM)-folic acid conjugates. Journal of medicinal chemistry, 53: 3262-3272.
• Zhao Y, Liu S, Li Y, Jiang W, Chang Y, Pan S, Fang X, Wang YA, Wang J, 2010. Synthesis and grafting of folate-PEG-PAMAM conjugates onto quantum dots for selective targeting of folate-receptor-positive tumor cells. Journal of colloid and interface science, 350: 44-50.
• Zhu S, Hong M, Zhang L, Tang G, Jiang Y, Pei Y, 2010. PEGylated PAMAM dendrimer-doxorubicin conjugates: in vitro evaluation and in vivo tumor accumulation. Pharmaceutical Research, 27: 161-174.