Binding of Serum Albumins With Bioactive Substances - Nanoparticles To Drugs

Journal of Photochemistry and Photobiology C: Photochemistry Reviews 14 (2013) 5371
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Journal of Photochemistry and Photobiology C: Photochemistry Reviews

journal homepage: www.elsevier.com/locate/jphotochemrev
Review
Binding of serum albumins with bioactive substances Nanoparticles to drugs

Selvaraj Naveenraj, Sambandam Anandan
Nanomaterials and Solar Energy Conversion Lab, Department of Chemistry, National Institute of Technology, Tiruchirappalli 620 015, India
a r t i c l e
i n f o
a b s t r a c t
The interactions of human and bovine serum albumins (HSA and BSA) with various drugs and nanomaterials receive great attention in the recent years owing to their signicant impact in the biomedical eld. Although there are various techniques available for studying such interactions, uorescence spectroscopy is the most appealing one due to its high sensitivity and straightforwardness. Detailed information about the interactions of drugs and nanomaterials with serum can be deducted from a mass of information accumulated by the uorescence quenching studies. The present review emphasizes the interaction of various nanomaterials, antibiotics, anticancer drugs, anti-inammatory agents, dyes, avonoids, and certain noxious materials with HSA and BSA. In particular, we focus on the interactions of serum albumin with nanomaterials having different size and stabilizing agents with various receptors. This review helps in understanding the structural features of drugs/nanomaterials crucial for not only their afnity for serum albumin but also their optimum pharmacological activities. 2012 Elsevier B.V. All rights reserved.
Article history: Received 11 May 2012 Received in revised form 5 September 2012 Accepted 11 September 2012 Available online 19 September 2012 Keywords: Serum albumins Fluorescence quenching Nanoparticles Quantum dots Anticancer agents Antibiotics Flavonoids Receptors
Contents 1. 2. 3. 4. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serum albumins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fluorescence quenching studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Binding capability of serum albumins with nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Metal nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Semiconductor nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organic molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Anti-inammatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Organic dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Noxious materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 54 55 58 58 60 61 61 61 63 64 65 66 69 69 69 69
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Corresponding author. Tel.: +91 431 2503639; fax: +91 431 2500133. E-mail addresses: sanand@nitt.edu, sanand99@yahoo.com (S. Anandan). 1389-5567/$20.00 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jphotochemrev.2012.09.001
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S. Naveenraj, S. Anandan / Journal of Photochemistry and Photobiology C: Photochemistry Reviews 14 (2013) 5371
Selvaraj Naveenraj obtained his undergraduate degree in Chemistry from the American College, India (2004) and his post graduate degree in Chemistry from Madurai Kamaraj University, India (2006). He also obtained his Master of Philosophy degree in Inorganic Chemistry from University of Madras, India (2007), where he worked on the synthesis of nanomaterials. Currently, he is a PhD student in the research group of Professor Anandan. He was awarded the P.S. Lakshminarayanan Prize for Prociency in Chemistry while doing his under graduation, and qualied in the Graduate Aptitude Test in Engineering. His research interests include synthesis of nanomaterials and their applications in photocatalysis and biosensors. To-date he has authored four research articles. Sambandam Anandan obtained his doctoral degree in Chemistry from the University of Madras, India under the supervision of Prof. P. Maruthamuthu, where he worked on Dye-Sensitized Solar Cells. After two postdoctoral terms at Chungnam National University in South Korea and Hong Kong University of Science & Technology, he worked as a visiting researcher at National Institute of Advanced Industrial Science and Technology (AIST) in Japan. Subsequently, he joined the Central Electrochemical Research Institute in India and later National Institute of Technology, Tiruchirappalli, where he is now an Associate Professor of Physical Chemistry, leading the research group Nanomaterials and Solar Energy Conversion Processes. He had also spent short periods at University of Melbourne, Feng Chia University, University of Loughborough, and University of Alicante. His recent research interests include hybrid semiconductor nanomaterials and their applications in, solar cells, photocatalysis, electrocatalysis, and biosensors. He is the author of ca 100 research articles.
Fig. 1. The crystal structure of HSA. The domains are color-coded as follows: red, domain I; green, domain II; blue, domain III. The A and B sub-domains within each domain are depicted in dark and light shades, respectively. From Ref. [9].
1. Introduction Investigations on the interactions of drug molecules and nanomaterials with various proteins receive considerable interest in the eld of chemistry, life science and clinical medicine for decades. The nature and the magnitude of these interactions inuence the biosafety, delivery rate, pharmacological response, therapeutic efcacy and the design of drugs. Hence studies on these interactions help in understanding the structural features essential for the bioafnity of drugs and nanomaterials toward the pharmacological activity [14]. Since serum albumin is essential in the drug delivery of vertebrates, it is the ideal model for studying the drugprotein interactions in vitro. Optical techniques such as absorption spectroscopy, circular dichroism, ellipsometry, differential light scattering, Raman spectroscopy, and uorescence spectroscopy are powerful tools for studying the drugprotein interactions in vitro due to their exceptional sensitivity, speed, theoretical foundations, and straightforwardness [47]. Among the various optical techniques, an incalculable amount of information is acquired about the structural uctuations and the microenvironment surrounding the uorescent labels of proteins from the measurements and analyses of uorescence spectra, uorescence lifetime, uorescence polarization, etc. Hence, uorescence spectroscopy plays a pivotal role in the investigation of interactions between the drug molecule and the receptor (serum albumins). In particular, uorescence quenching studies are widely utilized for revealing the accessibility of a drug/nanomaterial (quencher) to the uorophore moiety in a protein, which in turn helps us to understand the nature and the underlying mechanism of drugprotein interactions [8]. Here we review the recent literature about the interactions of human and bovine serum albumins (HSA and BSA) with various drug molecules and nanomaterials studied using uorescence spectroscopy. The review is organized as follows. Description about (i) HSA and BSA which are essential in the drug delivery; (ii) pivotal role of uorescence quenching studies in determining the interactions and binding of drugs with HSA/BSA; (iii) the biological applications of metal, semiconductor and metal-doped nanoparticles, and their binding capability toward serum albumins; and (iv) the binding capability of various organic molecules such as antibiotics, anticancer drugs, anti-inammatory agents, dyes, avonoids and noxious materials toward serum albumins. This review does not seek to provide an absolute review of all articles published on drugserum albumin interactions, rather it provides a snapshot of the assortment of uorescence quenching studies involving the interactions and emphasizes on some of the key research directions and paradigms emerging in this area. 2. Serum albumins Serum albumins, the most abundant soluble protein in the systemic circulation comprising 5260% in plasma, are synthesized by the parenchymal cells of the liver and exported as a non-glycosylated protein. They possess a half life in circulation of 19 days. Serum albumins consist of amino acid chains forming a single polypeptide with well-known sequence, which contain three homologous -helices domains (IIII) that assembled to form a heart shaped molecule whose dimensions are 80 A 80 A 30 A. Each domain contains 10 helices and is 80 A divided into anti-parallel six-helix and four domains (A and B) extensively cross-linked by disulde bridges. Fig. 1 shows the crystal structure of HSA illustrating IIII domains [9]. Serum albumins are clearly an extraordinary globular protein molecule of manifold biological and pharmacokinetic functions. They are capable of bind reversibly with a large variety of relatively insoluble endogeneous and exogeneous ligands even though their principal function is to transport metabolites such as nutrients, hormones, fatty acids and a variety of pharmaceuticals. Apart from an important role in maintaining colloidal osmotic pressure in blood, serum albumins can play a dominant role in the drug disposition and efcacy since it increases the apparent solubility of hydrophobic drugs in the plasma [914]. Serum albumins serve as the depot for the interacting bioactive substance and also it can be circulated through the system in the body. The binding afnity of any substance to serum
55
Fig. 2. Three dimensional structure of serum albumins [(a) HSA and (b) BSA], with tryptophan residues shown in green color. From Ref. [30].
albumin is one of the major factors that determine the pharmacokinetics i.e., time course of drug absorption, distribution, metabolism, and excretion. In addition to the time course, the binding afnity also determines the bioavailability of drugs [15]. If the binding afnity is low, the initial step of pharmacokinetics (drug absorption) is not feasible. In the case of moderate binding afnity of bioactive substances to serum albumins, the absorption and distribution of drugs to various tissues are feasible. On the other hand, when the binding afnity is high, the absorption of drug is feasible but its distribution to the required tissues is be limited due to the stability of the complex, which in turn adversely affects the pharmacokinetics of the drug. Among serum albumins, HSA and BSA are extensively studied due to their signicance in the pharmacology eld. Both HSA and BSA display approximately 80% sequence homology and a repeating pattern of disuldes. The molecular weights are 66 kDa for BSA and 66.5 kDa for HSA. The tertiary structures of HSA and BSA show 76% similarity [16]. Crystal structure analyses have revealed that HSA contains 585 amino acid residues with 17 tyrosyl residues and only one tryptophan (Trp) located at position 214 along the chain (subdomain IIA); whereas, BSA contains 582 amino acid residues with 20 tyrosyl residues and two tryptophans located at positions 134 and 212 and Trp-134 at the surface of the molecule [11,12,1620,10,2129]. The chemical microenvironment of Trp-212 in BSA is similar to that of Trp-214 in HSA. Fig. 2 shows the three dimensional structure of HSA and BSA with tryptophan residues in green color [30]. There are two principal binding sites present in serum albumins (shown in Fig. 1) located in the subdomain IIA (Sudlows site I: warfarin-binding site) and IIIA (Sudlows site II: indole/benzodiazepine site). Although they differ in their afnities, they appear to be homologs in both BSA and HSA [15,20]. Site I appears to be capacious; whereas, site II appears to be smaller, or narrower. Site II shows less exibility than that of site I because binding at site II is often strongly affected by stereoselectivity. The binding afnity offered by site I is mainly through hydrophobic interactions; whereas, site II involves a combination of hydrophobic, hydrogen binding, and electrostatic interactions [9,31]. Absorption peak maxima of serum albumins are around 280 nm. The intrinsic uorescence of serum albumins appears at 340 nm when excited at 280 nm which is originating from the three aromatic l-amino acid (tryptophan (Trp), tyrosine (Tyr), and phenylalanine (Phe)) residues. Indeed, the intrinsic uorescence of serum albumins is mainly contributed by the Trp and Tyr residues because of the low uorescence quantum efciency of
phenylalanine. The intrinsic uorescence characteristics are very sensitive to the microenvironment of the uorescent residues or changes in the local surroundings of serum albumins, such as conformational transition, biomolecular binding and denaturation [32]. 3. Fluorescence quenching studies Considering the interaction of various molecules with serum albumins, changes in their aggregation state may be easily deduced as intrinsically uorescent serum albumins are very sensitive to local changes in the polarity, conformation and/or exposure to the solvent. The interaction will lead to modications in uorescence intensity-decrease (quenching) or increase (enhancement). Fluorescence quenching may result from variety of processes such as excited state reactions, molecular rearrangements, energy transfer, ground-state complex formation (static quenching) or collisional interactions (dynamic quenching) [8]. The interacting molecule quenches the intrinsic uorescence of serum albumin with or without any shift (red- or blue-shift) in the emission peak maxima. If the interacting molecule quenches the uorescence without affecting the spectral maximum, the hydrophobicity and polarity in the microenvironment of the uorophore (Trp or Tyr) is not altered. For example, gold nanoparticles quench the uorescence of serum albumins [33] without having any effect on the uorescence spectral maximum (Fig. 3). If the interacted molecule quenches the uorescence with a blue-shift in the spectral maximum, it indicates a decrease in the polarity or an increase in the hydrophobicity of the microenvironment surrounding the uorophore site; whereas a red-shift should be indicative of an increase in the polarity or decrease in the hydrophobicity of the microenvironment [34]. For example, the uorescence of BSA quenched by silver nanoparticles (Fig. 4) is accompanied by a blue shift in the emission maximum of BSA [35]. The uorescence quenching for interacted molecule (quencher (Q)) and protein (P) can be analyzed by the SternVolmer equation [36]: F0 = 1 + KSV [Q ] = 1 + kq F
0 [Q ]
(1)
where F0 and F denotes the steady state uorescence intensities in the absence and the presence of the quencher Q, respectively, kq is the bimolecular quenching rate constant, 0 is the average lifetime of the protein, [Q] is the concentration of the quencher, KSV
56
a
Fluorescence intensity / a.u.
750
A G
500
250
0 300 350 400 450 500
Wavelength (nm)
Fig. 5. Classical SternVolmer plot of F0 /F versus [Au] for HSA in the presence of different gold nanoparticles having sizes: (1) 8, (2) 10, (3) 16, (4) 25, (5) 34, (6) 41, (7) 47, (8) 55, and (9) 70 nm. From Ref. [65].
b
160
120
80
40
300
350
400
450
500
Wavelength (nm)
Fig. 3. Fluorescence spectra of serum albumin (4 M) [(a) BSA and (b) HSA] quenched by gold nanoparticles in the concentration range of 08 M. From Ref. [33].
is the SternVolmer quenching constant [37]. The above equation is applied to determine KSV by linear regression of a plot of F0 /F against [Q]. For example, the classical SternVolmer plots for HSA in the presence of gold nanoparticles having different sizes are shown in Fig. 5. The SternVolmer quenching constants for serum albumins by various bioactive substances are summarized in Table 1. The uorescence quenching can either be dynamic or static. Dynamic quenching refers to a process where the uorophore and the quencher interact during the excited-state lifetime of the uorophore; whereas, static quenching refers to the formation of the uorophorequencher complex in the ground state. Static quenching can easily be distinguished from dynamic quenching by examining their temperature dependence, or by the lifetime measurements. If the quenching is dynamic, the bimolecular quenching constant, which is diffusion-dependent, increases with raise in temperature. Whereas in the case of static quenching, the quenching constant decreases with raise in temperature because the stability of the complex between the uorophore and the quencher is lowered at higher temperatures. Similarly, if an increase in the concentration of the quencher has no effect on the uorescence lifetime of serum albumins, then it reveals that the quenching follows
Table 1 SternVolmer constants, KSV , for the quenching of serum albumins by various bioactive substances. S. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 System BSAAu NP (8 nm) BSAAu NP (10 nm) BSAAu NP (16 nm) BSAAu NP (25 nm) BSAAu NP (34 nm) BSAAu NP (41 nm) BSAAu NP (47 nm) BSAAu NP (55 nm) BSAAu NP (70 nm) BSAMPA stabilized CdTe QDs BSACYS stabilized CdTe QDs BSATGA stabilized CdTe QDs BSAG4 PAMAM-OH dendrimers BSAG3.5 PAMAM dendrimers BSAG4 PAMAM dendrimers BSAG6.0 PAMAM-PC BSAG6.0 PAMAM-NH2 BSAG5.5 PAMAM-OH SternVolmer constant, KSV 5.95 108 5.79 108 5.13 108 4.37 108 3.60 108 2.90 108 2.63 108 2.39 108 2.09 108 1.20 106 1.79 106 2.84 106 2.87 103 3.83 103 8.38 103 48.52 103 25.78 103 7.84 103
Fig. 4. Fluorescence spectra (top to bottom) of BSA and BSA in presence of silver nanoparticles (ae) concentrations of 0.0903 109 , 0.225 109 , 0.451 109 , 0.677 109 and 0.8127 109 M. From Ref. [35].
57
100000
-0.2 -0.4
10000
HSA BSA
log [(F0-F)/F]
0 10 20 30 40 50
-0.6 -0.8 -1.0 -1.2
Counts
1000
100
10
-6.0
-5.8
-5.6
-5.4
-5.2
-5.0
Time (ns)
Fig. 6. Fluorescence decay curves of BSA in the presence of Au nanoparticles in the concentration range of 08 M. From Ref. [33].
log [Au]
Fig. 8. Modied SternVolmer plot for serum albumins in the presence of sonochemically synthesized gold nanoparticles. From Ref. [33].
the static mechanism; whereas, for dynamic quenching the uorescence lifetime of serum albumins decreases with increase in the quencher concentration [8,37,38]. For example, the addition of gold nanoparticles does not show any effect on the uorescence lifetime of BSA [33] (Fig. 6); whereas; the addition of benzo[a]phenazine (BAP) lowers the uorescence lifetime of BSA (Fig. 7) [39]. When drug molecules bind independently to a set of equivalent sites on serum albumin, the equilibrium between free and bound molecules is given log F0 F F = log KA + n log[Q ] (2)
the relation between the SternVolmer quenching constant and the binding constant is KSV = KA [Q ]n1 (3)
Table 2 The binding constant, KA , for the interaction of serum albumins with various bioactive substances. S. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 System HSAsonochemically synthesized Au NP BSAsonochemically synthesized Au NP HSAAu NP BSAAu NP BSAGSH stabilized CdTe QDs BSACYS stabilized CdTe QDs BSAMPA stabilized CdTe QDs HSACUR HSADAC BSACUR BSADAC HSAEDAC BSAEDAC HSADMACA BSADMACA HSAtangeretin HSAnobiletin HSAnaringenin HSAnaringin HSAnarirutin BSAgalangin BSAkaempferol BSAquercetin BSAmyricetin HSAavone HSA7-hydroxyavone HSAchrysin HSAbaicalein BSAavone BSA7-hydroxyavone BSAchrysin BSAbaicalein BSAmyricetin BSAdihydromyricetin BSAquercetin BSAquercitrin BSADDN BSADSS Binding constant, KA (M1 ) 5.68 104 3.71 104 1.12 107 7.71 107 8.89 105 2.01 105 1.11 105 3.12 105 6.36 102 3.42 106 2.92 103 3.55 104 7.41 103 5.13 104 4.17 104 3.52 104 3.66 106 2.73 104 2.78 103 4.68 104 6.43 105 2.58 106 3.65 107 4.54 108 1.95 104 3.55 106 1.07 106 9.12 105 1.95 104 1.48 107 1.20 106 4.68 105 1.84 108 1.36 104 3.65 107 6.47 103 6.26 103 1.51 104
where KA is the binding constant to a site and n is the number of binding sites. Hence the binding parameters, KA and n, can be calculated using the values of intercept and slope obtained from the plot of log[(F0 F )/F ] versus log[Q]. For instance, modied SternVolmer plot for serum albumins in the presence of sonochemically synthesized gold nanoparticles is shown in Fig. 8. The binding constant for the interaction of serum albumins with various bioactive substances is summarized in Table 2. If the value of the binding constant KA is in the range 115 104 M1 , then the binding afnity is moderate [31]. By considering Eqs. (1) and (2),
100000
10000
1000
Counts
100
10
10
20
30
40
50
Time (ns)
Fig. 7. Fluorescence decay curve of BSA (a) and BSA (b) in the absence and presence of BAP. [BAP] ranges from 0, 0.1, 0.2 and 0.3 M. From Ref. [39].
58
absorption 0.08 Overlap I ntegral J 0.04
150
100
50
KA2 1 ln = KA1 R
1 1 T1 T2
(4) (5)
0.00 300 350 400 0 450
G = RT ln KA =
HT S
where KA is the binding constant at the corresponding temperature T, and R is the gas constant. The negative value of G reveals that the interaction proceeds spontaneous at the standard state. According to the views of Ross and Subramanian [40], when H < 0 or H 0 and S > 0, the main force is due to electrostatic interactions; when H < 0 and S < 0, the main force is due to van der Waals or hydrogen bonding, and when H > 0 and S > 0, the main force is due to hydrophobic interactions. The thermodynamic parameters such as H, G, and S for the interaction of serum albumins with various bioactive substances are summarized in Table 3. Frster resonance energy transfer (FRET) [41] is a sensitive method for the detection of interactions between drug molecules and serum albumin. FRET efciency can be used to evaluate the distance between the bound drug molecule and the uorophore present in serum albumins [8,42]. According to FRET, the transfer of energy, which occurs through the direct electrodynamic interaction between the primarily excited molecules and their neighbors, is controlled by the following aspects: (1) the uorescence quantum yield of the donor, (2) the relative orientation of the transition dipoles of the donor and acceptor, (3) overlap integral between the uorescence spectrum of the donor and absorption spectrum of the acceptor, and (4) the distance (r0 ) between the donor and the acceptor [30]. The Frster theory points out that the energy transfer efciency E, in addition to its dependence on the distance between the acceptor and the donor, depends upon the critical energy transfer distance, R0 (Frster distance; the distance at which the efciency of energy transfer is 50%). Hence the efciency of energy transfer for a single donorsingle acceptor system is expressed by the following equation: E =1 R6 F = 6 0 6 F0 R0 + r0 (6)
Wavelength (nm)
Fig. 9. Overlap plots of uorescence spectra of HSA with absorption spectra of PTK. From Ref. [43].
spectra of HSA with the absorption spectra of perylene-3,4,9,10tetracarboxylate tetrapotassium salt [43]. Using the above three Eqs. (6)(8), the donor-to-acceptor distance, r0 , can be calculated. If r0 < 7 nm [44,45] and 0.5R0 < r0 < 1.5R0 [46], the probability of energy transfer from serum albumins to bioactive substances is high. Synchronous uorescence spectroscopy introduced by Lloyd [47,48], which involves the simultaneous scanning of excitation and the uorescence monochromators of a uorimeter, while ) between them, is a maintaining a xed wavelength difference ( simple and effective means to measure the uorescence quenching and the possible shift of the maximum emission wavelength ( max ) relative to the alteration of the polarity around the chromophore is stabilized at 15 nm or at physiological conditions. When 60 nm, synchronous uorescence offers the characteristics of tyrosine residues or tryptophan residues in the serum albumins [49]. In the synchronous uorescence spectra, the uorescence intensity decreases with or without any shift in the emission maximum. A decrease in uorescence intensity without any shift indicates that the microenvironment around that particular residue is not disturbed. Red-shift is indicative of an increase in the hydrophilicity around the uorophore in serum albumin. Blue-shift should be due to an increase in the hydrophobicity around the uorophore moiety [50,51]. Fig. 10 shows synchronous uorescence spectrum of HSA with = 15 nm in the absence and presence of (a) colloidal AgTiO2 and (b) colloidal TiO2 nanoparticles in the concentration range of 03 105 M [52,53]. 4. Binding capability of serum albumins with nanoparticles During the past decade, a tremendous attention has been focused on recognizing the interactions of nanomaterials with biomolecules [54]. The size-dependent tunable optical properties of nanomaterials make them promising for various innovative biomedical applications from diagnosis to therapy [55]. Hence evaluation of the interactions between nanomaterials and biomolecules such as serum albumins becomes noteworthy. 4.1. Metal nanoparticles Gold (Au) nanoparticles, one of the noble metal plasmonresonant nanoparticles where the collective coherent oscillation of free electrons enables intense light absorption [56,57], hold a great promise for biology and medicine due to their interesting size-dependent tunable optical properties. Moreover the biocompatibility and stability of Au nanoparticles make them excellent
The magnitude of R0 depends on the uorescence spectrum of the donor (serum albumins) and absorption spectrum of the acceptor (bound drug molecule). R0 is expressed as follows
6 R0 = 8.8 1025 [2 n4
D
J]
(7)
where 2 is the spatial orientation factor related to the geometry of the donor and acceptor dipoles, which is 2/3 for random orientation as in uid solution, n is the refractive index of the medium (1.36 for BSA and 1.336 for HSA), D is the uorescence quantum yield of the donor (0.118 for BSA and 0.15 for HSA), J is the spectral overlap integral, which is given by
J=
F ( )( )
0
F ( )d
(8)
where F( ) is the corrected uorescence intensity of the donor in ), with the total intensity the wavelength range from to ( + normalized to unity and ( ) is the molar extinction coefcient of the acceptor at . Fig. 9 shows the overlap plots of uorescence
which suggests that the SternVolmer quenching constant become equal to the binding constant when the number of binding sites is one. The force of interaction between drugs and biomolecules may include electrostatic interactions, multiple hydrogen bonds, weak van der Waals interactions, and hydrophobic interactions, which can be evaluated using the signs and magnitudes of thermodynamic parameters such as enthalpy change ( H), free energy change ( G) and entropy change ( S). These parameters can be calculated using the following Vant Hoff thermodynamic equations
0.12
Donor (HSA) fluorescence Quencher (PTK)
200
Absorbance
S. Naveenraj, S. Anandan / Journal of Photochemistry and Photobiology C: Photochemistry Reviews 14 (2013) 5371 Table 3 The thermodynamic parameters S. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
59
H,
G, and
S for the interaction of serum albumins with various bioactive substances. H (kJ mol1 ) 30.25 17.96 10.89 84.86 18.51 9.66 3.66 57.6 5.93 13.96 15.76 152.29 81.42 113.28 190.90 22.59 12.29 21.01 17.97 22.24 20.69 41.07 31.10 70.96 64.56 30.02 44.63 61.01 72.28 4.512 253.4 14.27 12.6 1.79 27.25 79.61 50.49 227.2 21.94 12.67 238.21 72.62 140.7 117.8 G (kJ mol1 ) 33.15 31.75 27.55 28.98 32.43 25.25 27.65 24.0 27.36 21.68 25.03 22.93 22.28 23.21 24.85 27.45 24.09 28.18 29.03 28.04 27.42 27.00 33.16 23.27 19.7 24.93 32.92 34.17 34.48 30.85 44.6 28.03 22.9 23.4 23.96 38.38 35.36 28.9 30.65 29.78 17.54 20.86 33.5 45.2 S (J mol1 K1 ) 9.76 46.31 56.27 186.57 47.52 121.22 82.45 111.0 74.16 26.92 32.68 590 350 460 720 16.23 19.47 24.71 36.52 19.60 23.37 49.72 6.87 318.35 167.97 133.89 264.68 324.86 364.38 88.38 1030 47.62 35.3 73.8 11.23 143.37 50.88 886 30.04 58.60 711.86 301.58 365.7 248.0
System HSAketaconazole BSAketaconazole HSAJatrorrhizine HSAPZFX HSAFarrerol HSAINOD HSAAHC BSASMZ BSARF HSAGEM BSAGEM HSAEDAC BSAEDAC HSADMACA BSADMACA HSAEGCG HSAtheasinesin HSAADNR HSAODNR HSAgenistein HSAtrans-resveratrol HSAdocetaxel HSAHNF BSATPP BSATMEOPP BSATClPP BSANCTPP BSANCTMPP BSANCTAPP HSAAR2 HSAAR73 HSADY9 BSASudan II BSASudan IV BSAMG BSARB BSAMordant Red BSADBSBL BSAAY BSACGR BSADDN BSADSS BSAC3 BSAC1.3
candidates for in vivo phototherapy of cancer [58], the sensitive detection of HIV-1 in plasma [59], cell imaging due to the sensitive detection of Adenosine triphosphate (ATP) in live cells [60], and distinguishing among various virus types [61]. Upon simple conjugation of gold nanoparticles onto therapeutically inactive monovalent small organic molecules, they can be converted into highly active drugs that effectively inhibit HIV-1 fusion to human T cells [62]. Due to the above vast biomedical applications, the study on interaction of gold nanoparticles with serum albumins becomes vital. The binding of serum albumins with gold nanoparticles synthesized using NaBH4 reduction method and sonochemical reduction method were investigated using optical techniques by Gao et al. [63] and Naveenraj et al. [33]. The effect of these gold nanoparticles, synthesized by different methods, on the uorescence spectra of serum albumins show gradual decrease in the uorescence intensity of serum albumins without any changes to their uorescence spectral shape and maximum, which indicates the formation of non-uorescent ground state complexes (static quenching mechanism). The same uorescence quenching trend is observed for the binding of gold nanospheres and gold nanorods with BSA in the study conducted by Iosin et al. [64]. The binding constant (Table 2, 12) of sonochemically synthesized gold nanoparticles with HSA deduced from modied SternVolmer plot (Fig. 8) is found to be
about 1.5 times greater than that of BSA. This binding constant indicates that the afnity of HSA for Au nanoparticles synthesized by the sonochemical method is more than that of BSA [33]; whereas, in the case of Au nanoparticles synthesized by the NaBH4 reduction method (Table 2, 34), BSA shows more afnity than HSA [63]. The difference in the binding afnity can be attributed to the fact that sonochemically synthesized nanoparticles have large surface area which induces a higher binding interaction with biomolecules and causes the rapid transfer of drugs to the tissue. Also, the sonochemically synthesized nanoparticles show uniform size and shape, which is evident from high resolution transmission electron micrographs. In the binding afnity study conducted by Pramanik et al. [65] using Au nanoparticles having diameters of 8, 10, 16, 25, 34, 41, 47, 55 and 70 nm, which are synthesized by varying the [Au] to citrate ratio, the SternVolmer constant, KSV (Table 1, 19) increases with decrease in the size of Au nanoparticles (Fig. 5). In other words, the uorescence quenching is more efcient in the case of smaller Au nanoparticles, which suggests that smaller particles will have more binding interaction due to the large surface area. Recently the interaction of silver (Ag) nanoparticles with BSA using uorescence spectroscopy was studied by Mariam et al. [35] owing to the fact that Ag nanoparticles have potential antimicrobial and antiplatelet/antithrombolytic activities. The silver nanoparticles quench the uorescence of BSA with a blue-shift in their
60
Fig. 10. Synchronous uorescence spectrum of serum albumin with = 15 nm in the absence and presence of colloidal Ag-TiO2 (a) and colloidal TiO2 (b) in the 5 concentration range of 03 10 M. From Ref. [52,53].
emission maximum (Fig. 4). The non-linearity of SternVolmer plots in Fig. 4 indicates that both static and dynamic quenching are involved. Further, n value obtained from the modied SternVolmer plot and the blue-shift in the synchronous uorescence spectra ( = 60 nm) indicate that Ag nanoparticles lower the polarity or increase the hydrophobicity of the microenvironment of the tryptophan residues in BSA. In this section, uorescence quenching studies on the interaction of metal nanoparticles such as gold and silver with serum albumins is discussed. These studies illustrate the effect of the size and stabilizing agent of metal nanoparticle on the hydrophobicity of the binding site. These studies will be valuable during the construction of nanomedicines based on Au and Ag nanoparticles. 4.2. Semiconductor nanoparticles Semiconductor nanocrystals (quantum dots) enthused over the past decade from electronic materials and physics to biological and biomedical areas [66] due to their unique photophysical properties. Semiconductor TiO2 nanoparticles, a well-known photocatalyst in the deactivation of microorganisms and viruses, of various sizes and morphologies exhibit cytotoxicity toward some tumors under ultraviolet light (UV) excitation. Also, interactions of nanosized TiO2 complexed with antibodies make it a visible light-induced phototoxic agent against human brain cancer [67]. Even in the dark condition, TiO2 nanoparticles deform the tumor cell colony pattern by arresting their growth [68]. Owing to the bactericidal properties either on their own or upon illuminated with UV light, TiO2 nanoparticles are used in many products including fabrics [69] and lters [70]. Further, it is used as a food colorant, additive in many cosmetic creams, and medicines [71]. It has been hypothesized that the doping of transition metal nanoparticles to titania improves the light absorption capability of TiO2 , increases its carrier lifetime by scavenging electrons from the surface of the semiconductor, and improves the biological activities [72]. PtTiO2 hybrid nanoparticles show efcient cytotoxicity toward microbial cells in
water when irradiated with near-UV light. PtTiO2 and AuTiO2 nanocrystals show effective cytotoxic effect toward cancer cells under near-UV light irradiation than that of undoped TiO2 nanoparticles [73]. Due to these fabulous applications of TiO2 nanoparticles, the interaction of commercially available TiO2 nanoparticles (20 nm) and TiO2 nanoparticles synthesized by hydrolysis method (1.4 nm) with human serum albumin were investigated by Sun et al. [71] and Kathiravan et al. [74]. The effect of commercially available TiO2 nanoparticles on the uorescence spectra of HSA is to decrease the uorescence intensity of HSA with a red shift in the emission maximum; whereas, TiO2 nanoparticles synthesized by the hydrolysis method show a decrease in uorescence intensity without any shift in the emission maximum. In both cases, the quenching follows the static mechanism i.e., the formation of ground state complexes. The synchronous uorescence spectra indicate that the commercially available TiO2 nanoparticles disturb the environments of both tyrosine and tryptophan residues present in HSA; whereas; TiO2 nanoparticles synthesized by the hydrolysis method only affects the microenvironment of tyrosine residues in HSA. The binding abilities of TiO2 nanoparticles and Ag doped TiO2 nanoparticles with serum albumins were investigated using optical techniques by Kathiravan et al. [52,53]. They inferred that both TiO2 and Ag-TiO2 nanoparticles quench the uorescence without any shift in the emission maxima. Lifetime measurements conrm that both nanoparticles follow the static quenching mechanism. In the synchronous uorescence spectra of serum albumins at = 60 nm, there is no shift in the emission wavelength, which conrms the absence of binding site near the tryptophan residue. In the synchronous uorescence spectra ( = 15 nm) of serum albumins, Ag-TiO2 addition showed a red-shift (Fig. 10a), which suggests that the binding site is near the tyrosine region and the environment is more polar (or less hydrophobic) [75] and more exposed to the solvent molecules [76]. On the other hand, pure TiO2 nanoparticles show a blue-shift (Fig. 10b), which suggests that the binding site is also near tyrosine region but it is in less polar (or more hydrophobic) environment and less exposed to the solvent molecules. Among various quantum dots (QDs), CdSe and CdSe/ZnS core/shell QDs are extensively applied in biological applications such as cell labeling and bio-imaging due to their exceptional stability and high photoluminescence quantum yield [77]. The interactions of CdSe and CdSe/ZnS core/shell QDs with BSA are investigated by Ju et al. [78] and Dzagli et al. [79]. Both CdSe and CdSe/ZnS QDs interact with BSA through static quenching (nonuorescent ground state complex formation). CdSe QDs quench the uorescence of BSA without any shift in the emission maximum; whereas, CdSe/ZnS quench the uorescence of BSA with blue-shift in the emission maximum. This observation suggests that the presence of ZnS in the shell reduces the polarity around the tryptophan residues, which is evident from the blue-shift in the emission maximum [80]. van der Waals force and hydrogen bonds play major roles in the interactions of CdSe QDs with BSA; whereas, electrostatic interactions important for CdSe/ZnS QDs. In continuation, due to the applications of CdTe QDs in the eld of bio-imaging, immunouorescence and phototherapy, the interaction of CdTe QDs with BSA are investigated by Liang et al. [81], Idowu et al. [82] and Wang et al. [83]. In the size comparative binding study conducted by Liang et al. [81], TGA stabilized CdTe QDs of size 1.8, 2.6 and 3.1 nm are synthesized just by varying the reaction time. As the size of TGA stabilized CdTe QDs is increased, their binding interaction with BSA increases. This behavior of CdTe QDs is probably due to the changes in the relative size of BSA and CdTe QDs during the binding. In the study conducted by Idowu et al. [82], CdTe QDs of size 2.3, 3.0 and 3.2 nm were synthesized by varying the stabilizers mercaptopropionic acid (MPA), l-cysteine (CYS),
61
and thioglycolic acid (TGA). SternVolmer quenching constants (Table 1, 1012) suggests that the binding ability of these QDs with BSA follows the order: QD (TGA) > QD (CYS) > QD (MPA). In other words, the binding ability of QDs increases with increase in size. In the study conducted by Wang et al. [83], CdTe QDs of mean diameter 3.2 nm are synthesized by varying the stabilizers [MPA, CYS and glutathione (GSH)]. The binding ability of these QDs with BSA (Table 2, 57) follows the order: QD (GSH) > QD (CYS) > QD (MPA), which suggests that the interaction depends on the capping agent of QDs. Xiao et al. [84] investigated the interaction of 2.04 nm green-emitting QDs (G-QDs) and 3.79 nm red-emitting QDs (R-QDs) with HSA. The binding constant suggests that the size of CdTe QDs affected the afnity for HSA; larger QDs show stronger binding. Owing to the applications of CdS nanoparticles in the eld of biology and medicine, the interaction studies of CdS nanoparticles with BSA is vital and are investigated by Jhonsi et al. [85] and Ghali [86]. Starch-capped, thioglycerol-capped, or uncapped CdS nanoparticles interact with BSA by the formation of ground state complex. Starch-capped CdS nanoparticles quench the uorescence of BSA with blue-shift in the emission maximum; whereas, thioglycerol capped CdS nanoparticles quench the uorescence of BSA with red-shift. In this section, studies on the interactions of semiconductor nanoparticles such as TiO2 , CdSe, CdSe/ZnS, CdTe and CdS nanoparticles or QDs with serum albumins are discussed. Illustrated are the effect of nanoparticle size, doping agents, capping agents and shell on the hydrophobicity of the binding site. These studies are of great importance for nanomedical and in vivo bioimaging applications. 4.3. Dendrimers Polyamidoamine (PAMAM) dendrimers, a nanoscopic polymer, have been applied as carrier molecules for magnetic resonance imaging (MRI) contrast agents, near-infrared (NIR) uorescent labels and transfection vectors in gene therapy [8789]. Due to these applications, the interaction of different generation PAMAM dendrimers with BSA has been investigated by Shcharbin et al. [90], Klajnert et al. [91,92] and Yanming et al. [93]. In the study by Shcharbin et al. [90], the interaction of generation 2 (G2) PAMAM dendrimers and generation 6 (G6) PAMAM dendrimers with BSA was evaluated. G2 PAMAM dendrimer has a diameter of 2.4 nm with highly exible structure, while G6 PAMAM dendrimer has a diameter of 6.5 nm with rigid spherical structure. SternVolmer constants suggested that G2 PAMAM dendrimers have more afnity than G6 PAMAM dendrimers toward BSA, which can be attributed to their size and structure. Klajnert et al. [91,92] investigated the interaction of G3.5 PAMAM dendrimers, G4 PAMAM dendrimers and G4 PAMAM-OH dendrimers with BSA. All these PAMAM dendrimers possess the same core molecule and have 64 end groups on their surface. Their diameters are similar and approximately equal to 4.0 nm. G3.5 PAMAM dendrimers, G4 PAMAM dendrimers and G4 PAMAMOH dendrimers are terminated with COOH groups, NH2 groups and OH groups, respectively. G3.5 PAMAM dendrimers and G4 PAMAM dendrimers quench the intrinsic uorescence of BSA with blue-shift in the emission maxima; whereas, G4 PAMAM-OH dendrimers quench the uorescence without any spectral shift. The SternVolmer constant (Table 1, 1315) suggests that the afnity toward BSA follows the order G4 PAMAM-OH dendrimers < G3.5 PAMAM dendrimers < G4 PAMAM dendrimers. This order in the afnity is related with their functional end groups. In a similar interaction study done by Yanming et al. [93], G5.5 and G6.0 PAMAM dendrimers are compared. These dendrimers quenched the intrinsic uorescence of BSA through statically. The quenching is accompanied by blue-shift in the case of G6.0
Fig. 11. Molecular structure of rifamycins. Rifamycin SV (RFSV), rifandin (RFD), rifampin (RFP) and rifapentine (RFPT).
PAMAM-NH2 and G5.5 PAMAM-OH; whereas, in the case of G6.0 PAMAM-PC, red-shift is observed. SternVolmer quenching constants (Table 1, 1618) suggest that the strength of interactions of BSA with the dendrimers is in the order: G6.0 PAMAM-PC > G6.0 PAMAM-NH2 > G5.5 PAMAM-OH. These results suggest that the strength of the interactions strongly depend on the functional groups on the surface of the dendrimer. In this section, the binding interactions of dendrimers with serum albumins are discussed. Studies illustrate that the generation and the functional end groups of dendrimers are critical for their interactions with serum albumins. In summary, a critical need in the eld of nanobiotechnology is the study of binding interactions of various nanoparticles with biomolecules such as serum albumins. The interactions of biologically signicant nanoparticles such as metal nanoparticles, semiconductor QDs and dendrimers with serum albumin are discussed. The results reviewed here illustrate the symbiotic relationship that nanotechnology shares with biology. 5. Organic molecules 5.1. Antibiotics The interaction of rifamycin antibiotics (Fig. 11), an antibacterial drug often used in the treatment of tuberculosis, with SA has been investigated by Yang et al. [94], which indicates that among the rifamycin antibiotics rifamycin SV (RFSV), rifandin (RFD), rifampin (RFP) and rifapentine (RFPT), the uorescence quenching occurs in the order RFPT > RFP > RFD > RFSV. This observation suggests that
62
increase in the bulkiness of the substituent (R2 moiety) in rifamycin is responsible for its high quenching efciency. RFP and RFPT quench the uorescence of SA with a red-shift (15 nm for HSA and 10 nm for BSA) in the emission maxima, which indicates increase in the polarity or decrease in the hydrophobicity of the microenvironment surrounding the uorophore site; whereas, no shift is observed in the case of RFSV. The interaction of RFD with HSA does not involve any shift in the emission maximum; whereas, their interactions with BSA accompany a red-shift (10 nm). The interactions of antibacterial agents curcumine (CUR) and diacetylcurcumine (DAC) with serum albumins are investigated by Mohammadi et al. [95]. Both CUR and DAC (lipophilic molecules) quench the uorescence of serum albumins statically. The binding constant (Table 2, 811) suggests that HSA is having more afnity toward curcumine than BSA. Even though DAC has more antibacterial activity than CUR against multiresistant bacteria, the binding constants suggest that CUR strongly binds with serum albumins than DAC, which indicates that the phenolic OH group of CUR plays an important role in the interaction; whereas, the phenolic acetyl group plays an important role in the antibacterial activity. The antiviral and antifungal agent 1-benzoyl-4-p-chlorphenyl thiosemicarbazide (BCPT) [96], the inhibition antibacterial agent tetracyclines [97,98], and the antifungal agent ketoconazole [99] quench the uorescence of serum albumins (HSA and BSA) with a blue shift in the emission maxima, which suggests increase of hydrophobicity in the region surrounding the tryptophan site. These antibiotics interact with serum albumin by the complex formation which is evident from their SternVolmer quenching constant at different temperatures. Using the thermodynamic parameters, it is suggested that the force acting on the complex formation of serum albumin with BCPT is hydrophobic interactions; whereas, for tetracyclines, it is electrostatic. The acting force between ketaconazole and BSA (Table 3, 12) is mainly electrostatic in addition to hydrophobic interactions; whereas, the force between Ketoconazole and HSA is synergy of electrostatic and hydrophobic interactions. In the case of BCPT, the quenching constant of HSA is more than that of BSA; whereas, in the case of tetracycline and ketoconazole, the quenching constant of BSA is more than that of HSA. However, in the case of BCPT and ketoconazole, FRET calculations indicate that the distance between BSA and acceptor is larger than that of HSA. The interactions of antibiotics such as Jatrorrhizine [100], Daunomycin [101], Pazuoxacin mesilate (PZFX) [102], Farrerol [103], indolone-N-oxide derivatives (INOD) [104], and 8-Acetyl7-hydroxycoumarin (AHC) [105] with HSA are also studied by uorescence techniques. Jatrorrhizine and Daunomycin lower the uorescence emission intensity of HSA with a conspicuous change in the emission spectrum. INOD lowers the uorescence intensity of HSA without any change in the emission maxima. PZFX lowers the uorescence intensity of HSA with red-shift in emission maxima; whereas, AHC lowers the uorescence intensity of HSA with blue-shift in emission maxima. Jatrorrhizine, Daunomycin, PZFX, Farrerol and INOD form complex with HSA which is conrmed from the binding constants at different temperatures. Using the thermodynamic parameters (Table 3, 37), the force of complex formation between Jatrorrhizine and HSA is hydrophobic and electrostatic interactions; whereas, the force of interaction of PZFX, Farrerol and AHC with HSA are hydrogen bonding and hydrophobic interactions. Such hydrogen bond formation of Farrerol (Fig. 12) and AHC (Fig. 13) around the hydrophobic cavity near Try-214 in HSA is also apparent from molecular docking studies [103,105]. The force of interaction between Daunomycin and HSA is hydrogen bonding and electrostatic interactions; whereas, hydrophobic interactions are responsible for the complexation of INOD with HSA. The interactions of antibacterial drug Sulfamethoxazole (SMZ) and antimycobacterial drug Rifampicin (RF) with BSA are studied by
of the Fig. 12. Interaction modes between Farrerol and HSA. Residues around 8 A ligand are displayed only. The residues of HSA and the ligand structure are represented using ball and stick model. Hydrogen bonds between the ligand and the protein are represented using yellow dashed lines. From Ref. [103].
Naik et al. [106] and Kamat and Seetharamappa [107], respectively. SMZ interacts with BSA to decrease the uorescence intensity and shift the emission maximum to the blue; whereas, RF interacts with BSA to decrease the uorescence intensity and shift the emission maximum to the red. The thermodynamic parameters suggest that the key force of binding between SMZ and BSA is weak van der Waals interaction and hydrogen bonding; whereas, for RF, it is
of the Fig. 13. Interaction mode between AHC and HSA, only residues around 6.5 A ligand are displayed. The residues of HSA and the ligand structure are all represented using stick model. The hydrogen bond between the ligand and the protein is represented using yellow dashed line. From Ref. [105].
63
System (T= 293K) BSA-TPP BSA-TMEOPP BSA-TClPP
KA
106 (M-1) 1.37 2.33 3.51
System BSA-NCTPP BSA-NCTMPP BSA-NCTAPP
KA
106 (M-1) 0.74 1.24 1.40
Fig. 14. Molecular structure of anticancer agents (a) (i) ()-epigallocatechin-3-gallate (EGCG) and (ii) theasinesin, (b) anthracycline derivatives (i) ADNR and (ii) ODNR, (c) porphyrins (i) TPP, (ii) TClPP, (iii) TMEOPP, and (d) N-confused porphyrins (i) NCTPP, (ii) NCTMPP, (iii) NCTAPP.
hydrophobic interactions. From the value of the number of binding sites, n, only one independent class of binding site (i.e., Trp-214) is apparent for the BSASMZ system; whereas, both the tryptophan residues of BSA are exposed during the interaction of BSA with RF. In this section, the binding interaction studies of antibiotics with serum albumins using uorescence quenching technique are discussed, which illustrate the effect of antibacterial, antiviral and antifungal agents on serum albumins. These studies are of great signicance in the pharmacology of antibiotics. 5.2. Anticancer agents The interactions of the antineoplastic agent Gemcitabine hydrochloride (GEM), and the antitumor agents 4-(dimethylamino)cinnamic acid (DMACA) and trans-ethyl-p(dimethylamino)cinnamate (EDAC) with serum albumins are investigated by Kandagal et al. [108], and Singh and Mitra [109]. GEM lowers the intrinsic uorescence of serum albumins without changing the emission maximum and the shape of the emission
spectrum; whereas, EDAC and DMACA induce a slight blue-shift and a red-shift in the emission maxima, respectively. The effect of temperature on the SternVolmer constants conrms that GEM, EDAC and DMACA quench the intrinsic uorescence through the static quenching mechanism. The binding constants (Table 2, 1215) suggest that DMACA interacts more strongly and preferentially with the albumins when compared with EDAC. The thermodynamic parameters (Table 3, 1015) suggest that both hydrogen bonding and hydrophobic interactions play a role in the binding of GEM to serum albumins; whereas, hydrophobic interaction and less electrostatic interaction play a role in the binding of both EDAC and DMACA to serum albumins. The interactions of ()-epigallocatechin-3-gallate (EGCG) and its polymer theasinesin with HSA are studied by Maiti et al. [110] and Ge et al. [111], respectively. Both EGCG and theasinesin (Fig. 14a), which are present in green tea, are anticancer agents or antioxidants. Both EGCG and theasinesin lower the intrinsic uorescence of HSA with red-shift in the wavelength maximum, which indicates a more polar environment in the static complexes
64
Fig. 15. Stereoview docking pose of HSA and EGCG. Residues of interest and EGCG have been represented as sticks. The protein chain has been truncated at different points for clarity. The binding pocket of site I is clearly visible with Trp-214 within hydrogen bonding distance of EGCG. The entrance to the pocket is lined with polar residues. From Ref. [110].
between the quencher and HSA. In both cases, the tryptophan residue (Trp-214) of HSA is involved in the interaction. The thermodynamic parameters (Table 3, 1617) deduced using the binding constants suggests that van der Waals interactions and hydrogen bonding are the forces for the binding of EGCG to HSA; whereas, hydrophobic and electrostatic interactions play major role in the binding of theasinesin with HSA. Molecular docking studies (Fig. 15) also support the hydrogen bonding and changes in the polarity during the interaction of EGCG with HSA [110]. The interactions of anthracycline derivatives (Fig. 14b) such as 30-azido-30-deamino daunorubicin (ADNR) [112] and 4 -O-(-lOleandrosyl)daunorubicin (ODNR) [113] with HSA are investigated in detail. Both ADNR and ODNR quench the intrinsic uorescence of HSA, which is accompanied by blue-shifts in the emission maximum through static quenching. SternVolmer quenching constants suggest that ADNR quenches HSA more efciently than ODNR due to its steric constraint. The thermodynamic parameters (Table 3, 1819) suggests that both hydrophobic and electrostatic interactions are the major forces involved in the interaction of ADNR with HSA; whereas, only hydrophobic interactions are involved in the interaction of ODNR with HSA. The interactions of anticancer agents such as genistein [7], docetaxel [114], chlorin derivatives [115], 2-hydroxy-3-nitro-9uorenone (HNF) [116] and trans-resveratrol [117] with HSA are investigated using uorescence spectroscopy. Genistein, chlorin derivatives, and trans-resveratrol lower the intrinsic uorescence of HSA with no other spectroscopic changes; whereas, docetaxel and HNF lower the uorescence intensity with slight blueshift in the emission maximum. Genistein, docetaxel, HNF, and trans-resveratrol interact with HSA through the static quenching mechanism; whereas, chlorin derivatives interact dynamically. The thermodynamic parameters (Table 3, 2023) suggest that genistein, and trans-resveratrol bound to HSA are mainly based on the hydrophobic and electrostatic interactions. It also suggests that the major binding forces that act on docetaxel are hydrogen bonding and van der Waals interactions; whereas, for HNF, it is hydrophobic interaction. The interactions of cancer therapeutic and diagnostic agents such as tetraphenylporphyrin (TPP), tetraparachlorophenylporphyrin (TClPP), and tetraparamethoxyphenylporphyrin (TMEOPP) with BSA are studied by Tian et al. [118]. All these porphyrin compounds (Fig. 14c) lower the intrinsic uorescence of BSA with blue-shift in the emission maximum, which suggests that all the derivatives can bind tightly to BSA. The binding constant, KA
(table in Fig. 14c) suggests that the porphyrins bind with BSA by complex-formation and it also suggests that the binding of TClPP to BSA is notably stronger than that of TMEOPP or TPP. The difference in the binding strength can be attributed to the effect of electron-withdrawing or electron-donating substitutions in the three porphyrin compounds. The thermodynamic parameters (Table 3, 2426) conrm that hydrophobic interactions play the major role in the binding of TPP and TClPP to BSA, while the binding of TMEOPP is mainly based on van der Waals interactions. In a similar study, the interactions of N-confused porphyrins such as N-confused tetraphenylporphyrin (NCTPP), N-confused tetraparamethylphenylporphyrin (NCTMPP) and N-confused tetraparaacetoxyphenylporphyrin (NCTAPP) with BSA are studied by Yu et al. [119]. All these porphyrin compounds (Fig. 14d) quench the intrinsic uorescence of BSA, which is accompanied by a blue-shift in the emission maximum. The binding constants suggest that the binding afnity (table in Fig. 14d) follows the trend: NCTPP < NCTMPP < NCTAPP, which means NCTAPP has the strongest ability to bind with BSA and NCTPP has the weakest. This difference in the strength of binding can be attributed to the presence of the longer branch chain (acetoxy group) which promotes strong binding. The thermodynamic parameters (Table 3, 2729) suggest that hydrophobic interactions play the major role in the spontaneous interaction of these porphyrin compounds with BSA. The results obtained from synchronous uorescence spectra indicate that the binding site of all these porphyrins is next to the tryptophan residue. The interactions of anticancer agents such as Gossypol, Vincristine sulfate (VS), and Berbamine are investigated by Yang et al. [120], Kamat and Seetharamappa [107], and Cheng et al. [121], respectively. Fluorescence quenching studies suggest that Gossypol, VS and Berbamine quench the uorescence intensity of BSA by the static quenching mechanism without any changes in the emission maximum. The thermodynamic parameters suggest that the binding of Gossypol to BSA might involve hydrophobic and electrostatic interactions; whereas, for VS, it is hydrophobic interactions. The binding forces that act on BerbamineBSA system are the weak van der Waals interactions and hydrogen bonding. The number of binding sites (n), for Gossypol and Berbamine is found to be 1. The synchronous uorescence spectrum conrms that Gossypol affects the conformation around the tyrosine residues in BSA. The upward curvature of SternVolmer plot for VSBSA system indicates that both tryptophan residues of BSA are exposed to the drug, VS. In this section, uorescence quenching studies on the interaction of anticancer agents with serum albumins is discussed. These studies illustrate the substituent effect on the hydrophobicity of the binding site. Generally, substitution of acetyl and methyl groups lowers the binding afnity but in the case of N-confused porphyrins, the substitution of acetyl and methyl group increases the binding afnity. These studies will be of considerable use in the eld of pharmacology and clinical medicine. 5.3. Anti-inammatory agents The interaction of Dexamethasone (DEX) with serum albumins has been investigated by Naik et al. [122] (Fig. 16). DEX, a potent synthetic member of the glucocorticoid class of steroid hormones, acts as an anti-inammatory agent and immunosuppressant. DEX lowers the uorescence intensity of serum albumins with a slight blue-shift in the emission maximum by the formation of a static complex. The number of binding sites, n, for DEXBSA and DEXHSA indicate that there is one independent class of binding site on BSA and HSA for DEX. The binding constant (table in Fig. 16) suggests that HSA and BSA have almost the same binding afnity toward DEX. The thermodynamic parameters suggest that the main interactions between DEX and HSA are hydrogen bonding and weak van
65
System (T= 288K) HSA-DEX BSA-DEX
KA x 104 (M-1) 3.80 3.78
of ground-state complexes. The thermodynamic parameters suggest that van der Waals interactions and hydrogen bonding are the interaction forces for the binding of Colchicine and EA with HSA. Electrostatic interactions play major roles in the binding of CS with HSA; whereas, hydrophobic interactions and hydrogen bonding are involved in the case of Shikonin. Fluorescence quenching studies on the interactions of steroidal and non-steroidal anti-inammatory agents with serum albumins are considered in this section. Even though serum albumins differ in their afnities, the anti-inammatory agent DEX shows equivalent binding afnity with both HSA and BSA.
5.4. Organic dyes As dyes (Fig. 17) are being increasingly used for clinical and medicinal purposes, studies of their interactions with serum albumin are vital. The interaction of thermoresponsive organic dye perylene-3,4,9,10-tetracarboxylate tetrapotassium salt (PTK) with serum albumin is investigated by Naveenraj et al. [43]. Perylene derivatives for biochemical and pharmacological applications are synthesized using PTK (Fig. 17a). PTK quenches the uorescence of serum albumins with the emergence of isoacitinic points (Fig. 18), which indicates that the quenching depends on the formation of a complex between PTK and serum albumins. The binding constant (table in Fig. 17a) suggests that the afnity of HSA for PTK is more than that of BSA. The value of G indicates the spontaneity in the binding of PTK to serum albumin. Synchronous uorescence spectra indicate the proximity of the binding site to the tyrosine moiety, and the changes in the microenvironment and molecular conformation of serum albumin. Due to the toxicity, carcinogenicity and the mutagenic nature of azo dyes, the interactions of azo dyes such as C.I. Acid Red 2 (AR2), C.I. Acid Red 73 (AR73) and C.I. Direct Yellow 9 (DY9) with HSA are investigated by Ding et al. [129], Guo et al. [130], and Yue et al. [131]. All these azo dyes quench the uorescence of HSA through the static quenching mechanism. The thermodynamic parameters (Table 3, 3032) suggest that both hydrophobic and hydrogen bond interactions play major roles in the interactions of AR2 and DY9 with HSA; whereas, only hydrophobic interactions are involved in the
Fig. 16. Molecular structure of Dexamethasone (DEX).
der Waals interactions; whereas, for BSA, hydrophobic and electrostatic interactions dominate. The interactions of non-steroidal anti-inammatory drugs Rofecoxib and Ketoprofen with HSA are investigated by Qi et al. [123], and Bi et al. [124], respectively. Rofecoxib quenches the intrinsic uorescence of HSA with a slight red-shift in the emission maximum; whereas, Ketoprofen quenches the intrinsic uorescence of HSA without affecting the emission maximum. The SternVolmer constants at different temperatures conrm that both Rofecoxib and Ketoprofen interact with HSA through the formation of a ground state complex. The thermodynamic parameters suggest that weak van der Waals and hydrogen bond interactions are the major forces underlying the binding of Rofecoxib to HSA; whereas, for Ketoprofen, electrostatic interactions and hydrogen bonding are involved. Anti-inammatory agents such as Colchicine [125], Ellagic acid (EA) [126], Cromolyn Sodium (CS) [127], and Shikonin [128] interact and bind with HSA. The uorescence intensity of HSA quenches along with a blue-shift in the emission maximum on the addition of Colchicine, EA, and Shikonin; whereas, the quenching is accompanied by a red-shift on the addition of CS. The interactions of Colchicine, EA, CS and Shikonin with HSA result in the formation
System (T= 298 K) HSA-PTK BSA-PTK
KA
104 (M-1) 49.4 3.72
System (T= 293 K) BSASudan II BSASudan IV
KA
104 (M-1) 1.22 1.48
Fig. 17. Molecular structure of dyes. (a) Perylene-3,4,9,10-tetracarboxylate tetrapotassium salt (PTK), (b) azo dyes (i) Sudan I, (ii) Sudan IV, (c) squaraine dyes (i) BHS, (ii) BBS and (iii) BIS.
66
a
300
200
100
Isoacitinic point
300 400 500
Wavelength (nm)
b
300
A
200
A
100
Isoacitinic point
300
400
500
Wavelength (nm)
Fig. 18. Fluorescence spectra ( ex = 280 nm) of serum albumin (3 M) [(a) HSA and (b) BSA] quenched by PTK in the concentration range of 04 M. From A to M curve, PTK concentrations are 0, 0.33, 0.67, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.33, 3.67, and 4 M. From Ref. [43].
binding of AR73 to HSA. Synchronous uorescence results indicate that the hydrophobicity decreases around the tryptophan residues during the interaction of AR2 with HSA; whereas, the hydrophobicity around the tryptophan residues increases during the interaction of DY9 with HSA. The interactions of anthraquinone dye Alizarin Red S (ARS), anionic dye C. I. Acid Green 1 (AG1) and uorescein dye Eosin B (EB) with HSA are investigated by Ding et al. [132], Yue et al. [133] and Yang et al. [134] owing to their biolabeling applications. ARS and AG1 quench the intrinsic uorescence of HSA without any shift in the emission maximum; whereas, EB quenches the uorescence with a blue-shift in the emission maximum. All these dyes quench the uorescence of HSA through the formation of non-uorescent ground-state complexes. The thermodynamic parameters suggest that hydrophobic interactions play major roles in the interaction of all the dyes with HSA, but during the interactions of ARS and EB with HSA, hydrogen bonding plays a role in addition to the hydrophobic interactions. The interactions of azo dyes such as Sudan II and Sudan IV (Fig. 17b) with BSA are investigated by Lu et al. [135] for toxicological importance. Both Sudan I and Sudan IV quench the intrinsic
uorescence of BSA through statically. The binding constant values (table in Fig. 17b) estimated for Sudan II and Sudan IV suggest that Sudan IV easily and stably binds with BSA when compared with Sudan II, which may be attributed to the structural peculiarities of Sudan IV (methylphenyl and azo groups). The thermodynamic parameters (Table 3, 3334) suggest that hydrogen bonding or van der Waals interactions plays major roles in the binding of Sudan II and Sudan IV with BSA. Jisha et al. [136] investigated the interactions of squaraine dyes (Fig. 17c) such as bis(2,4,6-trihydroxyphenyl)squaraine (BHS), bis(3,5-dibromo-2,4,6-trihydroxyphenyl) squaraine (BBS), and bis(3,5-diiodo-2,4,6-trihydroxyphenyl) squaraine (BIS) with serum albumins for their biological importance as NIR uorescent labels and photodynamic therapeutic agents. HSA shows higher afnity toward all these squaraine dyes than BSA. BHS binds with serum albumins at the binding site I; whereas, BBS and BIS bind at site II due to their steric constraints arising from the presence of halogen atoms. The uniqueness of these dyes is their substituent size-dependent selectivity at site II. The interactions of dyes such as Malachite Green (MG) and Rose Bengal (RB) with BSA are investigated by Zhang et al. [137] and Shaikh et al. [138], respectively. MG, a triarylaminnethane dye, is used as food colorant, medical disinfectant and fungicide, but it is exhibiting carcinogenic, genotoxic, mutagenic and teratogenic properties. RB, the ophthalmic dye, is used as a biological stain, an antiviral agent, and a detection tool for organic anions present in the liver plasma. The dyes MG and RB lower the intrinsic uorescence of serum albumins without any changes to the emission wavelength or the shape of the emisson bands. MG quenches the intrinsic uorescence through the static mechanism; whereas, RB quenches the intrinsic uorescence dynamically. The thermodynamic parameters (Table 3, 3536) suggest that van der Waals interactions and hydrogen bonding are the major forces of interactions of MG and RB with BSA. The interactions of mutagenic and carcinogenic dyes such as C.I. Mordant Red dye 3, Disperse Blue SBL (DBSBL), Acid Yellow 11 (AY) and Congo Red (CGR) with BSA are studied by Ding et al. [139], Guo et al. [140], Pan et al. [141] and Zhang et al. [142], respectively for their toxicological importance. Both anthraquinone dyes C.I. Mordant Red 3 and DBSBL quench the uorescence intensity of BSA, which is accompanied by blue-shift in the emission maxima; whereas, AY and CGR quench the uorescence intensity of BSA without any shift in the emission maxima. The thermodynamic parameters (Table 3, 3740) suggest that hydrophobic interactions are responsible for the binding of DBSBL with BSA; whereas, electrostatic interactions are responsible for the AY. Hydrogen bonding and van der Waals interactions are major binding forces for C.I. Mordant Red; whereas, hydrophobic interactions and hydrogen bonding are the forces for the binding of CGR to BSA. C.I. Mordant Red 3, AY and CGR show slight blue-shifts in the synchronous spectrum of BSA for the tyrosine residue. In the synchronous spectra, C.I. Mordant Red shows a slight shift in the emission maximum of tryptophan residue; whereas, no shift is observed in the case of AY or CGR. In this section, we discussed the uorescence quenching studies associated with the interactions of various dyes with serum albumins and illustrated the effect of different substituents on the binding interaction.
5.5. Flavonoids Flavonoids are a large group of polyphenolic natural products that are found ubiquitously in plants of higher genera and they possess novel nutritional and therapeutic properties of high potency and low systemic toxicity. Hence their interaction
67
with serum albumins is vital in understanding the role of these molecules in biological process. The interactions of avonoids such as quercetin, rutin, and hyperin (Fig. 19a) with HSA are investigated by Bi et al. [143]. Quercetin, rutin and hyperin quench the intrinsic uorescence of HSA through the static mechanism. The binding constant suggests that the binding capacity of these three avonoids with HSA is in the following order rutin < hyperin < quercetin, which can be attributed to the steric hindrance effect. The thermodynamic parameters indicate that the force of binding for these avonoids is mainly electrostatic. The interactions of avonoids chrysin [144], alpinetin [145], baicalein [146], and wogonin [147] (Fig. 19b) with BSA are also investigated by the uorescence quenching techniques. Alpinetin, baicalein, chrysin and wogonin are having anti-tumor and anti-inammatory properties. In addition, alpinetin shows anti-bacterial properties and chrysin shows antihypertension properties. Baicalein quenches the intrinsic uorescence of BSA without any shift in the emission maximum. The intrinsic uorescence of BSA is quenched upon the addition of alpinetin, which is accompanied by a red-shift in the emission maximum; whereas, chrysin and wogonin quench the intrinsic uorescence with a slight blue-shift in the emission maximum. The thermodynamic parameters suggest that hydrophobic interactions play a major role in the binding of alpinetin, baicalein, chrysin, and wogonin to BSA. In addition to the hydrophobic interactions, electrostatic force and hydrogen bonding are involved in the binding of wogonin and baicalein to BSA. Alpinetin shows a slight red-shift (from 283.6 to 286.8 nm) in the emission maximum in the synchronous uorescence spectrum of tryptophan residues; whereas, chrysin shows a slight blue-shift (from 284 to 281 nm). Alpinetin shows a slight blue shift (289.2286.4 nm) in the emission maximum in the synchronous uorescence spectrum of tyrosine residues; whereas, chrysin does not show any shift, which indicates that chrysin specifically binds with the tryptophan residues of BSA; whereas, alpinetin affects the microenvironment of both tryptophan and tyrosine. The interactions of avonones such as tangeretin and nobiletin (Fig. 19c) with HSA are investigated by Cao et al. [148]. Although SternVolmer plots are non-linear, the interactions of tangeretin and nobiletin with HSA follow the static quenching mechanism as their kq values are greater than the rate of collisional quenching. The binding constant of nobiletin (Table 2, 1617) is greater than that of tangeretin, which suggests that the afnity for HSA has been improved by the methylation of tangeretin at position 3 . Hydrophobic interactions play the major role in their interaction with HSA. The interactions of avonones such as naringin and narirutin (Fig. 19d) are investigated by Xiao et al. [149]. At 8.0 M, naringin and narirutin quenched 21.80% and 14.54% of BSAs uorescence through the static quenching mechanism, which indicates that naringin has more afnity toward BSA than narirutin. The binding constants also suggest that naringin has more afnity for BSA. The interactions of avonones such as naringenin, naringin and narirutin (Fig. 19d) with HSA are investigated by Cao et al. [148]. Naringenin quenches the uorescence of HSA, which is accompanied by a red-shift in the emission maximum; whereas, naringin quenches the uorescence without any spectral shift. The interactions of naringenin, naringin and narirutin with HSA follow the static quenching mechanism, which is evident from the linear SternVolmer relation. At 8.0 M, the uorescence quenching follows the trend: naringin < naringenin < narirutin. The same trend is followed in the binding afnity (Table 2, 1820) toward HSA. The interaction of avonoids such as hyperoside, myricetin (Myr), tiliroside and troxerutin (Fig. 19e) with BSA are investigated by Qin et al. [150], Tian et al. [151], Hu et al. [152] and Wang et al. [153]. Hyperoside and troxerutin quench the intrinsic uorescence of BSA with a blue-shift in the emission maximum; whereas, Myr
and tiliroside quench with a slight red-shift. From the thermodynamic parameters, it is apparent that hydrophobic interactions are the forces of interaction of hyperoside and troxerutin with BSA; whereas, both hydrophobic and electrostatic interactions play main roles in the interaction of Myr with BSA. The synchronous uorescence spectra suggest that hyperoside and troxerutin affect only the microenvironment of typtophan moiety in BSA; whereas, Myr and tiliroside affect the microenvironments of both typtophan and tyrosine moieties in BSA. The interactions of avonoids such as galangin, kaempferol, quercetin and myricetin (Fig. 19f) with BSA are investigated by Xiao et al. [154] because of their potential antioxidant activities. All these avonoids quench the intrinsic uorescence of BSA with blue-shift in the emission maximum and follow the static quenching mechanism. The binding constants (Table 2, 2124) follow the trend: galangin < kaempferol < quercetin < myricetin, which suggests that the binding afnity of avonoids toward BSA increases with increase in the number of hydroxyl groups on the B-ring. The interactions of avones such as avone, 7-hydroxyavone, chrysin and baicalein (Fig. 19g) with serum albumins are investigated by Xiao et al. [155]. Flavone quenches the intrinsic uorescence of serum albumins with red-shift in the emission maximum; whereas, 7-hydroxyavone, chrysin and baicalein quench with blue-shift in the emission maximum, which suggests that the presence of hydroxyl group increases the hydrophilicity around the binding site. SternVolmer constants and binding constants (Table 2, 2532) suggest that the afnity of avonoids toward serum albumins follows the trend: 7-hydroxyavone > chrysin > baicalein > avone. This trend indicates that 7-hydroxyavone containing only one hydroxyl group has the highest binding afnity. But hydroxyl groups introduced at positions C-5, C-6, and/or C-7 of avones weaken the afnities for serum albumins due to the formation of the intra-molecular hydrogen bond. These results show that the optimal number of hydroxyl groups introduced to the ring A of avones is one. The binding constant also suggests that BSA is having more afnity toward these avones than HSA. The interactions of myricetin and dihydromyricetin (Fig. 19h) with BSA are investigated by Liu et al. [156]. Myricetin quenches the uorescence of BSA with blue-shift in the emission maximum; whereas, dihydromyricetin quenches with red-shift. The binding constants (Table 2, 3334) suggest that myricetin has more afnity toward BSA than dihydromyricetin, which indicates that hydrogenation in ring C suppresses the binding interaction. The interactions of quercetin and quercitrin (Fig. 19i) with BSA are also investigated by Xiao et al. [154]. Quercitrin is the 3-O--glucoside of quercetin. Both quercetin and quercitrin quench the uorescence of BSA with blue-shift in the emission maxima, i.e. static quenching. The binding constant (Table 2, 3536) of quercetin is greater than that of quercitrin, which indicates that glycoside substitution at the C-ring position weakens the binding afnity due to steric hindrance. The same trend is followed in the case of other avonoids such as baicalein, genistein and daidzein [157]. The interactions of daidzein (DDN) and 3 -daidzein sulfonic sodium (DSS) are investigated (Fig. 19j) by Shang and Li [158]. Both DDN and DSS quench the uorescence of BSA through the non-uorescent ground-state complex formation (static quenching). The binding constants (Table 2, 3738) suggest that DSS has more afnity for BSA than DDN, which is attributed to the presence of SO3 Na. The thermodynamic parameters (Table 3, 4142) indicate that the interaction of DDN with BSA is driven mainly by hydrogen bonding and van der Waals interactions; whereas, the binding of DSS with BSA is driven mainly by hydrophobic forces. Xiao et al. [159] reported some of the structural elements that inuence the afnities of avonoids for HSA. One or more hydroxyl groups in the B ring of avonoids enhance the binding afnity for
68
Fig. 19. Molecular structure of avonoids (a) (i) quercetin, (ii) rutin, and (iii) hyperin, (b) (i) chrysin, (ii) alpinetin, (iii) baicalein and (iv) wogonin, (c) (i) tangeretin and (ii) nobiletin, (d) (i) naringenin, (ii) naringin and (iii) narirutin, (e) (i) hyperoside, (ii) myricetin (Myr), (iii) tiliroside and (iv) troxerutin, (f) (i) galangin, (ii) kaempferol, (iii) quercetin and (iv) myricetin, (g) (i) avone, (ii) 7-hydroxyavone, (iii) chrysin and (iv) baicalein, (h) myricetin and dihydromyricetin, (i) quercetin and quercitrin, (j) daidzein (DDN) and 3 -daidzein sulfonic sodium (DSS).
69
System (T= 293 K) BSAIDC BSAKDC
KA
104 (M-1) 2.8 1.0
System (T= 293K) BSAC3 BSA C1.3
KA
105 (M-1) 7.31 1050
Fig. 20. Molecular structure of noxious substances (a) neonicotinoids insecticide (i) IDC, (ii) KDC and (b) hydroxychromone derivatives of coumarin (i) 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-on (C3 ) (ii) 1,3-dihydroxy7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-on (C1.3 ).
HSA; whereas, the hydroxyl group in the C-ring weakens the afnity of avonoids. Methylation of hydroxyl groups enhances the afnities for HSA; whereas, hydrogenation of the C2 C3 double bond as well as glycosylation lower the afnities for HSA. In this section, reports on the interaction of various avonoids with serum albumins are summarized. In particular, the effects of different substituents such as methyl group, methoxy group, and glycosyl group on the binding interactions are summarized. Fluorescence quenching studies conrm that these substances interact dissimilarly with BSA/HSA due to the steric hindrance. 5.6. Noxious materials The interaction of organic phosphorous pesticide methyl parathion (MP) with SA is investigated by Silva et al. [160] for their toxicological importance. MP quenches the intrinsic uorescence of SA through the static mechanism. At 1:1 molar ratio of MP/SA, MP quenches about 6.0% uorescence of HSA and 4.3% uorescence of BSA, which suggest that MP quenches the intrinsic uorescence of HSA more efciently than that of BSA. The interactions of neonicotinoids insecticide (Fig. 20a) such as imidacloprid (IDC) and its keto analog (KDC) with HSA are investigated [161] for their toxicological importance. IDC quenches the intrinsic uorescence of HSA with red-shift in the emission maximum; whereas, KDC quenches without any shift, but both quenching follow the static mechanism. The binding constants (table in Fig. 20a) suggest that IDC has more afnity toward HSA than KDC, which may be attributed to the presence of the nitroimine group. The interactions of the fungicide thiophanate methyl (MT), the pesticide pentachlorophenol (PCP) and the herbicide bensulfuronmethyl (BM) with HSA are studied by Li et al. [162], Wang et al. [163] and Ding et al. [164]. Due to the interaction of MT with HSA, the intrinsic uorescence intensity of HSA decreases, which is accompanied by a blue-shift in the emission maximum; whereas, PCP and BM quench the intrinsic uorescence of HSA without any spectral shift. MT, PCP and BM interact with HSA to form complexes. The thermodynamic parameters suggest that hydrophobic interactions are the major forces of the interaction of MT, PCP and BM with HSA. Also, hydrogen bonding plays a role in the interaction of MT with HSA; whereas, hydrogen bonding and electrostatic interactions play key roles in the binding of BM with HSA. In the synchronous spectrum of HSA, both PCP and BM red-shift the
emission maximum of the tryptophan residue. On the other hand, PCP blue-shifts the emission maximum of the synchronous spectrum of tyrosine residue; whereas, BM does not produce any shift. The interactions of Toxic Cr4+ ion compounds such as potassium dichromate K2 Cr2 O7 and potassium chromate K2 CrO4 with BSA are studied by Zhang et al. [165]. Both the Cr4+ compounds quench the uorescence of BSA with blue-shift in the emission maximum, which suggests an increase in the hydrophobicity around the binding site and static quenching. The quenching constants suggest that K2 Cr2 O7 has more afnity than K2 CrO4 . The thermodynamic parameters suggest that the electrostatic interactions play a major role in the binding reaction. The interactions of two substituted hydroxychromone derivatives of coumarin (Fig. 20b) namely 3-hydroxy7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-on (C3 ) and 1,3-dihydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-on (C1.3 ) with BSA are investigated [166] for their hepatotoxic importance. C3 quenches the uorescence of BSA through both static and dynamic mechanisms; whereas, C1.3 quenches through the static quenching mechanism. The binding afnity of C1.3 toward BSA is more than that of C3 , which is related to the number of hydroxyl groups present. The thermodynamic parameters (Table 3, 4344) suggest that hydrogen bonding and van der Waals interactions play major roles in the binding of these two coumarin derivatives to BSA. Fluorescence quenching studies on the interaction of noxious materials including pesticides and insecticides with serum albumins are discussed in this section. Among these noxious materials, hepatotoxic coumarin derivatives C3 and C1.3 interact dissimilarly with BSA/HSA due to the presence of hydroxyl group, which suggests the role of substituents in the binding interactions. 6. Conclusion A critical need in the eld of pharmacology is the study of the in vitro binding interactions of various drugs with biomolecules such as serum albumins. Fluorescence spectroscopy is a powerful tool to accomplish this need. In this review, the uorescence quenching studies involving the interaction of bioactive substances with serum albumins are discussed. The results reviewed here exemplify the dependence of the size and stabilizing agent of nanoparticles on their interactions with BSA/HSA. The organic molecules such as antibiotics, anticancer drugs, anti-inammatory agents, avonoids and dyes having different substituents interact dissimilarly with serum albumins due to the steric hindrance which provides important clues for the design of effective drugs for the treatment of various diseases. Such molecular interactions between serum albumins and the drugs using uorescence quenching are vital pharmacokinetic processes such as drug distribution and transportation. In addition, the predicted concentrations of drugs in blood serum determine the pharmaceutical effects of the drug. Therefore, this review is of great signicance in the elds of pharmacology and clinical medicine. Acknowledgements Author SA thanks DST, New Delhi (SR/S1/PC-49/2009) for the sanction of major research grant. Also author SA thank DST for sanctioning FIST (SR/FST/CSI-190/2008 dated 16th March 2009) and Nanomission projects. Author SN thanks his institute for selecting him in MHRD fellowship. References
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Binding of Serum Albumins With Bioactive Substances - Nanoparticles To Drugs

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Journal of Photochemistry and Photobiology C: Photochemistry Reviews 14 (2013) 5371

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Journal of Photochemistry and Photobiology C: Photochemistry Reviews

Binding of serum albumins with bioactive substances Nanoparticles to drugs

0 300 350 400 450 500

-0.6 -0.8 -1.0 -1.2

absorption 0.08 Overlap I ntegral J 0.04

Fluorescence intensity / a.u.

Donor (HSA) fluorescence Quencher (PTK)

System (T= 293K) BSA-TPP BSA-TMEOPP BSA-TClPP

106 (M-1) 1.37 2.33 3.51

System BSA-NCTPP BSA-NCTMPP BSA-NCTAPP

106 (M-1) 0.74 1.24 1.40

System (T= 288K) HSA-DEX BSA-DEX

KA x 104 (M-1) 3.80 3.78

Fig. 16. Molecular structure of Dexamethasone (DEX).

System (T= 298 K) HSA-PTK BSA-PTK

104 (M-1) 49.4 3.72

System (T= 293 K) BSASudan II BSASudan IV

104 (M-1) 1.22 1.48

System (T= 293 K) BSAIDC BSAKDC

104 (M-1) 2.8 1.0

System (T= 293K) BSAC3 BSA C1.3

105 (M-1) 7.31 1050

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