Lanthanoid Endohedral Metallofullerenols for MRI Contrast Agents

Kato, H.; Kanazawa, Yôko; Okumura, M; Taninaka, Atsushi; Yokawa, Takashi; Shinohara, Hisanori

doi:10.1021/ja027555+

Cited by 282 publications

(247 citation statements)

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“…Metallofullerenes with gadolinium (Gd) have been demonstrated to be capable of effectively enhancing magnetic resonance image contrast (23). [Gd@C 82 (OH) 22 ] n , synthesized by our group, has been verified as a new generation of highly efficient contrast agents for magnetic resonance imaging (MRI) (24)(25)(26)(27). It is a hydroxylated fullerene forming a cage encapsulating gadolinium inside (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

Lü

Meng

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

235

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Cisplatin is a chemotherapeutic drug commonly used in clinics. However, acquired resistance confines its application in chemotherapeutics. To overcome the acquired resistance to cisplatin, it is reasoned, based on our previous findings of mediation of cellular responses by [Gd@C 82 (OH) 22 ] n nanoparticles, that [Gd@C 82 (OH) 22 ] n may reverse tumor resistance to cisplatin by reactivating the impaired endocytosis of cisplatin-resistant human prostate cancer (CP-r) cells. Here we report that exposure of the CP-r PC-3-luc cells to cisplatin in the presence of nontoxic [Gd@C 82 (OH) 22 ] n not only decreased the number of surviving CP-r cells but also inhibited growth of the CP-r tumors in athymic nude mice as measured by both optical and MRI. Labeling the CP-r PC-3 cells with transferrin, an endocytotic marker, demonstrated that pretreatment of the CPr PC-3-luc cells with [Gd@C 82 (OH) 22 ] n enhanced intracellular accumulation of cisplatin and formation of cisplatin-DNA adducts by restoring the defective endocytosis of the CP-r cancer cells. The results suggest that [Gd@C 82 (OH) 22 ] n nanoparticles overcome tumor resistance to cisplatin by increasing its intracellular accumulation through the mechanism of restoring defective endocytosis. The technology can be extended to other challenges related to multidrug resistance often found in cancer treatments.A s a major chemotherapeutic agent for tumor treatment, cisplatin remains a cornerstone of the present-day chemotherapy regimens against not only epithelial malignancies but also a number of metastatic and advanced malignancies (1, 2). However, because of high toxicity and easy development of drug resistance, successful treatment with cisplatin often is limited (3,4). Following the discovery of ATP-binding cassette (ABC) transporters and their roles in drug resistance in various types of tumors (5), much research has been done to explore the relationship between ABC transporter activity and specific chemotherapeutics, including cisplatin. Because no ABC transporter has been identified for "pumping" cisplatin out of cisplatin-resistant human prostate cancer (CP-r) cells (6-8), it would be difficult to sensitize CP-r cells by using any known strategy that targets resistant cancer cells by inhibiting multidrug resistance (MDR)-associated proteins on plasma membrane of the CP-r cells. Diffusion has been considered as a pathway for cisplatin to penetrate plasma membrane. Recently, studies have indicated that cisplatin entered cells by endocytosis and other mechanisms (9-12).To increase susceptibility of cancer cells to cisplatin, i.e., to reverse drug resistance, many efforts have been made through chemical modification, gene therapy, vector delivery, and other means (2, 9, 13). Combination of traditional chemotherapy with nanotechnology may provide a promising alternative for novel cancer treatments. The use of nanoparticles to sensitize tumor cells to cisplatin in vitro and in vivo has been described recently (14-16). In these studies, cisplatin-encap...

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Section: Resultsmentioning

confidence: 99%

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

Lü

Meng

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

235

160

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“…Pancreatic cancer is no exception; MMP-2 and MMP-9 show high levels of gene expression in clinical and experimental models relative to normal pancreas (5). Despite a growing concern about safety of engineered nanomaterials, the endohedral metallofullerenol Gd@C 82 (OH) 22 has recently been successfully demonstrated to have a high efficacy in interfering neoplastic activity, as well as metastasis, in a mouse cancer model, with almost no toxicity to normal cells in vivo and in vitro (6), where the metallofullerenol was originally developed for a high-contrast bioimaging agent such as in magnetic resonance imaging (MRI) by securing a toxic metal in the biocompatibly modified fullerenol cage (7)(8)(9).…”

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confidence: 99%

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine

Kang

Zhou

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

208

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Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C 82 (OH) 22 can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C 82 (OH) 22 effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Enzyme activity assays also show Gd@C 82 (OH) 22 not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C 82 (OH) 22 -MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C 82 (OH) 22 inhibits MMP-9 mainly via an exocite interaction, whereas the wellknown zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C 82 (OH) 22 exhibits specific binding modes near the ligand-specificity loop S1′, thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific binding mode make Gd@C 82 (OH) 22 a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.indirect inhibition mode | tumor metastasis | antiangiogenesis |

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“…13,14 In fact, self-aggregation may well be a common feature of all water-soluble fullerene chemistry, 15-17 and its understanding is, therefore, of general importance for fullerene-based drug delivery. In this communication, we report that proton relaxivity measurements for the water-soluble metallofullerenes, Gd@C 60 [C (COOH) 2 ] 10 and Gd@C 60 (OH) x (x≈27), can be used as a reporter to probe the aggregation (or disaggregation) characteristics of water-soluble fullerene materials in the presence of physiologically-encountered agents.…”

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confidence: 99%

“…With the aim of assessing the interaction between the aggregated gadofullerenes, Gd@C 60 (OH) x and Gd@C 60 [C(COOH) 2 ] 10 11,13 and physiologically encountered agents, we have carried out relaxivity measurements in the presence of human serum albumin (HSA) (4.5%) in phosphate-buffered saline (PBS; pH 7.4) at 60 MHz. The Solomon-BloembergenMorgan theory predicts that at this field r 1 is mainly determined by molecular rotation and tumbling and thus an interaction with HSA should lead to slower rotation and a subsequent relaxivity increase.…”

mentioning

confidence: 99%

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

et al. 2005

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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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Lanthanoid Endohedral Metallofullerenols for MRI Contrast Agents

Cited by 282 publications

References 35 publications

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine

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

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Lanthanoid Endohedral Metallofullerenols for MRI Contrast Agents

Cited by 282 publications

References 35 publications

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C 82 (OH) 22 and its implication for de novo design of nanomedicine

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

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Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine

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