Polyethylenimine-Grafted Cellulose Nanofibril ... - ACS Publications

Subscriber access provided by ERCIYES UNIV

Article

Polyethyleneimine-Grafted Cellulose Nanofibril Aerogels as Versatile Vehicles for Drug Delivery Jiangqi Zhao, Canhui Lu, Xu He, Xiaofang Zhang, Wei Zhang, and Ximu Zhang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/am507601m • Publication Date (Web): 06 Jan 2015 Downloaded from http://pubs.acs.org on January 16, 2015

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Applied Materials & Interfaces is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

1

Polyethyleneimine-Grafted Cellulose Nanofibril Aerogels

2

as Versatile Vehicles for Drug Delivery

3

Jiangqi Zhao†, Canhui Lu†, Xu He†, Xiaofang Zhang†, Wei Zhang*†,

4

Ximu Zhang*‡

5

† State Key Laboratory of Polymer Materials Engineering, Polymer Research

6

Institute at Sichuan University, Chengdu 610065, China.

7

‡State Key Laboratory of Oral Disease, West China Hospital of Stomatology,

8

Sichuan University, Chengdu 610041, China.

9 10

ABSTRACT

11

Aerogels from polyethyleneimine-grafted cellulose nanofibrils (CNFs-PEI) were

12

developed for the first time as a novel drug delivery system. The morphology and

13

structure of the CNFs before and after chemical modification were characterized by

14

scanning electron microscopy (SEM), Fourier transform infrared spectroscopy

15

(FTIR) and X-ray photoelectron spectroscopy (XPS). Water-soluble sodium

16

salicylate (NaSA) was used as a model drug for the investigation of drug loading

17

and release performance. The CNFs-PEI aerogels exhibited a high drug loading

18

capability (287.39 mg/g), and the drug adsorption process could be well described

19

by Langmuir isotherm and pseudo-second-order kinetics models. Drug release

20

experiments demonstrated a sustained and controlled release behavior of the

21

aerogels highly dependent on pH and temperature. This process followed quite well

22

the pseudo-second-order release kinetics. Owing to the unique pH- and

23

temperature- responsiveness together with their excellent biodegradability and

24

biocompatibility, the CNFs-PEI aerogels were very promising as a new generation

25

of controlled drug delivery carriers, offering simple and safe alternatives to the

26

conventional systems from synthetic polymers.

27

KEYWORDS 1

ACS Paragon Plus Environment


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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 38

28

aerogel, cellulose nanofibrils (CNFs) , controlled release, drug delivery,

29

polyethyleneimine (PEI).

30 31

INTRODUCTION

32

Conventional

drug formulations

33

gastrointestinal

34

anti-inflammatory drugs have short plasma elimination half-life (2-4 h) and must be

35

administered in multiple daily doses to maintain therapeutic blood levels.4 There

36

has been a significant interest in the development of drug delivery systems, as they

37

can provide a relatively steady release rate, reduce toxicity, optimize the drug

38

therapeutics and improve patient compliance and convenience.4,5 The rate of drug

39

delivery, the intensity and the duration of drug action have been the subject of

40

much multidisciplinary research.6,7 These factors tend to be influenced by external

41

conditions, such as pH, temperature8,9

or

renal

side

have

effects.1-3

many In

adverse addition,

effects, most

including

nonsteroidal

42

A number of polymers have been developed to achieve controlled release of

43

drugs.5 However, most of them, such as PE, PP and PDMS, are synthetic and

44

non-biodegradable.5,10,11 Currently, the use of natural polysaccharides or their

45

derivatives are attractive and regarded as key formulation ingredients for the

46

engineering of modified drug delivery systems because of their stability, availability,

47

renewability and low toxicity.12 Cellulose is the most abundant natural

48

polysaccharide in the world,13 possessing non-toxic, renewable, biodegradable and

49

biocompatible characteristics.14,15 In addition to the above-mentioned advantages

50

of cellulose, nanocellulose, particularly cellulose nanofibrils (CNFs) exhibit many

51

other unique characteristics, such as very large specific surface area,16 high

52

strength and stiffness,17 ease for chemical modification,18,19 and the ability to form

53

highly porous mesh.20 As a result, CNFs have gotten wide attention in various

54

research areas and also been studied as excipient in formulation of the

55

pharmaceutical dosage forms.21-23

56

Common drug delivery systems include ion exchange resins, films,24,25

2


Page 3 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


57

microspheres, gels, and so on.26,27 There is growing interest in aerogels as a

58

special class of highly porous materials with biomedical and pharmaceutical

59

applications because of their open pore structure and high surface area.12 However,

60

efforts in this regard have been mainly focused on silica or carbon aerogels.28,29

61

The polysaccharide-based aerogels have been developing very fast in drug

62

delivery research in the past several years, giving rise to enhanced drug

63

bioavailability and drug loading capacity.27,30 In particular, CNFs hydrogels can be

64

easily transformed into aerogels via freeze-drying.21,27 The unique structure of

65

CNFs aerogels provides them a broad range of applications, such as templates,31

66

adsorbents,32 and drug delivery.12,27 However, for pristine cellulose, the drug

67

loading capability is very low. Thus chemical modification of cellulose becomes an

68

important step to improve its practical usefulness in drug delivery.33,34 It is also

69

important to note that surface modification of materials can dramatically influence

70

their release profile and bioavailability of the entrapped drug.12 Amide groups are

71

commonly selected for conjugating drugs to polymers because they can bind a

72

variety of negatively charged drug molecules,35 In early work, polyethyleneimine

73

(PEI), which bears a large number of primary and secondary amine groups on the

74

molecules, has demonstrated excellent performance in drug delivery.36-38

75

The objective of this study was to develop a new class of drug delivery systems

76

based on CNFs. To this end, the PEI-grafted CNFs (CNFs-PEI) were synthesized

77

and subsequently converted into aerogels through freeze-drying. The morphology

78

and structure of the materials were characterized by SEM, FTIR and XPS. Sodium

79

salicylate (NaSA), a widely used medicine for curing diseases such as wound

80

healing,39 diabetes,40 arthritis,41 and cancer treatment,42,43 was adopted as a model

81

drug for investigating the drug loading and release performance of the CNFs-PEI

82

aerogel.

83 84

MATERIALS AND METHODS

85

Materials

3



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

86

Never-dried moso bamboo pulp (Figure 1a) was supplied by Yongfeng Paper Co.,

87

Ltd. (Sichuan, China). Its cellulose content was higher than 93% as reported by the

88

supplier. A branched polyethyleneimine (PEI, molecular weight of 25,000) was

89

purchased from Sigma–Aldrich. Sodium salicylate and other chemicals were of

90

analytical grade and supplied by Chengdu Kelong Chemicals Co., Ltd. (Sichuan,

91

China).

92

Preparation of CNFs

93

The bamboo pulp was dispersed in distilled water at a solid concentration of 1

94

wt%. A horn-type ultrasonic generator (JY99-IIDN, Scientz, China) was used to

95

treat the suspension (500 ml) at an output power of 1,200 W for 30 min. The

96

suspension was then diluted to the concentration of 0.5 wt% with distilled water.

97

Finally, a high shear homogenizer (T18, IKA, Germany) was used to isolate CNFs

98

at a rotation speed of 20,000 rpm for 1 h. The obtained CNFs could be well

99

dispersed in water, as shown in Figure 1a.

100

Preparation of CNFs-PEI Aerogel

101

A schematic depiction of the grafting process of PEI on CNFs was presented in

102

Figure 1b. First, amino-groups were introduced onto the surface of CNFs. For a

103

typical reaction, 1 g CNFs was dispersed in 100 mL methanol under nitrogen

104

atmosphere and 1.5 g methyl methacrylate was slowly added with cerium

105

ammonium nitrate (6mM) as an initiator. This free radical reaction was conducted at

106

room temperature for 3 h under magnetic stirring. The products were washed three

107

times with methanol and incubated with 1.5 g ethylenediamine in a methanol

108

solution. The transesterification reaction lasted for 24 h at 60 oC under magnetic

109

stirring. The as prepared amino-modified CNFs (CNFs-NH2) were purified through

110

repeated methanol washing. The CNFs-PEI was synthesized as follows: 2 g of

111

CNFs-NH2 was immersed in 100 mL PEI solution in methanol (2 wt% PEI) for 24 h

112

under magnetic stirring at room temperature. After that, it was transferred into 200

113

mL 1 wt% glutaraldehyde solution and stirred for 30 min. To ensure thorough

114

removal of methanol and glutaraldehyde, the resulting product was washed

115

repeatedly with distilled water and finally separated through centrifugation. The 4


Page 4 of 38

Page 5 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


116

obtained CNFs-PEI was re-dispersed in water at a solid concentration of about 1

117

wt%. The suspensions were rapidly frozen in liquid nitrogen (-196 oC) and placed in

118

a cold freeze-drying chamber (FD-1A-50, Biocool, China). The freeze-drying

119

process was maintained at -30

120

three-dimensional aerogel in light yellow color (Figure 1a).

121

Material Characterization

o

C for 72 h. The final product was a

122

The morphologies of cellulose fibers and CNFs-PEI were observed using

123

scanning electron microscopy (SEM, Inspect F 50, FEI, USA). Cross-sectional

124

features of the aerogel before and after drug release were also examined. The

125

specific surface area of the aerogels was determined by nitrogen adsorption using

126

Quantachrome NovaWin instrument (USA) and Brunauer-Emmett-Teller (BET)

127

analysis method.44 The chemical structure of samples was characterized by FTIR

128

and XPS, respectively. FTIR analysis was performed using a Nicolet 560 FTIR

129

spectrometer (Nicolet, USA). All spectra were scanned from 4000 to 500 cm-1 at a

130

resolution of 2 cm-1. XPS spectra were recorded on a Kratos XASAM 800

131

spectrometer (Kratos analysis, UK) with an Al Kα X-ray source (1486.6 eV) and an

132

X-ray beam of around 1 mm.

133

Drug Loading Studies

134

The CNFs-PEI aerogels as well as the neat CNFs aerogels were loaded with

135

NaSA through static adsorption. The stock solution was prepared by dissolving the

136

NaSA in twice distilled water. Working solutions of the desired concentrations were

137

obtained by successive dilutions. A series of batch adsorption experiments were

138

conducted to investigate the effects of pH and reaction time, and to estimate the

139

maximum adsorption capacity. The pH dependent adsorption behaviors were

140

studied in the pH range from 1 to 6 adjusted by 0.1 mol/L HCl or NaOH solutions.

141

The aerogels were added into NaSA aqueous solutions for drug adsorption at

142

ambient temperature for 24 h. The drug loading of aerogels could be determined

143

from the initial and final drug concentrations of the solutions. The effect of initial

144

drug concentration (NaSA concentration from 5 to 3000 mg/L) on the adsorption

145

performance was studied at pH=3 for 24 h. Meanwhile, the effect of contact time 5



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

146

was examined up to 24 h at pH=3.

147

Drug Release Studies

148

The effect of pH on the drug release behavior was evaluated. Drug-loaded

149

aerogels were suspended in simulated gastric fluid (SGF, 0.2% NaCl, pH=2) and

150

simulated intestinal fluid (SIF, 0.05 mol/L, NaH2PO4, pH=7.4) without protease,

151

maintaining at 37°C under a paddle rotation speed of 50 rpm. To study the

152

temperature dependent drug release behavior, the experiments were performed at

153

different temperatures (20, 37 and 50°C). Samples (5 ml) were withdrawn at

154

specific intervals and the incubation solution was replenished with 5 ml of SIF or

155

SGF after each sampling. The NaSA concentration were measured from the

156

maximum absorbance at 295 nm using a UV-vis spectrophotometer (UV-1600,

157

MAPADA, China).27 The cumulative percentage of drug release was calculated and

158

the mean of three determinations was used in data analysis.

159 160

RESULTS AND DISCUSSION

161

Characterization of The Materials

162

The morphologies of the materials were observed by SEM. Figure 2a and b

163

showed the SEM images of pristine bamboo pulp fibers and the as-prepared CNFs,

164

respectively. It was clear that the cellulose fibers had been almost completely

165

disintegrated into CNFs after the combined physical treatments. The diameters of

166

the pristine bamboo pulp fibers were about 10 µm, whereas most of the CNFs had

167

diameters in the range of 20-40 nm. Figure 2c showed the morphology of

168

CNFs-PEI. These modified CNFs exhibited obviously thicker fiber diameters

169

(50-150 nm) as compared with the precursor CNFs. The appearance of thicker

170

fibrils is consistent with the successful grafting of PEI. The cross-sectional feature

171

of CNFs-PEI aerogel was shown in Figure 2d. The aerogel possessed a highly

172

porous structure consisting of a network of interconnected nanofibrils and nanofibril

173

bundles, part of which had formed sheet-like structure. This is normal for

174

freeze-dried aerogels. The growth of ice crystals will push CNFs into sheets during

6


Page 6 of 38

Page 7 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


175

the freezing process.31,45 Due to the nano dimension of CNFs and the unique

176

porous structure, the CNFs-PEI aerogel had a much higher BET surface area (79

177

m2/g) than that of pristine bamboo pulp fibers (0.8 m2/g), which accounted for an

178

enhanced adsorption properties.46 It was noteworthy that the porous morphology of

179

the CNFs-PEI aerogel was not affected after drug release, as shown in Figure S1 in

180

the Supporting Information.

181

FTIR spectra (Figure 3) were collected to elucidate the chemical structure

182

changes after surface modification of CNFs. Compared with the CNFs sample, the

183

most relevant difference in the FTIR spectra of CNFs-NH2 and CNFs-PEI is the

184

appearance of bands at 1740, 1650, 1560 and 1450 cm-1. The absorption peak at

185

1740 cm-1 could be ascribed to the C=O stretching of the ester groups.47 It revealed

186

that methyl methacrylate had been grafted to CNFs. In the meantime, it also

187

suggested the reaction between esters and ethylenediamine was incomplete for

188

this solid-liquid reaction.47 The absorption at 1650 cm-1, 1560 and 1450 cm-1 were

189

the characteristic peaks of amide bond and amino group.48-50 The relative

190

intensities of these peaks in CNFs-PEI significantly increased as compared with

191

that of CNFs-NH2, indicative of the successful grafting of PEI onto CNFs.

192

XPS is a powerful analytical technique to study the surface chemical composition

193

of materials.51 With this tool, the chemical composition changes of CNFs during

194

surface modification could be revealed. As shown in Figure 4, the XPS spectrum of

195

CNFs did not display any signals in the N1s region, indicating there was no nitrogen

196

element presented in the CNFs.49,52 However, for the CNFs-NH2 spectrum, there

197

was also no N1s signal. This is possibly due to the very low content of amino groups

198

on CNFs-NH2, which outranged the detecting limits of the instrument. On the

199

contrast, a strong peak at 399.3 eV appeared in the CNFs-PEI spectrum. The

200

nitrogen content of CNFs-PEI was estimated to be as high as 4.24%, further

201

confirming the successful grafting of PEI to the CNFs’ surface. The presence of

202

these abundant amino groups were desirable for an enhanced drug loading

203

performance of CNFs-PEI aerogels.12

204 7



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

205

Drug Loading Studies

206

Influence of Solution pH

Page 8 of 38

207

pH is one of the most important factors that can affect the adsorption behavior

208

remarkably.36 In this study, a pH range of 1-6 was selected to investigate the drug

209

loading capacities under these conditions and the results were presented in Figure

210

5. As expected, the CNFs-PEI showed distinctly higher drug loading capacity than

211

CNFs throughout the pH range. For CNFs-PEI, when pH increased from 1 to 3, the

212

drug loading increased rapidly and reached the maximum at pH 3. In this condition,

213

the drug loading of CNFs-PEI was as high as 78.00 mg/g, more than 20 times that

214

of CNFs. However, when pH was over 3, the drug loading decreased sharply with

215

the increase of solution pH. This phenomenon could be ascribed to the different

216

interactions between the surface charges of the adsorbents and the SA- at different

217

pH. The -NH2 groups on the surface of CNFs-PEI varied in form at different pH

218

levels.36 Under acidic conditions, amino groups could be protonated to form

219

positively charged sites, e.g. -NH3+ groups.36 The electrostatic attraction between

220

-NH3+ and SA- gave rise to the increase of drug loading. The bell-shaped curve for

221

CNFs-PEI in Figure 5 could be predicted based on pKa values with

222

Henderson-Hasselbalch equations53,54

[SA ] + log −

223

pH = pK a1

224

pH = pK a2

[SA] [NH 2 ] + log

(1)

[NH ]

(2)

+

3

225

When pH increased, the concentration of H+ in the fluid decreased. It became

226

more difficult for -NH2 to be protonated and thus the NH3+ concentration decreased,

227

leading to a lower drug loading. The pKa1 for SA was about 3.55 At pH 3, the amino

228

groups on the CNFs-PEI (pKa2 = 8.8 for PEI)56 could be extensively protonated to

229

bear positive charges. Meanwhile, a half of SA was presented in its ionic form of

230

SA- in solution, leading to the maximum drug loading at pH 3. However, when pH

231

further decreased (pH < pKa1), the SA- concentration would be reduced rapidly.

232

Most of them would be transformed into salicylic acid, which could not be 8


Page 9 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


233

electrostatically attracted by the -NH3+ groups.57 As a result, the drug loading

234

capacities also decreased.

235

Adsorption Isotherms

236

Adsorption isotherms describe how adsorbates interact with adsorbents and are

237

important in optimizing the use of the latter. Similarly, adsorption isotherms have

238

great significance to elucidate the relationship between the drug carriers and drugs.

239

The equilibrium adsorption capacity was obtained using equation (3). The

240

equilibrium adsorption data were fitted with the Langmuir model (eq 4)58 and the

241

Freundlich model (eq 5)36, respectively:

242

243

244

qe =

(C o − C e ) × V m

qe =

qm K L C e 1 + K L Ce

qe = K F C

(3)

(4)

1 n e

(5)

245

Where Co and Ce (mg/L) are the initial and equilibrium concentrations of NaSA in

246

solution, V (L) is the volume of drug solution, m (g) is the dry mass of adsorbents,

247

qe (mg/g) is the equilibrium adsorption capacity, qm (mg/g) is the maximum

248

adsorption capacity, KL and KF are constants for Langmuir and Freundlich

249

isotherms, respectively, n is a Freundlich constant relating to adsorption intensity of

250

the adsorbents.59

251

The acquired data and the fitting curves were shown in Figure 6, and those

252

important parameters obtained from fitting were presented in Table 1. Compared

253

with the Freundlich isotherm, the Langmuir isotherm could better describe the

254

adsorption behaviors with a correlation coefficient R2> 0.95, indicating a monolayer

255

adsorption of NaSA onto the CNFs-PEI surface.58,60 The maximum adsorption

256

capacity of NaSA calculated from the Langmuir isotherm was 287.39 mg/g for

257

CNFs-PEI aerogel, representing an effective drug carrier.

258

Kinetics Studies

259

The adsorption kinetics was studied to manifest the adsorption rate of NaSA onto 9



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 38

260

the CNFs-PEI aerogel as well as the rate controlled equilibrium time. The

261

experimental data was analyzed using the pseudo-second-order equation (eq 6) as

262

follows.61

263 264

1 t 1  t = + qt k 2 qe2  qe 

(6)

Where qe is the adsorption capacity (mg/g) at equilibrium, qt (mg/g) is the

265

adsorption

capacity

at

time

266

pseudo-second-order adsorption.

t,

k2

(g/mgh)

is

the

rate

constant

of

267

The adsorption behavior of CNFs-PEI on NaSA as a function of contacting time

268

was shown in Figure 7a. At the initial stage, the adsorption of NaSA was very fast,

269

and then gradually reached the equilibrium in 2 h. The experimental data and the

270

linear fitting were shown in Figure 7b. The correlation coefficient and some other

271

important parameters obtained from the fitting were presented in Table 2. The plots

272

appeared in good linearity with a high correlation coefficient (R2 = 0.9990), and the

273

theoretical qe value (279.33 mg/g) was very close to the experimental data (278.54

274

mg/g). These results indicated the pseudo-second-order kinetics model described

275

quite well the experiment data.

276 277

Drug Release Studies

278

Effect of pH on Drug Release

279

The time dependence of NaSA release from the drug-loaded carriers in two

280

different solutions, SGF (pH=2) and SIF (pH=7.4), was investigated. The obtained

281

data was plotted in Figure 8. Compared with CNFs, the drug release rate of

282

CNFs-PEI significantly slowed down. For CNFs aerogel, the drug release generally

283

reached the equilibrium in 20 min. On the contrast, approximately 10 h was needed

284

for CNFs-PEI to reach the equilibrium, suggesting the surface grafting with PEI was

285

very effective to render CNFs aerogel sustained drug release performance. Since

286

the CNFs-PEI aerogels prolonged drug release time effectively (improved from

287

20min to 10 h with several tens times), and which were superior to many other drug 10


Page 11 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


288

deliveries,27,30,62 which demonstrate the high potential of CNFs-PEI aerogels for

289

pharmaceutical applications. The NaSA release rate from drug carriers could be

290

analyzed using pseudo-second-order equation (eq 7):63

291

 1  1 t  t = + Qt k 2 Q e2  Q e 

(7)

292

Where Qe (%) is the cumulative release at equilibrium, Qt (%) is the cumulative

293

release at time t, k2 (h-1) is the rate constant of pseudo-second-order equation.

294

The graphical representations and the corresponding parameters calculated from

295

the kinetics model were shown in Figure 8b and Table 3, respectively. The NaSA

296

release from all the drug carriers followed the pseudo-second-order kinetics model

297

with high correlation coefficients (R2 = 0.9979-0.9999). In addition, the drug release

298

from CNFs-PEI was highly pH-dependant. When in SGF (pH=2), the cumulative

299

drug release of CNFs-PEI was only 64.31%. However, when in SIF (pH=7.4), it

300

reached 92.59% with a much faster release rate. These results demonstrate a

301

remarkable pH responsiveness of the CNF-PEI aerogel.64,65 For clinical practices,

302

the CNFs-PEI aerogels could slow down the initial burst release of NaSA in

303

stomach and bring more drugs to the intestinal tract for a targeted drug delivery.

304

This would not only reduce the side effects on stomach but also improve the

305

absorption efficiency of drugs.66 In addition to the above two different pH for the

306

evaluation of drug release in SGF and SIF, pH 5 and 9 were also tested and the

307

results were presented in Figure S2 and Table S1 in the Supporting Information.

308

Effect of Temperature on Drug Release

309

The drug release behaviors of CNFs-PEI aerogel were also examined at different

310

temperatures in SIF (pH=7.4). As shown in Figure 9a, the temperature of fluid could

311

strongly affect the drug release. When the temperature rose up from 20 to 50 oC,

312

the cumulative drug release increased from 52.66% to 78.49% (Table 4). The

313

release rate also increased obviously. These results suggested that the desorption

314

of NaSA was an endothermic process and higher temperatures favored the drug

315

release. Moreover, the molecule diffusion rate would increase at a higher 11



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 38

316

temperature, which might lead to a faster drug release rate.67 The NaSA release

317

data

318

pseudo-second-order kinetics model. The kinetics studies could help understand

319

the drug release process in a particular environment and guide the dosage of drug

320

carriers for oral administration.68 The graphical representations and the

321

corresponding parameters calculated from the kinetics model were shown in Figure

322

9b and Table 4, respectively. At all temperatures, the pseudo-second-order model

323

provided a good fit to the kinetics data with high correlation coefficients (R2 =

324

0.9782-0.9990). Since some disease states manifest themselves by a change in

325

temperature,69 the CNFs-PEI aerogels with a sensitive temperature-responsive

326

drug release behavior may open up opportunities to construct a novel drug delivery

327

system in conjunction with localized hyperthermia. This strategy could achieve

328

temporal drug delivery control: drug expresses its activity for a time period defined

329

by local temperature change.70

at

different

temperatures

were

further

analyzed

using

the

330 331

CONCLUSION

332

In the present study, PEI modified CNFs aerogels were successfully developed

333

as an alternative biopolymer-based drug delivery system to substitute the

334

conventional synthetic ones. The aerogels were highly porous, bearing abundant of

335

functional groups. The NaSA loading capability of CNFs-PEI aerogels was

336

extraordinary. The maximum NaSA loading could be as high as 287.39 mg/g at pH

337

3, significantly higher than that of CNFs aerogels. The drug adsorption process

338

followed Langmuir isotherm and pseudo-second-order kinetics model. Drug

339

release studies indicated that the CNFs-PEI aerogels exhibited remarkable

340

sustained drug release behaviors. More interestingly, both pH and temperature

341

were discovered to affect the drug release profoundly, demonstrating strong

342

controlled release behaviors of this drug carrier. It was envisaged that the simple

343

fabricating process, the high drug loading capability, the controlled drug release

344

performance

together

with

the

intrinsic

nature

12


of

biodegradability

and

Page 13 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


345

biocompatibility of cellulose would make the CNFs-PEI aerogels a promising

346

candidate for future pharmaceutical industries.

347 348

ASSOCIATED CONTENT

349

Supporting Information

350

The morphology and discussion of the CNFs-PEI aerogel after drug

351

release, and the study of drug release behavior under other pH values

352

(5 and 9) are included in the Supporting Information.

353 354

AUTHOR INFORMATION

355

Corresponding Author

356

*Email: [email protected] (W. Z); [email protected] (X. Z.). Tel & Fax:

357

(+086) 28-5460607 (W. Z.)

358

Notes

359

The authors declare no competing financial interest.

360 361

ACKNOWLEDGEMENT

362

The authors would like to thank National Natural Science Foundation of China

363

(51303112, 51473100 and 51433006) for financial support of this work.

364 365

REFERENCES

366

(1)

Drugs. Am. J. Med. 1999, 107, 37-46.

367 368 369

McCarthy, D. M. Comparative Toxicity of Nonsteroidal Anti-Inflammatory

(2)

Gabriel, S. E.; Jaakkimainen, L.; Bombardier, C. Risk for Serious Gastrointestinal

Complications

Related

to

13


Use

of

Nonsteroidal


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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Anti-Inflammatory Drugsa Meta-Analysis. Ann. Intern. Med. 1991, 115, 787-796.

370 371

(3)

Polisson,

R.

Nonsteroidal

Anti-Inflammatory

Drugs:

Practical

and

Theoretical Considerations in Their Selection. Am. J. Med. 1996, 100, 31S-36S.

372 373

Page 14 of 38

(4)

Wang, N.; Wu, C.; Cheng, Y.; Xu, T. Organic–Inorganic Hybrid Anion

374

Exchange Hollow Fiber Membranes: A Novel Device for Drug Delivery. Int. J.

375

Pharm. 2011, 408, 39-49.

376

(5)

Controlled Drug Release. Chem. Rev. 1999, 99, 3181-3198.

377 378

Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S. Polymeric Systems for

(6)

Bhosale, S. V.; Bhosale. S. V. Yoctowells as a simple model system for the

379

encapsulation and controlled release of bioactive molecules. Sci. Rep. 2013, 22,

380

1982-1990.

381

(7)

Li, Z.; Barnes, J. C.; Bosoy, A.; Stoddart, J. F.; Zink, J. I. Mesoporous silica

382

nanoparticles in biomedical applications. Chem. Soc. Rev. 2012, 41,

383

2590-2605.

384

(8)

Theron, C.; Gallud, A.; Carcel, C.; Gary-Bobo, M.; Maynadier, M.; Garcia,

385

M.; Lu, J.; Tamanoi, F.; Zink, J. I.; Wong Chi Man, M. Hybrid Mesoporous Silica

386

Nanoparticles with pH-Operated and Complementary H-Bonding Caps as an

387

Autonomous Drug-Delivery System. Chem. Eur. J. 2014, 20, 9372-9380.

388

(9)

Okuda, T.; Tominaga, K.; Kidoaki, S.Time-programmed dual release

389

formulation by multilayered drug-loaded nanofiber meshes. J. Control. Release

390

2010, 143, 258-264.

391

(10)

Cardamone, K.; Lofthouse, S. A.; Lucas, J. C.; Lee, R. P.; O’Donoghue,

14


Page 15 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


392

M.; Brandon, M. R. J. In Vitro Testing of a Pulsatile Delivery System and Its in

393

Vivo Application for Immunisation Against Tetanus Toxoid. J. Control. Release

394

1997, 47, 205-219.

395 396 397

(11)

Sintzel, M. B.; Bernatchez, S. F.; Tabatabay, C.; Gurny, R. Biomaterials

in Ophthalmic Drug Delivery. Eur. J. Pharm. Biopharm. 1996, 42, 358-374. (12)

García-González, C. A.; Alnaief, M.; Smirnova, I. Polysaccharide-Based

398

Aerogels-Promising Biodegradable Carriers for Drug Delivery Systems.

399

Carbohyd. Polym. 2011, 86, 1425-1438.

400

(13)

Cranston, E.D., Eita, M., Johansson, E., Netrval, J., Salajkova, M., Arwin,

401

H., Wagberg, L. Determination of Young's Modulus for Nanofibrillated Cellulose

402

Multilayer Thin Films Using Buckling Mechanics. Biomacromolecules 2011, 12,

403

961-969.

404

(14)

Cranston, E. D., Gray, D. G., Rutland, M. W. Direct Surface force

405

Measurements of Polyelectrolyte Multilayer Films Containing Nanocrystalline

406

Cellulose. Langmuir 2010, 26, 17190-17197.

407

(15)

Kumar, A., Negi, Y. S., Choudhary, V., Bhardwaj, N. K. Microstructural and

408

Mechanical Properties of Porous Biocomposite Scaffolds Based on Polyvinyl

409

Alcohol, Nano-Hydroxyapatite and Cellulose Nanocrystals. Cellulose 2014, 21,

410

3409-3426.

411

(16)

Ma, H.; Burger, C.; Hsiao, B. S.; Chu, B. Ultra-Fine Cellulose Nanofibers:

412

New Nano-Scale Materials for Water Purification. J. Mater. Chem. 2011, 21,

413

7507-7510.

15



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

414

(17)

Page 16 of 38

Siro´, I., Plackett, D., Hedenqvist, M., Ankerfors, M., Lindstro¨m, T. Highly

415

Transparent Films from Carboxymethylated Microfibrillated Cellulose: The

416

Effect of Multiple Homogenization Steps on Key Properties. J. Appl. Poltm. Sci.

417

2011, 119, 2652-2660.

418

(18)

Pääkkö, M.; Ankerfors, M.; Kosonen, H.; Nykänen, A.; Ahola, S.; Österberg,

419

M.;Ruokolainen, J.; Laine, J.; Larsson, P. T.; Ikkala, O.; Lindström, T. Enzymatic

420

Hydrolysis

421

Homogenization

422

Biomacromolecules 2007, 8, 1934-1941.

423

(19)

Combined for

with

Mechanical

Nanoscale

Shearing

Cellulose

Fibrils

and

High-Pressure

and

Strong

Gels.

Kumar, A., Negi, Y. S., Choudhary, V., Bhardwaj, N. K. Characterization of

424

Cellulose Nanocrystals Produced by Acid-Hydrolysis from Sugarcane Bagasse

425

as Agro-Waste. J. Nonlinear. Opt. Phys. 2014, 2, 1-8.

426

(20)

Yang, X., Cranston, E. D. Chemically Cross-Linked Cellulose Nanocrystal

427

Aerogels with Shape Recovery and Superabsorbent Properties. Chem. Mater.

428

2014, 26, 6016-6025.

429 430 431

(21)

Kolakovic, R. Nanofibrillar Cellulose in Drug Delivery. Ph.D. Thesis,

University of Helsinki, Helsinki, Finland, 2013. (22)

Kolakovic, R.; Laaksonen, T.; Peltonen, L.; Laukkanen, A.; Hirvonen, J.

432

Spray-Dried Nanofibrillar Cellulose Microparticles for Sustained Drug Release..

433

Int. J. Pharm. 2012, 430, 47-55.

434 435

(23)

Bhattacharya, M.; Malinen, M. M.; Lauren, P.; Lou, Y.-R.; Kuisma, S. W.;

Kanninen, L.; Lille, M.; Corlu, A.; GuGuen-Guillouzo, C.; Ikkala, O.; Laukkanen,

16


Page 17 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


436

A.; Urtti, A.; Yliperttul, M. Nanofibrillar Cellulose Hydrogel Promotes

437

Three-Dimensional Liver Cell Culture. J. Control. Release 2012, 164, 291-298.

438

(24)

Kolakovic, R.; Peltonen, L.; Laukkanen, A.; Hirvonen, J.; Laaksonen, T.

439

Nanofibrillar Cellulose Films for Controlled Drug Delivery. Eur. J. Pharm.

440

Biopharm. 2012, 82, 308-315.

441

(25)

Kolakovic, R.; Peltonen, L.; Laukkanen, A.; Hellman, M.; Laaksonen, P.;

442

Linder, M. B.; Hirvonen, J.; Laaksonen, T. Evaluation of Drug Interactions with

443

Nanofibrillar Cellulose. Eur. J. Pharm. Biopharm. 2013, 85, 1238-1244.

444

(26)

Mohd Amin, M.C.I; Ahmad, N.; Halib, N.; Ahmad, I. Synthesis and

445

Characterization of Thermo-and pH-Responsive Bacterial Cellulose/Acrylic Acid

446

Hydrogels for Drug Delivery. Carbohyd. Polym. 2012, 88, 465-473.

447

(27)

Valo, H.; Arola, S.; Laaksonen, P.; Torkkeli, M.; Peltonen, L.; Linder, M. B.;

448

Serimaa, R.;

449

Nanoparticles Embedded in Four Different Nanofibrillar Cellulose Aerogels. Eur.

450

J. Pharm. Sci. 2013, 50, 69-77.

451

(28)

Kuga, S.; Hirvonen, J.; Laaksonen, T. Drug Release from

Guenther, U., Smirnova, I., Neubert, R.H.H. Hydrophilic Silica Aerogels as

452

Dermal Dug Delivery Systems–Dithranol as a Model Drug. Eur. J. Pharm.

453

Biopharm. 2008, 69, 935-942.

454 455 456 457

(29)

Moreno-Castilla, C., Maldonado-Ho´dar, F. J. Carbon Aerogels for Catalysis

Applications: An Overview. Carbon 2005, 43, 455-465. (30)

Mehling,

T.;

Smirnova,

I.;

Guenther,

U.;

Neubert,

R.

H.

H.

Polysaccharide-Based Aerogels as Drug Carriers. J. Non.-Crys. Solids. 2009,

17



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

458 459

355, 2472-2479. (31)

Pääkkö, M., Vapaavuori, J., Silvennoinen, R., Kosonen, H., Ankerfors, M.,

460

Lindström, T., Berglund, L. A., Ikkala, O. Long and Entangled Native Cellulose I

461

Nanofibers Allow Flexible Aerogels and Hierarchically Porous Templates for

462

Functionalities. Soft Matter 2008, 4, 2492-2499.

463

(32)

Chen, W., Li, Q., Wang, Y., Yi, X., Zeng,J., Yu, H., Liu, Y., Li, J. Comparative

464

Study of Aerogels Obtained from Differently Prepared Nanocellulose Fibers.

465

ChemSusChem 2014, 7, 154-161.

466

(33)

Rodrıg ́ uez, R.; Alvarez-Lorenzo,C.; Concheiro, A. Cationic Cellulose

467

Hydrogels: Kinetics of the Cross-Linking Process and Characterization as

468

pH-/Ion-Sensitive Drug Delivery Systems. J. Control. Release 2003, 86,

469

253-265.

470

(34)

Butun, S.; Ince, F.G.; Erdugan, H.; Sahiner, N. One-Step Fabrication of

471

Biocompatible Carboxymethyl Cellulose Polymeric Particles for Drug Delivery

472

Systems. Carbohyd. Polym. 2011, 86, 636-643.

473

(35)

Patri, A. K.; Kukowska-Latallo, J. F.; Baker Jr, J. R. Targeted Drug Delivery

474

with Dendrimers: Comparison of the Release Kinetics of Covalently Conjugated

475

Drug and Non-Covalent Drug Inclusion Complex. Adv. Drug. Deliver. Rev. 2005,

476

57, 2203-2214.

477

(36)

Liu, B.; Huang, Y. Polyethyleneimine Modified Eggshell Membrane as a

478

Novel Biosorbent for Adsorption and Detoxification of Cr (VI) from Water. J.

479

Mater. Chem. 2011, 21, 17413-17418.

18


Page 18 of 38

Page 19 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


480

(37)

Xia, T., Kovochich M., Liong, M., Meng, H., Kabehie, S., George, S., Zink J.

481

I., Nel, A. E. Polyethyleneimine Coating Enhances the Cellular Uptake of

482

Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA

483

Constructs. ACS Nano 2009, 3, 3273-3286.

484

(38)

Chertok, B., David, A. E., Yang, V. C. Polyethyleneimine-Modified Iron

485

Oxide Nanoparticles for Brain Tumor Drug Delivery Using Magnetic Targeting

486

and Intra-Carotid Administration. Biomaterials 2010, 31, 6317-6324.

487 488 489

(39)

Roseborough, I. E.; Grevious M. A. Lee, R. C. Prevention and Treatment of

Excessive Dermal Scarring. J. Int. Med. Res. 2004, 96, 108-116. (40)

Hosny, E. A., Al-Shora, H. I., Elmazar, M. M.A. Oral Delivery of Insulin from

490

Enteric-Coated Capsules Containing Sodium Salicylate: Effect on Relative

491

Hypoglycemia of Diabetic Beagle Dogs. Int. J. Pharm. 2002, 237, 71-76.

492

(41)

Ouimet, M. A.; Snyder, S. S.; Uhrich, K. E. Tunable Drug Release Profiles

493

from Salicylate-Based Poly (Anhydride-Ester) Matrices Using Small Molecule

494

Admixtures. J. Bioact. Compat. Pol. 2012, 27, 540-549.

495 496 497

(42)

Wu, K. K. Aspirin and Salicylate An Old Remedy With a New Twist.

Circulation 2000, 102, 2022-2023. (43)

Chung, Y. M., Bae, Y. S., Lee, S. Y. Molecular Ordering of ROS Production,

498

Mitochondrial

499

Salicylate-Induced Apoptosis. Free Radical Bio. Med. 2003, 34, 434-442.

500 501

(44)

Changes,

and

Caspase

Activation

during

Sodium

BRUNAUE S., EMMET P.H., TELL E. Adsorption of Gases in

Multimolecular Layers. J. Am. Chem. Soc. 1938, 60, 309-319.

19



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 38

502 503

(45)

Zhang, W., Zhang, Y., Lu, C., Deng, Y. Aerogels from Crosslinked Cellulose

504

Nano/Micro-Fibrils and Their Fast Shape Recovery Property in Water. J. Mater.

505

Chem. 2012, 22, 11642-11650.

506

(46)

Newcombe, G.; Hayesb, R.; Drikas, M. Granular activated carbon:

507

Importance of surface properties in the adsorption of naturally occurring

508

organics. Colloid. Surface. A 1993, 78, 65-71.

509

(47)

Zhang, Q.; Wang, N.; Xu, T.; Cheng, Y. Poly (Amidoamine) Dendronized

510

Hollow Fiber Membranes: Synthesis, Characterization, and Preliminary

511

Applications as Drug Delivery Devices. Acta Biomater. 2012, 8, 1316-1322.

512

(48)

Wang, J.; Zhao, L.; Duan, W.; Han, L.; Chen, Y. Adsorption of Aqueous Cr

513

(VI) by Novel Fibrous Aadsorbent with Amino and Quaternary Ammonium

514

Groups. Ind. Eng. Chem. Res. 2012, 51, 13655-13662.

515

(49)

Han,

K.

N.;

Yu,

B.

Y.;

Kwak,

S.

Y.

Hyperbranched

Poly

516

(Amidoamine)/Polysulfone Composite Membranes for Cd (II) Removal from

517

Water. J. Membrane Sci. 2012, 396, 83-91.

518 519 520 521 522 523

(50)

Pan, B.; Gao, F.; Gu, H. Dendrimer Modified Magnetite Nanoparticles for

Protein Immobilization. J. Colloid Interf. Sci. 2005, 284, 1-6. (51)

Swartz, W. E. X-ray Photoelectron Spectroscopy. Anal. Chem. 1973, 45,

788a-800a. (52)

Matuana, L. M., Balatinecz, J. J., Sodhi, R. N. S., Park, C. B. Surface

Characterization of Esterified Cellulosic Fibers by XPS and FTIR Spectroscopy.

20


Page 21 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


524 525 526 527

Wood SCI. Technol. 2001, 35, 191-201. (53)

Po, H. N.; Senozan, N. M. The Henderson-Hasselbalch Equation: Its

History and Limitations. J. Chem. Educ. 2001, 78, 1499-1503. (54)

Shapira, A.; Assaraf, Y. G.; Epstein, D.; Livney, Y. D. Beta-casein

528

Nanoparticles as an Oral Delivery System for Chemotherapeutic Drugs: Impact

529

of Drug Structure and Properties on Co-assembly. Pharm. Res. 2010, 27,

530

2175-2186.

531

(55)

UNGELL, A.-L.; NYLANDER, S.; BERGSTRAND, S.; SJOBERG, A.;

532

ENNERNAS, H. L. Membrane Transport of Drugs in Different Regions of the

533

Intestinal Tract of the Rat. J. Pharm. Sci. 1998, 87, 360-366.

534

(56)

Amara, M.; Kerdjoudj, H. Modification of cation-exchange membrane

535

properties by electro-adsorption of polyethyleneimine. Desalination 2003, 155,

536

79-87.

537 538 539 540 541

(57)

Dbus, I. G., Barriuso, E., Calvet, R. Sorption of Weak Organic Acids in Soils:

Clofencet, 2, 4-D and Salicylic Acid. Chemosphere 2001, 45, 767-774. (58)

Langmuir, I. The Adsorption of Gases on Plane Surfaces of Glass, Mica

and Platinum. J. Am. Chem. Soc. 1918, 40, 1361-1403. (59)

Dada, A. O.; Olalekan, A. P.; Olatunya, A. M.; Dada, O. Langmuir,

542

Freundlich, Temkin and Dubinin-Radushkevich isotherms studies of equilibrium

543

sorption of Zn2+ unto phosphoric acid modified rice husk. J. Appl. Chem. 2012,

544

3, 38-45.

545

(60)

Tao, A.; Kim, F.; Hess, C.; Goldberger, J.; He, R.; Sun, Y.; Xia, Y.; Yang, P.

21



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

546

Langmuir−Blodgett Silver Nanowire Monolayers for Molecular Sensing Using

547

Surface Enhanced Raman Spectroscopy. Nano Lett. 2003, 3, 1229-1233.

548

(61)

Shen, H.; Pan, S.; Zhang, Y.; Huang, X.; Gong, H. A New Insight on the

549

Adsorption Mechanism of Amino-Functionalized Nano-Fe3O4 Magnetic

550

Polymers in Cu(II), Cr(VI) Co-Existing Water System. Chem. Eng. J. 2012, 183,

551

180-191.

552

(62)

Cook, R. O.; Pannu, R. K.; Kellaway I. W. Novel sustained release

553

microspheres for pulmonary drug delivery. J. Control. Release 2005, 104,

554

79-90.

555

(63)

Yuan, X., Xing, W., Zhuo, S., Han, Z., Wang, G., Gao, X., Yan, Z.

556

Preparation and Application of Mesoporous Fe/Carbon Composites as a Drug

557

Carrier. Micropor. Mesopor. Mat. 2009, 117, 678-684.

558

(64)

Theron, C.; Gallud, A.; Carcel, C.; Gary-Bobo, M.; Maynadier, M.; Garcia,

559

M.; Lu, J.; Tamanoi, F.; Zink, J. I.; Wong Chi Man, M. Hybrid Mesoporous Silica

560

Nanoparticles with pH-Operated and Complementary H-Bonding Caps as an

561

Autonomous Drug-Delivery System. Chem. Eur. J. 2014, 20, 9372-9380.

562

(65)

Okuda, T.; Tominaga, K.; Kidoaki, S. Time-programmed dual release

563

formulation by multilayered drug-loaded nanofiber meshes. J. Control. Release

564

2010, 143, 258-264.

565

(66)

Mitchell, J. A., Akarasereenont, P., Thiemermann, C., Flower, R. J., Vane, J.

566

R. Selectivity of Nonsteroidal Antiinflammatory Drugs as Inhibitors of

567

Constitutive and Inducible Cyclooxygenase. P. Natl. Acad. Sc. U.S.A. 1993, 90,

22


Page 22 of 38

Page 23 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


568 569 570 571

11693-11697. (67)

Kost, J., Langer, R. Responsive Polymeric Delivery Systems. Adv. Drug.

Deliver. Rev. 2012, 64, 327-341. (68)

Patri, A. K., Kukowska-Latallo, J. F., Baker, J. R. Targeted Drug Delivery

572

with Dendrimers: Comparison of the Release Kinetics of Covalently Conjugated

573

Drug and Non-Covalent Drug Inclusion Complex. Adv. Drug. Deliver. Rev. 2005,

574

57, 2203-2214.

575

(69)

Zhang, L., Xu, T., Lin, Z. Controlled Release of Ionic Drug through the

576

Positively Charged Temperature-Responsive Membranes. J. Membrane Sci.

577

2006, 281, 491-499.

578

(70)

Chung, J. E., Yokoyama, M., Yamato, M., Aoyagi, T., Sakurai, Y., Okano, T.

579

Thermo-Responsive Drug Delivery from Polymeric Micelles Constructed Using

580

Block Copolymers of Poly(N-isopropylacrylamide) and Poly(Butylmethacrylate).

581

J. Control. Release 1999, 62, 115-127.

582

23



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

583

Page 24 of 38

Table 1. Isotherm constants for the adsorption of NaSA onto the CNFs-PEI aerogel. Langmuir model

Freundlich model

Sample CNFs-PEI

qm (mg/g)

KL (L/mg)

R2

n

KF (L/mg)

R2

287.39

0.011

0.9895

0.299

31.471

0.8991

584 585

24


Page 25 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


586

Table 2. Adsorption kinetics constants for the adsorption of NaSA onto the

587

CNFs-PEI aerogel. Sample CNFs-PEI

qe,exp

Pseudo-second-order kinetics model

(mg/g)

k2 (g/mgh)

qe,cal (mg/g)

R2

278.54

0.011

279.33

0.9990

588 589

25



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 38

590

Table 3. NaSA release kinetics from the drug-loaded CNFs and CNFs-PEI aerogels

591

at different pH values. Sample

pH value

Pseudo-second-order kinetic model

Qe,exp (%)

k2 (h-1)

Qe,cal (%)

R2

CNFs

7.4

91.07

0.938

91.24

0.9999

CNFs-PEI

2

59.53

0.007

64.31

0.9989

CNFs-PEI

7.4

86.32

0.008

92.59

0.9978

592 593

26


Page 27 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


594

Table 4. NaSA release kinetics from the drug-loaded CNFs-PEI aerogels at

595

different temperatures. Temperature

Qe,exp (%)

Pseudo-second-order kinetic model k2 (h-1)

Qe2,cal (%)

R2

20 oC

46.05

0.004

52.66

0.9782

37 oC

59.53

0.007

64.31

0.9989

50 oC

73.25

0.007

78.49

0.9990

596 597

27



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

598

Figure Captions

599

Figure 1. Schematic illustration of (a) the preparation process of the CNFs-PEI

600

aerogels, and (b) the reaction mechanism of the grafting process.

601

Figure 2. SEM images of the bamboo pulp fibers before (a) and after (b) the

602

combined physical treatments, (c) the as-prepared CNFs-PEI, and (d) the

603

cross-section of the aerogel.

604

Figure 3. FTIR spectra for (a) bamboo CNFs, (b) the as-prepared CNFs-NH2, and

605

(c) the as-prepared CNFs-PEI.

606

Figure 4. XPS N1s core-level spectra of (a) bamboo CNFs, (b) the as-prepared

607

CNFs-NH2, and (c) the as-prepared CNFs-PEI.

608

Figure 5. Effect of pH on drug loading of CNFs-PEI aerogels.

609

Figure 6. Two adsorption isotherms for CNFs-PEI aerogels.

610

Figure 7. (a) The adsorption curves for CNFs-PEI aerogel and (b) the linear fitting

611

of NaSA adsorption data using the pseudo-second-order equation.

612

Figure 8. (a) The NaSA cumulative release curves with time and (b) the

613

pseudo-second-order fitting on NaSA release data from CNFs and CNFs-PEI

614

aerogels at various pH.

615

Figure 9. (a) The NaSA cumulative release curves with time and (b) the

616

pseudo-second-order fitting on NaSA release data from CNFs-PEI aerogel at

617

various temperatures.

618

28


Page 28 of 38

Page 29 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


619

Figure 1.

620 621

29



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

622

Figure 2.

623 624

30


Page 30 of 38

Page 31 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


625

Figure 3.

626 627

31



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

628

Figure 4.

629 630

32


Page 32 of 38

Page 33 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


631

Figure 5.

632 633

33



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

634

Figure 6.

635 636

34


Page 34 of 38

Page 35 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


637

Figure 7.

638 639

35



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

640

Figure 8.

641 642

36


Page 36 of 38

Page 37 of 38

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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


643

Figure 9.

644 645

37



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 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

646

The table of contents entry

647 648

For the first time, aerogels from polyethyleneimine-grafted cellulose nanofibrils

649

(CNFs-PEI) were developed for drug delivery studies. These biopolymer-based

650

aerogels had a high drug loading capability and exhibited a remarkable sustained

651

and controlled release behavior highly dependent on pH and temperature, offering

652

a simple and safe alternative to the conventional drug delivery systems from

653

synthetic polymers.

38


Page 38 of 38

Polyethylenimine-Grafted Cellulose Nanofibril ... - ACS Publications

Recommend Documents