New-generation Jeffamine® D230 core amine, TRIS and carboxylterminated PAMAM dendrimers: Synthesis, characterization and the solubility application for a model NSAID drug Ibuprofen

Abstract

Many therapeutically active drugs are poor water soluble and,

therefore, bioavailability of these molecules in the living cells

is low and a major problem. In this study, new-generation

Jeffamine® D230 core, amine (NH2), Tris(hydroxymethyl)

aminomethane (TRIS), and carboxyl (COOH) terminated

poly(amidoamine) PAMAM dendrimers (PAMAMs) were

synthesized. Synthesized new-generation PAMAMs were

characterized by 1H NMR, 13C NMR, ATR-FTIR, and

investigated as solubility enhancer of a sample non-steroidal

anti-inflammatory drug (NSAID) Ibuprofen (IBU). The effect

of generation size (D2-D4), concentration (0-2.0 mM), and

surface functional group (NH2, COOH, TRIS) of the synthesized

new-generation PAMAMs on the aqueous solubility of IBU was

also investigated. The observed solubility enhancement of IBU

was in the order of D4.COOH (18.21 mg/mL)> D3.COOH

(13.21 mg/mL)> D4.TRIS (10.30 mg/mL)> D2.COOH (8.55

mg/mL)> D3.TRIS (6.04 mg/mL)> D4.NH2 (4.56 mg/mL)>

D3.NH2 (3.36 mg/mL)> D2.TRIS (2.42 mg/mL)> D2.NH2 (1.86

mg/mL). Results showed that synthesized PAMAMs improved

the solubility of IBU significantly (30 to 247-

Keywords

• Dendrimers,poly (amidoamine) PAMAM,Jeffamine,drug carrier,NSAID,ibuprofen

New-generation Jeffamine® D230 core amine, TRIS and carboxylterminated PAMAM dendrimers: Synthesis, characterization and the solubility application for a model NSAID drug Ibuprofen

Abstract

Birçok terapötik olarak aktif olan ilaçların sudaki çözünürlüğü

zayıf ve bundan dolayı canlı hücrelerde biyoyararlanımları

düşük ve büyük bir problem oluşturmaktadır. Bu çalışmada,

yeni nesil Jeffamine® D230 çekirdekli amin (NH2),

Tris(hidroksimetil)aminometan (TRIS) ve karboksil (COOH)

sonlu poli(amidoamine) PAMAM dendrimerler (PAMAMs)

sentezlendi. Sentezlenen yeni tip PAMAMs’lar 1H NMR, 13C

NMR, ATR-FTIR kullanılarak karakterize edildi ve örnek bir

non-steroidal anti-inflamatuar ilaç (NSAID) olan Ibuprofen

(IBU) için çözünürlük arttırıcı olarak araştırıldı. Sentezlenen

yeni nesil PAMAMs’ların, jenerasyon büyüklüğünün (D2-D4),

konsantrasyonun (0-2.0 mM) ve yüzey fonksiyonel gruplarının

(NH2, COOH, TRIS), IBU’nun çözünürlüğüne olan etkisi ayrıca

araştırıldı. IBU’nun gözlemlenen çözünürlük artışı, D4.COOH

(18.21 mg/mL)> D3.COOH (13.21 mg/mL)> D4.TRIS (10.30

mg/mL)> D2.COOH (8.55 mg/mL)> D3.TRIS (6.04 mg/mL)>

D4.NH2 (4.56 mg/mL)> D3.NH2 (3.36 mg/mL)> D2.TRIS

(2.42 mg/mL)> D2.NH2 (1.86 mg/mL) sırasındadır. Sonuçlar

gösteriyor ki, sentezlenen PAMAMs’ların jenerasyon büyüklüğü

ve konsantrasyonun artmasıyla birlikte IBU’nu çözünürlüğü

önemli ölçüde artmıştır (30 ile 247 kat arası).

Keywords

• Dendrimer,poly(amidoamin) PAMAM,Jeffamin,ilaç taşıyıcı,NSAID,ibuprofen

References

1. 1. Beezer AE, King ASH, Martin IK, Mitchel JC, Twyman LJ, WainCF. Dendrimers as potential drug carriers; encapsulation ofacidic hydrophobes within water soluble PAMAM derivatives.Tetrahedron 2003;59: 3873-80.
2. 2. Carriers D. ReferenceMD Available from: http://www.reference.md/files/D004/mD004337.html [10 Dem 2016].
3. 3. Felice B, Prabhakaran MP, Rodriguez AP, Ramakrishna S.Drug delivery vehicles on a nano-engineering perspective.Mater Sci Eng C 2014;41: 178-95.
4. 4. Fox ME, Szoka FC, Frechet JMJ. Soluble Polymer Carriersfor the Treatment of Cancer: The Importance of MolecularArchitecture. Acc Chem Res 2009;42: 1141-51.
5. 5. Vandamme TF, Brobeck L. Poly (amidoamine) dendrimers asophthalmic vehicles for ocular delivery of pilocarpine nitrateand tropicamide. J Controlled Release 2005;102: 23-38.
6. 6. Jia L, Xu J-P, Wang H, Ji J. Polyamidoamine dendrimerssurface-engineered with biomimetic phosphorylcholine aspotential drug delivery carriers. Colloids Surf B 2011;84: 49-54.
7. 7. Malik N, Wiwattanapatapee R, Klopsch R, Lorenz K, Frey H,Weener JW, et al. Dendrimers:: Relationship between structureand biocompatibility in vitro, and preliminary studies on thebiodistribution of 125I-labelled polyamidoamine dendrimersin vivo. J Controlled Release 2000;65: 133-48.
8. 8. Kesharwani P, Jain K, Jain NK. Dendrimer as nanocarrier fordrug delivery. Prog Polym Sci 2014;39: 268-307.9. Zhang L, Pornpattananangkul D, Hu C-M, Huang C-M.Development of nanoparticles for antimicrobial drug delivery.Curr Med Chem 2010;17: 585-94.

9. 10. Gupta U, Agashe HB, Asthana A, Jain N. Dendrimers: novelpolymeric nanoarchitectures for solubility enhancement.Biomacromolecules 2006;7: 649-58.
10. 11. Ly TU, Tran NQ, Hoang TKD, Phan KN, Truong HN, NguyenCK. Pegylated dendrimer and its effect in fluorouracil loadingand release for enhancing antitumor activity. J BiomedNanotechnol 2013;9: 213-20.
11. 12. Kumar PD, Kumar PV, anneer Selvam T, Rao KS. Prolongeddrug delivery system of PEGylated PAMAM dendrimers witha anti-HIV drug. Res Pharm 2015;3.
12. 13. Ozturk K, Erturk AS, Sarisozen C, Tulu M, Calis S. Cytotoxicityand in vitro characterization studies of synthesized JeffaminecoredPAMAM dendrimers. J Microencapsul 2014;31: 127-36.
13. 14. Jevprasesphant R, Penny J, Jalal R, Attwood D, McKeown NB,D’Emanuele A. The influence of surface modification on thecytotoxicity of PAMAM dendrimers. Int J Pharm 2003;252:263-66.
14. 15. Medina SH, El-Sayed ME. Dendrimers as carriers for deliveryof chemotherapeutic agents. Chem Rev 2009;109: 3141-57.
15. 16. Duncan R, Izzo L. Dendrimer biocompatibility and toxicity.Adv Drug Delivery Rev 2005;57: 2215-37.
16. 17. Twyman LJ, Beezer AE, Esfand R, Hardy MJ, Mitchell JC. Thesynthesis of water soluble dendrimers, and their applicationas possible drug delivery systems. Tetrahedron Lett 1999;40:1743-46.
17. 18. Erturk AS, Gurbuz MU, Tulu M, Bozdoğan AE. WatersolubleTRIS-terminated PAMAM dendrimers: microwaveassistedsynthesis, characterization and Cu (ii) intradendrimercomplexes. RSC Adv 2015;5: 60581-95.
18. 19. Erturk AS, Tulu M, Bozdoğan AE, Parali T. Microwave assistedsynthesis of Jeffamine cored PAMAM dendrimers. Eur PolymJ 2014;52: 218-26.
19. 20. Yin R, Zhu Y, Tomalia D, Ibuki H. Architectural copolymers:rod-shaped, cylindrical dendrimers. J Am Chem Soc 1998;120:2678-79.
20. 21. Gurbuz MU, Erturk AS, Tulu M. Synthesis of surface modifiedTREN cored PAMAM dendrimers and their effects on thesolubility of sulfamethoxazole (SMZ) as an analogue antibioticdrug. Pharm Dev Technol 2016: 1-33.
21. 22. Erturk AS, Gurbuz MU, Tulu M. The effect of PAMAMdendrimer concentration, generation size and surfacefunctional group on the aqueous solubility of candesartancilexetil. Pharm Dev Technol 2016: 1-34.
22. 23. Kleinman MH, Flory JH, Tomalia DA, Turro NJ. Effect ofprotonation and PAMAM dendrimer size on the complexationand dynamic mobility of 2-naphthol. J Phys Chem B 2000;104:11472-79.
23. 24. Kolhe P, Misra E, Kannan RM, Kannan S, Lieh-Lai M. Drugcomplexation, in vitro release and cellular entry of dendrimersand hyperbranched polymers. Int J Pharm 2003;259: 143-60.
24. 25. Higuchi T, Connors KA. Phase-solubility techniques. AdvanAnal Chem Instr 1965;4: 117-212.
25. 26. Feng ZV, Lyon JL, Croley JS, Crooks RM, Vanden Bout DA,Stevenson KJ. Synthesis and Catalytic Evaluation of Dendrimer-Encapsulated Cu Nanoparticles. An UndergraduateExperiment Exploring Catalytic Nanomaterials. Journal ofChemical Education 2009;86: 368.
26. 27. Zhao M, Sun L, Crooks RM. Preparation of Cu Nanoclusterswithin Dendrimer Templates. Journal of the AmericanChemical Society 1998;120: 4877-78.
27. 28. Chen P, Yang Y, Bhattacharya P, Wang P, Ke PC. A Tris-Dendrimer for Hosting Diverse Chemical Species. The Journalof Physical Chemistry C 2011;115: 12789-96.
28. 29. Chauhan AS, Jain NK, Diwan PV, Khopade AJ. Solubilityenhancement of indomethacin with poly(amidoamine)dendrimers and targeting to inflammatory regions of arthriticrats. J Drug Target 2004;12: 575-83.
29. 30. Devarakonda B, Hill R, Devilliers M. The effect of PAMAMdendrimer generation size and surface functional group onthe aqueous solubility of nifedipine. Int J Pharm 2004;284:133-40
30. 31. Yiyun C, Tongwen X. Dendrimers as potential drug carriers.Part I. Solubilization of non-steroidal anti-inflammatorydrugs in the presence of polyamidoamine dendrimers. Eur JMed Chem 2005;40: 1188-92.
31. 32. Chow DD, Karara AH. Characterization, dissolution andbioavailability in rats of ibuprofen-β-cyclodextrin complexsystem. Int J Pharm 1986;28: 95-101.