Interactions Between 5-Fluorouracil and PAMAM Dendrimers Studies by NMR Spectroscopy

doi:10.11938/cjmr20192743

Abstract

Abstract: Interactions between 5-fluorouracil (5-FU) and PAMAM in D₂O solution were studied by NMR spectroscopy. The results of ¹H NMR chemical shift titration experiments demonstrated that 5-FU molecules bonded to the surface of PAMAM, and the results of ¹³C NMR chemical shift titrations experiments disclosed that hydrogen-bond interactions and/or hydrophobic interaction ins existed in the interior pockets of PAMAM and 5-FU. These results were further supported by ¹H and ¹⁹F relaxation time measurements. The NOESY experiment was used to confirm the presence of 5-FU encapsulation in the PAMAM-5-FU complexes. This study provides a methodology for studying the interactions between dendrimers and drug molecules.

Key words: liquid-state NMR, interaction, PAMAM dendrimers, 5-fluorouracil

CLC Number:

O482.53

NING Cai-fang, MA Min-jun, GUO Zhao-hui, ZHANG Shu-huai, QIAO Yan, WANG Ying-xiong. Interactions Between 5-Fluorouracil and PAMAM Dendrimers Studies by NMR Spectroscopy[J]. Chinese Journal of Magnetic Resonance, 2019, 36(4): 555-562.

References

[1] MEKURIA S L, DEBELE T A, TSAI H C. PAMAM dendrimer based targeted nano-carrier for bio-imaging and therapeutic agents[J]. RSC Advances, 2016, 6(68):63761-63772.
[2] WU Q L, CHENG Y Y, HU J J, et al. Insights into the Interactions between dendrimers and bioactive surfactants:3. size-dependent and hydrophobic property-dependent encapsulation of bile salts[J]. J Phys Chem B, 2009, 113(39):12934-12943.
[3] HSU H J, BUGNO J, LEE S R, et al. Dendrimer-based nanocarriers:a versatile platform for drug delivery[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2017, 9(1):1-21
[4] KOLEY S, PANDA M R, BHARADWAJ K, et al. Spectroscopic and calorimetric studies of molecular recognitions in a dendrimer-surfactant complex[J]. Langmuir, 2018, 34(3):817-825.
[5] HU J J, XU T W, CHENG Y Y. NMR Insights into dendrimer-based host guest systems[J]. Chem Rev, 2012, 112(7):3856-3891.
[6] CHENG Y Y, ZHAO L B, LI T F. Dendrimer-surfactant interactions[J]. Soft Matter, 2014, 10(16):2714-2727.
[7] BUCZKOWSKI A, SEKOWSKI S, GRALA A, et al. Interaction between PAMAM-NH(2) G4 dendrimer and 5-fluorouracil in aqueous solution[J]. Int J Pharm, 2011, 408(1/2):266-270.
[8] CHEN C H, WANG Y, HILTY C. Intermolecular interactions determined by NOE build-up in macromolecules from hyperpolarized small molecules[J]. Methods, 2018, 138:69-75.
[9] ZHAO L B, LI C, ZHANG J H, et al. Interactions between dendrimers and ionic liquids revealed by pulsed field gradient and nuclear overhauser effect NMR studies[J]. J Phys Chem B, 2012, 116(24):7203-7212.
[10] MEDINA S H, EL-SAYED M E H. Dendrimers as carriers for delivery of chemotherapeutic agents[J]. Chem Rev, 2009, 109(7):3141-3157.
[11] TEKADE R K, KUMAR P V, JAIN N K. Dendrimers in oncology:an expanding horizon[J]. Chem Rev, 2009, 109(1):49-87.
[12] KESHARWANI P, LYER A K. Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery[J]. Drug Discov Today, 2015, 20(5):536-547.
[13] SZTERNER P. Solubilities in water of uracil and its halogenated derivatives[J]. J Chem Eng Data, 2008, 53(8):1738-1744.
[14] MARKOVA N, ENCHEV V, IVANOVA G. Tautomeric equilibria of 5-fluorouracil anionic species in water[J]. J Phys Chem A, 2010, 114(50):13154-13162.
[15] LAQUINTANA V, DENORA N, LOPALCO A, et al. Translocator protein ligand-PLGA conjugated nanoparticles for 5-fluorouracil delivery to glioma cancer cells[J]. Mol Pharm, 2014, 11(3):859-871.
[16] SHOBANA S, SUBRAMANIAM P, DHARMARAJA J, et al. Morphological and pharmacological investigation on some biopotent materials derived from substituted pyrimidine and imidazole enzyme constituents[J]. Spectrochim Acta A, 2014, 126:242-253.
[17] JANGIR D K, CHARAK S, MEHROTRA R, et al. FTIR and circular dichroism spectroscopic study of interaction of 5-fluorouracil with DNA[J]. J Photoch Photobio B, 2011, 105(2):143-148.
[18] PARIKH R H, PARIKH J R, DUBEY R R, et al. Poly(D,L-lactide-co-glycolide) microspheres containing 5-fluorouracil:optimization of process parameters[J]. AAPS PharmSciTech, 2003, 4(2):E13.
[19] GUO L J, WANG C H, YANG C P, et al. Morpholino-terminated dendrimer shows enhanced tumor pH-triggered cellular uptake, prolonged circulation time, and low cytotoxicity[J]. Polymer, 2016, 84:189-197.
[20] BUCZKOWSKI A, WALISZEWSKI D, URBANIAK P, et al. Study of the interactions of PAMAM G3-NH2 and G3-OH dendrimers with 5-fluorouracil in aqueous solutions[J]. Int J Pharm, 2016, 505(1/2):1-13.
[21] BUCZKOWSKI A, OLESINSKI T, ZBICINSKA E, et al. Spectroscopic and calorimetric studies of formation of the supramolecular complexes of PAMAM G5-NH(2) and G5-OH dendrimers with 5-fluorouracil in aqueous solution[J]. Int J Pharm, 2015, 490(1/2):102-111.
[22] BUCZKOWSKI A, URBANIAK P, PALECZ B. Thermochemical and spectroscopic studies on the supramolecular complex of PAMAM-NH(2) G4 dendrimer and 5-fluorouracil in aqueous solution[J]. Int J Pharm, 2012, 428(1/2):178-182.
[23] TOKARCZYK K, JACHIMSKA B. Characterization of G4 PAMAM dendrimer complexes with 5-fluorouracil and their interactions with bovine serum albumin[J]. Colloid Surface A, 2019, 561:357-363.
[24] GAO D L, SUN P, WANG Q W, et al. Interactions between albumin and fatty acids studied by NMR spectroscopy[J]. Chinese J Magn Reson, 2018, 35(3):338-344. 高东莉, 孙鹏, 王倩文, 等. 运用NMR研究白蛋白与脂肪酸的相互作用[J]. 波谱学杂志, 2018, 35(3):338-344.
[25] HU J J, CHENG Y Y, MA Y R, et al. Host-guest chemistry and physicochemical properties of the dendrimer-mycophenolic acid complex[J]. J Phys Chem B, 2009, 113(1):64-74.
[26] CHEN X Y, YU G J, MAO S Z, et al. An NMR study on how steric effects affect synergistic effects in surfactant mixtures[J]. Chinese J Magn Reson, 2018, 35(1):75-80. 陈晓瑛, 俞刚金, 毛诗珍, 等. ¹H NMR探究空间效应对表面活性剂复配体系中协同作用的影响[J]. 波谱学杂志, 2018, 35(1):75-80.
[27] CHENG Y Y, LI Y W, WU Q L, et al. New insights into the interactions between dendrimers and surfactants by two dimensional NOE NMR spectroscopy[J]. J Phys Chem B, 2008, 112(40):12674-12680.
[28] OOYA T, LEE H. Amino acid-dependent host-guest interaction:polyglycerol dendrimer of generation 3 encapsulates amino acids bearing two amino groups[J]. Chemnanomat, 2015, 1(4):264-269.
[29] MARKOWICZ M, SZYMANSKI P, CISZEWSKI M, et al. Evaluation of poly(amidoamine) dendrimers as potential carriers of iminodiacetic derivatives using solubility studies and 2D-NOESY NMR spectroscopy[J]. J Biol Phys, 2012, 38(4):637-656.
[30] ZHAO B, LI Y L, LI M, et al. An NMR Study of Capsaicin/β-cyclodextrin Complex[J]. Chinese J Magn Reson, 2013, 30(4):576-584. 赵兵, 李艺蕾, 李明, 等. 辣椒碱与β-环糊精包合物的核磁共振研究[J]. 波谱学杂志, 2013, 30(4):576-584.