nanocomposite hydrogels: 3d polymer nanoparticle ...and environmental responses are specific to...

MERINO ET AL. VOL. 9 ’ NO. 5 ’ 4686–4697 ’ 2015

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May 04, 2015

C 2015 American Chemical Society

Nanocomposite Hydrogels: 3DPolymer�Nanoparticle Synergiesfor On-Demand Drug DeliverySonia Merino,*,† Cristina Martı́n,† Kostas Kostarelos,‡ Maurizio Prato,*,§ and Ester Vázquez*,†

†Departamento de Química Orgánica, Facultad de Ciencias y Tecnologías Químicas-IRICA, Universidad de Castilla�La Mancha, 13071 Ciudad Real, Spain,‡Nanomedicine Lab, Faculty of Medical and Human Sciences & National Graphene Institute, AV Hill Building, The University of Manchester, Manchester M13 9PT,United Kingdom, and §Department of Chemical and Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy

The development of multifunctionalpolymer-based matrices for controlleddrug delivery purposes has been thesubject of intense research during the last sixdecades.1 After initial efforts for understand-ing drug release mechanisms and for main-taining a constant drug concentration in theblood, research moved into the advance-ment of polymers or hydrogels, as smartmaterials where the delivery of the drug istriggered by changes in environmental fac-tors. The generation of clinical products withthe ability to deliver drug molecules, at theright place and according to patients' needs,has been a challenge that has gained evenmore attention with the development ofnanotechnology. The achievements of thisnew applied science have encouraged sev-eral research groups to use nanoparticles,as advanced systems with the promise ofdelivering drugs to target cells, especially incancer therapy.2 However, clinical applica-tions of these systems are still scarce.In general, precise control over the drug

quantity and the release rate, in specific partsof the body, has numerous advantages over

conventional drug release, such as enhan-cing bioavailability and minimizing deleter-ious side effects. These benefits are evenmore important for patients suffering fromchronic diseases that require multiple do-sage regimes. In these cases, the route ofdrug administration is also important, notonly because it affects drugmetabolism anddose, but also because it can improvepatients' quality of life. Nevertheless, themost challenging delivery systems are theones with reversible on�off switching cap-ability. Many vital functions, frequentlyfound in a living body, are regulated bypulses of active molecules at specific timeand place; the release of insulin is an exam-ple of this mechanism. In general, a pulsatiledelivery can be achieved if the drug carrier isdesigned to exhibit predictable and repro-ducible changes in response to an internalor external stimulus within a matter ofminutes, or even seconds.Among the synthetic andnatural polymers

that can be used for drug delivery, hydrogelsrepresent a class of softmaterials of particularinterest.3 Previous review articles have been

* Address correspondence [email protected],[email protected],[email protected].

Received for review March 6, 2015and accepted May 4, 2015.

Published online10.1021/acsnano.5b01433

ABSTRACT Considerable progress in the synthesis and technology of hydrogels

makes these materials attractive structures for designing controlled-release drug

delivery systems. In particular, this review highlights the latest advances in

nanocomposite hydrogels as drug delivery vehicles. The inclusion/incorporation of

nanoparticles in three-dimensional polymeric structures is an innovative means for

obtaining multicomponent systems with diverse functionality within a hybrid hydrogel

network. Nanoparticle-hydrogel combinations add synergistic benefits to the new 3D

structures. Nanogels as carriers for cancer therapy and injectable gels with improved

self-healing properties have also been described as new nanocomposite systems.

KEYWORDS: hydrogel . nanoparticle . nanocomposite . nanogel . self-healing . on-demand delivery . stimuli-response . external field

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published covering various aspects of novel and smartbiocompatible hydrogels,4,5 including supramoleculargels6 and low-molecular weight gelators.7 Recenttrends have focused on incorporating nanoparticles,such as polymeric, metallic, and carbon-based nano-materials, within the hydrogel network to obtain nano-composite hydrogels8,9 with reinforced propertiesfor various biomedical applications.The objective of this review is to focus the attention

on the synergies resulting from the combinationof these materials. Nanoparticles can promote theresponse of hydrogels to a new stimulus, which canbe modulated in a versatile way, with the modifica-tion of the nanoparticle. Moreover, the hybrid systemscould enable routes of drug administration with lim-ited systemic absorption but that can be useful in long-term delivery systems. On the other hand, hydrogelscould provide nanoparticles with the clinically usefulformulation needed for their clinical applications. Thereview, which includes a survey of recent advancescombining nanoparticles and hydrogels, is not meantto be an exhaustive review of hydrogel technology. Itaims to highlight some noteworthy examples and dis-cuss some novel perspectives in order to offer research-ers consideration of this synergic combination for thedesign of novel on-demand drug delivery systems.

HYDROGELS AS ON-DEMAND DELIVERY SYS-TEMS: A BRIEF OVERVIEW

A hydrogel is a physically or chemically cross-linkednatural or synthetic 3D network, which has the capacityto absorb a large fraction of water (up to thousands oftimes their dry weight), although typically of limitedsolubility in this media. The water retention capacity ofhydrogels arises mainly from the presence of hydro-philic groups (amido, amino, carboxyl, hydroxyl, etc.) inthe polymer chains and the degree of swelling can bemodulated by the polymer composition and the den-sity and nature of cross-links in the gel matrix. Thewater content of a hydrogel determines its uniquephysicochemical characteristics that can resemblethose of living tissues more than any other class ofsynthetic biomaterials. These are largely attributed totheir high water content, their soft and elastic consis-tency, and low interfacial tension when in contact withwater or biological fluids. The porous structure of thehydrogel also allows drug loading into the gel matrix,and protects them from hostile environments, such asthe presence of enzymes or low pH in the stomach.Additionally, hydrogels can control drug release due

to changes (swelling, dissolution or degradation) in thegel structure in response to internal or external stimuli.These types of environment-sensitive hydrogels areknown as “intelligent” hydrogels.10 The way the drug isincorporated into the hydrogel matrix has a greatinfluence on controlling drug release.11 When bioac-tive molecules are covalently bound to hydrogels,12,13

their release requires the cleavage of the linking bondbetween the hydrogel and the drug. This chemicalresponse is due to an enzymatic or chemical reaction,changes in pH, or an external stimulus such as light.However, in hydrogels containing the drug encapsu-lated by physical14 or supramolecular interactions,15

the release of the drug is due not only to a chemicalresponse, but also to a physical change in the structureof the hydrogel, such as deswelling, which could betriggered by changes in pH, temperature, etc.The incorporation of stimulus sensitive components

into hydrogels has allowed the design of systems thatexclusively release their content on-demand. Glucose-sensitive hydrogels are an example of such stimuli-responsive systems. This type of intelligent systemscan adjust the insulin release rate in response to thechange of glucose concentration, to keep blood glu-cose level within the recommended range. Somehydrogel systems have been developed to modulateinsulin levels, and all of them contain a glucose sensorbuilt into the system.16 Glucose-sensitive hydrogels arecommonly based on enzymatic oxidation of glucoseby glucose oxidase (GOx), binding of glucose withconcanavalin A (Con A), or reversible covalent bondformation between glucose and boronic acids.Despite the huge potential of stimuli-responsive

hydrogels, in many cases these systems have limiteduse as drug delivery platforms today, since they exhibitpoor mechanical properties, relatively rapid release ofdrugs from the gel (particularly in the case of hydro-philic drugs), and/or inefficient hydrophobic drugloading. Moreover, there are still problems associatedwith the control of the pulsatile delivery.3,17

NANOCOMPOSITE HYDROGELS: NEW SYNER-GIES FOR ON-DEMAND DRUG DELIVERY

Over the last decades, nanotechnology has emergedas a potent tool to approach processes involvingbiological systems. In particular, nanocomposite hy-drogels, i.e., molecular networks physically or cova-lently cross-linked with nanoparticles or nanostruc-tures, have been proposed as innovative means toovercome some of the challenges associated with theuse of hydrogels in pulsatile drug delivery systems.

VOCABULARY: Hydrogel � 3D network which has thecapacity to swell and retain a large fraction of water within

its structure;Nanocomposite � material that incorpo-rates nanosized particles into a matrix of standard materi-

al; Intelligent hydrogel � hydrogel that undergoeschanges in the gel structure in response to internal or

external stimuli;Nanogel � nanosized network of chemi-cally or physically cross-linked polymers that swell in a

good solvent; Self-healing materials � smart materialsthat have the capability of repairing themselves after

being damaged;

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Various types of nanoparticles such as inorganic/ceramic nanoparticles (hydroxyapatite, silica, sili-cates, calcium phosphate), polymeric nanoparticles(hyper-branched polyesters, cyclodextrins, etc.), metal/metal-oxide nanoparticles (gold, silver, iron-oxide), andcarbon-based nanomaterials (carbon nanotubes (CNTs),graphene) are combined with the polymeric networkto create reinforced polymeric hydrogels, developingnanocomposites with tailored physical properties andcustom-made functionalities (Figure 1). The type ofnanoparticle incorporated regulates the kind of stimulithat can be used to release the drug under the desiredconditions, enhances the delivery in different parts ofthe body, allows the transport of hydrophobic drugs, oris responsible of multistimuli-response systems. Thereis a growing interest in this field, aiming to achieverationally designed advanced hydrogels with tunableproperties, which are not commonly found in poly-mers. We will see some examples of this in the follow-ing sections.

Stimuli-Responses Triggered/Enhanced by the Type of Nano-particle. There are numerous reviews showing the dif-ferent spectrum of stimuli-responsive hydrogels,detailing their mechanisms in controlling release.18,19

Time controlled systems have been used in differentadministration routes such as oral, ocular or nasal.In these cases, drug release is controlled by diffusionor by the dissolution or degradation of the polymer,and environmental responses are specific to limitedregions within the body. Thermo- and/or pH-sensitivehydrogels have been widely used in those situations,based on the elevated temperature and low pH foundin the body. Specifically, the pH-sensitive ones aremost frequently applied as controlled release systemsfor oral drug delivery.10,20 The incorporation of nano-sized materials has improved their response andtheir mechanical properties.21,22 Moreover, the use of

nanocomposite hydrogels gives access to new releasesystems allowing the delivery in different parts ofthe body. We will focus in this section on severalrepresentative examples of hydrogels whose re-sponses are triggered or enhanced by nanoparticlesunder external stimulus (e.g., electric and magneticfields, near-IR light).

Electro-Responsive Hydrogels. Transdermal drugdelivery provides a valuable alternative to the tradi-tional dosage methods such as oral delivery andinjections.23 This approach not only avoids the gastricdegradation and hepatic first-pass metabolism butalso could greatly help in popular chronic treatments,eliminating the phobia and the pain associated withinjections. Notwithstanding, the low permeability ofthe skin restricts the utility of this approach and majorresearch is devoted to develop methodologies toincrease the delivery of drug across this barrier. Forexample, Giri et al.24 investigated the use of compo-sites based on carboxymethyl guar gum and multi-walled carbon nanotubes (MWCNTs) as a transdermalsystem for sustained release of diclofenac sodium. Inthis case, the nanoparticle offers superior thermalstability, higher drug loading, and enhances drugretention efficiency within the hydrogel.

It has been found that electrical stimulation is aneffective method to enhance and control the quantityof released drug from transdermal or subcutaneouslyimplanted systems. Hydrogels sensitive to an electricalcurrent are usually made of both synthetic and naturalpolyelectrolytes, separately or in combination. Underthe influence of an electric field, electro-responsivehydrogels generally deswell or bend, depending onthe shape and the orientation of the gel between theelectrodes.25 Electrically responsive drug release oc-curs via a number of different mechanisms, for exam-ple, a charged drug migrates toward the oppositely

Figure 1. Nanoparticles such as carbon-based nanomaterials, polymeric nanoparticles, and metallic nanoparticles arecombined with the polymeric network to create reinforced nanocomposite hydrogels.

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charged electrode or, more commonly, hydrogel con-traction results in ejection of drugs out of the gels onelectrical stimulation (Figure 2). Three main mechan-isms have been proposed for electro-induced geldeswelling: (i) the development of a stress gradientin the hydrogel; (ii) changes in local pH around theelectrodes as a result of the electrolysis of water (anincreased pH in the cathode and a decreasing pH in theanode); and (iii) electro-osmosis of water coupled toelectrophoresis. In practice, depending on the natureof the gel and on the experimental conditions used,anisotropic gel deswelling occurs by a combination ofsome or all of the mechanisms discussed above. How-ever, the major limitations of these systems are slowresponse times, nonlinear control between stimulationand drug release,26 and gel fatigue with time andelectrical stimulations.27

The progress in nanocomposite hydrogels, al-though in its initial stages, could generate a stepforward in applications for skin. We will discuss belowsome examples in which the incorporation of differentnanoparticles (carbon nanotubes, graphene, nano-clays) were used to improve both mechanical andelectrical properties of hybrid hydrogels.

Numerous research groups have used carbon nano-tubes as conductive additives to increase the elec-tro-sensitivity of the hydrogels with special focus onthe development of transdermal drug release.28 Forexample, Servant et al.29 prepared polymethacrylicacid (PMAA)/MWCNT hydrogel hybrids at differentMWCNT concentrations. The incorporation ofMWCNTsin the PMAA based hydrogels significantly enhanced

the gel response to the applied electric field andallowed the in vivo delivery of radiolabeled (14C)sucrose as a therapeutically hydrophilic drug undershort stimulation times and low electrical voltage.

On the other hand, the addition of synthetic silicatenanoparticles, also known as nanoclays, significantlyincreases both the physical and mechanical propertiesof polymeric hydrogels.30,31 In a recent study, anamphiphilic chitosan�silica hybrid hydrogel has beenprepared for electrically modulated release of an anti-convulsant drug, ethosuximide. Drug release wascontrolled by applying voltage to the compositehydrogel. In this case, the electrical stimulus causesmodulated drug release profiles in vitro rangingfrom burst-like to slow-elution patterns due to thecombination of electrophoretic and electro-osmoticmechanisms.32

Graphene has also attracted attention due to itsfascinating properties, such as high electron mobility,thermal conductivity and mechanical stability. Reducedgraphene oxide (rGO) has been employed in thepreparation of an electrically responsive drug releasesystem. With the use of lidocaine hydrochloride as amodel hydrophilic substance, the drug release behaviorof the reduced graphene oxide�poly(vinyl alcohol)(rGO�PVA) hydrogels has been explored. When largeramounts of rGO were incorporated, the rGO�PVApolymeric network became more negatively charged,which enhanced the action of electro-osmosis andreduced the intermolecular interactions between rGOand lidocaine. As a result, the lidocaine release rate wasincreased.33

Figure 2. Schematic illustration showing the main mechanisms for electro-induced gel deswelling.

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Although pristine graphene has greater thermal,mechanical, and electrical properties than grapheneoxide, only scarce examples of graphene-based hydro-gels in drug delivery systems have been published.One of themajor limitations of electro-responsive drugdelivery systems is their potential temperature in-crease resulting from electrical stimulation, a processknown as resistive heating. In a recent work by ourgroups,34 it was demonstrated that the incorporationof graphene, at low concentrations, into an electro-responsive PMAA hydrogel almost completely elimi-nated the “resistive heating” from the hydrogel matrix,while significantly enhanced the mechanical proper-ties of the hydrogels, compared to their carbon-nano-tube-based hydrogel counterparts. This fact improvedin vivo drug release under short stimulation times atlow voltage, showing an excellent on�off switchingcapability. The graphene used in this study was ob-tained by ball-milling treatment35 and contained sig-nificantly fewer defects than GO and rGO, retaining theelectrical, mechanical, and thermal properties of thegraphene structure. Ball-milled graphene material in-corporation allowed the gels to be more responsivethan their CNT counterparts at lower concentrations,using lower voltages, and displaying a reduced tem-perature increase upon electrical stimulation (Figure 3).

Magnetically Responsive Hydrogels. The applicationof magnetic micro- and nanoparticles in drug deliverywas explored in the late 1970s as potential carriers forspecific drug targeting. External magnetic fields can beused to transport the drugs, for example, to the tumorsites. Although apparently simple, the approach hassome important issues, one being the potential accu-mulation of the nanoparticles, blocking the blood flowor concentrating in diverse organs. It is well-knownthat metal nanoparticles show the ability to generateheat when subjected to alternating magnetic fields.Consequently, nanocomposite hydrogels in which thehydrogelmatrix is combinedwithmetal ormetal-oxidenanoparticles can be remotely heated by means ofa magnetic field. This phenomenon has been usedto control drug release in temperature responsive

hydrogels.36 Therefore, by incorporating magneticnanoparticles within a hydrogel network, the nano-composite network can rapidly respond to an externalmagnetic field, enabling their enhanced controllabilityand accelerating drug release. Some strategies toimprove the delivery of drugs in magnetically respon-sive hydrogels are discussed below.

Liu et al.37 prepared magnetic hydrogels by mixingPVAmatrices and Fe3O4 nanoparticles. They found thatthe amount of drug release can be finely tuned bycontrolling the switching duration time. It was demon-strated that the magnetic field induces the metalnanoparticles to aggregate reducing the porosity ofthe hydrogel. In this state, the drugwas confined in thenetwork, leading to reduction in the diffusion of thedrug through the hydrogel. On the contrary, when thefield was turned off, a higher level of drug release wasachieved (Figure 4). They also observed that the parti-cle size had significant influence in the drug releasebehavior, showing that large nanoparticles offered thebest magneto-sensitive effects.

To avoid large cluster agglomeration, these mag-netic nanoparticles should be stabilized by protectiveagents. Silica is one of the best studied protectiveagents, and a novel hydrogel based on chitosancross-linked β-cyclodextrin grafted with silylated mag-netic nanoparticles was synthesized as a drug deliverysystem for indomethacin.38

As mentioned previously, metal nanoparticles arealso incorporated into thermosensitive or temperature-pH sensitive hydrogels with the aim of inducingchanges in the hydrogel temperature and thereforeachieve remotely controlled pulsatile release of drugs.When the temperature is increased above the lowercritical solution temperature (LCST), the hydrogelstructure collapses, resulting in the expulsion of theincorporated drug molecules. Specifically, a novelbiodegradable and injectable thermosensitive hydrogelbased on chitosan and Fe3O4 has been prepared, andits drug release under an applied magnetic field hasbeen studied. This gel has been used to modulatethe release of Bacillus-Calmete-Guérin (BCG) whichincreased the antitumor effect and caused a high localimmune activity in bladder.39

In another study, alternating magnetic field (AMF)has been applied to control release from an injectablehydrogel containing both superparamagnetic ironoxide nanoparticles (SPIONs) and thermoresponsivemicrogels. Such combination permits optimal pulsatilerelease of small molecule drugs over several weeks,due to the relationship between the microgel volumephase transition temperature (VPTT) and the baselineincubation temperature. The heat generated bySPIONS under an AMF increases the temperature ofthe microgels over their VPTT, generating free volumeinside the composite and, therefore, enhances drugdiffusion across the hydrogel.40

Figure 3. Schematic illustration of the pulsatile drug releaseupon application of electrical stimulus in an electro-respon-sive graphene based hydrogel.

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In addition, the introduction of magnetic nanopar-ticles into hydrogels contributes to the preparation ofnew materials with self-healing properties. In general,gels are exposed to stress-induced formation of fis-sures that may affect the integrity of the networkstructures, resulting in the loss of functionality. Toaddress this challenge, self-healing gels which possessthe ability to repair themselves have emerged as anovel class of soft materials.41 The design of self-healing hydrogels is desirable, not only because itincreases the lifetime of the material, but also becauseit can permit the preparation of injectable materials42

which can be gelated in situ and stay at the targetposition. In this regard,Wei's group preparedmagneticand self-healing hydrogels by introduction of carboxymodified Fe3O4 nanoparticles into chitosan�PEG hy-drogels. The fragments of the hydrogel could moveunder an external magnetic field and then mergetogether in an integral gel after several minutes. Thisresearch constitutes an innovative solution for theissues associated with ordinary injectable polymer-based materials.43

Light-Responsive Hydrogels. The stimulus of light isinstantaneous and can be distributed with high accu-racy in simple and available ways, which renders light-responsive materials very advantageous for differentapplications. The response of nanoparticles to electro-magnetic stimulus has also been applied to the pre-paration of light responsive hydrogels which can beuseful for drug delivery purposes. A photorespon-sive hybrid hydrogel loaded with core�shell lantha-nide doped upconverting nanoparticles (UCNPs) hasbeen used to convert near-infrared (NIR) light into UVlight. When the hydrogel is irradiated with 980 nmlight, photodegradation and subsequent release of theembedded therapeutics occur.44 (Figure 5)

Following a different approach, carbon nanotubeshave been used for the preparation of light responsivegels. These nanomaterials are ideal candidates forphotothermal therapy because of their strong optical

absorbance in the NIR region, which could releasesignificant heat and enhance thermal destruction ofcells. For this purpose, multiwalled carbon nanotubes(MWCNTs) were employed as molecular antennae forNIR light combined with thermal-responsive PNIPAmto enhance the photothermal conversion effect inhydrogels.45

Graphene oxide is also considered a NIR responsivenanomaterial.46 It can absorb NIR light and convert itinto heat efficiently. In a recent example, Wu et al.47

have prepared a supramolecular gel for pulsatile drugrelease in vivo. Since these soft materials are formedthrough noncovalent interactions, it is difficult toregulate the drug release properly (physical diffusionor degradation of the hydrogel). To overcome thislimitation, the authors incorporated graphene oxidesheets (GOS) into the gel. The obtained hydrogel pos-sesses high mechanical stability, syringe-injectability,and low erosion rate, and the release of the drug isremotely controlled by NIR irradiation.

Gold nanoparticles are also able to absorb visible toNIR light and this fact can be used to generate a localheat. Recently, Strong et al.48 reported the incorpora-tion of NIR absorbing silica�gold nanoparticles ontopoly(N-isopropylacrylamide-co-acrylamide) (NIPAAm-co-AAm) hydrogel with potential application in cancertherapy. The local heating, produced by the nano-particles after light stimulation, is capitalized to causetissue necrosis, together with controlled delivery of theentangled chemotherapeutic molecules.

Delivery of Hydrophobic Drugs. As already discussed inthe introduction, conventional hydrogels are 3D net-works of hydrophilic polymers, which typically tend toabsorb hydrophilic drugs. In this regard, nanocompo-site hydrogels have been designed as innovative solu-tions to overcome limitations as inefficient hydro-phobic drug loading.

For example, hydroxyapatite (HA) nanoparticleswere used as drug delivery systems for a water-inso-luble anticancer drug, paclitaxel (Tax). The Tax-loaded

Figure 4. Schematic illustration of the mechanism of pulsatile drug release under magnetic fields. Adapted with permissionfrom ref 37. Copyright 2006, American Chemical Society.

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HA was embedded in a collagen gel to result in aTax/HA/Col gel, which exhibited higher levels of cyto-toxic activity than the Tax-containing collagen gel,particularly in highly metastatic MDA-MB-231 cellsthan the poorly metastatic MCF-7 cells.49

Other types of organic�inorganic hybrid materialsconsisting of layered metal hydroxides (LMHs) havebeen used. LMHs are widely studied as drug deliverynanocarriers, as they can accommodate various kindsof anionic drugs and transport them into cellularsystems efficiently. For example, Gwak et al. prepareda hydrogel�inorganic hybrid material, in which aga-rose and zinc basic salt (ZBS), a type of layered metalhydroxide, were combined to exhibit sustained releaseof loaded anionic molecules, such as ferulic acid.50

Polymeric nanoparticles such as hyper-branchedpolymers, liposomes, micelles, microspheres, and cy-clodextrins, which are widely used as drug deliverysystems, have also been incorporated into hydrogels toutilize their drug releasing ability, as well as to improvetheir mechanical properties.9 For example, Zhonget al.51 first prepared a dual-drug delivery systemof poly(D,L-lactic) microspheres embedded in analginate hydrogel. In this system, glycyrrhetinic acid(a hydrophobic drug) was encapsulated in the micro-spheres, while bovine serum albumin (a hydrophilicdrug) was loaded in the hydrogel. In another example,Liu et al.52 encapsulated erythromycin (EM) in micellesformed by Pluronic F-127 and then obtained anEM/PF127 hydrogel under a low-intensity UV light, inorder to extend EM release and prevent side effects ofthe drug. One of the main drawbacks of some che-motherapeutic agents is their high hydrophobicitywhich can be related with dangerous side effects. Forthis reason, and to increase their water solubility,Paclitaxel (TAX) was loaded in an injectable micelle�hydrogel hybrid system based on Polaxamer 407 andchitosan. In vivo studies revealed a reduction in theprogression rate of the tumor and diminution in sideeffects compared with TAX.53

A sophisticated example has been recently devel-oped by Nagahama et al.54 in order to control drugrelease in a novel way. They prepared a new injectablegel through the self-assembly of copolymer micelles,

clay nanodisks (CNDs), and doxorubicin (DOX). Thedrug incorporated into the hydrogel not only servesas cross-linker for gel networks formation, but alsocontrols its own release.

Cyclodextrins (CDs) have also been widely studiedas drug delivery systems.55 As a result of their molec-ular structure and shape, they are usually used tocomplex poorly water-soluble drugs, increasing theiraqueous solubility. Therefore, incorporation of CDs intohydrogel systems is appropriate for maintaining theswelling properties of the hydrogel, and their hydro-phobic interior can facilitate the capture and controlledrelease of hydrophobic drugs. Cyclodextrin-containinghydrogels can be prepared in many ways.56 The mainstrategies can be classified in three broad groups: (i)direct cross-linking of CDs that can be obtained directlyusing cross-linkers such as ethylene glycol diglycidy-lether to release cyclosporine A; (ii) copolymerizationof CDs with vinyl- or acrylic-co-monomers; and (iii)grafting of CDs to preformed polymer networks. Mostsimply, preformed cyclodextrin�drug complexes canbe added into the hydrogel during or after gel cross-linking. The driving forces leading to inclusion com-plexes are hydrophobic and van derWaals interactions,hydrogen bonding, and changes in surface tension.Recently, Kuang et al.57 prepared an injectable andbiodegradable supramolecular hydrogel, using a nu-cleobase (adenine/thymine)-terminated poly(ethyleneoxide)s (A-PEG-A/T-PEG-T) and R-CD. In vitro evalua-tion indicated that the supramolecular hydrogels haveadequate biocompatibility, and are appropriate fordeveloping sustained and controlled-release systemsof antitumor drugs. Furthermore, these nanocompo-site hydrogels showed significant efficacy in inhibitionof tumor growth in vivo.

Graphene oxide (GO), the “hydrophilic” derivativeof graphene, contains a range of reactive functionalgroups, including hydroxyl, epoxy and carboxylic acidgroups. GO and its derivatives as well as compositeshave been considered ideal materials for the prepara-tion of drug scaffolds by taking advantage of its water-solubility, high specific surface area and good biocom-patibility. Moreover, the 2D plane of GO sheets pro-vides large specific surface area to carry drugs via

Figure 5. NIR-light-triggered degradation of a photosensitive hydrogel using the UV light generated by encapsulatedupconverting nanoparticles. Adapted with permission from ref 44. Copyright 2012, American Chemical Society.

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surface adsorption, hydrogen bonding, and othertypes of interactions.58 Covalent attachment of folicacid, polyethylene glycol, and chitosan to GO providesa potential platform for delivering anti-inflammatoryand water-insoluble anticancer drugs such as doxor-ubicin (DOX), and SN38 (a camptothecin analogue).59

Multiresponsive and Multifunctional Systems. Sometimesthe swelling kinetics of the smart hydrogels are not asfast as desirable for some applications. The design ofhybrid materials, which can deliver their cargo inresponse of multiple stimuli, allows the preparationof faster responding systems compared to the onesacting in response of a single stimuli. Moreover, toimprove the temporal control over drug release, astimulating solution is the preparation of nanogels,nanoscale networks that provide several advantagesinherent in their nanoscale size. In addition, theintroduction of nanoparticles in these materials canintroduce new functionalities and applicability to thestructure.

Targeted drug delivery systems have captivatedincreased attention in cancer therapy. Active targetingrequires the attaching of a ligand which recognizes aspecific receptor. The nanoscale size of nanogels, withtheir high specific surface area, makes it feasible theconjugation of active targeting agents. In addition, dueto the higher temperature and lower pH of cancertissues related to normal tissues, nanogels whichstructure changes at small pH ranges are very usefulto deliver drugs to tumor sites. Hence thermo- andpH-responsive nanogels, with bovine serum albumin

encapsulated gold nanoparticles conjugated onto theirsurface, have been synthesized and further functiona-lizedwith a tumor targeting peptide. Chemotherapeuticdrug DOX was introduced by electrostatic absorptionand cytotoxicity studies proved that the system coulddeliver the drug, specifically to the tumor with en-hanced efficacy and controlled release. Moreover, thered fluorescence emission from gold nanoclusters wasused to identify and follow the nanogel in vitro.60

Wu et al.61 have also reported the preparation ofmultifunctional core�shell nanogels for simultaneousoptical temperature sensing, targeted tumor and com-bined chemical and photothermal treatment. Thethermoresponsive PEG based nanogels had an Ag�Aubimetallic nanoparticle core and hyaluronic acid chainsas targeting ligands. The fluorescence intensity of theAg�Au core can be used for imaging, but also totrigger the release of the anticancer drug under thelocal temperature increase of targeted zones, inducedby NIR irradiation (Figure 6).

In a recent report, the combination of pH sensitivenanogels, a hydrophobic dendrimer, and folic acid astarget agent has been used for the delivery of pacli-taxel. The incorporation of hydrophobic segments intothe nanogel core through cross-coupling of H-40-poly-(ε-caprolactone) (H40-PCL) dendrimer allows hydro-phobic drugs loading.62

In another example, the covalent attachment ofcyclodextrin particles to nanogels gives them theability to form inclusion complexes, providing in thisway a new drug loading and releasemechanism based

Figure 6. Schematic illustrationofmultifunctional core�shell nanogel. Adaptedwith permission from ref 61. Copyright 2010,Elsevier.

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on these complexes and thus preventing drug releaseupon media dilution.63

CONCLUSIONS AND PERSPECTIVES

On the basis of all the results described in thisreview, we can conclude that the introduction of nano-particles in hydrogels can be an innovative means forcreating multicomponent systems aiming to achieve arational design of advanced delivery systems withtunable properties.Nanoparticles can not only enhance the mechan-

ical properties of the gels but alsomodulate efficientlyits response to different stimuli. We have shownexamples of electric, magnetic, and light responsivehydrogels (Table 1). However, with the preparation ofnew or modified nanoparticles, further stimuli can bestudied, like ultrasonication or pressure in responsivesystems. As an example, microwaves have been em-ployed recently in thermotherapy, producing diather-mia (heating up to 41 �C), hyperthermia (heating intothe interval of 41�45 �C), and thermoablation (over45 �C). Carbon nanostructures are excellent micro-wave absorbent, and thus, in thermoresponsive gels,the electromagnetic-induced hyperthermia fromcarbon nanomaterials could cause the volumetricchange in the hydrogel, inducing the release ofthe drug. In this sense, a volume change in a smarthydrogel/conductive polymer nanocomposite in-duced by microwave irradiation has recently beenreported.64

Moreover, the introduction of nanoparticles trans-fers new functionalities to the system. Some furtherexamples could be the formation of polymeric net-works with quantum dots (QDs), which has already

been used for the development of materials withphotoluminescent properties and thus for sensingand drug delivery applications.65 Likewise, novel silvernanocomposite hydrogels based on acrylamide havebeen reported.66 These structures are potentially use-ful in treating infections due to the antibacterial prop-erties of silver.Considering the possibility of functionalization/

modification of nanoparticles, the development ofhydrogels incorporating these modified structurescan be also considered in order to further introducenew functionalities and applicability to the system,paving the way for the development of hybrid hydro-gels with specific molecular responses, for example, toglucose. Some examples have been already discussedabout the synthesis of gels with targeting and imagingagents, but the advancement in hydrogel technologywill produce new systems that enhance diagnosticsand controlled drug release. Carbon-based nanoparti-cles, such as carbon nanotubes and graphene, haveattractedmuch attention in recent years owing to theirexcellent properties (i.e., mechanical strength, flexibil-ity, thermal, electrical, and optical conductivity). There-fore, these structures are considered highly promisingmaterials to incorporate multifunctionality in stimuli-responsive hydrogels. Carbon nanostructures can in-teract physically or covalently with the polymericchains, and although they have usually a hydrophobicnature, different techniques have been developed toenhance their dispersions within the composite net-work. Moreover, carbon nanomaterials can be functio-nalized in order to introduce polar groups in theirstructure, and these chemical modifications can pro-vide newpossibilities for precisemolecular recognitionevents. Composite materials based on carbon nano-tubes and polymeric hydrogels have been applied asinnovative drug delivery devices combining propertiesof both hydrogels and CNTs.67

In recent years, there has been noticeable progressin the development of clinically applied hydrogels,while clinical uses of nanoparticles are rare. The com-bination nanoparticle�hydrogel could overcome thelimitations and drawbacks associated with the use ofnanoparticles as drug delivery systems. Additionally,there is still a need for studies focusing on the interac-tions between nanoparticles and polymers inside thehydrogel in order to tailor their properties to specialdrug delivery requirements.The preparation of nanogels has also been de-

scribed. Compared to macroscopic hydrogels, nano-gels show faster responsiveness, and due to theirnanometric size, they have been proposed as idealdrug delivery systems for various organs includingbrain and lungs.3 It has been postulated that theswellable nanogels have limited clearance by thelungs, allowing a longer term release of the drug, byslow degradation, once these particles are inhalated.

TABLE 1. Examples of Nanocomposite Hydrogels Whose

Properties Are Triggered or Enhanced by Nanoparticles

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Nanogels have also shown good potential to safelytransport macromolecules across the blood brain bar-rier. Progress in this field would have impact in newclinical treatments. Recently, some authors have de-scribed an efficient nanocarrier scaffold with sequen-tial intraintercellular delivery as an innovative mech-anism for deep tumor penetration. It consists of areversible pH-responsive nanogel that can be interna-lized by the cancer cells. At the endosomal or lysoso-mal pH, the gel protonates, producing an electrostaticrepulsion which triggers the swelling of the gel alongwith the release of the drug. The large volume of thepositively charged hydrogel produces the bursting ofthe endolysosomes and the nanogel is transported intothe cytosol where it returns to its original size, due tohigher pH in that region. The shrunk gel escapes fromthe dead cell, and it reproduces the process infecting anew cell.68 The layer by layer assembly technique hasalso been used in the preparation ofmultilayer ultrathinfilms, obtaining hydrogel nanocomposite films withhigher loading capacity.69

The development of self-healing hydrogels has alsobeen discussed in this review. Self-healing materialsare commonly found in living organisms, but thisbehavior is unusual in artificial systems. Interestingly,some authors have recently shown that the self-recoverytime of some gels is shortened by the introduction ofcarbon nanotubes or reduced graphene oxide withinthe gel.70 The hybrid gels also exhibited semiconduct-ing behavior what facilitates new functionalities.Finally, the use of hydrogels for delivering therapeu-

tic cells is another interesting aspect to consider inregenerativemedication. In this case, the objective is touse hydrogels as platforms where cells can reorganizeinto more sophisticated tissues.71 This strategy to-gether with the use of carbon nanotubes could beapplied, for example, to neuronal growth. Carbonnanotubes have already shown to have a remarkableaffinity for neurons,72 and their integration in 3D net-works could contribute to the developing of thesecells. The combination of new approaches usingmicro-engineering and 3D hydrogels will be a potent tool inthe design and tailoring of these materials.73

Conflict of Interest: The authors declare no competingfinancial interest.

Acknowledgment. Part of the work described in this articlehas been supported, by the Spanish Ministerio de Economía yCompetitividad (project CTQ2011-22410 and project IPT-2012-0429-420000), the University of Trieste and the Italian Ministryof Education MIUR (cofin Prot. 2010N3T9M4 and FIRB prot.RBAP11ETKA) and the EU FP7-ICT-2013-FET-F GRAPHENE Flag-ship project (No. 604391).

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