the in-flow capture of superparamagnetic nanoparticles for targeting therapeutics

Available online at www.sciencedirect.com

Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 19–29www.nanomedjournal.com

Original Article: Clinical Nanomedicine

The in-flow capture of superparamagnetic nanoparticlesfor targeting therapeutics

Nicholas J. Darton, PhD, Bart Hallmark, MEng, PhD, CEng, MIChemE, Xuan Han, MEng,Sarah Palit, MEng, Nigel K.H. Slater, PhD, CEng, FIChemE, FREng,⁎

Malcolm R. Mackley, PhD, FIChemE, FInstP, FREngDepartment of Chemical Engineering, University of Cambridge, Cambridge, United Kingdom

Abstract Superparamagnetic nanoparticles have been synthesized that could potentially be used to

Received 24 AuguThe authors wou

Physical Sciences Resogy and Biologicalfinancial support.

⁎Corresponding aMuseums Site, Pembr

E-mail address: nk

1549-9634/$ – see frodoi:10.1016/j.nano.20

Please cite this articlfor targeting therape

magnetically target therapeutics within the body. The magnetic targeting and successful in-flowcapture of 330-nm and 580-nm agglomerates of these magnetite nanoparticles was performed using a0.5-T magnet. Optical observation of magnetic nanoparticle capture in microcapillary flow providesa useful preliminary way of establishing conditions for the magnetic capture of nanoparticles withdirect relevance to blood vessels for magnetically directed therapy. A stable nanoparticle layer of580-nm agglomerates could be formed at mean capillary flow velocities of up to 2.5 cm s–1 and forthe 330-nm agglomerates at velocities up to 4.4 cm s–1. These data show that smaller nanoparticleagglomerates form a layer that is impervious to erosion by fluid shear. Capillary blocking bynanoparticles, analogous to an embolism, was not detected in these experiments.© 2008 Elsevier Inc. All rights reserved.

Key words: Superparamagnetic nanoparticles; Magnetic capture; In-flow deposition; Targeted therapy

One of the key problems that hampers the advancement ofchemotherapeutic and gene therapy strategies is the targetingof the therapeutic to the site of disease. The use of magnetictargeting of therapeutic-tagged superparamagnetic nanopar-ticles for this purpose is an exciting possibility, because itcould potentially provide a noninvasive, precise, andinexpensive solution.

Magnetic nanoparticles are already in use clinically ascontrast agents in magnetic resonance imaging as well as cellsorting and immunoassays.1 The delivery of cytotoxic drugs

st 2007; accepted 13 November 2007.ld like to acknowledge both the Engineering andearch Council, United Kingdom, and the Biotechnol-Sciences Research Council, United Kingdom, for

uthor: Department of Chemical Engineering, Newoke St., Cambridge CB2 3RA, United [email protected] (N.K.H. Slater).

nt matter © 2008 Elsevier Inc. All rights reserved.07.11.001

e as: N.J. Darton, B. Hallmark, X. Han, S. Palit, N.K.H. Slatutics, Nanomedicine: NBM 2008;4:19-29, doi:10.1016/j.nan

by magnetic targeting was investigated in early work withmagnetic microparticles.2,3 Most recently implanted mag-nets have been used to target intravenously administered200-nm paramagnetic nanoparticle–linked doxorubicin totumors in vivo.4

The use of paramagnetic nanoparticles for targeting ofvirus-based gene therapy vectors was proposed from an invitro study by Hughes et al.5 Subsequently in vivo genedelivery by this method has been successfully demonstratedin mice.6

Promising in vivo results have led to three early-stageclinical trials of magnetic targeting of cytotoxic drugs totumors. In two of these trials, epirubicin-linked 100-nmparamagnetic nanoparticles administered intravenously weresuccessfully targeted to tumors with an externally applied0.2- to 0.8-T magnet placed beside the tumor.7,8 Wilson et al9

delivered a sample of intra-arterially administered doxor-ubicin-linked 0.5- 5-μm paramagnetic nanoparticles totumors in patients with an external 1.5-T magnet placedadjacent to the tumor.

er, M.R. Mackley, The in-flow capture of superparamagnetic nanoparticleso.2007.11.001

mailto:[email protected]

http://dx.doi.org/10.1016/j.nano.2007.11.001

igure 1. Transmission electron microscopy image of a cluster of 10-nmuperparamagnetic magnetite nanoparticles.

20 N.J. Darton et al. / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 19–29

Superparamagnetic magnetite (Fe3O4) nanoparticles canbe synthesized cheaply and efficiently by co-precipitation ofFe2+ and Fe3+ aqueous salt solutions by addition of a baseunder an oxygen-free, nonoxidizing environment. Controlof size, shape, and composition of nanoparticles depends onthe type of salts, Fe2+ and Fe3+ ratio, pH and ionic strengthof the media.10 The addition of a polymer such as dextranduring the precipitation process results in coated particlesthat can be attached to different ligands, such asantibodies,11 that can bind therapeutics. A problem facingthis precipitation method of nanoparticle formation is thatthe 6- to 10-nm magnetite nanoparticles produced have ahigh propensity to agglomerate. This problem can bereduced with the addition of polymethacrylic acid (PMAA)followed by ultrasonication.12

Some previous observations have been made of magnetictargeting of 500-nm ferromagnetic particles in flow througha microcapillary tube as a model of targeting in bloodvessels.13 These have had only limited success and have notused superparamagnetic nanoparticles or realistic flow rates.Thus far little experimental investigation has been done intothe effect of fluid flow rate on the dynamics of super-paramagnetic nanoparticle capture and buildup of particlesat the magnetically targeted site. This work addresses theseissues and also studies the stability of the capturednanoparticle layer by increasing the fluid flow rate andobserving the patterns of erosion that result. Magneticcapture of superparamagnetic nanoparticles was performedwith fluid viscosity, density, and velocities representative ofthose of blood in medium-sized venules and arterioles inthe human body, thus ensuring that the shear stress onthe capillary walls in vitro are of a similar order to thosein vivo.

Methods

FeCl3·6H2O, FeCl2·4H2O, 25% NH3 ·H2O, and HCl wereobtained from Fisher Scientific (Loughborough, UnitedKingdom) and PMAA from Sigma Aldrich (St. Louis,Missouri). The plastic capillary arrays were manufactured inhouse from a commercially available plastomer (DowAffinity) using a novel extrusion-based process that hasbeen documented elsewhere.14,15

Synthesis of superparamagnetic nanoparticles

Superparamagnetic magnetite nanoparticles with noadditional polymer coating were synthesized so thatpossible surface coat unevenness or interactions would bereduced. The method for fabricating nanoparticles wasadapted from Xia et al16 using overhead mixing rather thanultrasonication to mix the reaction. First, 9.6 mL of 1.5 MFeCl3·6H2O was added to 6.4 mL 0.5 M FeCl2 · 4H2O,then made up to 80 mL with degassed MilliQ (Millipore,Watford, United Kingdom) H2O. This mixture was filteredthrough a 0.22-μm filter membrane then mixed for 15

Fs

minutes at 60°C under nitrogen. Then, 6 mL 25% NH3

·H2O was added dropwise over 5 minutes with vigorousstirring (900 rpm) with an overhead stirrer. As the base wasadded, the solution changed in color from brown to black.This reaction was stirred for a total of 15 minutes at 60°Cunder nitrogen. The resulting black nanoparticle solutionwas then dialyzed in 12-kDa cutoff dialysis tubing againstthree changes of MilliQ H2O. To reduce agglomeration ofthe superparamagnetic nanoparticles, 3% by weight PMAAwas added and the pH adjusted to 7.4.12 This resulted insuperparamagnetic nanoparticle agglomerates of 575 ±8.0 nm in size as measured in a Brookhaven ZetaPALSsizer (Brookhaven, Holtsville, New York). To get a smalleragglomerate size of 328 ± 3.5 nm, a sample ofnanoparticles in 3% by weight PMAA was sonicated witha 330 W ultrasonic cell crusher (Heat Systems XL-2020,Farmingdale, New York) on full power for 10 minutes.

The morphology of magnetite nanoparticles in MilliQH2O was analyzed on a Philips CM100 (FEI Europe,Eindhoven, The Netherlands) transmission electron micro-scope (Figure 1). Roughly spherical nanoparticles with anaverage size of 10 nm could be observed on transmissionelectron microscopy (TEM) to be gathered in clusters.Dehydration of the sample in preparation for TEM alwaysresulted in the presence of nanoparticle clusters, so theagglomerates observed by Zeta-sizing could not be distin-guished. Measurements of the iron oxide lattice structure inthe nanoparticles by high-resolution electron microscopyindicated that the nanoparticles were composed of magnetite,Fe3O4. Measurements of magnetic moment by SQUIDmagnetometery at 293 K from –1 to 1 T showed thatthe particles were superparamagnetic with a magneticsusceptibility of 1.57 × 10–4.

Figure 2. Schematic diagram of the flow loop, observation, and injection system used to image the deposition and erosion of the superparamagneticmagnetite nanoparticle.

21N.J. Darton et al. / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 19–29

Apparatus and protocol for the in-flow capture and erosionof superparamagnetic nanoparticles

A key criterion for an experimental apparatus toobserve the deposition and erosion of superparamagneticnanoparticles was that observation of the flow should beinhibited as little as possible by curved-surface refractioneffects. To achieve this a novel plastic capillary array wasused, termed a microcapillary film or MCF,14,15 containingcapillaries of 410-μm diameter. A useful feature of MCFsis that the circular capillaries that they contain areembedded in an essentially flat film, thus facilitatingeasier optical observation of the capillary internals. TheMCFs were fabricated in house from a commerciallyavailable polymer resin, Dow Affinity Plastomer, using anovel extrusion process.15 Previous research had alreadyquantified the characteristics of fluid flows in MCFs.17

Only 1 of the 19 available capillaries was used in eachfilm. Other important criteria were precise control of theflow rate of fluid containing the nanoparticle suspension; areliable, reproducible means of introducing a pulse ofnanoparticle-PMAA solution into the flow system; and amagnet with a high field strength to permit nanopar-ticle capture. These considerations were met by using anHPLC pump (Kontron 422, Kontron Instruments, Milan,Italy), an electromechanical injection valve unit (VICIValco, Houston, TX), and a 0.5-T magnet (e-magnets UK,Sheffield) held in position such that it was placed within afew millimeters of one side of the MCF. The apparatusdiagram is shown in Figure 2.

Once the pump had been calibrated and the microscope(Intel Digital Blue QX3, Intel, Santa Clara, California) andlight source positioned for optimal clarity, experiments werecarried out on two sizes of nanoparticle aggregate, 330 nmand 580 nm, in two distinct phases. The first phase ofexperimentation was deposition. It was found that flow ratesless than 1 mL min–1 were optimal for deposition; henceflow rates between 0.1 mL min–1 and 0.5 mL min–1 wereexamined in steps of 0.05 mL min–1. These volumetric flowrates correspond to fluid velocities of 1.3 cm s–1 and 6.3 cms–1, respectively, with steps of 0.6 cm s–1. The Reynoldsnumbers corresponding to these flow velocities are 1.7 and8.0, respectively, using a measured fluid viscosity of 3% byweight PMAA solution of 2.5 × 10–3 Pa s and a density of1024 kg m–3. The flow was, as expected, laminar.Additionally, the physical properties of the 3% by weightPMAA solution were close to those of blood, with values ofblood viscosity reported about 3.3 × 10-3 Pa s–1 18 anddensity between 1043 kg m–3 and 1051 kg m–3.19 A pulse,approximately 2 mL in volume of 40 mg mL–1 nanoparticlesin 3% by weight PMAA solution, was injected via theelectromechanical valve into the established flow. Thisdeposition phase was continued until one of two criteriawere met; either a steady thickness of deposited nanoparticleswas held for over an hour after the injected pulse, or the initiallayer had subsequently been eroded by the flow. Erosionbecame the dominant behavior at the upper end of the flow-rate range explored.

The second phase of the experimental protocol was toobserve the erosion of an established nanoparticle layer. The

Figure 3. Sequence of images at (A) 0 minutes, (B) 7 minutes, (C) 32 minutes, and (D) 90 minutes showing the in-flow deposition of superparamagneticmagnetite nanoparticles. The cluster size of the nanoparticles was 580 nm, and the flow rate 0.1 mL min–1. The location of magnet is shown schematically by thecross-hatched rectangle in each image.


flow rate of fluid was incremented from the originaldeposition flow rate in steps of 0.05 mL min–1 such that anew steady-thickness nanoparticle layer was achieved for aperiod of 10 minutes at each flow rate. This procedure wasrepeated until the fluid flow completely eroded thenanoparticle layer.

Results

Deposition

The sequence of optical micrographs shown in Figure 3illustrates the observed nanoparticle deposition behaviorwhere a steady-state nanoparticle layer thickness wasachieved—in this case using 580-nm nanoparticles at aflow rate of 0.1 mL min–1. In this sequence of photographsthe location of the capillary walls and of the magnet isshown schematically.

Sequences of micrographs were taken for both 580-nmand 330-nm nanoparticles over the flow-rate range studied,and subsequent image analysis was used to quantify thethickness of the nanoparticle layer in millimeters. Anestimate of the error in these measurements was alsoobtained by taking into account the uncertainty of theexact border between the nanoparticle layer and the fluid,and of the layer's unevenness.

The series of plots shown in Figure 4 illustrate thedeposition kinetics for 580-nm nanoparticles for flow rates

between 0.1 mL min–1 and 0.25 mL min–1. In all four ofthese cases a stable thickness of the nanoparticle layer wasquickly reached. For flow rates above 0.3 mL min–1,corresponding to a fluid velocity of 3.8 cm s–1, a stable layerwas not attained as the initially formed layer of nanoparticlesunderwent subsequent erosion.

The sequence of plots shown in Figure 5 illustrates thedeposition kinetics for the 330-nm nanoparticles. In thiscase, it was found that stable nanoparticle layers were formedat flow rates up to 0.35 mL min–1 (corresponding to a fluidvelocity of 4.4 cm s–1), higher than the maximum flow ratethat yielded a stable layer of 580-nm nanoparticles.

Erosion

The sequence of optical micrographs shown in Figure 6illustrates the erosion of an established layer of nanoparticleswith further increases in flow rate. In this particular case thelayer of 580-nm nanoparticles was deposited at a flow rate of0.1 mL min–1 until steady-state behavior was reached. Then,the flow rate was incremented in steps of 0.05 mL min–1

until a new steady-state thickness was established. It wasobserved that there was an upper flow-rate limit, dependenton nanoparticle diameter, for which a steady-thickness layercould be achieved before the layer was advected away withthe flow. The plots shown in Figures 7 and 8 quantify thisbehavior for 580-nm and 330-nm nanoparticles, respectively.The plot with open symbols on each figure corresponds to

Figure 4. Plots showing the deposition kinetics of 580-nm nanoparticles for (A) 0.10 mL min–1 and 0.15 mL min–1, and (B) 0.20 mL min–1 and 0.25 mL min–1.The dashed horizontal line serves as a visual guide for the approximate location of the steady-state region.


the erosion behavior of a layer of nanoparticles deposited at0.15 mL min–1, whereas the plot with closed symbolscorresponds to both the deposition and erosion behavior at0.5 mL min–1 since a steady-thickness layer was notachieved at this flow rate for either particle diameter.

Discussion

The results presented for the deposition of the 580-nm and330-nm nanoparticles demonstrate that it is possible tocapture superparamagnetic nanoparticles that are beingadvected in a fluid flow by using a magnetic field from a0.5-T magnet adjacent to a plastic capillary. The thicknessand stability of the captured layer of nanoparticles is stronglyaffected by both the fluid flow rate and the mean hydraulic

diameter of the nanoparticle aggregates. If the plots inFigures 4 and 5 are compared, then it is evident that the largernanoparticles form a thicker layer, typically between0.26 mm and 0.16 mm, for flow rates between 0.1 mLmin–1 and 0.25 mL min–1, respectively. In contrast, the330-nm nanoparticles tend to form a more consistently,smaller sized layer, typically between 0.12 mm and 0.09 mmfor flow rates of 0.1 mL min–1 and 0.35 mL min–1,respectively. From the optical observations reported in thisarticle it is clear that the magnetic field is capable ofattracting the nanoparticles to the walls of the capillary andthat the thickness of the nanoparticle layer that is formed issensitive to flow conditions.

A possible explanation for the smaller deposited layer of330-nm nanoparticles is that each particle contains a smaller

Figure 5. Plots showing the deposition kinetics of 330-nm nanoparticles for (A) 0.10 mL min–1 and 0.20 mL min–1, and (B) 0.30 mL min–1 and 0.35 mL min–1.The dashed horizontal line serves as a visual guide for the approximate location of the steady-state region.


mass of magnetic material when compared with a nanopar-ticle of 580-nm diameter; the smaller particles, therefore,experience a weaker force as a result of the applied magneticfield, hence a smaller amount are likely to be captured fromthe fluid flow. The 580-nm nanoparticles, however, contain alarger amount of magnetic material, and hence theyexperience a larger force due to the applied magnetic field,resulting in a greater amount being captured. In terms of theerosion behavior of the nanoparticles at increasing flowrates, the observation that the layer of 580-nm nanoparticlesis unable to be maintained at flow rates at which the 330-nmnanoparticle layer is still present could be explainedqualitatively in terms of the applied shear stress on theparticle layer due to the fluid flow. The thicker layer of

nanoparticles results in a more constricted flow, hence theflow velocity in the capillary is higher for a given volumetricflow rate. This increased flow velocity, in turn, leads tohigher shear stresses on the nanoparticle surfaces and hence agreater driving force to erode the particles. The thinner layerof nanoparticles, on the other hand, results in less flowconstriction, and therefore lower shear stresses are present onthe particles. In this way the layer of 330-nm nanoparticlescan exist at higher volumetric flow rates when comparedwith the layer of 580-nm nanoparticles.

The hypothesis, therefore, is twofold. First, the amount ofparticles captured, hence the final thickness of the layer thatforms, is dependent on both the magnetic force and thehydrodynamic force experienced by the particle. When

Figure 6. Sequence of images showing the erosion of a pre-established nanoparticle layer, deposited at 0.1 mL min–1, with increasing flow rate. Image (A)corresponds to the initial steady-state layer when the flow rate was first increased, (B) 25 minutes later, (C) 27 minutes later, and (D) 30 minutes later. Thecluster size of the nanoparticles was 580 nm, and the flow rate 0.1 mL min–1. The location of magnet is shown schematically by the cross-hatched rectangle ineach image.


magnetic forces dominate the hydrodynamic forces, then aparticle is captured. However, when hydrodynamic forcesbecome dominant when compared with the magnetic forces,the nanoparticle layer is eroded by the flow. This lessens theflow constriction caused by the nanoparticle layer on thecapillary wall and hence lowers the hydrodynamic forces;thus a new equilibrium is achieved.

These qualitative explanations can also account for thetransient behavior that can be observed in Figures 7 and 8.These two figures present, at first sight, seemingly contra-dictory trends. The thickness of the layer of 580-nmnanoparticles can be seen to decrease with increasing flowrate until either a new steady-state thickness is formed orthe layer erodes away completely. Given the proposedhypothesis, the trend of erosion displayed by the 580-nmnanoparticles with increasing flow rate is expected. Incontrast, the layer of 330-nm nanoparticles can be seen atfirst to increase with increasing flow rates, before becomingsteady and then finally eroding away. A proposed mechan-ism for this observation is that the smaller amount ofmagnetic material present in the 330-nm nanoparticlesresults in lower magnetic forces and hence fewer particlesfrom the 2-mL pulse being captured when the initial layerwas formed. This layer results in only a small amount ofconstriction of the fluid flow, not enough for hydrodynamicforces to become dominant. If any additional nanoparticleswere present in the flow, they would still therefore be

captured. When the flow rate is increased, nanoparticlescaptured outside the field of view of the microscope, in anarea of weaker magnetic field further away from the magnet,are eroded but then subsequently recaptured onto thenanoparticle layer in the field of view. This leads to theobservation that the thickness of the nanoparticle layer atfirst increases with an increase in volumetric flow rate. Thisincrease is enough to reach equilibrium between magneticand hydrodynamic forces; thus, subsequent increases in flowrate serve to erode the nanoparticle layer away.

Further insight into this mechanism can be had bycalculating an estimate of the shear stress on the top of thenanoparticle layer for a given flow rate. This has been doneby approximating the area available for fluid flow as a largesegment of the circular capillary cross section, whereas theremaining, smaller segment of the capillary represents thenanoparticle layer. An equivalent diameter is then found forthe segment containing the flow and the shear stresscalculated by assuming that the flow is Poiseuille flow of aNewtonian fluid through a circular capillary with solid wallsof the equivalent diameter that had been calculated; this isshown schematically in Figure 9. Despite this approachmaking some first-order approximations about the nature ofthe boundary condition on the nanoparticle layer and alsothe shape of the flow geometry, a reasonable estimate of theshear stress on the nanoparticle layer can be obtained; thisestimate is of a similar magnitude to shear stresses reported

Figure 8. Plot of erosion kinetics for 330-nm nanoparticles for increasing erosion flow rates where the initial deposition flow rates were 0.15 mL min–1 (opensymbols) and 0.5 mL min–1 (closed symbols).

Figure 7. Plot of erosion kinetics for 580-nm nanoparticles for increasing erosion flow rates where the initial deposition flow rates were 0.15 mL min–1 (opensymbols) and 0.5 mL min–1 (closed symbols).


for the onset of erosion of biomass in filtration systems.20

Figure 10 shows the nanoparticle layer thickness that wasdetailed in Figures 7 and 8 replotted as a function of the shear

stress exerted on it by the fluid flow for the case where both330-nm and 580-nm nanoparticles were initially deposited at0.15 mL min–1 and then subjected to flow-rate increments of

Figure 10. Plot of the calculated shear stress on the top surface of the nanoparticle layer as a function of layer thickness for 330-nm nanoparticles (open symbols,dotted line) and for 580-nm nanoparticles (closed symbols, dashed line). The initial deposition flow rate was 0.15 mL min–1 in both cases, and the lines markedon the plot are for visual guidance only.

Figure 9. Schematic diagram showing the transformation of the real flow domain into one suitable for the estimation of the maximum fluid shear stress on the topsurface of the layer of captured nanoparticles.


0.05 mL min–1 until the layer had fully eroded away. Theshape of the two trends shown on this plot adds credence tothe proposed hypothesis; the applied stress on the 330-nmnanoparticle layer first increases markedly before erosion,suggesting that particle recapture may be occurring as aresult of poor initial capture. The applied stress on the

580-nm nanoparticle layer, however, is seen to onlyincrease by a small amount, whereas initial particleerosion rather than capture is occurring before rapiderosion of the layer takes place.

It is interesting to note that the stress at which rapiderosion occurs is different in both cases, suggesting that its


underlying mechanism is complex, possibly involvingvariables such as nanoparticle packing, how the nano-particles were initially deposited, and their interactionwith the surface of the film and with each other. Furtherinvestigation is needed to probe this behavior suchthat fundamental understanding of this phenomenon canbe gained.

It must be noted that the environment in which thesedeposition and erosion experiments have been carried out isa highly simplified model of a circulatory system. Theregime of flow is one of constant flow rate rather than theconstant pressure drop that one would expect to find across acapillary network, and the fluid carrying the nanoparticlesdoes not contain any particulate matter such as blood cells.The physics underlying the interaction between the hydro-dynamic and magnetic forces acting on an immobilizedlayer of nanoparticles, however, is similar, and theexperiments detailed in this article allow one to gainfundamental insight into this system. Future work willinvolve repeating these experiments in an environment ofconstant pressure drop that will be more analogous to theregime found in a circulatory system.

In this work superparamagnetic nanoparticles have beensuccessfully captured in microcapillaries of 410 μm indiameter in a flow of up to 0.3 mL s–1, equivalent to avelocity of 3.8 cm s–1. This is of particular relevance totherapeutic nanoparticle targeting, because this is the bloodvelocity expected in a medium-sized human venule orarteriole.21 The measured viscosity of the 3% by weightPMAA solution used in our capture experiments of 2.5 ×10–3 Pa s–1 is also closer than water to that of blood, about3.3 × 10–3 Pa s–1.18 The effectiveness of nanoparticlecapture supports the successful results of magnetic targetingof intravenously7,8 and intra-arterially9 administered nano-particles in initial clinical trials. Interestingly, furtheranalysis of nanoparticle deposition layer thickness andstability indicates that these properties are dependent onnanoparticle size. The larger 580-nm particles deposit toform a thicker layer quicker that is more susceptible tosubsequent erosion. The smaller 330-nm particles initiallydeposit to form a more stable thinner layer that increases inthickness as flow rates are increased until a critical flow rateis reached and erosion begins. It has been hypothesized inthis article that this observed behavior is due to the effectof shear stress on the nanoparticle layer. The shear stressincreases as the capillary flow is constricted, causingthe nanoparticle layer to reach an equilibrium where theforce of the magnetic attraction on the nanoparticles,proportional to particle size, balances the shear stressexerted by the fluid. This would also explain why completeblocking of the capillary with nanoparticles was reassur-ingly not observed.

In future clinical work, nanoparticle agglomerates ofbetween 300 and 600 nm in size could be used for delivery ofbound drug or gene-therapy vector to sites of disease withinthe body. Nanoparticle agglomerates in this size range have

the advantage that they can be trapped and manipulated at thesite of disease by inexpensive permanent magnets as small as0.5 T but are still superparamagnetic. Once magneticallydelivered to the site of interest, the nanoparticles may crossinto the cells as 10-nm nanoparticles by pinocytosis or aslarger agglomerates by phagocytosis to deliver their payload.These findings will provide a useful basis for futurenanoparticle design for effective magnetic targeting oftherapeutics in vivo.

References

1. Pankhurst QA, Connolly J, Jones SK, Dobson J. Applications ofmagnetic nanoparticles in biomedicine. J Phys D Appl Phys 2003;36:R167-81.

2. Senyei A, Widder K, Czerlinski G. Magnetic guidance of drug-carryingmicrospheres. J Appl Phys 1978;49:3578-83.

3. Widder KJ, Morris RM, Poore GA, Howard DP, Senyei AE. Selectivetargeting of magnetic albumin microspheres containing low-dosedoxorubicin-total remission in Yoshida sarcoma-bearing rats. Eur JCancer Clin Oncol 1983;19:135-9.

4. Fernandez-Pacheco R, Marquina C, Valdivia JG, Gutiérrez M, RomeroMS, Cornudella R. Magnetic nanoparticles for local drug delivery usingmagnetic implants. J Magn Magn Mater 2007;311:318-22.

5. Hughes C, Galea-Lauri J, Farzaneh F, Darling D. Streptavidinparamagnetic particles provide a choice of three affinity-based captureand magnetic concentration strategies for retroviral vectors. Mol Ther2001;3:623-30.

6. Morishita N, Nakagami H, Morishita R, et al. Magnetic nanoparticleswith surface modification enhanced gene delivery of HVJ-E vector.Biochem Biophys Res Commun 2005;334:1121-6.

7. Lubbe AS, Bergemann C, Brock J, McClure DG. Physiological aspectsin magnetic drug-targeting. J Magn Magn Mater 1999;194:149-55.

8. Lubbe AS, Bergemann C, Riess H, et al. Clinical experiences withmagnetic drag targeting: a phase I study with 4′-epidoxorubicin in 14patients with advanced solid tumors. Cancer Res 1996;56:4686-93.

9. Wilson MW, Kerlan RK, Fidelman NA, et al. Hepatocellular carcinoma:regional therapy with a magnetic targeted carrier bound to doxorubicinin a dual MR imaging/conventional angiography suite-initial experiencewith four patients. Radiology 2004;230:287-93.

10. Gupta AK, Gupta M. Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications. Biomaterials 2005;26:3995-4021.

11. Duan HL, Shen ZQ, Wang XW, Chao FH, Li JW. Preparation ofimmunomagnetic iron-dextran nanoparticles and application in rapidisolation of E.coliO157:H7 from foods. World J Gastroenterol 2005;11:3660-4.

12. Mendenhall GD, Geng Y, Hwang J. Optimization of long-term stabilityof magnetic fluids from magnetite and synthetic polyelectrolytes.J Colloid Interface Sci 1996;184:519-26.

13. Kikura H, Matsushita J, Kakuta N, Aritomi M, Kobayashi Y. Clusterformation of ferromagnetic nano-particles in micro-capillary flow.J Mater Process Tech 2007;181:93-8.

14. Hallmark B, Gadala-Maria F, Mackley MR. The melt processing ofpolymer microcapillary film (MCF). J Non-Newton Fluid 2005;128:83-98.

15. Hallmark B, Mackley MR, Gadala-Maria F. Hollow microcapillaryarrays in thin plastic films. Adv Eng Mater 2005;7:545-7.

16. Xia ZF, Wang GB, Tao KX, Li JX. Preparation of magnetite-dextranmicrospheres by ultrasonication. J Magn Magn Mater 2005;293:182-6.

17. Hornung CH, Hallmark B, Hesketh RP, Mackley MR. The fluid flowand heat transfer performance of thermoplastic microcapillary films.J Micromech Microeng 2006;16:434-47.


18. Lowe G, Rumley A, Norrie J, et al. Blood rheology, cardiovascular riskfactors, and cardiovascular disease: The West of Scotland CoronaryPrevention Study. Thromb Haemostasis 2000;84:553-8.

19. Hinghofer-Szalkay HG, Greenleaf JE. Continuous monitoring of bloodvolume changes in humans. J Appl Physiol 1987;63:1003-7.

20. Bustnes TE, Kaminski CF, Mackley MR. The capture and release ofbiomass in a high voidage fibrous microstructure: mechanisms andshear stress levels. J Membrane Sci 2006;276:208-20.

21. Sherwood L. Human physiology from cells to systems. New York:Wadsworth; 1997.

the in-flow capture of superparamagnetic nanoparticles for targeting therapeutics

Documents