Inclusion of Tetracycline Hydrochloride within Supramolecular Gels

Mar 27, 2009 - Three amphiphilic 3,4,5-trihydroxybenzoic derivatives with alkyl chains of different lengths were designed and synthesized. A small amo...
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Inclusion of Tetracycline Hydrochloride within Supramolecular Gels and Its Controlled Release to Bovine Serum Albumin† Liqin Chen, Junchen Wu, Lihui Yuwen, Tianmin Shu, Miao Xu, Mingming Zhang, and Tao Yi* Department of Chemistry and Laboratory of Advanced Materials, Fudan University, 220 Handan Road, Shanghai 200433, China Received December 30, 2008. Revised Manuscript Received March 13, 2009 Three amphiphilic 3,4,5-trihydroxybenzoic derivatives with alkyl chains of different lengths were designed and synthesized. A small amount of these compounds can trap a large quantity of the water-soluble drug tetracycline hydrochloride (TH) within a stable gel in aqueous ethanol. Release experiments were carried out with solutions of bovine serum albumin (BSA) and various concentrations of L-isoleucine, L-phenylalanine, and L-tryptophan. The results indicate that the release rate of TH for a BSA solution (10 mg/mL) was faster than that with the other solutions because of the strong interaction between TH and BSA. Furthermore, to gain an insight into the release dynamics, we studied the release ratios as a function of the square root of time (t1/2). During the initial 1.75 h, diffusion is the dominant release process in water, whereas intermolecular interaction controls TH release in the BSA solution.

Introduction Low-molecular-weight gels (LMWGs) have received considerable attention in the past decade.1,2 The self-assembly of small organic molecules plays a key role in gelation through specific intermolecular interactions such as hydrogen bonding, π-π stacking, van der Waals forces, hydrophobic interaction, charge-transfer interactions, and so forth.3 These noncovalent interactions give rise to the formation of supramolecular structures of gelators and subsequently result in the immobilization of the fluid. Despite their predominantly liquid composition, these systems have the appearance and rheological behavior of solids. Intriguingly, some of the properties of LMWGs, such as biodegradability, biocompatibility, and gentle physical and chemical profiles, represent considerable potential in the fields of biomedicinal applications and drug delivery.4,5 LMWGs may provide an environment that enhances the stability of encapsulated drug molecules and helps to limit enzymatic degradation during drug delivery.6 An additional benefit of using self-assembled gels is realized during the formulation of drug-loaded material. In principle, compared to methods that diffuse a drug into a † Part of the Gels and Fibrillar Networks: Molecular and Polymer Gels and Materials with Self-Assembled Fibrillar Networks special issue. *Corresponding author. E-mail: [email protected].

(1) (a) Terech, P.; Weiss, R. G. Chem. Rev. 1997, 97, 3133–3160. (b ) van der Laan, S.; Feringa, B. L.; Kellogg, R. M.; van Esch, J. Langmuir 2002, 18, 7136–7140. (c) Estroff, L. A.; Hamilton, A. D. Chem. Rev. 2004, 104, 1201–1218. (2) (a) Abdallah, D. J.; Weiss, R. G. Adv. Mater. 2000, 12, 1237–1247. (b ) van Bommel, K. J. C.; Friggeri, A.; Shinkai, S. Angew. Chem., Int. Ed. 2003, 42, 980–999. (3) (a) George, S. J.; Ajayaghosh, A. Chem.;Eur. J. 2005, 11, 3217–3227 and references therein. (b) Ajayaghosh, A.; Chithra, P.; Varghese, R. Angew. Chem., :: Int. Ed. 2007, 46, 230–233. (c) Zhang, X.; Chen, Z.; Wurthner, F. J. Am. Chem. Soc. 2007, 129, 4886–4887. (d) Boerakker, M. J.; Botterhuis, N. E.; Bomans, P. H. H.; Frederik, P. M.; Meijer, E. M.; Nolte, R. J. M.; Sommerdijk, N. A. J. M. Chem.; Eur. J. 2006, 12, 6071–6080. (e) Cai, W.; Wang, G. T.; Xu, Y. X.; Jiang, X. K.; Li, Z. T. J. Am. Chem. Soc. 2008, 130, 6936–6937. (f) Jang, W. D.; Jiang, D. L.; Aida, T. J. Am. Chem. Soc. 2000, 122, 3232–3233. (4) (a) Kiyonaka, S.; Sugiyasu, K.; Shinkai, S.; Hamachi, I. J. Am. Chem. Soc. 2002, 124, 10954–10955. (b) Zhou, S. L.; Matsumoto, S.; Tian, H. D.; Yamane, H.; Ojida, A.; Kiyonaka, S.; Hamachi, I. Chem.;Eur. J. 2005, 11, 1130–1136. (5) (a) Zhang, Y.; Gu, H.; Yang, Z.; Xu, B. J. Am. Chem. Soc. 2003, 125, 13680–13681. (b) Sangeetha, N. M.; Maitra, U. Chem. Soc. Rev. 2005, 34, 821–836. (c) Yang, Z.; Xu, B. J. Mater. Chem. 2007, 17, 2385–2393. (6) Branco, M. C.; Pochan, D. J.; Wagner, N. J.; Schneider, J. P. Biomaterials 2009, 30, 1339–1347.

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preformed gel, precise concentrations of therapeutics can be encapsulated directly within the gel network during the selfassembly process, which can enable prolonged activity if the rate of release of the drug can be controlled.6 However, many important questions remain unanswered. For example, gel components could be chosen according to their compatibility with intended applications, such as nontoxic solvents for pharmaceutical formulations. Furthermore, some supramolecular gels are currently limited by the fast diffusion of LMW drug molecules out of the matrix and/or by water infiltration into the latter.7 Nevertheless, the optimization of sustained drug release is generally thought to be possible by fine tuning the LMWG structure and possibly the nature of the organic phase.8 Control of drug dosing in terms of quantity, location, and time is a key goal for drug delivery science because improved control maximizes the therapeutic effect while minimizing side effects.9 Therefore, stimulus-responsive supramolecular gels are attractive in drug delivery because of their release of entrapped molecules in response to slight changes in environment, such as light,10 sound,11 electrochemical stimulus,12 pH,13 temperature,14 enzymatic action,15 and biomolecules.16 For example, Das et al. (7) Vintiloiu, A.; Leroux, J. C. J. Controlled Release 2008, 125, 179–192. (8) Couffin-Hoarau, A. C.; Motulsky, A.; Delmas, P.; Leroux, J. C. Pharm. Res. 2004, 21, 454–457. (9) Langer, R. Science 2001, 293, 58–59. (10) (a) Murata, K.; Aoki, M.; Suzuki, T.; Harada, T.; Kawabata, H.; Komori, T.; Ohseto, F.; Ueda, K.; Shinkai, S. J. Am. Chem. Soc. 1994, 116, 6664–6676. (b ) :: Ahmed, S. A.; Sallenave, X.; Fages, F.; Mieden-Gundert, G.; Muller, W. M.; :: :: Muller, U.; Vogtle, F.; Pozzo, J. L. Langmuir 2002, 18, 7096–7101. (c) Koumura, N.; Kudo M.; Tamaoki N. Langmuir 2004, 20, 9897–9900. (11) (a) Naota, T.; Koori, H. J. Am. Chem. Soc. 2005, 127, 9324–9325. (b ) Wu, J.; Yi, T.; Shu, T.; Yu, M.; Zhou, Z.; Xu, M.; Zhou, Y.; Zhang, H.; Han, J.; Li, F.; Huang, C. Angew. Chem., Int. Ed. 2008, 47, 1063–1067. (12) (a) Kawano, S. I.; Fujita, N.; Shinkai, S. J. Am. Chem. Soc. 2004, 126, 8592–8593. (b ) Wang, C.; Zhang, D. Q.; Zhu, , D. B. J. Am. Chem. Soc. 2005, 127, 16373–16374. (13) Aggeli, A.; Bell, M.; Boden, N.; Keen, J. N.; Knowles, P. F.; McLeish, T. C. B.; Pitkeathly, M.; Radford, S. E. Nature (London) 1997, 386, 259–262. (14) Li, S. K.; D’Emanuele, A. J. Controlled Release 2001, 75, 55–67. (b) Kong, G.; Anyarambhatla, G.; Petros, W. P.; Braun, R. D.; Colvin, O. M.; Needham, D.; Dewhirst, M. W. Cancer Res. 2000, 60, 6950–6957. (c) Bae, Y. H.; Okano, T.; Hsu, R.; Kim, S. W. Makromol. Chem., Rapid Commun. 1987, 8, 481–485. (15) Fischelghodsian, F.; Brown, L.; Mathiowitz, E.; Brandenburg, D.; Langer, R. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 2403–2406. (16) Miyata, T.; Uragami, T.; Nakamae, K. Adv. Drug Delivery Rev. 2002, 54, 79–98.

Published on Web 03/27/2009

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Letter Scheme 1

developed pH-responsive hydrogels by using amino acid-based amphiphilic hydrogelators that were systemically fine-tuned at the headgroup to control the release rate of entrapped biomolecules by the pH difference.17 McCoy et al. reported a molecular method for light-triggered drug delivery of various drug classes using low-energy long-wavelength radiation with the drug dose being controlled precisely by the duration of exposure to light.18 Recently, biomolecular sensitive organogels that can response to specific biomolecules have become increasingly important because of their potential applications in the development of drug delivery systems with specific association mechanisms. Studies of protein-sensitive control of drug release are important in pharmacology and pharmacokinetics because drug-protein binding affects the pharmacological activity and drug distribution. Serum albumins are the most abundant proteins in plasma, and their most outstanding property is the ability to reversibly bind a large variety of small drug molecules, such as tetracycline hydrochloride (TH). TH is of particular interest because it is often used as a broad-spectrum antibiotic affecting anaerobic and facultative organisms, gram-positive and gram-negative bacteria, and mycoplasms through potent bacteriostatic activity. Bi et al. studied the interaction between tetracycline antibiotics and human or bovine serum albumin (BSA) and found that the attractive forces between tetracycline and albumin were mainly electrostatic.19 In this study, we synthesized 3,4,5-trihydroxybenzoic derivatives with linkers of different lengths (1a, 1b, and 1c; Scheme 1) and found two amphiphiles (1b and 1c) that could gelate aqueous ethanol in the presence of TH. Here, the release profiles for various concentrations of BSA were obtained, and the effects of some amino acids at various concentrations are also discussed. Furthermore, we investigated the release kinetics of various solutions during the initial time and found that diffusion plays a dominant role in the release process for various amino acids whereas electrostatic forces control the release of TH in BSA solutions.

Experiment Synthesis. Details of the synthesis process and characterization of compounds 1a-1c are provided as Supporting Information. Gelation and Entrapment Experiment. The gelation experiment was carried out as follows: a weighed amount of gelator (1a-1c or 1(a-c) + TH) was mixed with solvent in a 1.5 mL glass vial and heated until the solid was dissolved. Upon cooling the homogeneous fluid mixture below the gelation temperature (Tg), the complete volume was immobilized and could support its own weight, after which the sample was allowed to cool to room temperature. As a consequence of the sol-gel process, TH was trapped within the gel. (17) Shome, A.; Debnath, S.; Das, P. K. Langmuir 2008, 24, 4280–4288. (18) McCoy, C. P.; Rooney, C.; Edwards, C. R.; Jones, D. S.; Gorman, S. P. J. Am. Chem. Soc. 2007, 129, 9572–9573. (19) Bi, S.; Song, D.; Tian, Y.; Zhou, X.; Liu, Z.; Zhang, H. Spectrochim. Acta A 2005, 61, 629–636.

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Determination of Gel-Sol Transition Temperature (Tg). The gel-sol transition temperature (Tg) was determined by placing an inverted screw-capped glass vial with an i.d. of 10 mm containing a gel in a thermostatted oil bath. The temperature was raised at a rate of 1 °C /min. Tg was defined as the temperature at which the gel flows down the glass vial. Release Studies. The controlled release of entrapped drug molecules was investigated as follows.6,17,20,21 A sample (0.45 mL) of solutions of various biomolecules at different concentrations was carefully placed on top of each gel containing TH, prepared as described above. (This gel-solution twophase system is stable for days.) After the desired length of time (0.25, 0.75, 1.75, 3.75, 6.75, 11.75, or 20.75 h), a quantitative amount of the supernatant solution (5-10 μL) was removed and replaced with fresh solution. The concentration of TH in the supernatant was analyzed by UV/visible spectroscopy to determine the amount of TH that had been released from the gel. The absorption/concentration equation for TH was determined by measuring the maximum absorbance of TH solutions at known concentrations (TH has Amax at 357 nm); see Supporting Information Figure S1. Release experiments of TH from the xerogel of 1c + THmax were also carried out under sink conditions at 37.0 °C. The xerogel was made by freeze-drying the 1c + THmax gel in a glass vial under vacuum for 2 days. Sink conditions were obtained by dropping 0.45 mL of solution into the glass vial. All experiments were carried out in triplicate.

Results and Discussion Gelation Capability. In earlier studies, we found that 3,4,5trihydroxybenzoic derivatives with linkers of different lengths are excellent gelators and that their gelation property can be tuned by a simple modification of tail length.22 Derivatives 1a, 1b, and 1c are structurally similar, but the gelation properties are quite different (Table S1 in Supporting Information). 1a and 1b are quite soluble in organic solvents such as THF, DMF, and alcohol, but they are insoluble in water. 1a precipitates from aqueous ethanol after heating-cooling; however, 1b can form a gel in aqueous ethanol. In contrast, 1c can gelate most of the organic solvents tested but is insoluble in aqueous ethanol even when heated. These results indicate that the balance of the hydrophilic head and hydrophobic tails plays a key role in the solubility of the gelator, which affects the gelation ability. Therefore, enhancing the hydrophilic head by introducing a hydrophilic drug through intermolecular interaction may be an effective way to construct a hydrogel with entrapped medicine for drug delivery. TH is a nice selection because it possesses an amine moiety and several hydroxyl and carbonyl groups, which should form strong hydrogen bonds via the imide group and carboxylic acid groups of the amphiphiles. Moreover, TH is very soluble in water and has electronic absorption in the UV range, allowing release from the gel to be followed by UV/visible spectroscopy. It is exciting that when 1b or 1c is mixed with TH, the mixture can exist as a gel in aqueous ethanol at room temperature after a heating-cooling process (Figure S2 in Supporting Information). The component in the composite and the gelling properties are given in Table 1. The minimum gelation concentration (MGC in wt %) of TH in gels of 1b + TH is around 83.1 and around 90.7 in 1c + TH gels. Because strong (20) Friggeri, A.; Feringa, B. L.; Esch, J. J. Controlled Release 2004, 97, 241–248. (21) Cao, S.; Fu, X.; Wang, N.; Wang, H.; Yang, Y. Int. J. Pharm. 2008, 357, 95–99. (22) (a) Yang, H.; Yi, T.; Zhou, Z.; Zhou, Y.; Wu, J.; Xu, M.; Li, F.; Huang, C. Langmuir 2007, 23, 8224–8230. (b) Zhou, Y.; Yi, T.; Li, T.; Zhou, Z.; Li, F.; Huang, W.; Huang, C. Chem. Mater. 2006, 18, 2974–2981. (c) Zhou, Y.; Xu, M.; Yi, T.; Xiao, S.; Zhou, Z.; Li, F.; Huang, C. Langmuir 2007, 23, 202–208.

DOI: 10.1021/la8043208

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Letter Table 1. Gelation Capability of TH in 1b and 1c at Different Weight Percentages of Gelator 1b + TH (C2H5OH/H2O 3:1 v/v) TH (wt %)

concentration of gel (mg/mL)

state

1c + TH (C2H5OH/H2O 5:1 v/v) Tg (°C)

concentration of gel (mg/mL)

state

57.5 PG 19.2 PG 82.60a 59.0 G (min) 27.0 19.7 PG 83.05a 78.0 G 26.0 PG 87.18a 108.0 G 36.0 G (min) 90.74a 115.0 G (max) 26.5 39.4 G 91.53a 120.0 PG 40.0 G 91.67a 257.7 PG 86.0 G (max) 96.12a a 259.7 PG 86.6 PG 96.15 120.0 G 27.5 87.50b 117.5 G 27.0 89.36c 89.3 G 92.54b c 87.7 G 94.30 a 1b = 10 mg/mL and 1c = 3.3 mg/mL. b 1b = 15.0 mg/mL and 1c = 6.67 mg/mL. c 1b = 12.5 mg/mL and 1c = 5 mg/mL.

interactions occurred between 1c and TH, a loading of 96.1% could be achieved without gel disruption, whereas there was a maximum loading of 91.5% with 1b as a result of the weaker hydrophobic interaction compared with that for 1c. In addition, the amount of TH loading in the composite gels had a weak effect on Tg. The values of Tg for 1b + THmin and 1b + THmax are 27.0 and 26.5 °C, respectively, and those for 1c + THmin and 1c + THmax are 57.5 and 56.0 °C, respectively. The thermal stability of the composite gels was slight improved when the concentration (wt %) of 1b or 1c increased with the constant amount of loading of TH whereas the speed of gel formation is evidently accelerated. It is obvious that the gelation ability of the composite in aqueous ethanol comes from a balance between hydrophobicity and hydrophilicity. Noncovalent interactions such as hydrogen bonding, π-π stacking, and electrostatic and van der Waals forces between the composites collectively maintain this balance, resulting in the formation of a stable gel. A comparison of the FT-IR spectra of the 1c + TH gel with those of TH and 1c (Figure S4 in Supporting Information ) shows that the vibrational band of carbonyl groups of 1c at 1726 cm-1 is moved to 1665 cm-1 in the 1c + TH gel because of the strong intermolecular hydrogen bonding interaction between 1c and TH, which increases the aqueous solubility of the composite and can gel a quantity of water. Further investigation on electronic absorption spectra between TH solution and the component gels was therefore undertaken (Figure S5). The maximum absorbance slightly red-shifted in 1c + THmax (Δλ = 11 nm), 1c + THmin (Δλ = 9 nm), 1b + THmax (Δλ = 6 nm), and 1b + THminx (Δλ = 5 nm) in the gel state compared to that in the TH solution (3.21  10-5 mol/L), which proves the existence of intermolecular interaction between the amphiphiles and TH. It was very interesting that a small number of low-molecularweight molecules were able to entrap a large amount of TH to a certain extent. Morphology of the Gel. To obtain better insight into the molecular organization within the gels, the morphology of the composite xerogels was investigated by scanning electron microscopy (SEM). The morphology of the xerogels is strongly dependent on the composition of the gels. As shown in Figure 1a, the xerogel of 1b from aqueous ethanol shows regular knots of 5-8 μm in size, connected by thin ribbons. With the addition of a small amount of TH, the 1b + THmin gel exhibits entangled fibers with widths from 25 nm to >1.5 μm, which may provide the matrices of the gel (Figure 1b). Flake morphology was observed for the 1b + THmax gel with a large amount of TH (Figure 1c), whereas 1c in ethanol had the appearance 8436 DOI: 10.1021/la8043208

Tg (°C)

57.5 56.0

59.0 58.0

of spacious silklike soft ribbons (Figure 1d). These ribbons changed to flakes with the addition of TH to the composite gels (Figure 1e,f). Release Process Responding to Biomolecules. A drug release experiment was done to investigate the effect of BSA on the release of entrapped TH from the composite gel. The cumulative release percentages of TH from the 1c + THmax gel were appreciably different for various concentrations of BSA in aqueous solution (0, 1, and 10 mg/mL), and the pattern is shown in Figure 2a. Approximately 7 h later, equilibrium was reached between TH entrapped within the gel and TH in the solution on top of the gel. After 20.75 h, 63-67% of the TH was released, and the maximal release was from the gel with a 10 mg/mL BSA aqueous solution. The amount of TH released in the initial 3.75 h had the highest release rate; for example, TH released from 1c + THmax was 61.2% for 10 mg/mL of BSA aqueous solution and 56.8% for pure water. This indicates that the interaction between TH and BSA can promote the release rate of TH. It is noteworthy that this gel/solution two-phase system is still stable after the release experiment and no obvious volume change happens during the release process (Figure S3 in Supporting Information). Moreover, to compare small amino acids with BSA in the release process of TH, we studied the release from 1c + THmax into various external solutions, such as L-isoleucine, L-phenylalanine, and L-tryptophan. We found that the TH release efficiency from the 1c + THmax gel varied with the concentration of the amino acid (Figure S6a-c in Supporting Information). Figure 2b shows the release profiles of TH for 2.0 equiv of L-isoleucine, L-phenylalanine, and L-tryptophan. Among the three amino acid solutions, the amount of TH released in the initial 3.75 h was in the order of L-isoleucine > L-phenylalanine > L-tryptophan. These results show that steric hindrance of the guest biomolecule affects the release rate of TH. Because the aqueous solutions of L-isoleucine, L-phenylalanine, and L-tryptophan have different pH values (6.65, 7.73, and 7.32, respectively), we investigated the influence of pH on the release efficiency of TH from the 1c + THmin gel. There is no obvious difference between the release patterns of TH in buffer solutions of pH 3.5 and 5.5 (Figure 7Sa in Supporting Information), which proved that pH, at least in this range, did not affect the release process. Experiments with solutions of 1 and 10 mg/ mL BSA in a buffer at pH 5.5 gave very different results (Figure 7Sb in Supporting Information). It is clear that the concentration of BSA in the top solution has a great impact on the release ratio and the cumulative release percentage of TH. In addition, profiles of TH released from the 1b + TH gel into various concentrations of aqueous BSA solution (1 mg/mL, Langmuir 2009, 25(15), 8434–8438

Letter

Figure 1. SEM images of xerogels: (a) 1b (C2H5OH/H2O 4:1 (v/v), 12 mg/mL, scale bar 10 μm); (b) 1b + THmin (C2H5OH/H2O 3:1 (v/v), 59 mg/mL, [TH] = 80.5 wt %, scale bar 10 μm); (c) 1b + THmax (C2H5OH/H2O 3:1 (v/v), 115 mg/mL, [TH] = 91.3 wt %, scale bar 5 μm); (d) 1c in C2H5OH (6.7 mg/mL, scale bar 5 μm); (e) 1c + THmin (C2H5OH/H2O 5:1 (v/v), 36.0 mg/mL, [TH] = 90.7 wt %, scale bar 1 μm); (f) 1c + THmax (C2H5OH/H2O 5:1 (v/v), 86.0 mg/mL, [TH] = 96.1 wt %, scale bar 1 μm).

Figure 2. Percentage of TH released at 37 °C over time from 1c + THmax gels into (a) BSA aqueous solutions of 10 mg/mL (4), 1 mg/mL (O), and pure water (0) and (b) 2.0 equiv of L-isoleucine (0), L-phenylalanine (O), and L-tryptophan (4).

3 mg/mL and 10 mg/mL) at 25 °C (Tg is 26.5-27.0 °C) were also studied (Figure S8 in Supporting Information ). Unlike the results for the 1b + THmin gel, there was a marked difference in the release ratio and cumulative amount of TH released from the 1b + THmax gel. The maximal release (70.6% within 20.75 h) was from the 1b + THmax gel into a 10 mg/mL BSA aqueous solution. Meanwhile, the release ratio and cumulative percentage of release of TH from the 1b + TH gel into a 10 mg/mL BSA aqueous solution were higher than those from the 1c + TH gel (Figure S9), most likely because of the poorer stability of the 1b + THmax gel due to weaker hydrophobic interaction. To understand the dynamics of TH release from the gel, plots were made of release ratios as a function of the square root of time (t1/2). According to the Higuchi rule,23 if the gel-solution two-phase system is stable during the whole release process and there is a linear correlation between the percentage of guest molecule released from the gel and the square root of time, then (23) Higuchi, T. J. Pharm. Sci. 1961, 50, 874–875.

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the mechanism of the release of the guest molecule should be by diffusion over that period of time. From Figure 3, it is clear that linearity (correlation coefficient of 0.9972) is obtained in pure water, indicating that over 1.75 h the release of TH proceeds by a diffusion mechanism. Similarly, linearity is observed in solutions of 2.0 equiv of L-isoleucine, L-phenylalanine, and L-tryptophan (Figure S6d in Supporting Information). However, a nonlinear relation between the release ratio and t1/2 in a BSA solution during the initial 1.75 h proves that in this case the release mechanism of TH is mainly due to intermolecular interaction. In addition, the release studies of TH from the 1c + THmax xerogel were carried out under sink conditions, and the pattern is shown in Figure S10a. The cumulative release percentages of TH from the 1c + THmax xerogel were evidently different in BSA aqueous solution (10 mg/mL) with pure water. Apparently, after about 2 h an equilibrium situation is reached between the TH entrapped in the xerogel and that in the BSA aqueous solution above (10 mg/mL). However, the TH concentration in the top solution reaches a maximum after about 7 h, responding to pure DOI: 10.1021/la8043208

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Conclusions

Figure 3. Plot of release ratios of TH for the 1c + THmax gel into a 10 mg/mL BSA aqueous solution (9) and pure water (b) as a function of t1/2.

water. This further proves that the intermolecular interaction between TH and BSA has a great effect on the release process. It is interesting that the release ratio and cumulative release percentage of TH from the xerogel are both higher than those in the gel state. This means that the drug is uniformly distributed in the gel matrix and protected from the outside environment. The release mechanism of TH for the xerogel responding to BSA solution and water is similar to that for the gel state (Figure S10b in Supporting Information).

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In this study, an attempt was made to tune the hydrophilicity of 3,4,5-trihydroxybenzoic derivatives by a simple modification of the tail length. Three amphiphilic compounds 1a, 1b, and 1c were synthesized, and 1b and 1c were found to gelate aqueous ethanol in the presence of TH. It is important that a small number of low-molecular-weight molecules can entrap a large amount of TH medicine, up to 91.5%. The different release profiles of four composite gels (1b + THmin, 1b + THmax, 1c + THmin, and 1c + THmax) into various concentrations of BSA and amino acids were studied. The dramatic enhancement in the release rate of TH into aqueous BSA solution (10 mg/mL) in the initial 1.75 h and the retention of the gel structure after the release makes them suitable for serum albumin-sensitive drug delivery. Acknowledgment. This work was supported by the National Science Foundation of China (20571016, 20771027, and 30890141), the National Basic Research Program of China (2009CB930400), Shanghai Sci. Tech. Comm. (08JC1402400), and the Shanghai Leading Academic Discipline Project (B108). Supporting Information Available: Supplementary experimental details on the synthesis, gelling properties, and release process. This material is available free of charge via the Internet at http://pubs.acs.org.

Langmuir 2009, 25(15), 8434–8438