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Colloids and Surfaces B: Biointerfaces 133 (2015) 81–87

Contents lists available at ScienceDirect

Colloids and Surfaces B: Biointerfaces

j o ur nal ho me pa ge: www.elsev ier .com/ locate /co lsur fb

esponsive foams for nanoparticle delivery

hristina Tanga,b, Edward Xiaoa, Patrick J. Sinkoc, Zoltan Szekelyc,obert K. Prud’hommea,∗

Department of Chemical Engineering, Princeton University, Princeton, NJ 08544, United StatesDepartment of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA 23284, United StatesDepartment of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States

r t i c l e i n f o

rticle history:eceived 13 December 2014eceived in revised form 12 May 2015ccepted 20 May 2015vailable online 27 May 2015

a b s t r a c t

We have developed responsive foam systems for nanoparticle delivery. The foams are easy to make,stable at room temperature, and can be engineered to break in response to temperature or moisture.Temperature-responsive foams are based on the phase transition of long chain alcohols and could beproduced using medical grade nitrous oxide as a propellant. These temperature-sensitive foams couldbe used for polyacrylic acid (PAA)-based nanoparticle delivery. We also discuss moisture-responsive

eywords:oamsanoparticleurfactantuick-break

foams made with soap pump dispensers. Polyethylene glycol (PEG)-based nanoparticles or PMMA latexnanoparticles were loaded into Tween 20 foams and the particle size was not affected by the foamformulation or foam break. Using biocompatible detergents, we anticipate this will be a versatile andsimple approach to producing foams for nanoparticle delivery with many potential pharmaceutical andpersonal care applications.

© 2015 Published by Elsevier B.V.

. Introduction

Foams are promising drug delivery vehicles when compared toonventional ointments and creams, lotions or gels [1,2]. In topicalpplications, foams products can be applied and spread easily overarge areas without leaving greasy residue [3,4]. Ideally, the foamsre sufficiently stable at room temperature to facilitate application,ut would break to a liquid state upon application to a desired sitehus delivering the active ingredient. Foams are attractive vehi-les to replace gels for vaginal and rectal delivery since foams offeronvenient, single-step application while avoiding leakage of flu-ds that occurs with current formulations [2,5]. Since foams provideoverage of large surface areas and access to difficult to reach areas,hey have been used for nasal and auditory canal delivery [6,7]. Inhese applications, the foam is made in the desired body cavity.se of a foam can increase the surface area of application. Foams

hat would break into a small amount of liquid immediately (withineconds to minutes) upon application may serve to minimize anyotential discomfort.

Our goal is to develop responsive foams for the delivery ofanoparticle therapeutics. Foams provide uniform application ofctives over large surface areas with minimal liquid volume. The

∗ Corresponding author. Tel.: +1 609 258 4577; fax: +1 609 258 0211.E-mail address: prudhomm@princeton.edu (R.K. Prud’homme).

ttp://dx.doi.org/10.1016/j.colsurfb.2015.05.038927-7765/© 2015 Published by Elsevier B.V.

responsive aspect of the delivery comes from designing a “trig-gered” response to a physiologically relevant state that occursduring administration. Upon triggering, the foam should break todeliver the therapeutic nanoparticles to the tissue surface withminimal free aqueous phase [1,2,8–10]. We focused on usingmethods that are easy to use to allow for self-administration [5],which involve only biocompatible components, and for whichthere are current foam delivery devices. The selection of bio-compatible components in generating foams with high foam toliquid volume fractions is a significant challenge. Many existingfoam systems with such as shaving cream utilize hydrocarbon orhydrofluoralkane based propellants which are inappropriate fordrug delivery applications. Nanoparticles are of interest becausethey enable sustained release of therapeutics. Our specific interestis in nanoparticle formulations of HIV drugs that can be deliveredby foams to rectal or vaginal sites, which will quickly break, andwhich do not involve large liquid boluses. Such formulations wouldenhance patient compliance and, therefore increase the effective-ness of treatment and prevention.

We have developed two platforms for foam delivery of nanopar-ticles; one uses thermal triggered breakage at 37 ◦C, and anotheruses wet surfaces as the trigger mechanism. The first is a propellant-

based foam using medical grade nitrous oxide as a propellant. Thetemperature responsiveness comes from long chain alcohol crystalsthat stabilize the foams, but the crystals melt and are solubi-lized near physiological temperature. The second is a mechanically

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enerated foam for which the responsiveness comes from localilution of the surfactant stabilizer upon contact with a wet surface.anoparticle loading in both foam systems was explored.

. Materials and methods

Stearyl alcohol, potassium hydroxide, poly(ethylene glycol)ith an average Mn of 4600 (PEG5K) and Tween 20 were

btained from Sigma Aldrich (St. Louis, MO.). TetrahydrofuranHPLC grade), propylene glycol and absolute ethanol were pur-hased from Fisher Scientific (Waltham, MA). Cetyl alcohol and,3′-dioctadecyloxacarbocyanine percholorate (DiO) was obtainedrom MP Biomedicals (Santa Ana, CA) and Invitrogen (Carls-ad, CA), respectively. Polystyrene (PS) and block copolymers,olystyrene (1.6 kDa)-b-polyethylene glycol (5 kDa) (PS-b-PEG)nd polystyrene (2.2 kDa)-b-polyacrylic acid (11.5 kDa) (PS-b-PAA)ere bought from Polymer Source, Inc. (Montreal, Canada) and

ranched, 50–100 kDa polyethylenimine (PEI) was obtained fromolysciences, Inc. Hostasol Yellow 3G and phosphate bufferedaline were obtained from Clariant Pigments (Tianjin) andonza (Basel, Switzerland), respectively. Red food coloring fromcCormick & Company, Inc., (Sparks, MD) and 8 g cartridges ofedical grade nitrous oxide N2O from whip-it!TM brand (Van-

ouver, Canada) were used. Acrylic-latex particles (300 nm) werebtained from Arekma. Dialysis tubing with a 6–8 kDa MWCO wasbtained from Spectrum Labs. All materials were used as received.

Nanoparticles were prepared using Flash NanoPrecipitation in confined impinging jet mixer as previously described [11–13].or PEG based nanoparticles, PS-b-PEG (10 mg/mL) and Hosta-ol Yellow 3G (10 mg/mL) were dissolved in THF. Equal volumes0.5 mL) of the THF stream and ultrapure water (Milli-Q) wereapidly mixed and immediate dispersed into ultrapure water (4 mL,nal THF:water 1:9 by volume). Similarly, PAA based nanoparticlesere formulated by dissolving PS-b-PAA (5 mg/mL), PS (5 mg/mL)

nd DiO (0.1 mg/mL) in 1:1 volume mixture of THF and DMSO.he organic stream was rapidly mixed and immediately dispersednto PBS (1:9 organic:PBS by volume). Nanoparticle samples wereialyzed (6000–8000 MWCO Spectra/Por®, Spectrum Labs) againstltrapure water (1:100 volume of nanoparticle sample to volumef water) for 24 h with four changes of water. Nanoparticle sizehydrodynamic diameters (peak size from intensity distribution)nd polydispersity indices (PDI)) before dialysis, after dialysis andfter foam break was measured by dynamic light scattering (DLS)sing a Malvern-Zetasizer Nano Series DLS.

.1. Temperature-responsive foam formulations

Temperature-responsive foam formulations were prepared byombining ethanol, cetyl alcohol, stearyl alcohol, Polysorbate 60nd propylene glycol in various proportions (sample formulation

s provided in Table 1) based on previous reports [14] and stirringriefly at room temperature until homogenous. Water and aqueousolutions potassium hydroxide (10 wt.%) were combined with redood coloring, PEG5K, PEG-based or PAA-based nanoparticles and

able 1ample temperature-responsive foam formulation.

Component Amount (wt.%)

Ethanol 58.21Cetyl alcohol 1.16Stearyl alcohol 0.53Polysorbate 60 0.42Propylene Glycol 2.11Ultrapure water 36.21Potassium hydroxide (10 wt.% aq.) 0.11Food coloring 1.25

Biointerfaces 133 (2015) 81–87

stirred briefly at room temperature. Immediately prior to foam pro-duction, the ethanol and water solutions were combined and stirredbriefly. A small amount of the foam formulation with and withoutPolysorbate 60 was placed between crossed polarized and imagedwith an optical microscope (Nikon Eclipse E200) at room temper-ature and with heating. Approximately 50 mL of the mixture wasloaded in a reusable stainless steel foam dispenser (Whip-It BrandSpecialist Plus 1/2-liter, North Vancouver, BC, Canada), chargedwith nitrous oxide and prepared according to the manufacturer’sspecifications. Foams (approximated 3 g) were dispensed onto glasspetri dishes which were at either room temperature or heated to37 ◦C and the time for foam breaking was measured based on visualinspection. Foam-to-liquid volume ratios were also measured andratios of at least 5 were considered “acceptable”; however, higherratios are desirable to maximize surface coverage and minimizeleakage of the vehicle [2,5].

2.2. Moisture-responsive foams

Moisture-responsive foams were produced by dissolving a smallamount (0.5–5 wt.%) of Tween 20 in DI water. In some samples,PEG5K, PEG-based nanoparticles, or Acrylic-latex particles werealso included. Foams (∼2 g) were dispensed from 10 mL Tween20 solution using pumps manufactured by Paragon MarketingGlobal, Inc. (BF50, New Hill, NC). Foam-to-liquid volume ratios weremeasured. Stability when the foam was applied to a dry surface(polystyrene Petri dishes) or moist surface (a section of dialysistubing presoaked in water) was monitored for up to 1 h.

3. Results and discussion

3.1. Temperature responsive foam for nanoparticle delivery

Using red coloring for visualization, we examined the stabilityof the temperature-responsive foams at room temperature and at37 ◦C. The composition of the foam is given in Table 1. At room tem-perature, the foam is relatively stable, as shown in Appendix (Fig.A.1), with only a minimal amount of drainage after 10 min. Somefoam remains after 30 min and no further breakage is observed. Incontrast, when applied to a plate initially heated to 37 ◦C the foamhas broken completely in less than 3.5 min.

The mechanism of foaming and temperature responsivenessarises from the state of the long chain alcohols in the formulation.As shown in Fig. 1, the foam formulations without Polysorbate 60(Fig. 1a) are opaque at room temperature due the cetyl and stearylalcohol crystals in suspension. When placed between two crossedpolarizers, birefringence from the long-chain (fatty) alcohols par-ticulates can be observed at ambient temperature. Upon dispensingwith the nitrous oxide, the formulation solidifies due to freezing ofthe long-chain alcohols. Optical microscopy of the bulk formulationat room temperature (Fig. 1a) demonstrates the particulate natureof the long-chain alcohol crystals which provide foam structure.The foam lamellae are stabilized by solid particles of long-chainalcohols and the amphiphilic surfactant Polysorbate 60 (Fig. 3a)[15,16], as is seen in other foam systems and Pickering emulsions[17]. Colloidal stabilization of foams has been used to create mag-netically responsive [18] and Fameau et al. created temperatureresponsive foams; however, the temperature of foam rupture waslimited to 60 ◦C [19]. The long-chain alcohols are solid at room-temperature, thus, the foams at room temperature are relativelystable.

The foam break is triggered by melting of the long-chain alcoholcrystals that stabilize the foam. The components of the formulation,specifically the concentration of the long-chain alcohols, has beenchosen to tune the melting temperature to 37 ◦C. Upon heating,

C. Tang et al. / Colloids and Surfaces B: Biointerfaces 133 (2015) 81–87 83

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In 60 wt.% ethanol, the PEG-coating does not provide sufficientsteric stabilization to the particles and the particles aggregatedue to van der Waals interactions as previously reported [26].Since the nanoparticles have a negative surface charge of ∼−10 mV

ig. 1. Foam formulations visualized between crossed polarizers (a) at room temperaulk samples are included as insets.

he long-chain alcohols melt, the samples become transparent andirefringence from the particulates that stabilize the foam disap-ear (Fig. 1b). As the long-chain alcohols melt, they are soluble inhe alcohol–water mixture containing the Polysorbate 60 surfac-ant. In the absence of the Pickering particles, the foam rapidlyuptures. A representative video (at 2× speed) of the change inirefringence upon heating is included in the Supporting materials.

With Polysorbate 60, the crystal size created during formulationith the aqueous phase (aqueous quench) was smaller than crys-

als created without the surfactant (Fig. A.2). This is consistent withhat is known about Polysorbate 60 as a crystal modifier, affect-

ng the size and melting temperature of the fatty acids [20]. Theodified crystal structure resulted in a slightly lower melting tem-

erature as indicated by the transition to a transparent solution.he formulation of Polysorbate 60 transitioned from opalescento transparent at ∼32 ◦C whereas the melting transition for theormulation without Polysorbate 60 occurred at ∼34 ◦C. Thus, themount of Polysorbate 60 in the formulation can be used to adjusthe size of the long-chain alcohol particulates that constitute theoam structure to tune the melting temperature and time to break.

The ethanol concentration in the formulation is important inreating foams with the desired foam volume to liquid volume ratios it greatly affects the solubility of the propellant nitrous oxideN2O). For uniform foaming, the blowing agent must be uniformlyissolved in the fluid phase so that upon depressurization homoge-eous nucleation occurs. For example, whipped cream foams (with

arge foam volumes) can be produced only with milk containing0% butterfat because the fat globules become the reservoirs to sol-bilize N2O. In these formulations, the foaming propellant nitrousxide (N2O) is miscible with organic media i.e. ethanol, but notater. Fig. 2 shows that there is a small window of ethanol concen-

ration between 52 and 58 wt.% ethanol that yield acceptable foamsfoam volume to liquid volume ratios of at least 5). Below 52 wt.%thanol N2O is not solubilized sufficiently to produce homogeneousoams. Above 60 wt.% ethanol, Polysorbate 60 is soluble and doesct as an amphiphilic stabilizer. Therefore, stable foams are notroduced. This result suggests that the surfactant is required forhe foaming and indicates that the foam lamellae are stabilized byolid particles of long-chain alcohols and the amphiphilic surfac-ant Polysorbate 60. Thus, formulations containing 58 wt.% ethanolere used for all further formulations.

The therapeutic nanoparticles we intend to deliver via theseoams have a dense PEG steric coating to allow them to penetrate

ucous layers in vaginal and rectal applications [21–25]. Thereparation of the particles involves lyophilization using PEG

eated without Polysorbate 60, (b) heated without Polysorbate 60. The corresponding

as a lyoprotectant to produce dry powders that redisperse tonanoparticle form without aggregation. Therefore, we examinedthe effect of adding PEG5K on foaming, foam stability and foamdegradation kinetics by including 1–10 wt.% PEG5K homopolymerto the aqueous phase. The PEG-loaded foams were stable at roomtemperature. Further, the addition of the PEG5K (up to 10 wt.% ofthe foam formulation) did not significantly affect the foam-volumeto liquid-volume ratio (Supporting information Fig. A.3) nor thetime to break when applied to a plate at 37 ◦C. The additionof the PEG and PEG-coated nanoparticles are not expected toaffect the long-chain alcohol crystals, thus the foam stability andresponsiveness at 37 ◦C should not be affected which agrees withour experimental observations.

Next, nanoparticles containing Hostasol Yellow dye for visual-ization encapsulated with PS-b-PEG (1.6K-b-5K) were added to theliquid phase at 0.02 wt.%. The foams were thermally responsive andbroke within 2 min of dispensing onto the 37 ◦C surface (Fig. 3b).However, dye-containing nanoparticle aggregation was observed.

PEG-coated nanoparticles were not stable in 60 wt.% ethanolas the 68 nm nanoparticles grew or aggregated to over 1 �m.

Fig. 2. Foam to liquid volume ratios as a function of ethanol concentration for nitrousoxide based foams.

84 C. Tang et al. / Colloids and Surfaces B: Biointerfaces 133 (2015) 81–87

Fig. 3. (a) Schematic of temperature responsive foam structure stabilized by solidified particulates (at room temperature) of long-chain alcohols stabilized in the ethanol/waterliquid phase of the foam by the amphiphilic polysorbate 60. At 37 ◦C, the long-chain alcohols melt and are soluble in the ethanol–water liquid phase, destabilizing the foams tempy the pf

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tructure. (b) PEG-based nanoparticle loaded nitrous oxide foam breakage at roomellow dye for visualization and green tape was used to adhere the thermocouple tooam break.

27,28], we attempted to stabilize the nanoparticles by encap-ulation within a coacervate based on electrostatic interactionsith a cationic polymer. The addition of the positively chargedolymer polyethylene imine (PEI) forms a coacervate layer withhe negatively charged PEG-coated nanoparticles. The electrostaticolymer complex adds steric stabilization and limits aggregationf the nanoparticles. In the absence of PEI nanoparticles grew from

7 ± 2 nm to over 1 �m, whereas with a 20 fold weight ratio ofEI:NP the size increased only to 104 ± 4 nm, as shown in Fig. 4.ue to the large excess of PEI used, electrostatic repulsion may alsorovide stabilization [26].

ig. 4. PEG-based nanoparticle size distributions in water (solid circles) in 60%thanol (solid squares) with 5:1 wt. PEI:wt. NP (empty triangles), 10:1 wt. PEI:wt.P (empty circles), 20:1 wt PEI: wt. NP (empty squares) measured by DLS.

erature and applied to a surface initially at 37 ◦C. Nanoparticles contain Hostasollate during the heated plate experiment. Nanoparticle aggregation is evident upon

An alternative approach to stabilizing the NPs in 60 wt.% ethanolis to replace the PEG-block of the amphiphilic block copolymerwith a polymer that is less soluble in the mixed ethanol and watersolvent system so that the block copolymer is not solubilized inthe alcohol solution. For proof of concept, we demonstrate thisapproach using PAA instead of PEG by replacing the PS-b-PEGwith PS-b-PAA. The less soluble PS-b-PAA polymer conferred suf-ficient stability in 60% ethanol that the size and size distributionof the PAA-based nanoparticles in water and in 60% ethanol werecomparable (Fig. A.4.). Further, the foaming process i.e. the imbi-bition of N2O and subsequent gas nucleation, did not affect theparticle size or size distribution (Fig. A.4.). The nanoparticle-loadedfoams broke quickly (less than 1 min) when applied to a plateinitially heated to 37 ◦C (Fig. A.4.). Based on these results, thePAA-based particles are promising for delivery from ethanol-basedtemperature-responsive foams.

3.2. Moisture responsive foam for nanoparticle delivery

As a second, complementary, foam platform for nanoparticledelivery, we explored the use of surfactant based foams dis-pensed by pumps for propellant-free formulations. The pumpmechanisms produce foams by forcing a surfactant liquid for-mulation and air through a porous mesh. Surfactants with highhydrophilic–lipophilic balance (HLB) were considered. HLB for non-ionic surfactants is a measure of the molecular weight of thehydrophilic portion of a surfactant compared to the molecularweight of the entire molecule. Surfactants with HLBs ∼15 are con-sidered detergents and are expected to foam using pumps designed

for dispensing soap foams. Using the pumps, we made foams froma range of sorbate-based surfactants (Tweens from Croda Ltd.) at2 wt.%, concentrations, well above the critical micelle concentra-tion [29] for any of the surfactants (Appendix, Table A1). Tween 20

C. Tang et al. / Colloids and Surfaces B: Biointerfaces 133 (2015) 81–87 85

Fig. 5. (a) Moisture-responsive foam structure: steric stabilization of Tween 20 micelles in liquid phase of foam stabilizes the foam. When in contact with a moist surface,l ed suc

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ocal dilution of the micelles destabilizes the foam. (b) PEG-based nanoparticle loadontain hostasol yellow dye for visualization.

ith an HLB of 16.7 yielded the highest foam volume ratios withbove 10.

In the case of the mechanically made surfactant foams, theoam forms due to the assembly of the surfactant. Air bubblesre stabilized by a surfactant–water–surfactant film which pro-ide the foam structure. Since the small sorbitan head group ofhe Tween 20 and its relatively small tail make it an ineffective

olecular stabilizer, high concentrations are required to produceoams. The best foams were achieved for surfactant concentrations70 times higher than the CMC. For formulations at concentra-ions substantially above the CMC, two mechanism of stabilizationave been observed. One involves lamellar structures that areemplate parallel to the liquid interface [30,31]. In these cases,he interfacial regions are birefringent; this was not observed inur systems. The second mechanism is the steric repulsion ofpherical micelles in the surfactant–water–surfactant thin films32–34]. This has been observed in several experiments involv-ng direct observation of the thinning of liquid films. Therefore,he moisture-responsive foams are stabilized by steric repulsionf the Tween 20 micelles in the surfactant-water-surfactant filmFig. 5a).

The moisture responsiveness of these foams are a result of theolubility of the surfactant. The high HLB surfactants which resultn foams with high foam volume to liquid volume ratio are alsooluble in water. Upon contact with a wet surface local dilution ofhe foam liquid phase decreases the volume of micelle phase andestabilizes the film.

Since PEG-based nanoparticles are of considerable therapeuticnterest [35,36], and since PEG is expected to be an excipient that

ill be part of the nanoparticle formulation, we examined how theddition of PEG5K affected the foam properties, namely the foam-o-liquid volume ratio. PEG5K without surfactant did not produceoams with appreciable volume ratios (Appendix, Table A.1). How-ver, formulations of Tween 20 with and without PEG5K had foam

olume of liquid volume ratios over 10 (Table A.2). Tween concen-ration from 0.5 to 5 wt.% (CMC 0.0074 wt.%) and PEG loading up to0% (based on mass of Tween) had only a small effect on the foamolume ratio.

rfactant based foam when applied to a dry surface or moist surface. Nanoparticles

The effect of nanoparticle additives on foaming were studiedTween foams with PEG-based nanoparticle loaded with HostasolYellow dye for visualization. The foams are stable when applied toa dry surface at room temperature over with no drainage observedover 10 min (Fig. 5b). When applied to a moist surface, the sur-factant in contact with the moisture solubilizes, the foam breaks,and the nanoparticles are delivered. For example, when nanopar-ticle loaded foams were applied to a moist surface, drainage beganimmediately upon application to a moist surface and completedwithin 10 min as shown in the Fig. 5b. The addition of the nanoparti-cles did not affect the foam structure or stability, which suggests thenanoparticles are likely in the aqueous phase stabilized by surfac-tant micelles. Since we did not observe a significant change in foamproperties (bubble size based on the digital images, stability andtime to break on a wet surface) upon addition of the nanoparticles tothe formulation, further characterization of bubble size using opti-cal microscopy were not pursued. In contrast to the ethanol-basedfoams considered above, the Tween had no effect on nanoparti-cle size or aggregation (Fig. A.5). The hydrophobic anchoring blockdoes not partition into the aqueous phase and particle stability isnot compromised.

The foams are to perform as carriers for therapeutic nanopar-ticles and delivery of high concentrations of nanoparticles maybe allow for local delivery of high drug concentrations. We testedthe effect of particle loading on foaming, foam stability, and foambreakage using both PEG-based nanoparticles and anionic PMMAlatex (300 nm), serving as a model nanoparticle. Foams with highnanoparticle loading could be achieved (Appendix, Fig. A.6) whichstill demonstrated triggered breakage. Formulations with 2 wt.%Tween 20 and 34 wt.% PMMA-latex nanoparticle also producedfoams with foam volume to liquid volume ratios of at least 10that also began to drain immediately when applied to a moist sur-face at room temperature. The mechanism for breaking on a wetsurface is thought to be related to the mechanism of interfacial

stabilization by micellar structures. Certainly, a more quantitativeunderstanding of the dependence of foam stability and the vol-ume of the micelle phase in the presence of high concentrations ofnanoparticles would be of interest.

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Non-ionic surfactants with an HLB ∼15 and a could pointear physiological temperature may yield a temperature respon-ive foam similar to the system achieved with the long-chainlcohol, propellant based foam we described earlier. The melt-ng of the crystals provides a much sharper transition fromtable-to-unstable than would be obtained using a surfactant thatnderwent a cloud point phase change. Those phase changesccur over a wider temperature range than the first order melt-ng transition. Since surfactants with high HLB are preferred foroaming using the existing soap pump dispensers are soluble inater, they are responsive to moisture. When applied to a moist

urface such as an internal body cavity, the foam will break due toocal dilution as desired. For the intended application, foams thatreak upon application to physiological temperature or a moisturface is sufficient. Thus, non-ionic surfactants with high HLB∼15) required for foaming and a cloud point near physiologicalemperature for potential temperature responsiveness were notonsidered.

. Conclusions

We have developed and evaluated two foam systems foranoparticle delivery and triggered release The common require-ent is that the foam has a high volume fraction of gas so that upon

reakage the nanoparticles can be delivered with minimal deposi-ion of free liquid. The foams are stable at room temperature butan be designed to break in response to temperature or moisture.emperature-responsive foams were formulated with long chainlcohols using medical grade nitrous oxide as a propellant and bio-ompatible Polysorbate 60 surfactant. The long chain alcohols arensoluble at room temperature producing a particulate-stabilizedoam. The melting temperature of the long chain alcohol is tunedo that at physiological conditions of 37 ◦C the melted alcohol isolubilized, which triggers foam collapse. Fine tuning of the alco-ol concentration to between 50–60 wt.% was required to balancehe solubility of the N2O foaming agent and the interfacial activityf the surfactants. In this narrow range of alcohol content foamsith volume ratios greater than 6 were produced. The alcohol had

n adverse effect on PEG-b-PS (5 kDa-b-1.6 kDa) nanoparticles butarticles made with a less soluble PAA-b-PS (11.5-b-2.2K) weretable.

Moisture-responsive foams were made with commerciallyvailable foam pump dispensers and biocompatible Tween 20urfactants. With these mechanically generated foams, high foam-olume to liquid-volume ratios (≥10) were produced. They coulde loaded with PEG-stabilized therapeutic nanoparticles or with upo 30 wt.% model latex colloids. We anticipate that both approachesill be applicable vaginal and rectal therapeutic administrationhere temperature and moisture are potential triggering mech-

nisms. In vivo studies, which we are pursuing, will be requiredo determine which foam formulation route is best. The decreasediquid volume fractions required for the mechanically generatedoams, and the stability of nanoparticles in the simpler surfactant

ixtures, are advantages of the mechanically generated foams.he in vivo results on foam breakage and nanoparticle deposi-ion will ultimately determine which foam administration route topply.

cknowledgements

This work was supported by Princeton University’s IP Accel-

rator Fund and by the National Institutes of Health (Award No.RO1CA155061-1), the National Institutes of Health CounterACTrogram through the National Institute of Arthritis and Muscu-oskeletal and Skin Diseases (AwardU54AR055073).

[

Biointerfaces 133 (2015) 81–87

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.colsurfb.2015.05.038

References

[1] Y. Zhao, S.A. Jones, M.B. Brown, Dynamic foams in topical drug delivery, J.Pharm. Pharmacol. 62 (2010) 678–684.

[2] A. Arzhavitina, H. Steckel, Foams for pharmaceutical and cosmetic application,Int. J. Pharm. 394 (2010) 1–17.

[3] C.H. Purdon, J.M. Haigh, C. Surber, E.W. Smith, Foam drug delivery in dermatol-ogy, Am. J. Drug Deliv. 1 (2003) 71–75.

[4] D. Tamarkin, D. Friedman, A. Shemer, Emollient foam in topical drug delivery,Expert Opin. Drug Deliv. 3 (2006) 799–807.

[5] W.-Z. Li, N. Zhao, Y.-Q. Zhou, L.-B. Yang, W. Xiao-Ning, H. Bao-Hua, K. Peng,Z. Chun-Feng, Post-expansile hydrogel foam aerosol of PG-liposomes: a noveldelivery system for vaginal drug delivery applications, Eur. J. Pharm. Sci. 47(2012) 162–169.

[6] T. Marom, R. Yelin, A. Goldfarb, Y. Rakover, L. Shlizerman, E. Eilat, Y. Roth,Comparison of safety and efficacy of foam-based versus solution-basedciprofloxacin for acute otitis externa, Otolaryngol. Head Neck Surg. 143 (2010)492–499.

[7] H. Batchelor, Nasal, ocular and otic drug delivery, in: D. Bar-Shalom, K. Rose(Eds.), Pediatric Formulations, Springer, New York, 2014, pp. 273–301.

[8] Y. Zhao, M. Moddaresi, S.A. Jones, M.B. Brown, A dynamic topical hydrofluo-roalkane foam to induce nanoparticle modification and drug release in situ,Eur. J. Pharm. Biopharm. 72 (2009) 521–528.

[9] Y. Zhao, M.B. Brown, S.A. Jones, Pharmaceutical foams: are they the answer tothe dilemma of topical nanoparticles? Nanomedicine 6 (2010) 227–236.

10] X. Huang, H. Tanojo, J. Lenn, C.H. Deng, L. Krochmal, A novel foam vehi-cle for delivery of topical corticosteroids, J. Am. Acad. Dermatol. 53 (2005)S26–S38.

11] L. Shi, J. Shan, Y. Ju, P. Aikens, R.K. Prud’homme, Nanoparticles as deliveryvehicles for sunscreen agents, Colloids Surf. A 396 (2012) 122–129.

12] B.K. Johnson, R.K. Prud’homme, Flash nanoprecipitation of organic actives andblock copolymers using a confined impinging jets mixer, Aust. J. Chem. 56(2003) 1021–1024.

13] M. Akbulut, P. Ginart, M.E. Gindy, C. Theriault, K.H. Chin, W. Soboyejo,R.K. Prud’homme, Generic method of preparing multifunctional fluorescentnanoparticles using flash nanoprecipitation, Adv. Funct. Mater. 19 (2009)718–725.

14] A.Z. Abram, B.T. Hunt, Pharmaceutical foam, U.S. Patent No. 7,374,747 B2(2008).

15] E. Dickinson, Food emulsions and foams: stabilization by particles, Curr. Opin.Colloid Interface Sci. 15 (2010) 40–49.

16] T.S. Horozov, Foams and foam films stabilised by solid particles, Curr. Opin.Colloid Interface Sci. 13 (2008) 134–140.

17] U.T. Gonzenbach, A.R. Studart, E. Tervoort, L.J. Gauckler, Ultrastable particle-stabilized foams, Angew. Chem. Int. Ed. 45 (2006) 3526–3530.

18] S. Lam, E. Blanco, S.K. Smoukov, K.P. Velikov, O.D. Velev, Magnetically respon-sive pickering foams, J. Am. Chem. Soc. 133 (2011) 13856–13859.

19] A.L. Fameau, A. Saint-Jalmes, F. Cousin, B. Houinsou Houssou, B. Novales, L.Navailles, F. Nallet, C. Gaillard, F. Boué, J.P. Douliez, Smart foams: switchingreversibly between ultrastable and unstable foams, Angew. Chem. Int. Ed. 50(2011) 8264–8269.

20] N. Krog, Functions of emulsifiers in food systems, J. Am. Oil Chem. Soc. 54 (1977)124–131.

21] M. Dawson, E. Krauland, D. Wirtz, J. Hanes, Transport of polymeric nanoparticlegene carriers in gastric mucus, Biotechnol. Progr. 20 (2004) 851–857.

22] S.K. Lai, K. Hida, S. Shukair, Y.-Y. Wang, A. Figueiredo, R. Cone, T.J. Hope,J. Hanes, Human immunodeficiency virus type 1 is trapped by acidicbut not by neutralized human cervicovaginal mucus, J. Virol. 83 (2009)11196–11200.

23] S.K. Lai, Y.-Y. Wang, K. Hida, R. Cone, J. Hanes, Nanoparticles reveal that humancervicovaginal mucus is riddled with pores larger than viruses, Proc. Natl. Acad.Sci. U. S. A. 107 (2010) 598–603.

24] B.C. Tang, M. Dawson, S.K. Lai, Y.-Y. Wang, J.S. Suk, M. Yang, P. Zeitlin, M.P. Boyle,J. Fu, J. Hanes, Biodegradable polymer nanoparticles that rapidly penetrate thehuman mucus barrier, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 19268–19273.

25] Y.Y. Wang, S.K. Lai, J.S. Suk, A. Pace, R. Cone, J. Hanes, Addressing the PEGmucoadhesivity paradox to engineer nanoparticles that slip through the humanmucus barrier, Angew. Chem. Int. Ed. 47 (2008) 9726–9729.

26] S.Y. Kim, C.F. Zukoski, Particle restabilization in silica/PEG/ethanol suspensions:how strongly do polymers need to adsorb to stabilize against aggregation?Langmuir 27 (2011) 5211–5221.

27] J.L. Perry, K.G. Reuter, M.P. Kai, K.P. Herlihy, S.W. Jones, J.C. Luft, M. Napier, J.E.

Bear, J.M. DeSimone, PEGylated PRINT nanoparticles: the impact of PEG densityon protein binding, macrophage association, biodistribution, and pharmacoki-netics, Nano Lett. 12 (2012) 5304–5310.

28] Z. Zhu, Effects of amphiphilic diblock copolymer on drug nanoparticle forma-tion and stability, Biomaterials 34 (2013) 10238–10248.

ces B:

[

[

[

[

[

[drainage of thin liquid films, Langmuir 8 (1992) 3027–3032.

[35] V. Torchilin, PEGylated Pharmaceutical Nanocarriers, Long Acting Injections

C. Tang et al. / Colloids and Surfa

29] L.J. Peltonen, J. Yliruusi, Surface pressure, hysteresis, interfacial tension, andCMC of four sorbitan monoesters at water–air, water–hexane, and hexane–airinterfaces, J. Colloid Interface Sci. 227 (2000) 1–6.

30] S.E. Friberg, C. Solans, Surfactant association structures and the stability ofemulsions and foams, Langmuir 2 (1986) 121–126.

31] S.E. Friberg, Emulsion stability, Emulsions—A Fundamental and PracticalApproach, Springer, 1992, pp. 1–24.

32] A. Nikolov, D. Wasan, Ordered micelle structuring in thin films formed fromanionic surfactant solutions: I. Experimental, J. Colloid Interface Sci. 133 (1989)1–12.

[

Biointerfaces 133 (2015) 81–87 87

33] V. Bergeron, C. Radke, Equilibrium measurements of oscillatory disjoiningpressures in aqueous foam films, Langmuir 8 (1992) 3020–3026.

34] V. Bergeron, A. Jimenez-Laguna, C. Radke, Hole formation and sheeting in the

and Implants, Springer, 2012, pp. 263–293.36] J.V. Jokerst, T. Lobovkina, R.N. Zare, S.S. Gambhir, Nanoparticle PEGylation for

imaging and therapy, Nanomedicine 6 (2011) 715–728.