Destroying Gadofullerene Aggregates by Salt Addition in Aqueous Solution of Gd@C₆₀(OH)_x and Gd@C₆₀[C(COOH₂)]₁₀

Abstract

A combined proton relaxivity and dynamic light scattering study has shown that aggregates formed in aqueous solution of water-soluble gadofullerenes can be disrupted by addition of salts. The salt content of fullerene-based materials will strongly influence properties related to aggregation phenomena, therefore their behavior in biological or medical applications. In particular, the relaxivity of gadofullerenes decreases dramatically with phosphate addition. Moreover, real biological fluids present a rather high salt concentration which will have consequences on fullerene aggregation and influence fullerene-based drug delivery.Water-soluble fullerene derivatives possess potential for biomedical applications as antioxidants, 1 anti-HIV drugs, 2 X-ray contrast agents, 3 bone-disorder drugs 4,5 and photosensitizers for photodynamic therapy. 6 In addition, endohedral metallofullerenes (M@C 2n ) have been suggested as nuclear medicines (M = Ho 3+ ) 7,8 , fluorescent tracers (M = Er 3+ ) 9 and MRI contrast agents (M = Gd 3+ ) 10-13 largely because the closed fullerene cage insures against toxic metal-ion release in vivo. Water-soluble members of the Gd@C 60 family The proton relaxivity, r 1 , which is the gauge of contrast agent efficiency, is remarkably higher (up to 10 times) for gadofullerenes than for typical clinical agents (r 1 is the paramagnetic longitudinal relaxation rate enhancement of water protons, referred to 1 mM concentration). 10-13 The electronic structure of Gd@C 60 involves the transfer of three electrons from the Gd atom to the cage resulting in seven unpaired electrons on the Gd 3+ center and one unpaired electron on the cage. The large relaxivity of the gadofullerenes has been attributed to their slow tumbling in solution and to the large number of surrounding water molecules. 13 This slow tumbling/rotation is related to aggregation phenomena in aqueous solution, and recently, in a variable-pH proton relaxation and dynamic light scattering (DLS) study, we confirmed a pHdependent aggregation of the gadofullerenes and proposed them as pH-responsive MRI contrast agents. 13With the aim of assessing the interaction between the aggregated gadofullerenes, Relaxivity is an ideal reporter of aggregation phenomena in paramagnetic solutions, as previously demonstrated in micellization of amphiphilic Gd 3+ chelates. 19 Disaggregation of the gadofullerenes leads to smaller and more rapidly tumbling entities, which will directly translate into lower relaxivities. On increasing PBS concentration in a gadofullerene solution, the relaxivity, indeed, decreases dramatically, indicating aggregate disruption (Figure 1)In order to separate the disaggregating effect of phosphate and sodium chloride in PBS, we have performed a relaxometric and DLS study of gadofullerene solutions at variable NaCl concentration (no phosphate). As Figure 2 shows, the relaxivity decrease on NaCl addition is also accompanied by a decrease of the hydrodynamic diameter, D H , thus confirming disaggregation as the most likely reason f...

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