Ternary complex formation dramatically enhances metal-sorbing vesicle selectivity

Journal of Membrane Science 194 (2001) 263–272

Rapid communication

Ternary complex formation dramatically enhances metal-sorbing vesicle selectivity Ivan Stanish1 , Harold G. Monbouquette∗ Chemical Engineering Department, University of California, Los Angeles, CA 90035-1592, USA Received 19 January 2001; received in revised form 20 July 2001; accepted 6 August 2001

Abstract Conventional wisdom derived from experimental and theoretical studies of metal ion transport in liquid membrane systems suggests that the selective behavior of closely-related metal-sorbing vesicles (MSVs) should depend on independent interaction of ions with the membrane-bound carrier and with the encapsulated water soluble chelator. From a theoretical perspective, however, interdependent interactions between carrier, chelator and metal ion in a ternary complex can be designed into MSVs to augment significantly their metal ion selectivity. In this paper, we compare and contrast two transport models so as to elucidate MSV selectivity based on initial metal ion uptake rates from single and multi-component metal ion solutions. Our findings show that metal ion transport mechanisms that allow for interdependent interactions between the carrier and chelator, namely formation of a ternary metal ion–carrier–chelator complex at the inner vesicle wall, can enhance the overall selectivity of MSVs in accordance with a multiplicative, rather than additive, function of equilibrium metal–ligand binding constants. Therefore, design of MSVs that rely on metal ion transport mechanisms involving ternary complex formation may provide for a more economic route to extremely selective systems that employ less extensively tailored and less expensive metal-binding ligands. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Facilitated transport; Liposomes; Vesicles; Water treatment; Metal extraction

1. Introduction Over the past several years, engineered surfactant vesicles have been investigated as a means for rapid removal of toxic heavy metal ions from dilute aqueous solutions [1–7]. Metal-sorbing vesicles (MSVs) consist of phospholipid vesicles harboring a lipophilic ∗ Corresponding author. Tel.: +1-213-825-8946; fax: +1-213-206-4107. E-mail addresses: [email protected] (I. Stanish), [email protected] (H.G. Monbouquette). 1 Present address: US Naval Research Laboratory, 4555 Overlook Ave SW, Washington, DC 20375, USA.

metal ion carrier in the lipid bilayer and encapsulating a water soluble chelating agent in the aqueous vesicle interior (Fig. 1). The carrier facilitates transport of cationic species across the otherwise impermeable bilayer membrane, while the chelator provides a driving force for metal ion uptake. MSVs have advantageous properties such as high surface area and low membrane mass transfer resistance [8–11]. Further, MSVs exhibit highly selective metal ion sorption profiles, which derive from their unique dependence on metal ion binding interactions at two levels, that of the membrane-bound carrier as well as that of the encapsulated chelator [12–18]. MSV selectivity increases with increasing carrier and chelator specificity

0376-7388/01/$ – see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 0 3 7 6 - 7 3 8 8 ( 0 1 ) 0 0 6 2 1 - 4

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I. Stanish, H.G. Monbouquette / Journal of Membrane Science 194 (2001) 263–272 aq

aq

Here, MI and MII , and Cmemb represent the free metal ion in the outer and inner aqueous phases and the free carrier, respectively, and the quantities in parentheses represent metal–carrier complexes within the membrane. The initial metal ion uptake rate, ν0M , is defined as: ν0M

d[M]I ≡− dt

aq

=

[M] kdc–m

Iaq [C]memb

KcD–m

,

(1)

aq

Fig. 1. Metal-sorbing vesicles are composed of lipid surfactants that encapsulate water soluble chelating agents and that harbor catalytic amounts of lipophilic metal ion carrier.

[19,20], but typically not without increased cost due to the synthetic complexity of highly tailored metalbinding ligands. This cost issue is more critical with respect to the chelator, which provides the capacity for MSVs. Only catalytic amounts of the membranebound carrier are needed since these ligands turnover rapidly within the 3.7 nm thick bilayer membrane. Here, we describe design of an MSV system with the capability for high selectivity but potentially without the need for intricately tailored, hence expensive, metal ion binding agents.

2. Theory A Michaelis–Menten-based transport mechanism is the simplest reactions for describing carrier-assisted metal ion membrane transport into MSVs (Fig. 2a). As shown below (Reaction (I)), the Michaelis–Menten model assumes (1) equilibrium at the outer membrane interface with a metal ion–carrier equilibrium dissociation constant, KcD–m and (2) an irreversible rate controlling dissociation step of the metal ion–carrier complex at the inner vesicle wall with rate constant, kdc–m [21,22]: 1

aq

MI + Cmemb ↔(M–C)memb , 2

aq

(M–C)memb →Cmemb + MII ,

(I)

where [M]I and [C]memb signify the external metal ion concentration and the free (unbound) carrier concentration within the vesicle membrane, respectively. Eq. (1) is based on the assumption of zero intravesicular metal ion concentration, which is applicable for short times. From this equation, we see that the ratio of initial uptake rates for two different metal ions, or selectivity, depends on two parameters, kdc–m and KcD–m . The hyperbolic dependence of MSV metal ion uptake rate on external metal ion concentration can be obtained by eliminating [C]memb with a total carrier mass balance ([C]memb = [C]memb + [M–C]memb ) tot and by substituting the metal ion–carrier equilibrium dissociation constant. The initial uptake rate is then given by [21]: k c–m [M]I [C]memb tot = d D . aq Kc–m + [M]I aq

ν0M

(2)

Here, [C]memb is the total carrier concentration includtot ing that complexed with metal ions. Eq. (2) is expected to describe the initial metal ion uptake behavior of MSVs well without any description of mass transfer since the characteristic times for diffusion to these colloidal (∼100 nm diameter) species, for transport across their ∼4 nm thick bilayers, and for diffusion within the encapsulated aqueous space all are many orders of magnitude smaller than the characteristic time for metal ion–carrier dissociation kinetics. Some carriers, with appropriate geometrical configuration, can bind to metal ions, facilitate their transport across the vesicle wall, and present metal ion bonding orbitals for chelator attachment in a ternary carrier/metal ion/chelator complex at the vesicle inner wall (Fig. 2b). Linear carriers have been reported which form ternary complexes with metal ions and chelators and that can dissociate with the metal ion bound to the chelator [23]. This process may occur within MSVs. Carriers and chelators that

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265

Fig. 2. Metal ion transport across vesicle membranes is modeled according to two modes of facilitated membrane transport: (a) based on Michaelis–Menten kinetics and (b) based on formation of a ternary, carrier/chelator/metal ion complex at the inner vesicle wall. C, Ch, H+ , M2+ , and hyphenated names represent the metal ion carrier, chelator, proton, divalent metal ion, and chelates, respectively.

interact together in this “tug-of-war” fashion could give rise to MSV selectivities in metal ion uptake rate that depend on both carrier and chelator binding characteristics. The reaction mechanism (Reaction (II)) is described below as: aq

1

MI + Cmemb ↔(M–C)memb , 2

aq

aq

(M–C)memb + ChII ↔(C–M–Ch)memb/II , aq

3

aq

(C–M–Ch)memb/II →Cmemb + Ch–MII ,

(II)

aq

aq

where, ChII , (Ch–M)II , and (C–M–Ch)memb/II represent the intravesicular free chelator, the intravesicular chelated metal ion, and the interfacial ternary chelator–carrier–metal ion complex, respectively. Relative to simple Michaelis–Menten kinetics, this transport mechanism involves an additional step describing reversible formation of a ternary complex at the inner surface of the vesicle bilayer. For simplicity of theoretical argument, it is assumed that the carrier–metal ion complex, (M–C)memb , does not

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dissociate irreversibly as in Reaction (I) to deposit free metal ion in the MSV. Inclusion of such a step would merely result in an additional additive term to Eq. (3) below which diminishes in importance as the equilibrium formation of the ternary complex is favored. The initial metal ion uptake rate for the case described by Reaction (II) is derived in similar fashion to that described by Eq. (2). The equilibrium dissociation constants associated with steps 1 and 2 are used to eliminate the binary and ternary complex concentrations to give an expression analogous to Eq. (1) for the initial metal ion uptake rate: aq

[M]I [C]memb [Ch]tot ν0M = kdc–m–ch . KcD–m KcD–m–ch

(3)

= [C]memb + Finally, the carrier balance ([C]memb tot aq memb memb/II [M–C] + [C–M–Ch] ) is used to give an : equation in terms of [C]memb tot aq k c–m–ch [M]I [C]memb [Ch]tot /[Ch]tot +KcD–m–ch tot ν0M = d D . aq D Kc–m Kc–m–ch /([Ch]tot +KcD–m–ch )+[M]I

(4) Here kdc–m–ch , KcD–m , and KcD–m–ch represent the ternary dissociation rate constant and equilibrium dissociation constants of carrier–metal ion and carrier–chelator–metal ion complexes, respectively, for steps 1–3 in Reaction (II) above. Terms in brackets represent the concentrations of external metal ions, total internal chelator, and total membrane-bound carrier. In Eq. (4), we assume that the total chelator concentration approximates the free chelator concentration, which occurs for short times or excess chelator. We see that the initial uptake rate described by Eq. (4) approaches its limiting value, kdc–m–ch [C]memb , only tot when both the external metal ion concentration and the total internal chelator concentration become relatively large, whereas in Eq. (2), the uptake rate saturates with respect to external metal ion concentration only.

3. Experimental 3.1. Reagents and solutions l-␣-Phosphatidylcholine (>99%) derived from egg yolk was purchased from Avanti Polar Lipids.

Cd(NO3 )2 (99.999%), Pb(NO3 )2 (99.999%), KNO3 (99.99%), KOH (99.99%), and ethylenediammine tetraacetic acid (EDTA, 99.999%), nitrilotriacetic acid (NTA, 99.9%), and 8-hydroxyquinalidine (98%) were obtained from Aldrich. Diaminecyclohexane tetracetic acid (CyETDA, 99%), A23187 (free acid) and the Good’s buffer, piperazine N,N-bis(2-ethanesulfonic) acid (PIPES, 99%), were purchased from Sigma. The lipophilic metal ion carrier, designated Rebek B, was prepared according to published work [32,33]. All aqueous solutions were prepared with water purified with a Milli-Q system. Buffer solutions were titrated with standard KOH to pH 7 using a calibrated Orion pH. 3.2. Vesicle preparation, characterization, metal ion uptake measurements and simulations Vesicle stock solutions of ∼100 nm in diameter at 20 mg/ml lipid that encapsulate 40 mM of the desired chelator were prepared by extrusion (Lipex Biomembrane, BC, Canada), followed by size-exclusion chromatography (5000 MWCO, Kiwik, Pierce) to remove extravesicular chelator [3]. The vesicle suspension was doped to the appropriate concentration by external addition of carrier dissolved in ethanol. Vesicle size and concentration were determined by multi-angle laser light scattering [6] coupled with a mass balance incorporating inner, outer, and total vesicle dry weight. Cd2+ and Pb2+ uptake by metal-sorbing vesicles from a buffered solution of known concentration and pH was followed with a solid-state ion selective electrode and a double junction silver/silver chloride reference electrode containing saturated silver chloride in 4 M potassium nitrate in the inner compartment and 0.1 M potassium nitrate in the outer compartment (Orion). Several hundred microliters of vesicle stock solution was pipetted into the magnetically stirred reservoir to initiate the metal ion uptake process giving a final vesicle concentration based on lipid mass of 0.01–0.02% (w/v). An Orion 720A pH/ISE meter (Boston, MA) interfaced via a BNC connector board (National Instruments, MA) to a MacIntosh computer was used to record data every 2 s using LabView software (National Instruments, MA). Mathematical simulations were executed on a MacIntosh PowerBook G3 using Mathematica 3.0TM software.

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4. Results and discussion As a first approximation in the analysis of MSV selectivity, it can be assumed that the carrier and chelator contribute independently to metal ion uptake: the chelator provides a “driving force” and the carrier facilitates metal ion transport across the vesicle membrane (Fig. 2a). The chelator can be viewed as having a thermodynamic effect, and the carrier a kinetic effect on MSV selectivity. This view is supported by observing no change in Cd2+ or Pb2+ initial uptake rate (intravesicular Cd2+ and Pb2+ concentration ∼0 for short times) upon a change in encapsulated chelator type, hence binding strength (Fig. 3); however, the equilibrium MSV capacity (or loading capacity) for a particular ion may be affected strongly. In Fig. 3, MSVs contain one carrier and either of two chelators, where all binding agents have strong affinity for Cd2+ and Pb2+ . Since the carrier is highly lipophilic and the chelator highly hydrophilic, the two commonly are considered to be non-interacting. Under these common circumstances, the carrier controls selectivity in metal ion uptake rate for short times as described by Reaction (I), and the chelator determines equilibrium loading capacities for specific ions at long times. However, when carrier and chelator interact to form a ternary complex with metal ion, the chelator also impacts initial uptake rate. A comparison of Eqs. (2) and (4) illustrates the effect of ternary, carrier/chelator/metal ion, complex

Fig. 3. Uptake of 10.8 ␮M M2+ at pH 7 by MSVs which harbor 8-hydroxyquinalidine at 1.3 mM (based on reservoir volume) and that encapsulate 40 mM NTA for Pb2+ (䉫) and Cd2+ (䊐) or 40 mM EDTA for Pb2+ ( ) and Cd2+ (䊊). Apparent affinity constants are tabulated as an inset [35,36,49,50].

267

formation on initial metal ion uptake kinetics. In Eq. (2), the maximum initial metal ion uptake rate is given by kdc–m [C]memb ; whereas in Eq. (4), it is a functot tion of the total chelator concentration and the equilibrium dissociation constant for the ternary complex, kdc–m–ch [C]memb [Ch]tot /([Ch]tot + KcD–m–ch ). Theretot fore, in the latter case, the maximum uptake rate can saturate with respect to [Ch]tot . Also in Eq. (4), a more complex term, KcD–m KcD–m–ch /([Ch]tot + KcD–m–ch ), replaces KcD–m found in the denominator of Eq. (2). When [Ch]tot KcD–m–ch , this term in Eq. (3) reduces to ≈KcD–m ; however at larger values of [Ch]tot it is KcD–m–ch would rise more steeply to a greater maximum uptake rate than when [Ch]tot > KcD–m–ch . The above analysis shows that individual metal ion uptake by MSVs can be highly selective and readily controlled by three accessible parameters, kdc–m–ch , KcD–m and KcD–m–ch , and by [Ch]tot . In Fig. 4A, theoretical differences between the initial carrier turnover number as a function of metal ion concentration are shown. Here, the initial carrier turnover number, TO#0 (s−1 ), is defined as the initial metal ion uptake rate (mole/s), given by Eqs. (2) and (4), divided by the moles of carrier in the system. The parameters chosen are representative of typical MSV uptake experiments. Typical vesicle concentrations (% (w/v)) give rise to an inner to outer volume ratio of ∼1000. Affinity constants were chosen to be of moderate strength and the dissociation constants are comparable to previously reported turnover numbers [3,5,6]. This simulation clearly shows the much higher initial metal uptake rates (presented here normalized with respect to carrier amount to give TO#0 ) expected with carriers and chelators that form ternary complexes with metal ions. The potential improvement in selectivity of these systems is even more impressive. For the case of a binary system of metal ions, M1 and M2 , the ratio of initial metal ion uptake rates is obtained by writing Eq. (3) for each ion and taking the quotient: ν0M1 ν0M2

=

kdc–m1 –ch [M1 ]I

aq

KcD–m1 KcD–m1 –ch


c–m –ch −1 aq kd 2 [M2 ]I KcD–m2 KcD–m2 –ch

. (5)

Here, the free carrier concentrations cancel out and the relative initial transport velocities of metal

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Fig. 4. (A) Initial metal ion turnover numbers based on Eqs. (2) and (4) are represented by the dashed and solid curves, respectively. Total carrier and chelator concentration equal 0.1 ␮M and 0.5 M, respectively. Outer to inner vesicle volume is 1000 and, KcD–m , KcD–m–ch , kdc–m , and kdc–m–ch equal 10−5 , 10−5 M; 1, and 1 s−1 , respectively. (B) For a binary component system, log10 ratios of initial metal ion uptake rates vs. ratios of metal ion concentrations are plotted. The dashed and dot-dashed curves represents the Michaelis–Menten model (Reaction (I)) given by Eq. (6) and the ternary model (Reaction (II)) given by Eq. (5) with a 10-fold difference in favor of M1 for all kinetic and equilibrium parameters, respectively. The solid line represents MSV selectivity using the ternary model with a 103 -fold difference in KcD–m–ch in favor of M1 and with the other two parameters fixed at a 10-fold difference as above.

ions is expressed in terms of three parameters (kdc–m–ch , KcD–m , KcD–m–ch ) for each metal ion. In the simpler scenario where the metal ion dissociates from the carrier before binding to the chelator (Reaction (I)), the simpler expression for the ratio of uptake rates dependent on two parameters for each ion follows from Eq. (1) and is given by: ν0M1 ν0M2

k c–m1 [M1 ]I = d D Km1 –c

aq


c–m −1 aq kd 2 [M2 ]I . D Km 2 –c

(6)

The anticipated increase in selectivity for the proposed MSV system with the Reaction (II) mechanism arises

from the fact that both the carrier and chelator binding contribute to the metal uptake rate in multiplicative fashion. For instance, a 10-fold difference in affinities and dissociation rates between two metal ions can lead to a 1000-fold difference in MSV selectivity according to Eq. (5). The results of example calculations are shown in Fig. 4B. For the case where a ternary system forms (Reaction (II)), orders of magnitude greater selectivities are expected as compared to simple Michaelis– Menten metal ion transport (Reaction (I)). Simulations using both transport models (Eqs. (5) and (6)) are presented in Fig. 4B to illustrate MSV selectivity for metal ion uptake in binary metal ion solutions. For aq equimolar initial metal ion concentrations ([M1 ]I / aq I [M2 ] ), a 10-fold difference for all kinetic constants favoring M1 over M2 leads to a 102 -fold M1 selectivity by Reaction (I) (Fig. 3, dashed curve) and a 103 -fold selectivity by Reaction (II) (Fig. 3, dot-dashed curve). For a 10-fold difference in initial aq aq metal ion concentrations ([M1 ]I /[M2 ]I = 10), selectivity increases to 103 for Reaction (I) and 104 for Reaction (II). The 10-fold difference in selectivity between the two transport models is attributed to the 10-fold difference in the equilibrium dissociation constant of the ternary carrier–chelator–metal ion complexes, KcD–m–ch , that factor into Reaction (II) only. The potential to tune metal ion uptake with KcD–m–ch can lead to several orders of magnitude improvements in MSV selectivity. For example, a 103 -fold difference in KcD–m–ch for one metal ion over another leads directly to a 103 -fold greater selectivity of Reaction (II) MSVs (solid curve in Fig. 4B) relative to those exhibiting simple Michaelis–Menten, or Reaction (I), transport (dashed curve). Large differences in values for KcD–m–ch may be expected since large binding energies, driven entropically, are due principally to multi-dentate chelation. For instance, for octahedral metal ion coordination (i.e. six available metal ion binding sites), a tridentate carrier can occupy three metal ion binding orbitals and allow for strong binding of the three unoccupied metal ion orbitals by a tridentate chelator. On the other hand, for metal ions having tetrahedral coordination (i.e. four available metal ion binding sites), a tridentate carrier can bind to three of the available four metal ion binding sites and allow only one site (i.e. a relatively weaker level of interaction) for carrier–metal–chelator bind-

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269

Fig. 5. Predicted formation of an intermediate ternary complex whereby cadmium ligated by the synthetic membrane-bound carrier, Rebek B, coordinates further upon exposure to the water soluble chelator, ethylenediamine tetraacetic acid.

ing. These differences in ternary complex formation (i.e. carrier–metal–chelator association quantified by KcD–m–ch ) can lead to large differences in KcD–m–ch , and dramatically affect metal ion transport in MSVs (see Reaction (II) and Eq. (5)). Several examples of ternary binding complexes have been reported in aqueous and mixed solvent media [24–31]. Metal ions with multiple coordination sites bound by carrier molecules that occupy a fraction of those sites allow for the chelator to complex with the remaining unoccupied metal bonding orbitals. For instance the binding agent, Rebek B [32,33], based on the dimethyldiaminobenzene spacer is an acyclic, lipophilic, doubly ionizable, bidendate ligand with the most probable coordination number of 4 (see Fig. 5). Cd2+ , being a relatively large metal ion, can have coordination numbers ranging from 4 to 8 with octahedral geometry the most commonly found [34]. Presumably, water molecules coordinated to the neutral Cd–Rebek B agent complex are expected to be bound loosely. At the inner vesicle wall, encapsulated EDTA [35,36] which also is acyclic can easily displace bound water molecules to form a ternary carrier–chelator–metal ion complex (Fig. 5). The relative bond strengths of the carrier and of the chelator to the metal ion will determine whether the ternary complex is relatively stable and whether the rate at which metal ions are deposited is catalytic. If the dissociation rate is slow enough,

then formation of an intermediate ternary complex, which can profoundly alter the chemical environment of the carrier–metal ion complex, will approach equilibrium. Experimentally, this phenomenon may be applicable to MSV systems harboring ionophores designed by Rebek et al. [32] and Rebek and coworkers [33] (Fig. 6). No detectable uptake of Cd2+ is observed when vesicles encapsulate 58 mM EDTA,

Fig. 6. Uptake of 10.8 ␮M Cd2+ at pH 7 by MSVs which harbor Rebek B at lipid to carrier molar ratio of 300:1 and that encapsulate 58 mM Na4 –EDTA (×) or 58 mM Na4 –CyEDTA (䊊). Apparent affinity constants are tabulated as an inset [14,35,36], except for Rebek B, determined potentiometrically in aqueous ethanol (1:1 (w/w)).

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but uptake does occur with the encapsulation of 58 mM CyEDTA under nearly identical conditions. In control experiments, MSVs without carrier but encapsulating the desired chelator show no detectable uptake of Cd2+ over the duration of the experiment (data not shown). By encapsulating CyETDA, the chelator binding strength increases by 2.8 orders of magnitude relative to that of EDTA. If the model of Eq. (3) applies, it is undetermined whether the chelator affects more strongly the dissociation rate of the ternary complex or the apparent metal ion affinity of these MSVs. Further experimental study of MSVs harboring Rebek carriers, or similar metal ion transporters, and appropriate chelators could lead to verification of ternary complex formation and the predicted improvements in metal ion uptake rate and selectivity.

5. Concluding remarks Although the Michaelis–Menten formulae is an oversimplification of the binding and transport events occurring within the MSV membrane, it does provide for an easily understood depiction of the potential magnitude for MSV selectivity. Inhibitive effects due to protons and dissolved salts, alternative carrier to metal ion stoichiometries, Donnan potentials, and transmembrane complex translocation may need to be considered for a more comprehensive analysis. Nonetheless, the selective metal ion uptake behavior of MSVs can reduce to that described by Eq. (4) under certain circumstances. For short times, the initial internal metal ion concentration is zero which is analogous to imposing irreversibility. It also is likely that the assumed, irreversible dissociation step is rate limiting since rates of formation reactions [26,37–40] and carrier–metal ion translocation times [41–43] across vesicles membrane are expected to occur within microseconds, whereas carrier–metal ion dissociation rates and turnover numbers have been reported to occur on the scale of milliseconds to minutes [1,3,4,6,26,44,45]. Generally, pseudo-steady state is invoked for biomembrane transport since the carrier concentration is much lower than the external metal ion [21,22]. Transport equations derived from a pseudo-steady-state analysis that follow a Briggs–Haldane formula can be reduced to transport reactions that invoke equilibrium for the complexed

species, but only if the vesicle membrane is asymmetric [46,47]. Membrane asymmetry does exist for the curved bilayers of MSVs and an indication of this asymmetry is given proportionally by the square ratio of the membrane thickness to the vesicle outer radius [48]. Therefore, the smaller the vesicle diameter, the more disparate the inner and outer vesicle bilayer microenvironments, favoring the flow of metal ions in a given direction. In any case, the capsular geometry of MSVs provides a means to exploit cooperative interactions between the carrier, chelator and metal ion so as to facilitate rapid and selective uptake of metal ions. In MSV systems where ternary, chelator–carrier–metal ion complexes form, the overall selectivity in metal ion uptake rate is proportional to the product of carrier and chelator selectivity. In other metal ion extraction systems, selectivity is dependent solely on the binding characteristics of one species. Thus, it should prove more convenient and economical to engineer highly selective MSVs with carriers and chelators that bind in ternary complexes to metal ions rather than to design and synthesize highly tailored metal-binding agents for use in other extraction processes. References [1] J.H. van Zanten, H.G. Monbouquette, Biomimetic metalsorbing veicles: Cd2+ uptake by phophatidylcholine vesicles doped with ionophore A23187, Biotechnol. Prog. 8 (1992) 546–552. [2] A.J. Walsh, H.G. Monbouquette, Extraction of Cd2+ and Pb2+ from dilute aqueous solution using metal-sorbing vesicles in a hollow-fiber cartridge, J. Membr. Sci. 84 (1993) 107–121. [3] B.M. Shamsai, H.G. Monbouquette, A23187-mediated Cd2+ uptake by highly stable polymerized metal-sorbing vesicles, J. Membr. Sci. 130 (1997) 173–181. [4] J.H. van Zanten, D.S.W. Chang, I. Stanish, H.G. Monbouquette, Selective extraction of Pb2+ by metal-sorbing vesicles bearing ionophores of a new class, J. Membr. Sci. 99 (1995) 49–56. [5] The hazardous waste consultant, Remediation technologies for ground and surface water contaminated with heavy meal ions, Focus (1999) 4.1–4.25. [6] I. Stanish, H.G. Monbouquette, Selective sequestration of dilute heavy metal ions in the presence of excess Mg2+ and Ca2+ using metal-sorbing vesicles, J. Membr. Sci. 179 (2000) 127–136. [7] M.C. Annesini, F. Cioci, R. Lavecchia, L. Marrelli, Selective removal of heavy metals by engineered vesicles: a simplified model for uptake, Anal. Chim. 85 (1995) 683–695. [8] E.L. Cussler, Diffusion: Mass Transfer in Fluid Systems, Cambridge University Press, New York, NY, 1992.

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