Resveratrol nanoformulations: Challenges and opportunities

G Model

IJP 14586 1–9 International Journal of Pharmaceutics xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

1

Review

2

Resveratrol nanoformulations: Challenges and opportunities

3 Q1

Natalie Summerlin a,1, Ernest Soo a,1, Sachin Thakur a , Zhi Qu a , Siddharth Jambhrunkar a , Amirali Popat a,b, *

4 5 6 7

a

School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia Mucosal Diseases Group, Mater Research Institute – The University of Queensland, Translational Research Institute, 37 Kent St., Woolloongabba, Queensland 4102, Australia b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 1 November 2014 Received in revised form 29 December 2014 Accepted 2 January 2015 Available online xxx

Resveratrol, a naturally occurring polyphenol and phytoalexin, has received significant attention in recent years due to its vast therapeutic effects including anticancer, antioxidant and anti-inflammatory effects. However, poor pharmacokinetic properties such as low aqueous solubility, low photostability and extensive first pass metabolism result in poor bioavailability, hindering its immense potential. Conventional dosage forms such as dry powder capsules and injections have met with limited success, demonstrating challenges faced in developing an effective formulation. Recently, nanotechnology-based formulations (nanoformulations) are being looked upon as a novel method for improving the pharmacokinetic properties, as well as enhancing targetability and bioavailability of resveratrol. This review outlines the therapeutic potential of resveratrol, explores its mechanisms of action and pharmacokinetic limitations, and discusses the success and challenges of resveratrol-encapsulated nanoparticles in the last decade. Potential techniques to improve encapsulation of the drug within nanoparticles, thereby enhancing its clinical potential are highlighted. ã 2015 Published by Elsevier B.V.

Keywords: Resveratrol Anticancer Nanoformulation Targeting Solubility enhancement

Contents 1. 2. 3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . Therapeutic properties of resveratrol Resveratrol nanoformulations . . . . . . Liposomes . . . . . . . . . . . . . . . . 3.1. Polymeric nanoparticles . . . . . 3.2. Solid lipid nanoparticles . . . . . 3.3. Cyclodextrins . . . . . . . . . . . . . 3.4. Conclusions and prospects . . . . . . . . Acknowledgements . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

8

1. Introduction

9

Resveratrol (3,5,40 -trihydroxystilbene) is a naturally occurring polyphenol and phytoalexin (Guo et al., 2013a). It was first isolated from the roots of the Japanese plant Polygonum cuspidatum, where it

10 11

Q2

* Corresponding author at: School of Pharmacy, The University of Queensland, Cornwall St., Brisbane, Queensland 4102, Australia. Tel.: +61 433981797. E-mail address: [email protected] (A. Popat). 1 These authors contributed equally to the preparation of the manuscript.

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

00 00 00 00 00 00 00 00 00 00

is produced in response to environmental stress factors such as injury, fungal infections and UV irradiation (Aluyen et al., 2012; Burns et al., 2002; Kristl et al., 2009; Ndiaye et al., 2011; Neves et al., 2012). The presence of these stress factors triggers the rapid activation of the stilbene synthase enzyme, which in turn facilitates the biosynthesis of resveratrol by acting on its precursor, phenylalanine (Lopez-Hernandez et al., 2007; Neves et al., 2012). Resveratrol is also found in products commonly consumed in the human diet such as red wine, grapes and peanuts (Karthikeyan et al., 2013). Fig. 1 shows the molecular structure of trans-resveratrol. The molecule is highly hydrophobic with a partition coefficient

http://dx.doi.org/10.1016/j.ijpharm.2015.01.003 0378-5173/ ã 2015 Published by Elsevier B.V.

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003

12 13 14 15 16 17 18 19 20 21 22

G Model

IJP 14586 1–9 2

N. Summerlin et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx

Fig. 1. Schematic representation demonstrating various resveratrol encapsulated nanoformulations developed to improve its physicochemical properties.

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 61 62 63

(log Po/w) of 3.1 and an aqueous solubility of 0.03 g/L (Mattarei et al., 2013; NCBI, 2014). Despite its poor aqueous solubility, the compound is expected to demonstrate high membrane permeability due to its lipophilicity. However, resveratrol shows markedly high solubility in organic solvents such as ethanol and DMSO (50 and 16 g/L, respectively) (NCBI). Resveratrol exists in two geometric isomers, cis- and trans (Montsko et al., 2008). The trans-isomer is more abundant and biologically active than the cis-isomer (Augustin et al., 2013; Rius et al., 2010). However, trans-resveratrol can be easily isomerized to the cis-isomer when exposed to sunlight, high intensity white light or ultraviolet (UV) light, at 360 and 254 nm (Lopez-Hernandez et al., 2007; Montsko et al., 2008). When pure trans-resveratrol was exposed to UV light at 366 nm for 120 min, 90.6% was converted to cis-resveratrol (Trela and Waterhouse, 1996). More recent studies found that the rate of conversion to cis-resveratrol was linearly proportional to light intensity until the ratio of cis-isomer to its trans-isomer reached equilibrium at about 2 h (Montsko et al., 2008; Silva et al., 2013). In the absence of light, trans-resveratrol was shown to be stable for at least 28 days in the pH range of 1–7 (Trela and Waterhouse, 1996). The oral absorption of resveratrol in humans is high (75%) and occurs primarily through transepithelial diffusion (Walle, 2011; Walle et al., 2004). However, resveratrol’s bioavailability is less than 1% due to extensive metabolism in the intestine and liver involving glucuronic acid conjugation and sulfation to generate the key metabolites, trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate, respectively (Cottart et al., 2010; Rotches-Ribalta et al., 2012; Walle, 2011; Yu et al., 2002). Consequently, only trace concentrations of free drug can be found in the systemic circulation (Cottart et al., 2010; Walle, 2011). In humans, orally dosed resveratrol reaches a peak plasma concentration after 1 h and a second peak is seen after 6 h indicating enteric recirculation, resulting in an observed half-life of 9.2 h (Almeida et al., 2009; Walle et al., 2004; Zu et al., 2014). To overcome the above challenges, a myriad of resveratrol nanoformulations have been prepared and evaluated. Among these formulations are liposomes, solid lipid nanoparticles, polymeric nanoparticles and cyclodextrins (Fig. 1) which have been studied in great detail. The purpose of this review is to examine the limitations of resveratrol’s pharmacokinetic

properties and assess the successes and challenges of formulations that have been designed to overcome these limitations.

64

2. Therapeutic properties of resveratrol

66

Interest in the therapeutic potential of resveratrol has intensified in the past decade (Fig. 2) owing to its demonstration of antioxidant, cardioprotective, anti-inflammatory and anticancer properties (Aluyen et al., 2012; Kraft et al., 2009; Yang et al., 2014). Jang et al. (1997) were the first to establish that resveratrol affects the three major stages of carcinogenesis, exhibiting anti-initiation, anti-promotion and anti-progression activities. Resveratrol’s anticancer activity has been reported to vary among different cancer cell lines. Nonetheless, the exact pharmacology of the drug is unknown and recent studies have sought to gain a better understanding of mechanisms which enable the molecule to induce apoptosis and cell cycle arrest (Karthikeyan et al., 2013; Miki et al., 2012; Sun et al., 2008). It is believed that resveratrol exerts its anticancer activity via regulation of reactive oxygen species (ROS) levels, which trigger downstream signaling pathways. Many studies have conferred contradictory findings since the

67

Fig. 2. Number of publications in the past decade retrieved using the search term “Resveratrol” from Web of Science (http://apps.webofknowledge.com/; results for a search conducted on 31st October 2014).

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003

65

68 69 70 71 72 73 74 75 76 77 78 79 80 81 82

G Model

IJP 14586 1–9 N. Summerlin et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148

molecule was found to act either as antioxidant or pro-oxidant, rendering it difficult to conclude which of the two mechanisms is more dominant. Oxidative stress is known to contribute to carcinogenesis, with free radicals causing lipid peroxidation and DNA damage. ROS can interact with the polyunsaturated phospholipids on cell membranes, causing subsequent generation of products that could detrimentally react with cellular proteins and DNA (Marnett, 2002). Senggottuvelan et al. conducted an in vivo study on Wistar male rats to investigate the role of resveratrol in reducing ROS levels. The animals were injected with 1,2-dimethylhydrazine (DMH) to induce colon carcinogenesis and received resveratrol (8–12 mg/kg) daily for two weeks. The results revealed that long-term supplementation significantly ameliorated DNA damage induced by DMH (Sengottuvelan et al., 2009). The phenolic groups of resveratrol have anti-peroxidative effects, which can scavenge lipid hydroperoxyl, hydroxyl and superoxide anion radicals (Murias et al., 2005). Chronic supplementation of the drug was also found to enhance antioxidant activity in cells by elevating levels of superoxide dismutase (SOD), catalase and other antioxidant enzymes, as well as increasing levels of various co-factors such as glutathione, vitamin C, vitamin E and b-carotene (Sengottuvelan et al., 2009). These findings suggest that resveratrol may play a major role in preventing the initiation of carcinogenesis and that this benefit is more evident with long-term supplementation. Apart from being the cellular powerhouse, the mitochondrion also controls the cell cycle (McBride et al., 2006). Khan et al. (2013) found that resveratrol increased the expression of SOD in PC-3, HepG2 and MCF-7 cells. Since SOD catalyses the conversion of superoxide anions to H2O2, disproportional upregulation of the enzyme causes H2O2 accumulation in the mitochondria which subsequently leads to cellular apoptosis (Chong et al., 2014; Khan et al., 2013). This effect of resveratrol was cell specific, as MCF7 cells did not exhibit increased apoptosis after resveratrol treatment (Khan et al., 2013). Additionally, elevation of ROS level in hypoxic conditions of the tumor microenvironment causes the activation and stabilization of hypoxia-induced factor (HIF). This transcriptional factor is responsible for glucose metabolism and suppression of apoptosis in cells (Gordan et al., 2007). Jung et al. (2013) proposed that ROS and HIF-1a could potentially link resveratrol to its anticancer effects in Lewis lung carcinoma (LLC), T47D breast cancer and HT29 colon cancer cells. Resveratrol’s anticancer efficacy was found to be dependent on its capacity to sequester intracellular ROS. The therapeutic markedly reduced ROS level, which in turn downregulated the expression of HIF-1a. Consequently, low HIF-1a levels decreased glucose uptake by cancer cells, leading to low expression of glucose transporter 1 (GLUT-1) and poor glycolytic metabolism. Conversely, treatment with ROS inducers successfully reversed the antioxidant activity of resveratrol (Jung et al., 2013). The polyphenol was also shown to prevent the uptake of hexoses by interacting directly with GLUT-1 at the endofacial binding site of glucose (Salas et al., 2013). These findings are in agreement with a study performed by Fouad et al. (2013) which claimed that this calorie restriction pathway could contribute to resveratrol anticancer activities in human colorectal cancer cell lines (HCT116 and Caco2). Glucose consumption by the cancer cells was considerably reduced as a result of the resveratrol-mediated decrease in uptake and metabolism of the sugar, creating a state which mimicked cell starvation (Fouad et al., 2013). Conversely, resveratrol may exhibit pro-oxidant activity in the presence of elevated intracellular copper ions within cancer cells, a property that has been extensively studied by Khan and colleagues (Khan et al., 2011, 2014; Ullah et al., 2013). The group found that MCF-10A cells, which do not possess detectable copper ion,

3

demonstrated no response to resveratrol and other polyphenols. When these cells were cultured in copper-enriched media, they became sensitized to polyphenol-induced growth inhibition (Khan et al., 2014). It is postulated that the polyphenols directly interact with copper ions at the DNA level and cause localized generation of hydroxyl radicals, which are responsible for ROS-mediated DNA breakage (Ullah et al., 2013). Tumor cells are more susceptible to oxidative stress due to their heightened basal ROS level. Hence, further ROS generation can potentially harm the oxidative balance and cause apoptosis (Khan et al., 2011). An in vitro study conducted on gastric cancer cells also associated cellular apoptosis to ROS-mediated DNA damage, as apoptosis was significantly inhibited after the cells were treated with ROS scavengers such as SOD and/or catalase enzymes (Wang et al., 2012). Moreover, resveratrol was proven to be able to generate phenoxyl radicals via the peroxidase-H2O2 system, which could promote subsequent oxygen uptake to generate ROS (Shao et al., 2009). Yaseen et al. (2012) observed the synergistic effects of resveratrol co-administered with histone deacetylase inhibitors (HDACIs) in triggering apoptosis of human acute myeloid leukemia (AML) cells. The combination led to a sustained generation of ROS, which was accompanied by pronounced increases in DNA cleavage and cell apoptosis, effects which neither treatment was able to achieve on its own. Furthermore, the combination also activated the ROS-dependent expression of death receptors (DR5), leading to the activation of caspase enzymes. Ultimately, the synergy between both agents activated the extrinsic pro-apoptotic cascade in the cancer cells (Yaseen et al., 2012). Similar results were obtained in human colon cancer cells, HT-29 and COLO 201, as resveratrol also induced caspase-dependent apoptosis through ROS production. With elevated ROS production, resveratrol could potentially cause apoptosis via the death receptor pathway and autophagy (Miki et al., 2012). Despite these promising findings on the anticancer effects of resveratrol, the in vitro nature of all studies has limited applicability in vivo due to the lack of suitable drug carrier to target tumor cells in the body. It is reported that resveratrol’s cardioprotective effects are the result of its ability to scavenge H2O2 (which increases vascular resistance to oxidative), stimulation of endothelial nitric oxide synthase (which inhibits platelet aggregation and induces vasodilation) and inhibition of LDL oxidation (Catalgol et al., 2012). On the other hand, the compound also exerts neuroprotective effects against neurodegenerative diseases. For instance, resveratrol is able to inhibit the formation and aggregation of b-amyloid peptide which is responsible for neuronal dysfunction and death associated with Alzheimer’s disease due to its ROS generating actions (Richard et al., 2011).

149

3. Resveratrol nanoformulations

197

Resveratrol is currently marketed as a nutritional supplement available in traditional dosage forms including tablets, capsules and powders, although data regarding their efficacy is scarce (Rossi et al., 2012). Novel drug delivery systems, such as polymeric nanoparticles, cyclodextrins, micelles and liposomes, provide several advantages over traditional forms including the ability to enhance resveratrol’s aqueous solubility and bioavailability, improve physico-chemical stability and enable targeted and controlled drug release (da Rocha Lindner et al., 2013; Gokce et al., 2012; Venuti et al., 2014) (Fig. 1). Nano-sized formulations are additionally advantageous in cancer therapeutics due to the enhanced permeation and retention (EPR) effect, by which these molecules accumulate preferentially in cancer tissues. Maeda et al. were among the pioneers who proposed the EPR effect to explain the selective accumulation of nanocarriers around solid

198

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003

150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196

199 200 201 202 203 204 205 206 207 208 209 210 211 212

G Model

IJP 14586 1–9 4 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241

N. Summerlin et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx

tumors and had since then developed numerous drug delivery strategies to exploit this phenomenon (Fang et al., 2003; Iyer et al., 2006; Maeda, 2001a,b; Maeda et al., 2009; Matsumura and Maeda, 1986). Since blood vessels surrounding the tumor tissues are highly fenestrated with pore sizes ranging from 380 nm to 780 nm (Hobbs et al., 1998), nanoparticles can easily diffuse out of the vasculature and accumulate in the interstitial fluid as the lymphatic system of the cancerous tissues is also impaired (Fang et al., 2011). In this section we have reviewed well-studied nanoformulations focused on enhancing therapeutic potential of Q3 resveratrol in the past decade (Table 1). 3.1. Liposomes Liposomes were among the first nanoformulations to make the transition from concept to clinical use. The vesicles consist of an aqueous core enclosed within a phospholipid bilayer, giving them stark resemblance to the mammalian plasma membrane (Allen and Cullis, 2013; Lasic, 1992; Seguin et al., 2013). Various additional constituents including cholesterol may be incorporated into the liposomal bilayer to improve stability of the vesicle (Lee et al., 2005). Depending upon the method of synthesis, liposomes can be formulated to a range of sizes, varying from tens of nanometers to several microns (Fenske et al., 2008; Lasic, 1992). Based on the size and the number of bilayers, liposomes can be identified as multilamellar (MLV; >1 bilayer), giant unilamellar (GUV; >0.5 mm), large unilamellar (LUV; >0.1 mm) or small unilamellar (SUV; <0.1 mm) vesicles (Moscho et al., 1996; Sharma and Sharma, 1997). Liposomes offer unique opportunities to carry hydrophilic drugs in the aqueous core and accommodate lipophilic drugs within the phospholipid bilayer (Zhang et al., 2010).

Liposomes can also prevent the photochemical degradation of a variety of drugs and biomolecules. For instance, Coimbra et al. (2011) reported that chemical stability of trans-resveratrol was retained when loaded in liposomes and stored away from light at 4 and 37  C for 48 h. They also found that 70% of encapsulated trans-resveratrol remained intact after 16 min of UV light exposure, as compared to only 10% in the free form (Coimbra et al., 2011), consolidating the useful role of liposomes in preventing photochemical isomerisation. Furthermore, Detoni et al. (2012) also obtained consistent results wherein resveratrol loaded liposomes provided the highest photostability among all the nanoparticle systems tested with only 29.3% isomerisation to cis-resveratrol after 4 h of exposure to UV radiation. Interestingly, the liposomes were found to be unstable after prolonged UV exposure (8 h). Photoisomerization of resveratrol may have potentially disrupted the integrity of the liposomal bilayer as the compound is embedded in the lipid compartment. While the linear configuration of the trans-isomer does not affect the bilayer integrity, subsequent isomerization to the non-linear cis-isomer may have caused the molecule to destabilize and fragment the liposomes (Detoni et al., 2012). Therefore, the modest prevention of resveratrol photochemical isomerisation by liposomes does not eliminate the need to store the formulations away from light. Recently, polyphenols such as curcumin have been stabilized by the use of colloidosomes prepared via pickering emulsion approach. For instance, Tikekar et al., stabilized curcumin within tight network of colloidal silica nanoparticles leading to 100-fold higher stability compared to free curcumin. We believe that resveratrol encapsulated in such a stable inorganic network could improve its photoisomerization compared to its other nanocounterparts (Tikekar et al., 2013; Zhao et al., 2014).

Table 1 Properties of resveratrol formulations. Nanoformulation

Size (nm)

Encapsulation efficiency

Observations

Liposomes

100– 120

95%

Increased resveratrol’s aqueous solubility (Catania et al., 2013; Coimbra et al., 2011; Lu et al., 2012a; Narayanan et al., 2009; Wang et al., 2011) Enhanced cytotoxicity in HeLa and HepG2 cell lines in vitro Reduced growth of subcutaneous head and neck squamouscell carcinoma Very poor drug loading capacity <3% and poor stability Increased efficacy and selectivity for HER2 over-expressing JIMT1 cells but not MCF-7 cells Enhanced cellular uptake and selective accumulation at the mitochondria on human lung cancer A549 Inhibited cell growth and induced apoptosis in vitro and in vivo of PTEN-CaP 8 cells

Solid lipid nanoparticles

150– 586

3–70%

Ease of synthesis and low cost (Carlotti et al., 2012; Jose et al., 2014; Neves et al., 2013; Greater cytostatic effects, intracellular delivery, solubility and Teskac and Kristl, 2010) stability of resveratrol in vitro Poor drug loading

Polymeric nanoparticles

90– 365

42–98%

Increase resveratrol absorption rate constant and area under curve in vivo Increased cytotoxicity and cell uptake in DU-145 and LNCaP cell lines Tedious and costly synthesis Scarcity of safe polymers Moderate drug loading

(Guo et al., 2013a; Sanna et al., 2013; Singh and Pai, 2014)

Polymeric micelles

<100

89%

Good drug loading Protect from b-amyloid peptide toxicity Difficult to scale up synthesis techniques

(Lu et al., 2009)

Cyclodextrins

5–10

1:1 ratio

Increase resveratrol’s aqueous solubility from 0.03 mg/mL to 1.1 mg/mL Improve resveratrol’s cytotoxicity in HeLa, Hep3B and MCF7 cell lines Costly to produce Poor targeting in cancer therapy

(Ansari et al., 2011; Lu et al., 2012b; Silva et al., 2014; Venuti et al., 2014)

Reference

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003

242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272

G Model

IJP 14586 1–9 N. Summerlin et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338

Resveratrol-loaded liposomes have demonstrated adequate physical stability when kept refrigerated at 4  C for up to two months with no significant changes to the particle size or polydispersity (Coimbra et al., 2011; Isailovic et al., 2013; Kristl et al., 2009). Liposomal stability depends in part on the surface zeta (z)-potential, a parameter which provides predictions of electrostatic stabilization in a colloidal system (Doane et al., 2011). A high z-potential (positive or negative) indicates good dispersion stability as charged surfaces prevent aggregation and fusion of the liposomes by electrostatic repulsion. Caddeo et al. (2008) had included dicetyl phosphate and lechitin into their liposomal formulations to obtain negative z-potentials. The zeta potential and particle size were evaluated over the period of 60 days to assess the stability of their formulations on storage at 4  C. No substantial change was observed in the two parameters. Several experiments performed in recent years investigated the feasibility and efficacy of resveratrol-loaded liposomes in targeting cancer cells. The size of liposomes used in the studies ranged from 70 nm to 200 nm, with most of these nanoparticles being designed for passive targeting of cancer by exploiting the pathophysiological abnormalities of the tumor vasculature as previously described. The liposomal surface can be customized to exhibit unique characteristics with the use of different compositions or types of phospholipids. Surface modifications are often performed to improve cellular uptake of liposomes, protect the vesicles from metabolic clearance in vivo and target specific proteins. For instance, Lu et al. (2012a) worked to further reduce the particle size of their lyophilised formulations with the inclusion of poly (ethylene glycol-2000)-grafted distearyl phosphotidylethanolamine (DSPE-PEG2000) in resveratrol-loaded liposomes. The presence of DSPE-PEG2000 reduced average particle size from 120 nm to 100 nm. This observation was attributed to the increased lateral repulsion of the surface in the presence of extensive hydration shell around the polar head group of DSPE-PEG2000. Therefore, surface curvature had to increase to counteract the increased repulsion forces, thereby reducing the overall particle size (Lu et al., 2012a). This effect was in congruence to the results observed by Sriwongsitanont and Ueno (2004). The study found that liposomes with lipid components only had a particle size of 250 nm whereas those containing DSPE-PEG had a decreased size, ranging from 50 nm to 250 nm depending on their DSPE-PEG content. The sizes of large liposomes (>130 nm) were further reduced with repeated freeze-thawing process. Lu et al. (2012a) further tested the anti-cancer effect of resveratrol on HeLa cervical carcinoma and Hep G2 hepatocellular carcinoma cells. The drugloaded DSPE-PEG2000 liposomes were slightly more cytotoxic than standard liposomes, achieving 77.8% HeLa cell death vs. 72.3% after 48 h. On the Hep G2 cells, DSPE-PEG2000 liposomes caused 56.23% cell death after two days, only a slight 0.53% increase in cytotoxicity as compared to vacant liposomes. Furthermore, a cationic liposomal formulation which comprised 1,2-dipalmitoyl-sn-glycero-3-phosphocoline (DPPC, zwitterionic) and 3b-(N0 ,N0 -dimethylaminoethane-carbamoyl) cholesterol (DC-CHOL, cationic) was developed by Bonechi et al. (2012) to deliver resveratrol in vitro. The cationic liposomes demonstrated an improved cellular uptake when compared to their zwitterionic counterparts, which could be due to charge-dependent binding (Bonechi et al., 2012; Krasnici et al., 2003) or electrostatic interactions between the particles and the anionic cell membrane proteins (Guo et al., 2013b). Zwitterionic liposomes rely on clathrin-dependent or independent endocytosis for cellular uptake; however, this process is often inefficient (<1% internalization) (Csiszar et al., 2014). Similarly, Csiszar et al. (2014) synthesized cationic liposomes using 1,2dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoly-sn-glycero-3-phosphoethanolamine (DOPE) for the delivery of resveratrol to primary cerebromicrovascular endothelial cells.

5

Their results were consistent to those of Bonechi et al. as improved cellular uptake was also observed. The group further proposed that resveratrol itself could enhance membrane fusion as a result of the interaction between the cationic liposomes and the delocalized conjugated p electrons on polyphenols (Csiszar et al., 2014). Arguably, sole reliance on passive targeting via the EPR effect may be inadequate for resveratrol delivery. Conventional liposomes may not reach tumor cells but localize in tissue stroma or macrophages (Catania et al., 2013). Through conjugation with antibodies or targeting molecules, the vesicles can actively target cells, which express specific receptors or antigens. Immunoliposomes containing the polyphenols, curcumin and resveratrol have been successfully designed and developed by Catania et al. (2013). Human epidermal growth factor receptor (HER2)-targeting trastuzumab-conjugated immunoliposomes were proven to be successful in targeting breast cancer cells (Barrajon-Catalan et al., 2010). The immunoliposomes showed greater accumulation compared to conventional liposomes in cells which over-express HER2 receptors, leading to improvements in the selectivity, potency and antiproliferative effects of resveratrol on these cells. Meanwhile, it was found that conventional liposomes demonstrated comparable efficacy to immunoliposomes in cells with low HER2 expression (Catania et al., 2013), implying that the potency of these immunoliposomes was dependent on the level of receptor expression of the cells (Barrajon-Catalan et al., 2010). Perhaps one of the most innovative breakthroughs in nanoparticle delivery of resveratrol is the discovery of mitochondrial-targeting liposomes. Modified dequalinium polyethylene glycol-distearoylphosphatidyl ethanolamine (DQA-PEG2000-DSPE) was synthesized by Wang et al. (2011) to allow selective uptake of resveratrol-loaded liposomes by treatment resistant lung cancer cells. The induction of apoptosis in these cells was due to both the increased cellular uptake and accumulation of the drug within the mitochondria, leading to decreased mitochondrial depolarization. As resveratrol was found to potentiate the effects of other anti-cancer agents, this mitochondrial targeting approach could be used as a combinatorial tool in chemotherapy (Sareen et al., 2006; Wang et al., 2011). Recent work done by Mohan et al. (2014) combined the encapsulation of resveratrol with 5-fluorouracil into DSPEPEG2000, egg phosphatidylcholine liposomes to test their synergistic effects on the NT8e head and neck squamous carcinoma cell line. The presence of DSPE-PEG2000 and resveratrol tremendously affected the encapsulation efficiency of 5-fluorouracil in the formulation. Conversely, resveratrol encapsulation was not affected by the presence of 5-fluorouracil but was reduced upon DSPEPEG2000 introduction, potentially because of the enhanced hydrophilicity conferred to the liposomal surface. Regarding formulation cytotoxicity, co-encapsulation with 5-fluorouracil greatly reduced the amount of resveratrol required to attain 50% cell death (5.2 mM vs. 31 mM). More importantly, it was also observed that high resveratrol concentrations had synergistic effects with 5-fluorouracil whereas low concentrations antagonized the chemotherapeutic effects of the drug. These findings provide a promising prelude to the future prospects and efficacies of resveratrol co-encapsulation with other chemotherapeutic agents. However, a major drawback of resveratrol-loaded liposomes remains its low loading capacity. There is limited space available in the phospholipid bilayer to occupy lipophilic drugs before the vesicles lose their structural integrity due to overloading (Chen et al., 2014). The shelf life of liposomal formulations is also short and the formulations require cold storage.

339

3.2. Polymeric nanoparticles

400

Various polymers have been utilized to fabricate nanoparticles with drug compatibility, biocompatibility and degradation kinetics

401

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003

340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399

402

G Model

IJP 14586 1–9 6 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468

N. Summerlin et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx

dictating polymer selection (Parveen and Sahoo, 2008). Commonly used polymers include poly(lactide-co-glycolide) (PLGA), polyethelene glycol (PEG), polycaprolactone (PCL) and polylactide (PLA) (da Rocha Lindner et al., 2013; Parveen and Sahoo, 2008; Singh and Pai, 2014). Drugs can be conjugated to the polymers or dispersed within the polymer matrix and are released by diffusion or due to controlled erosion of the particle (Parveen and Sahoo, 2008). Encapsulating drugs into polymeric nanoparticles protects them from degradation, enables sustained release, enhances intracellular penetration and improves bioavailability (Sanna et al., 2013). Sanna et al. (2013) loaded resveratrol into PCL: PLGA-PEG nanoparticles to compare its cytotoxicity to free resveratrol in DU-145 and LNCaP cell lines in vitro. The synthesized nanoparticles were spherical, had an average diameter of 150 nm, a polydispersity index of 0.125 and z-potential of 25.7 mV (Sanna et al., 2013). Encapsulation efficiency ranged from 73% to 98% and drug loading was between 1.5% and 4% w/w depending upon the synthesized formulation. The nanoparticles showed increased cellular uptake, sustained release over 24 h and increased cytotoxicity in DU-145 and LNCaP cells compared to free resveratrol. However the low drug loading capacity severely hinders their use and increases the expense of this formulation. Singh and Pai (2014) encapsulated resveratrol in PLGA nanoparticles to examine the effect on its release profile and bioavailability in vivo. Varying the quantity of PLGA and emulsifier created thirteen varieties of nanoparticles. The produced nanoparticles ranged in diameter between 90 nm and 365 nm, had a z-potential between 24.7 mV and 27.6 mV and encapsulation efficiencies between 42% and 72%. Resveratrol was released over 12 days and the nanoparticles remained stable for at least 6 months. Their results revealed that encapsulation of resveratrol into PLGA nanoparticles increased the absorption rate constant 7-fold and the area under the curve 10-fold compared with both pure drug and a marketed resveratrol product, indicating a significant enhancement in bioavailability. Guo et al. (2013a) produced resveratrol loaded PEG-PLA nanoparticles (PNP) and transferrin modified PEG-PLA nanoparticles (Tf-PNP) to investigate resveratrol’s antitumor activity in gliomas in vitro and in vivo. Transferrin receptors are exclusively expressed on brain capillaries enabling targeted delivery. Both nanoparticles were approximately 150 nm in diameter with an encapsulation efficiency of 80% and drug loading of 4.4% w/w. An in vitro release study showed both nanoparticles exhibited sustained release with no more than 10% of resveratrol released in the first 24 h. Free resveratrol, PNP and TfPNP all showed cytotoxicity in C6 glioma and U87 cells although the drug-encapsulated particles showed far greater cytotoxicity than the native compound. For example in C6 cells the IC50 value of free resveratrol was 42.37 mmol/L whereas for PNP and Tf-PNP it was 10.72 mmol/L and 4.11 mmol/L, respectively. The empty nanoparticles demonstrated no cytotoxicity. Resveratrol, PNP and Tf-PNP all accumulated in brain tumor and significantly decreased tumor volume, allowing prolonged survival in rats with C6 glioma. Furthermore, Yin et al. (2014) prepared resveratrol loaded methoxy-PEG-PCL nanoparticles (mPEG-PCL-NP) to evaluate the antioxidant activity of the drug. They found loaded mPEGPCL-NP exhibited greater radical scavenging and anti-lipid peroxidization compared to free resveratrol in aqueous solution. The polymers PLGA, PEG, PCL and PLA are biocompatible, biodegradable and non-toxic and therefore has been approved for use by the FDA; however, their fabrication into nanoparticles is both time consuming and expensive (Parveen and Sahoo, 2008). PLA use is hindered by its poor solubility in water (Parveen and Sahoo, 2008), whilst PCL degrades more slowly than other polymers, thus is best suited for sustained release (Parveen and Sahoo, 2008). A common challenge preventing growth in this discipline has been the scarcity of nontoxic polymers that may be

utilized to generate nanoparticles (Kamble et al., 2010). Overall incorporating resveratrol into polymeric nanoparticles overcomes some of the therapeutic pharmacokinetic hindrances, however again poor drug loading impedes their use. Additionally, Lu et al. (2009) prepared resveratrol loaded polymeric micelles to investigate the drug’s protective ability against b-amyloid peptide toxicity in PC12 cells. Polymeric micelles are synthesized from block-copolymers, which consist of hydrophilic and hydrophobic monomer units (Xu et al., 2013). They are able to self-assemble into nanoparticles when the block copolymer concentration increases above the critical micelle concentration (Lu et al., 2009; Xu et al., 2013). Polymeric micelles possess a hydrophilic shell and a hydrophobic core where poorly water-soluble drugs can be incorporated (Lavasanifar et al., 2002). The polymeric micelles prepared by Lu et al. (2009) were not larger than 100 nm, with an encapsulation efficiency of 89% and drug loading of 20% w/w. In vitro drug release studies showed an initial burst of 35% over 8 h followed by sustained release over five days. When the cells were pre-incubated with resveratrol loaded polymeric micelles for 12 h they were protected from b-amyloid peptide toxicity in a dose dependent manner. This was due to the drug attenuating intracellular oxidative stress and caspase-3 activity. However, a major limitation of polymeric micelles is the difficulty in scaling up current synthesis techniques, impacting their commercial attractiveness (O’Reilly et al., 2006). The use of polymeric micelles is also hindered by their limited stability in blood (Kim et al., 2010).

469

3.3. Solid lipid nanoparticles

495

There is growing interest in solid lipid nanoparticles (SLN) as they combine advantages of polymeric nanoparticles and lipid emulsions whilst overcoming some of their disadvantages (Ekambaram et al., 2012). SLN are spherical and composed of a lipid core surrounded by a surfactant, consequently they have a hydrophilic surface with a hydrophobic core (Souto and Muller, 2010). This allows for easy loading of hydrophobic drugs such as resveratrol into the core, although hydrophilic drugs may also be incorporated into the particles (Souto and Muller, 2010). SLN increase the chemical stability of loaded drugs more so than liposomes, by protecting the compound from hydrolysis, oxidation and photodegradation, whilst also enhancing bioavailability (Teskac and Kristl, 2010). SLN are typically synthesized using high pressure homogenization, which is cost effective and allows large scale production (Jenning et al., 2002). A key benefit of this technique over other nanoformulations is the ability to avoid the use of organic solvents in their production, thus avoiding associated toxicological problems (Parveen and Sahoo, 2008). Other methods for SLN production include high shear homogenization, solvent evaporation and film-ultrasound dispersion (Ekambaram et al., 2012). SLN are biocompatible, stable and able to pass through cell membranes without altering cell morphology (Souto and Muller, 2010). However the particles suffer from limitations such as reduced drug loading and drug expulsion due to polymeric transition during storage (Kamble et al., 2010; Yadav et al., 2013). Cellular uptake of SLN can be manipulated by altering their surface properties, allowing cell targeting. Teskac and Kristl (2010) prepared resveratrol loaded SLN to investigate cellular uptake, transport and internalization in keratinocytes in vitro. The loaded SLN were 180 nm in diameter, had a polydispersity index of 0.3 and z-potential of 38 mV. These characteristics were retained for at least four weeks. An initial burst release of resveratrol was observed from the SLN, indicative of entrapment in the shell, followed by sustained release over 5 h presumably from the core. The particles readily crossed the cell membrane in as little as 15 min. In comparison with resveratrol in solution, the SLNencapsulated drug exhibited greater cytostatic effects, intracellular

496

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003

470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494

497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532

G Model

IJP 14586 1–9 N. Summerlin et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx 533

577

delivery, solubility and stability. Carlotti et al. (2012) prepared resveratrol-loaded SLN to evaluate their uptake and lipoperioxidative activity in vitro. The synthesized particles ranged from 293 nm to 586 nm in diameter depending upon the formulation used. They had an average z-potential of 42.5 mV, a polydispersity index of 0.284 and encapsulation efficiency of 52.3%. It was concluded that compared to free resveratrol in solution, SLN were able to protect the drug from photodegredation, enhance its uptake in porcine ear skin and improve its anti-lipoperioxidative activity. SLN appear to be a promising delivery system however, more studies involving resveratrol encapsulation are necessary. Neves et al. (2013) produced resveratrol loaded SLN to evaluate the physical and chemical protection conferred to the drug. It was also examined whether this would lessen the molecules instability and control its release, therefore enhancing its therapeutic effects. The SLN ranged from 150 nm to 250 nm with a polydispersity index of 0.2 and z-potential of 30 mV. These characteristics remained unchanged for two months indicating good stability. The average entrapment efficiency was higher than previous studies reaching 70%. To predict the in vivo kinetics, an in vitro simulation of gastrointestinal transit was performed. This showed an initial burst release (8%) in the simulated gastric fluid (pH 1.2) over 3 h followed sustained release in the simulated intestinal fluid (pH 7.4). Therefore it was concluded SLN would be suitable for oral administration due to their ability to protect resveratrol and control its release. Jose et al. (2014) prepared resveratrol loaded glyceryl behenate SLN to investigate the possibility of brain targeting. SLN were synthesized with varying drug–lipid ratios (1:5–1:15) and it was noted particle size increased from 236 nm to 570 nm with the increasing ratio. Encapsulation efficiency also increased accordingly from 3% to 37%, most likely due to the additional space. However the maximum drug loading was only 3% w/w which is extremely low considering the dose of Res. The resveratrol SLN exhibited a sustained release in phosphate buffer in vitro as well as being equally as cytotoxic as free resveratrol in C6 glioma cell lines, while the empty SLN showed no cytotoxicity. In vivo biodistribution was examined in rats and demonstrated that SLN significantly increased brain concentrations of resveratrol when compared with free resveratrol, 17.3 mg/g and 3.5 mg/g. This was thought to be due to the inclusion of Tween 80 in within the shell formation, which through its hydrophilic nature may reduce its uptake by other organs. Whilst SLN offer several advantages over other systems, low drug loading capacity serves as their primary limitation and a lot of work is needed in order to prepare clinically relevant formulation based on SLN.

578

3.4. Cyclodextrins

534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576

579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596

Cyclodextrins (CD) are cyclic oligosaccharides produced from starch that possess a hydrophilic surface and hydrophobic inner cavity (Tiwari et al., 2010). CD are typically between 1 nm and 2 nm in diameter and have a truncated shape which allows the entrapment of foreign molecules inside their inner cavity (Lu et al., 2012b). Commonly found natural CD include a, b and g, which contain 6, 7 and 8 glucopyranose units respectively (Tiwari et al., 2010). CD can easily be modified to enhance their properties (Tiwari et al., 2010). The sugars have attracted attention as a pharmaceutical delivery system due to their ability to form inclusion complexes with drugs and their recognition by the FDA for being “generally regarded as safe” (Administration, 2013). These complexes enhance the aqueous solubility, dissolution rate and bioavailability of drugs, prevent crystallization and improve stability (Tiwari et al., 2010). The use of CD is hindered by potential nephrotoxicity and the potential to alter the pharmacokinetics of drugs when rapid dissociation does not occur (Peters, 2012). Bulk CD production is possible albeit limited by high costs (Szejtli,

7

2004). Venuti et al. (2014) formed a resveratrol sulfobutyletherb-CD complex in a 1:1 ratio to examine the influence on drug aqueous solubility and anticancer efficacy against MCF-7 cells in vitro. The study concluded that the complexation strongly increased aqueous solubility, from 0.03 mg/mL to 1.1 mg/mL at 25  C, and positively influenced cytotoxic activity of the drug. The CD molecule without resveratrol had no effect on cell viability. Lu et al. (2012b) formed resveratrol inclusion complexes with both b-CD and 2-hydroxypropyl-b-CD to evaluate its impact on drug cytotoxicity in both cancerous (HeLa and Hep3B) and healthy (HUVEC) cell populations. The complexes improved drug cytotoxicity in cancer cells yet demonstrated no detrimental effect on healthy cells. Free resveratrol concentration in water was 0.077 mmol/L, and when complexed in 8 mM CD, drug concentration increased 12.6-fold in b-CD and 50.5-fold in 2-hydroxypropylb-CD. Silva et al. (2014) formed resveratrol inclusion complexes with hydropropyl-b-CD (HP-b-CD), hydropropyl-g-CD (HP-g-CD) in a 1:1 ratio, to increase formulation solubility. The CD complexes greatly increased resveratrol’s aqueous solubility, showing a roughly 5-log fold increase for both the HP-b-CD and HP-g-CD. The maximum solubility for the HP-b-CD complex was 38.7 mg/mL whereas in the case of the HP-g-CD complex, it was 22.7 mg/mL. It was also found that HP-b-CD increased the photostability of resveratrol more significantly then HP-g-CD. Interestingly, Silva et al. also compared the change in solubility using bile salts, which were less effective. In addition, Ansari et al. (2011) concluded that CD complexation increases the photostability of resveratrol. CD complexes greatly increase resveratrol’s aqueous solubility however their use in cancer therapy is limited due to their lack of targeting and high production costs.

597

4. Conclusions and prospects

627

Resveratrol has emerged as an extremely promising natural molecule due to its vast therapeutic prospects. However, the potential of the drug is immensely hindered by its poor pharmacokinetic properties. In hope of overcoming these limitations, resveratrol has been incorporated into various drug delivery formulations. In recent years nanoencapsulation has emerged as a promising new area for drug delivery. Such nanoformulations are able to target drug to specific cells, reducing the required doses and thereby toxicity. It can be seen that incorporating resveratrol into nanoformulations successfully overcomes some of the barriers to resveratrol’s physicochemical properties. However, nanoencapsulation of resveratrol is still in its infancy. A lot of challenges remain such as long-term safety of nanoparticles, its interaction with biological systems, forming reproducible and colloidally stable nanoformulations and improving the loading capacity of resveratrol to make it cost effective. Therefore a rational design is necessary to formulate nanoformulations of resveratrol with high loading capacity, colloidal stability, which will allow us to leverage the pharmacological properties of resveratrol at the most. Additionally, there is some evidence that resveratrol exerts synergistic effect with other drugs such as curcumin and 5-FU, but further testing needs to be done to confirm this hypothesis in different cell lines and in pre-clinical models. Recent advances in nanomaterial synthesis and rapid research in inorganic nanoparticle field may provide an attractive alternative over traditional nanocarriers in delivering hydrophobic drugs such as resveratrol more effectively. So far resveratrol nanoformulations have shown anticancer, anti-inflammatory effects and improved bioavailability mainly in vitro models or cell lines. More comprehensive pre-clinical and clinical testing is warranted to further attest its potential as a sole therapeutic agent for the treatment of cancer or cardiovascular disease.

628

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003

598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626

629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660

G Model

IJP 14586 1–9 8

N. Summerlin et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx

661

Acknowledgements

662 664

We acknowledge the Australian Research Council, the National Health and Medical Research Council Early Career Fellowship and The University of Queensland for their support.

665

References

663

666 Q4 Administration, U.S.F.D.A., 2013. Agency Response Letter GRAS Notice No. GRN 155. 667 Allen, T.M., Cullis, P.R., 2013. Liposomal drug delivery systems: from concept to 668 clinical applications. Adv. Drug Deliv. Rev. 65, 36–48. 669 Almeida, L., Vaz-da-Silva, M., Falcao, A., Soares, E., Costa, R., Loureiro, A.I., 670 Fernandes-Lopes, C., Rocha, J.F., Nunes, T., Wright, L., Soares-da-Silva, P., 2009. 671 Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose 672 study in healthy volunteers. Mol. Nutr. Food Res. 53, S7–15. 673 Aluyen, J.K., Ton, Q.N., Tran, T., Yang, A.E., Gottlieb, H.B., Bellanger, R.A., 2012. 674 Resveratrol: potential as anticancer agent. J. Diet. Suppl. 9, 45–56. 675 Ansari, K.A., Vavia, P.R., Trotta, F., Cavalli, R., 2011. Cyclodextrin-based nanosponges 676 for delivery of resveratrol: in vitro characterisation, stability, cytotoxicity and 677 permeation study. AAPS PharmSciTech 12, 279–286. 678 Augustin, M.A., Sanguansri, L., Lockett, T., 2013. Nano- and micro-encapsulated 679 systems for enhancing the delivery of resveratrol. Ann. N.Y. Acad. Sci. 1290, 680 107–112. 681 Barrajon-Catalan, E., Menendez-Gutierrez, M.P., Falco, A., Carrato, A., Saceda, M., 682 Micol, V., 2010. Selective death of human breast cancer cells by lytic 683 immunoliposomes: correlation with their HER2 expression level. Cancer Lett. 684 290, 192–203. 685 Bonechi, C., Martini, S., Ciani, L., Lamponi, S., Rebmann, H., Rossi, C., Ristori, S., 2012. 686 Using liposomes as carriers for polyphenolic compounds: the case of trans687 resveratrol. PLoS One 7, 1–11. 688 Burns, J., Yokota, T., Ashihara, H., Lean, M.E., Crozier, A., 2002. Plant foods and herbal 689 sources of resveratrol. J. Agric. Food Chem. 50, 3337–3340. 690 Caddeo, C., Teskac, K., Sinico, C., Kristl, J., 2008. Effect of resveratrol incorporated in 691 liposomes on proliferation and UV-B protection of cells. Int. J. Pharm. 363, 692 183–191. 693 Carlotti, M., Sapino, S., Ugazio, E., Gallarate, M., Morel, S., 2012. Resveratrol in solid 694 lipid nanoparticles. J. Dispers. Sci. Technol. 33, 465–471. 695 Catalgol, B., Batirel, S., Taga, Y., Ozer, N.K., 2012. Resveratrol: French paradox 696 revisited. Front. Pharmacol. 3, 141. 697 Catania, A., Barrajon-Catalan, E., Nicolosi, S., Cicirata, F., Micol, V., 2013. 698 Immunoliposome encapsulation increases cytotoxic activity and selectivity of 699 curcumin and resveratrol against HER2 overexpressing human breast cancer 700 cells. Breast Cancer Res. Treat. 141, 55–65. 701 Chen, J., Lu, W.L., Gu, W., Lu, S.S., Chen, Z.P., Cai, B.C., Yang, X.X., 2014. Drug-in702 cyclodextrin-in-liposomes: a promising delivery system for hydrophobic drugs. 703 Exp. Opin. Drug Deliv. 11, 565–577. 704 Q5 Chong, S.J., Low, I.C., Pervaiz, S., 2014. Mitochondrial ROS and involvement of Bcl 705 -2 as a mitochondrial ROS regulator. Mitochondrion (in press). 706 Coimbra, M., Isacchi, B., van Bloois, L., Torano, J.S., Ket, A., Wu, X., Broere, F., 707 Metselaar, J.M., Rijcken, C.J., Storm, G., Bilia, R., Schiffelers, R.M., 2011. Improving 708 solubility and chemical stability of natural compounds for medicinal use by 709 incorporation into liposomes. Int. J. Pharm. 416, 433–442. 710 Cottart, C.H., Nivet-Antoine, V., Laguillier-Morizot, C., Beaudeux, J.L., 2010. 711 Resveratrol bioavailability and toxicity in humans. Mol. Nutr. Food Res. 54, 7–16. 712 Csiszar, A., Csiszar, A., Pinto, J.T., Gautam, T., Kleusch, C., Hoffmann, B., Tucsek, Z., 713 Q6 Toth, P., Sonntag, W.E., Ungvari, Z., 2014. Resveratrol encapsulated in novel 714 fusogenic liposomes activates Nrf2 and attenuates oxidative stress in 715 cerebromicrovascular endothelial cells from aged rats. J. Gerontol. A: Biol. Sci. Med. Sci.. 716 da Rocha Lindner, G., Khalil, N.M., Mainardes, R.M., 2013. Resveratrol-loaded 717 Q7 polymeric nanoparticles: validation of an HPLC-PDA method to determine the 718 drug entrapment and evaluation of its antioxidant activity. Sci. World J. 2013, 719 506083. 720 Detoni, C.B., Souto, G.D., da Silva, A.L., Pohlmann, A.R., Guterres, S.S., 2012. 721 Photostability and skin penetration of different E-resveratrol-loaded 722 supramolecular structures. Photochem. Photobiol. 88, 913–921. 723 Doane, T.L., Chuang, C.-H., Hill, R.J., Burda, C., 2011. Nanoparticle zeta-potentials. Acc. 724 Chem. Res. 45, 317–326. 725 Ekambaram, P., Sathali, A., Priyanka, K., 2012. Solid lipid nanoparticles: a review. Sci. 726 Rev. Chem. Commun. 2, 80–102. 727 Fang, J., Sawa, T., Maeda, H., 2003. Factors and mechanism of EPR effect and the 728 enhanced antitumor effects of macromolecular drugs including SMANCS. Adv. 729 Exp. Med. Biol. 519, 29–49. 730 Fang, J., Nakamura, H., Maeda, H., 2011. The EPR effect: unique features of tumor 731 blood vessels for drug delivery, factors involved, and limitations and 732 augmentation of the effect. Adv. Drug Deliv. Rev. 63, 136–151. 733 Fenske, D.B., Chonn, A., Cullis, P.R., 2008. Liposomal nanomedicines: an emerging 734 field. Toxicol. Pathol. 36, 21–29. 735 Fouad, M.A., Agha, A.M., Merzabani, M.M., Shouman, S.A., 2013. Resveratrol inhibits 736 proliferation: angiogenesis and induces apoptosis in colon cancer cells: calorie 737 restriction is the force to the cytotoxicity. Hum. Exp. Toxicol. 32, 1067–1080. 738 Gokce, E.H., Korkmaz, E., Dellera, E., Sandri, G., Bonferoni, M.C., Ozer, O., 2012. 739 Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid

carriers: evaluation of antioxidant potential for dermal applications. Int. J. Nanomed. 7, 1841–1850. Gordan, J.D., Thompson, C.B., Simon, M.C., 2007. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12, 108–113. Guo, W., Li, A., Jia, Z., Yuan, Y., Dai, H., Li, H., 2013a. Transferrin modified PEG-PLAresveratrol conjugates: in vitro and in vivo studies for glioma. Eur. J. Pharmacol. 718, 41–47. Guo, X.-X., He, W., Zhang, X.-J., Hu, X.-M., 2013b. Cytotoxicity of cationic liposomes coated by N-trimethyl chitosan and their in vivo tumor angiogenesis targeting containing doxorubicin. J. Appl. Polym. Sci. 128, 21–27. Hobbs, S.K., Monsky, W.L., Yuan, F., Roberts, W.G., Griffith, L., Torchilin, V.P., Jain, R.K., 1998. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. U. S. A. 95, 4607–4612. Isailovic, B.D., Kostic, I.T., Zvonar, A., Dordevic, V.B., Gasperlin, M., Nedovic, V.A., Bugarski, B.M., 2013. Resveratrol loaded liposomes produced by different techniques. Innov. Food Sci. Emerg. Technol. 19, 181–189. Iyer, A.K., Khaled, G., Fang, J., Maeda, H., 2006. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov. Today 11, 812–818. Jang, M., Cai, L., Udeani, G.O., Slowing, K.V., Thomas, C.F., Beecher, C.W., Fong, H.H., Farnsworth, N.R., Kinghorn, A.D., Mehta, R.G., Moon, R.C., Pezzuto, J.M., 1997. Cancer chemopreventive activity of resveratrol a natural product derived from grapes. Science (New York, N.Y.) 275, 218–220. Jenning, V., Lippacher, A., Gohla, S.H., 2002. Medium scale production of solid lipid nanoparticles (SLN) by high pressure homogenization. J. Microencapsul. 19, 1–10. Jose, S., Anju, S.S., Cinu, T.A., Aleykutty, N.A., Thomas, S., Souto, E.B., 2014. In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery. Int. J. Pharm. 474, 6–13. Jung, K.H., Lee, J.H., Thien Quach, C.H., Paik, J.Y., Oh, H., Park, J.W., Lee, E.J., Moon, S.H., Lee, K.H., 2013. Resveratrol suppresses cancer cell glucose uptake by targeting reactive oxygen species-mediated hypoxia-inducible factor-1alpha activation. J. Nucl. Med.: Off. Publ. Soc. Nucl. Med. 54, 2161–2167. Kamble, V., Jagdale, D., Kadam, V., 2010. Solid lipid nanoparticles as drug delivery system. Int. J. Pharma Bio Sci. 1, 1–9. Karthikeyan, S., Rajendra Prasad, N., Ganamani, A., Balamurugan, E., 2013. Anticancer activity of resveratrol-loaded gelatin nanoparticles on NCIH460 non-small cell lung cancer cells. Biomed. Prev. Nutr. 3, 64–73. Khan, H.Y., Zubair, H., Ullah, M.F., Ahmad, A., Hadi, S.M., 2011. Oral administration of copper to rats leads to increased lymphocyte cellular DNA degradation by dietary polyphenols: implications for a cancer preventive mechanism. Biometals: Int. J. Metal Ions Biol. Biochem. Med. 24, 1169–1178. Khan, M.A., Chen, H.C., Wan, X.X., Tania, M., Xu, A.H., Chen, F.Z., Zhang, D.Z., 2013. Regulatory effects of resveratrol on antioxidant enzymes: a mechanism of growth inhibition and apoptosis induction in cancer cells. Mol. Cells 35, 219–225. Khan, H.Y., Zubair, H., Faisal, M., Ullah, M.F., Farhan, M., Sarkar, F.H., Ahmad, A., Hadi, S.M., 2014. Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: a mechanism for cancer chemopreventive action. Mol. Nutr. Food Res. 58, 437–446. Kim, S., Shi, Y., Kim, J.Y., Park, K., Cheng, J.X., 2010. Overcoming the barriers in micellar drug delivery: loading efficiency, in vivo stability, and micelle–cell interaction. Exp. Opin. Drug Deliv. 7, 49–62. Kraft, T.E., Parisotto, D., Schempp, C., Efferth, T., 2009. Fighting cancer with red wine? Molecular mechanisms of resveratrol. Crit. Rev. Food Sci. Nutr. 49, 782–799. Krasnici, S., Werner, A., Eichhorn, M.E., Schmitt-Sody, M., Pahernik, S.A., Sauer, B., Schulze, B., Teifel, M., Michaelis, U., Naujoks, K., Dellian, M., 2003. Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels. Int. J. Cancer 105, 561–567. Kristl, J., Teskac, K., Caddeo, C., Abramovic, Z., Sentjurc, M., 2009. Improvements of cellular stress response on resveratrol in liposomes. Eur. J. Pharm. Biopharm. 73, 253–259. Lasic, D., 1992. Liposomes. Am. Sci. 80, 20–31. Lavasanifar, A., Samuel, J., Kwon, G.S., 2002. Poly(ethylene oxide)-block-poly(Lamino acid) micelles for drug delivery. Adv. Drug Deliv. Rev. 54, 169–190. Lee, S.-C., Lee, K.-E., Kim, J.-J., Lim, S.-H., 2005. The effect of cholesterol in the liposome bilayer on the stabilisation of incorporated retinol. J. Liposome Res. 15, 157–166. Lopez-Hernandez, J., Paseiro-Losado, P., Sanches-Silva, A.T., Lage-Yusty, M.A., 2007. Study of the changes of trans-resveratrol caused by ultraviolet light and the determination of trans- and cis-resveratrol in Spanish white wines. Eur. Food Res. Technol. 225, 789–796. Lu, X., Ji, C., Xu, H., Li, X., Ding, H., Ye, M., Zhu, Z., Ding, D., Jiang, X., Ding, X., Guo, X., 2009. Resveratrol-loaded polymeric micelles protect cells from Abeta-induced oxidative stress. Int. J. Pharm. 375, 89–96. Lu, X.-Y., Hu, S., Jin, Y., Qiu, L.-Y., 2012a. Application of liposome encapsulation technique to improve anti-carcinoma effect of resveratrol. Drug Dev. Ind. Pharm. 38, 314–322. Lu, Z., Chen, R., Fu, R., Xiong, J., Hu, Y., 2012b. Cytotoxicity and inhibition of lipid peroxidation activity of resveratrol/cyclodextrin inclusion complexes. J. Incl. Phenom. Macrocycl. Chem. 73, 313–320. Maeda, H., 2001a. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzym. Regul. 41, 189–207.

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003

740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821

G Model

IJP 14586 1–9 N. Summerlin et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896

Maeda, H., 2001b. SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv. Drug Deliv. Rev. 46, 169–185. Maeda, H., Bharate, G.Y., Daruwalla, J., 2009. Polymeric drugs for efficient tumortargeted drug delivery based on EPR-effect. Eur. J. Pharm. Biopharm.: Off. J. Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 71, 409–419. Marnett, L.J., 2002. Oxy radicals: lipid peroxidation and DNA damage. Toxicology 181–182, 219–222. Matsumura, Y., Maeda, H., 1986. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392. Mattarei, A., Azzolini, M., Carraro, M., Sassi, N., Zoratti, M., Paradisi, C., Biasutto, L., 2013. Acetal derivatives as prodrugs of resveratrol. Mol. Pharm. 10, 2781–2792. McBride, H.M., Neuspiel, M., Wasiak, S., 2006. Mitochondria: more than just a powerhouse. Curr. Biol. 16, R551–R560. Miki, H., Uehara, N., Kimura, A., Sasaki, T., Yuri, T., Yoshizawa, K., Tsubura, A., 2012. Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int. J. Oncol. 40, 1020–1028. Mohan, A., Narayanan, S., Sethuraman, S., Krishnan, U.M., 2014. Novel resveratrol and 5-fluorouracil coencapsulated in PEGylated nanoliposomes improve chemotherapeutic efficacy of combination against head and neck squamous cell carcinoma. BioMed Res. Int. 2014, 424239. Montsko, G., Nikfardjam, M.S.P., Szabo, Z., Boddi, K., Lorand, T., Ohmacht, R., Mark, L., 2008. Determination of products derived from trans-resveratrol UV photoisomerisation by means of HPLC-APCI-MS. J. Photochem. Photobiol. A: Chem. 196, 44–50. Moscho, A., Orwar, O., Chiu, D.T., Modi, B.P., Zare, R.N., 1996. Rapid preparation of giant unilamellar vesicles. Proc. Natl. Acad. Sci. U. S. A. 93, 11443–11447. Murias, M., Jager, W., Handler, N., Erker, T., Horvath, Z., Szekeres, T., Nohl, H., Gille, L., 2005. Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure–activity relationship. Biochem. Pharmacol. 69, 903–912. Narayanan, N.K., Nargi, D., Randolph, C., Narayanan, B.A., 2009. Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice. Int. J. Cancer 125, 1–8. NCBI, 2014. PubChem Substance Database; SID 6374. Ndiaye, M., Kumar, R., Ahmad, N., 2011. Resveratrol in cancer management: where are we and where we go from here? Ann. N. Y. Acad. Sci. 1215, 144–149. Neves, A.R., Lucio, M., Lima, J.L.C., Reis, S., 2012. Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug delivery, and membrane interactions. Curr. Med. Chem. 19, 1663–1681. Neves, A.R., Lucio, M., Martins, S., Lima, J.L., Reis, S., 2013. Novel resveratrol nanodelivery systems based on lipid nanoparticles to enhance its oral bioavailability. Int. J. Nanomed. 8, 177–187. O'Reilly, R.K., Hawker, C.J., Wooley, K.L., 2006. Cross-linked block copolymer micelles: functional nanostructures of great potential and versatility. Chem. Soc. Rev. 35, 1068–1083. Parveen, S., Sahoo, S., 2008. Polymeric nanoparticles for cancer therapy. J. Drug Target. 16, 108–123. Peters, S., 2012. Physiologically-based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the Pharmaceutical Industry. John Wiley & Sons, Sweden. Richard, T., Pawlus, A.D., Iglesias, M.L., Pedrot, E., Waffo-Teguo, P., Merillon, J.M., Monti, J.P., 2011. Neuroprotective properties of resveratrol and derivatives. Ann. N. Y. Acad. Sci. 1215, 103–108. Rius, C., Abu-Taha, M., Hermenegildo, C., Piqueras, L., Cerda-Nicolas, J.M., Issekutz, A. C., Estan, L., Cortijo, J., Morcillo, E.J., Orallo, F., Sanz, M.J., 2010. Trans- but not cisresveratrol impairs angiotensin-II-mediated vascular inflammation through inhibition of NF-kappaB activation and peroxisome proliferator-activated receptor-gamma upregulation. J. Immunol. (Baltimore, Md.: 1950) 185, 3718–3727. Rossi, D., Guerrini, A., Bruni, R., Brognara, E., Borgatti, M., Gambari, R., Maietti, S., Sacchetti, G., 2012. trans-Resveratrol in nutraceuticals: issues in retail quality and effectiveness. Molecules (Basel, Switzerland) 17, 12393–12405. Rotches-Ribalta, M., Andres-Lacueva, C., Estruch, R., Escribano, E., Urpi-Sarda, M., 2012. Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Pharmacol. Res.: Off. J. Ital. Pharmacol. Soc. 66, 375–382. Salas, M., Obando, P., Ojeda, L., Ojeda, P., Perez, A., Vargas-Uribe, M., Rivas, C.I., Vera, J. C., Reyes, A.M., 2013. Resolution of the direct interaction with and inhibition of the human GLUT1 hexose transporter by resveratrol from its effect on glucose accumulation. Am. J. Physiol. Cell Physiol. 305, C90–99. Sanna, V., Siddiqui, I.A., Sechi, M., Mukhtar, H., 2013. Resveratrol-loaded nanoparticles based on poly(epsilon-caprolactone) and poly(D,L-lactic-coglycolic acid)-poly(ethylene glycol) blend for prostate cancer treatment. Mol. Pharm. 10, 3871–3881. Sareen, D., van Ginkel, P.R., Takach, J.C., Mohiuddin, A., Darjatmoko, S.R., Albert, D. M., Polans, A.S., 2006. Mitochondria as the primary target of resveratrolinduced apoptosis in human retinoblastoma cells. Invest. Ophthalmol. Visual Sci. 47, 3708–3716. Seguin, J., Brulle, L., Boyer, R., Lu, Y.M., Ramos Romano, M., Touil, Y.S., Scherman, D., Bessodes, M., Mignet, N., Chabot, G.G., 2013. Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy. Int. J. Pharm. 444, 146–154.

9

897 Sengottuvelan, M., Deeptha, K., Nalini, N., 2009. Resveratrol ameliorates DNA 898 damage, prooxidant and antioxidant imbalance in 1,2-dimethylhydrazine 899 induced rat colon carcinogenesis. Chem. Biol. Interact. 181, 193–201. 900 Shao, J., Li, X., Lu, X., Jiang, C., Hu, Y., Li, Q., You, Y., Fu, Z., 2009. Enhanced growth 901 inhibition effect of resveratrol incorporated into biodegradable nanoparticles 902 against glioma cells is mediated by the induction of intracellular reactive 903 oxygen species levels. Colloids Surf. B Biointerfaces 72, 40–47. 904 Sharma, A., Sharma, U.S., 1997. Liposomes in drug delivery: progress and limitations. 905 Int. J. Pharm. 154, 123–140. 906 Silva, C.G., Monteiro, J., Marques, R.R., Silva, A.M., Martinez, C.L.M.C., Faria, J.L., 2013. 907 Photochemical and photocatalyic degradation of trans-resveratrol. Photochem. 908 Photobiol. Sci. 12, 638–644. 909 Silva, Figueiras, A., Gallardo, E., Nerin, C., Domingues, F.C., 2014. Strategies to 910 improve the solubility and stability of stilbene antioxidants: a comparative 911 study between cyclodextrins and bile acids. Food Chem. 145, 115–125. 912 Singh, G., Pai, R.S., 2014. Optimized PLGA nanoparticle platform for orally dosed 913 trans-resveratrol with enhanced bioavailability potential. Exp. Opin. Drug Deliv. 914 11, 647–659. Q8 915 Souto, E.B., Muller, R.H., 2010. Lipid nanoparticles: effect on bioavailability and 916 pharmacokinetic changes. Handb. Exp. Pharmacol. 115–141. 917 Sriwongsitanont, S., Ueno, M., 2004. Effect of freeze-thawing and polyethylene 918 glycol (PEG) lipid on fusion and fission of phospholipid vesicles. Chem. Pharm. 919 Bull. 52, 641–642. 920 Sun, W., Wang, W., Kim, J., Keng, P., Yang, S., Zhang, H., Liu, C., Okunieff, P., Zhang, L., 2008. Anti-cancer effect of resveratrol is associated with induction of 921 apoptosis via a mitochondrial pathway alignment. Adv. Exp. Med. Biol. 614, 922 179–186. 923 Szejtli, J., 2004. Past, present, and future of cyclodextrin research. Pure Appl. Chem. 924 76, 1825–1845. 925 Teskac, K., Kristl, J., 2010. The evidence for solid lipid nanoparticles mediated cell 926 uptake of resveratrol. Int. J. Pharm. 390, 61–69. 927 Tikekar, R., Yuanjie, P., Nitin, N., 2013. Fate of curcumin encapsulated in silica 928 nanoparticle stabilized pickering emulsion during storage and simulated 929 digestion. Food Res. Int. 51, 370–377. Tiwari, G., Tiwari, R., Rai, A., 2010. Cyclodextrins in delivery systems: applications. J. Q9 930 931 Pharm. Bioallied Sci. 2. 932 Trela, B.C., Waterhouse, A.L., 1996. Resveratrol: isomeric molar absorptivities and 933 stabilities. J. Agric. Food Chem. 44, 1253–1257. 934 Ullah, M.F., Ahmad, A., Khan, H.Y., Zubair, H., Sarkar, F.H., Hadi, S.M., 2013. The 935 prooxidant action of dietary antioxidants leading to cellular DNA breakage and 936 anticancer effects: implications for chemotherapeutic action against cancer. 937 Cell Biochem. Biophys. 67, 431–438. 938 Venuti, V., Cannava, C., Cristiano, M.C., Fresta, M., Majolino, D., Paolino, D., 939 Stancanelli, R., Tommasini, S., Ventura, C.A., 2014. A characterization study of 940 resveratrol/sulfobutyl ether-beta-cyclodextrin inclusion complex and in vitro 941 anticancer activity. Colloids Surf. B Biointerfaces 115, 22–28. 942 Walle, T., 2011. Bioavailability of resveratrol. Ann. N. Y. Acad. Sci. 1215, 9–15. 943 Walle, T., Hsieh, F., DeLegge, M.H., Oatis Jr., J.E., Walle, U.K., 2004. High absorption 944 but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos: 945 Biol. Fate Chem. 32, 1377–1382. 946 Wang, X.X., Li, Y.B., Yao, H.J., Ju, R.J., Zhang, Y., Li, R.J., Yu, Y., Zhang, L., Lu, W.L., 2011. 947 The use of mitochondrial targeting resveratrol liposomes modified with a 948 dequalinium polyethylene glycol-distearoylphosphatidyl ethanolamine 949 conjugate to induce apoptosis in resistant lung cancer cells. Biomaterials 32, 950 5673–5687. 951 Wang, Z., Li, W., Meng, X., Jia, B., 2012. Resveratrol induces gastric cancer cell 952 apoptosis via reactive oxygen species: but independent of sirtuin1. Clin. Exp. 953 Pharmacol. Physiol. 39, 227–232. 954 Xu, W., Ling, P., Zhang, T., 2013. Polymeric micelles, a promising drug delivery 955 system to enhance bioavailability of poorly water-soluble drugs. J. Drug Deliv. 956 2013, 340315. 957 Yadav, N., Khatak, S., Vir Singh Sara, U., 2013. Solid lipid nanoparticles – a review. Int. 958 J. Appl. Pharm. 5, 8–18. 959 Yang, X., Li, X., Ren, J., 2014. From french paradox to cancer treatment: anti-cancer 960 activities and mechanisms of resveratrol. Anti-Cancer Agents Med. Chem.. 961 Yaseen, A., Chen, S., Hock, S., Rosato, R., Dent, P., Dai, Y., Grant, S., 2012. Resveratrol 962 sensitizes acute myelogenous leukemia cells to histone deacetylase inhibitors 963 through reactive oxygen species-mediated activation of the extrinsic apoptotic 964 pathway. Mol. Pharmacol. 82, 1030–1041. 965 Yin, H., Si, J., Xu, H., Dong, J., Zheng, D., Lu, X., Li, X., 2014. Resveratrol-loaded 966 nanoparticles reduce oxidative stress induced by radiation or amyloid-beta in 967 transgenic Caenorhabditis elegans. J. Biomed. Nanotechnol. 10, 1536–1544. 968 Yu, C., Shin, Y.G., Chow, A., Li, Y., Kosmeder, J.W., Lee, Y.S., Hirschelman, W.H., 969 Pezzuto, J.M., Mehta, R.G., van Breemen, R.B., 2002. Human, rat, and mouse 970 metabolism of resveratrol. Pharm. Res. 19, 1907–1914. 971 Zhang, L., Pornpattananangku, D., Hu, C.M., Huang, C.M., 2010. Development of 972 nanoparticles for antimicrobial drug delivery. Curr. Med. Chem. 17, 585–594. 973 Zhao, Y., Pan, Y., Nitin, N., Tikekar, R., 2014. Enhanced stability of curcumin in 974 colloidosomes stabilized by silica aggregates. Food Sci. Technol. 58, 667–671. 975 Zu, Y., Zhang, Y., Wang, W., Zhao, X., Han, X., Wang, K., Ge, Y., 2014. Preparation and in 976 vitro/in vivo evaluation of resveratrol-loaded carboxymethyl chitosan 977 nanoparticles. Drug Deliv. 1–11.

Please cite this article in press as: Summerlin, N., et al., Resveratrol nanoformulations: Challenges and opportunities. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.01.003