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1.
ACS Appl Mater Interfaces ; 11(42): 38405-38416, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31556594

RESUMO

Intervertebral disc degeneration associated back pain is the most common cause of disability worldwide; however, no safe and effective treatments have been available. Here, we report a new functionalized nanofullerene conjugated with a peptide that binds specifically to a formyl peptide receptor-1 (FPR-1) expressed on activated macrophages. The new nanoparticle (aka FT-C60) was synthesized by conjugating carboxyl-C60 with the primary amine group of the peptide with a fluorescence dye for easy detection. The new nanoparticle was characterized by X-ray photoelectron spectroscopy, mass spectroscopy, and gel electrophoresis. It possessed effective radical (hydroxyl and superoxide anions) scavenging capabilities in electron paramagnetic resonance spectroscopy. In cultured cells, the nanoparticle FT-C60 demonstrated preferential binding to FPR-1 on activated macrophages and significantly attenuated mRNA expressions of proinflammatory factors including interleukin-6, interleukin-1, tumor necrosis factor-alpha, and cyclooxygenase-2. In vivo animal studies exhibited that a single intravenous injection of FT-C60 effectively alleviated pain in an established mouse model of radiculopathy for up to post-operation day (POD) 12. Ex vivo near-infrared fluorescence imaging of the mouse spine confirmed the targeting property of FT-C60 toward the injured disc on POD 14. Quantitative analysis of histological staining on spine sections showed that nanoparticle FT-C60 dramatically reduced inflammation at the local injury site compared to injury only on POD 7. In summary, we developed a novel targeted nanoparticle for treatment of lumbar radiculopathy by systemic delivery. This is a first-of-its-kind study for developing a novel class of targeted and systemic nanoparticle therapeutics to treat degenerative disc diseases.


Assuntos
Fulerenos/química , Degeneração do Disco Intervertebral/tratamento farmacológico , Nanopartículas/química , Receptores de Formil Peptídeo/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Radicais Livres/química , Inflamação/etiologia , Inflamação/prevenção & controle , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Nanopartículas/metabolismo , Nanopartículas/uso terapêutico , Nanopartículas/toxicidade , Imagem Óptica , Manejo da Dor , Células RAW 264.7 , Coluna Vertebral/diagnóstico por imagem
2.
Chemistry ; 25(54): 12545-12551, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31268197

RESUMO

Purified samples of Ho3 N@C2 (22010)-C78 and Tb3 N@C2 (22010)-C78 have been isolated by two distinct processes from the rich array of fullerenes and endohedral fullerenes present in carbon soot from graphite rods doped with Ho2 O3 or Tb4 O7 . Crystallographic analysis of the endohedral fullerenes as cocrystals with Ni(OEP) (in which OEP is the dianion of octaethylporphyrin) shows that both molecules contain the chiral C2 (22010)-C78 cage. This cage does not obey the isolated pentagon rule (IPR) but has two sites where two pentagons share a common C-C bond. These pentalene units bind two of the metal ions, whereas the third metal resides near a hexagon of the cage. Inside the cages, the Ho3 N or Tb3 N unit is planar. Ho3 N@C2 (22010)-C78 and Tb3 N@C2 (22010)-C78 use the same cage previously found for Gd3 N@C2 (22010)-C78 rather than the IPR-obeying cage found in Sc3 N@D3h -C78 .

3.
Angew Chem Int Ed Engl ; 58(18): 5891-5896, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30786125

RESUMO

The azafullerene Tb2 @C79 N is found to be a single-molecule magnet with a high 100-s blocking temperature of magnetization of 24 K and large coercivity. Tb magnetic moments with an easy-axis single-ion magnetic anisotropy are strongly coupled by the unpaired spin of the single-electron Tb-Tb bond. Relaxation of magnetization in Tb2 @C79 N below 15 K proceeds via quantum tunneling of magnetization with the characteristic time τQTM =16 462±1230 s. At higher temperature, relaxation follows the Orbach mechanism with a barrier of 757±4 K, corresponding to the excited states, in which one of the Tb spins is flipped.

4.
Chem Commun (Camb) ; 54(19): 2425-2428, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29457159

RESUMO

We show increased dynamic nuclear polarization by adding a low dosage of a S = 15/2 Gd based endohedral metallofullerene (EMF) to DNP samples. By adding 60 µM Gd2@C79N, the nuclear polarization of 1H and 13C spins from 40 mM 4-oxo-TEMPO increases by approximately 40% and 50%, respectively, at 5 T and 1.2 K. Electron-electron double resonance (ELDOR) measurements show that the high spin EMF shortens the electron relaxation times and increases electron spectral diffusion leading to the increased DNP enhancement.

5.
ACS Appl Mater Interfaces ; 9(21): 17681-17687, 2017 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-28516768

RESUMO

Antioxidative and anti-inflammatory effects of trimetallic nitride endohedral fullerenes carboxyl-Gd3N@C80, a newly developed magnetic resonance imaging (MRI) contrast agent, were investigated. All hydrochalarone and carboxyl-functionalized fullerenes showed effective radical (hydroxyl and superoxide anion) scavenging, whereas the carboxyl-Gd3N@C80 more efficiently attenuated lipopolysaccharide (LPS) induced oxidative stress in macrophages. Carboxyl-Gd3N@C80 also suppressed LPS-elicited mRNA expression of pro-inflammatory inducible nitric oxide synthase and tumor necrosis factor-alpha, and upregulated antioxidative enzyme axis Nrf2 and heme oxygenase-1, possibly via ERK but not AKT signaling pathways. Therefore, carboxyl-Gd3N@C80 held a great promise in becoming a novel theranostic nanoplatform for simultaneously deliver MRI contrast and therapeutic functions to inflammation-related diseases.


Assuntos
Fulerenos/química , Meios de Contraste , Gadolínio , Inflamação , Estresse Oxidativo , Nanomedicina Teranóstica
6.
Bioconjug Chem ; 28(2): 649-658, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28061526

RESUMO

Differential diagnosis of chronic post-traumatic osteomyelitis (CPO) from aseptic inflammation remains challenging, since both pathological processes share similar clinical symptoms. Here we utilized a novel targeted metallofullerene nanoparticle based magnetic resonance imaging (MRI) probe IL-13-TAMRA-Gd3N@C80(OH)30(CH2CH2COOH)20 to detect CPO in mouse tibia via overexpressed IL-13Rα2 receptors. The functionalized metallofullerene was characterized by X-ray photoelectron spectroscopy. Upon lipopolysaccharide (LPS) stimulation, macrophage Raw 264.7 cells showed elevated IL-13Rα2 expression via immunofluorescence staining and increased MRI probe binding via built-in TAMRA fluorescence imaging. Trauma was induced in both tibia of mice and bacteria soaked suture was inserted into the right tibia to initiate infection. During the acute phase (1.5 weeks), luminol-bioluminescence imaging revealed much higher myeloperoxidase activity in the infected tibia compared to the sham. In the chronic phase (4 weeks), X-ray radiography illustrated bone deformation in the infected tibia compared to the sham. With T1 weighted sequences, the probe clearly exhibited hyperintensity in the infection foci at both acute and chronic phases, which was not observed in the sham tibia. Histological analysis revealed severe bone structural destruction and massive inflammatory cell infiltration in the infected tibia. Immunohistochemistry confirmed abundant expression of IL-13Rα2 in the infection site. In summary, we developed a noninvasive imaging approach to detect and differentiate CPO from aseptic inflammation using a new IL-13Rα2 targeted metallofullerene MRI probe. In addition, for the first time, IL-13Rα2 was investigated as a unique biomarker in the context of osteomyelitis. Our data established a foundation for the translational application of this MRI probe in the clinical differentiation of CPO.


Assuntos
Fulerenos/química , Gadolínio/química , Subunidade alfa2 de Receptor de Interleucina-13/análise , Interleucina-13/química , Imagem por Ressonância Magnética/métodos , Osteomielite/diagnóstico por imagem , Tíbia/diagnóstico por imagem , Sequência de Aminoácidos , Animais , Biomarcadores/química , Doença Crônica , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Nanopartículas/química , Células RAW 264.7 , Receptores de Interleucina-13
7.
Small ; 13(8)2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28026111

RESUMO

The carbonaceous nanomaterials known as metallofullerenes have attracted considerable attention due to their attractive properties. The robust nature of the "Trojan Horse" fullerene cage provides an important structural component, which isolates the metal cluster from the bioenvironment. The large carbon surface area is ideally suited for multiple exo-functionalization approaches to modify the hydrophobic cage for a more hydrophilic bioenvironment. Additionally, peptides and other agents are readily covalently attached to this nanoprobe for targeting applications. The recent progress in developing metallofullerenes for next-generation biomedical applications is described. Of special interest are magnetic resonance imaging (MRI) contrast agents. Several recent studies reported cumulative gadolinium deposition in the brain and bones of individuals using commercial clinical MRI contrast agents. Gadolinium-based metallofullerenes provide 2-3 orders of magnitude improvement in MRI relaxivity and potentially lower clinical levels of toxic Gd3+ ions deposited. Other potential biomedical applications are also reviewed herein.


Assuntos
Tecnologia Biomédica/métodos , Fulerenos/química , Nanopartículas Metálicas/química , Metais/química , Animais , Humanos , Imagem por Ressonância Magnética , Distribuição Tecidual
9.
J Am Chem Soc ; 137(24): 7881-8, 2015 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-26022213

RESUMO

The development of new nanoparticles as next-generation diagnostic and therapeutic ("theranostic") drug platforms is an active area of both chemistry and cancer research. Although numerous gadolinium (Gd) containing metallofullerenes as diagnostic magnetic resonance imaging (MRI) contrast agents have been reported, the metallofullerene cage surface, in most cases, consists of negatively charged carboxyl or hydroxyl groups that limit attractive forces with the cellular surface. It has been reported that nanoparticles with a positive charge will bind more efficiently to negatively charged phospholipid bilayer cellular surfaces, and will more readily undergo endocytosis. In this paper, we report the preparation of a new functionalized trimetallic nitride template endohedral metallofullerene (TNT EMF), Gd3N@C80(OH)x(NH2)y, with a cage surface bearing positively charged amino groups (-NH3(+)) and directly compare it with a similar carboxyl and hydroxyl functionalized derivative. This new nanoparticle was characterized by X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS), and infrared spectroscopy. It exhibits excellent (1)H MR relaxivity. Previous studies have clearly demonstrated that the cytokine interleukin-13 (IL-13) effectively targets glioblastoma multiforme (GBM) cells, which are known to overexpress IL-13Rα2. We also report that this amino-coated Gd-nanoplatform, when subsequently conjugated with interleukin-13 peptide IL-13-Gd3N@C80(OH)x(NH2)y, exhibits enhanced targeting of U-251 GBM cell lines and can be effectively delivered intravenously in an orthotopic GBM mouse model.


Assuntos
Meios de Contraste/química , Fulerenos/química , Gadolínio/química , Glioblastoma/diagnóstico , Interleucina-13/química , Nanopartículas/química , Aminação , Animais , Linhagem Celular Tumoral , Humanos , Imagem por Ressonância Magnética/métodos , Camundongos Nus , Modelos Moleculares
10.
J Am Chem Soc ; 136(6): 2630-6, 2014 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-24432974

RESUMO

Water-soluble derivatives of gadolinium-containing metallofullerenes have been considered to be excellent candidates for new magnetic resonance imaging (MRI) contrast agents because of their high relaxivity and characteristic encapsulation of the lanthanide ions (Gd(3+)), preventing their release into the bioenvironment. The trimetallic nitride template endohedral metallofullerenes (TNT EMFs) have further advantages of high stability, high relative yield, and encapsulation of three Gd(3+) ions per molecule as illustrated by the previously reported nearly spherical, Gd3N@I(h)-C80. In this study, we report the preparation and functionalization of a lower-symmetry EMF, Gd3N@C(s)-C84, with a pentalene (fused pentagons) motif and an egg-shaped structure. The Gd3N@C84 derivative exhibits a higher (1)H MR relaxivity compared to that of the Gd3N@C80 derivative synthesized the same way, at low (0.47 T), medium (1.4 T), and high (9.4 T) magnetic fields. The Gd3N@C(s)-C84 derivative exhibits a higher hydroxyl content and aggregate size, as confirmed by X-ray photoelectron spectroscopy (XPS) and dynamic light scattering (DLS) experiments, which could be the main reasons for the higher relaxivity.


Assuntos
Meios de Contraste/química , Fulerenos/química , Gadolínio/química , Imagem por Ressonância Magnética
11.
PLoS One ; 8(9): e74679, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24040316

RESUMO

A critical limiting factor of chemotherapy is the unacceptably high toxicity. The use of nanoparticle based drug carriers has significantly reduced the side effects and facilitated the delivery of drugs. Source of the remaining side effect includes (1) the broad final in vivo distribution of the administrated nanoparticles, and (2) strong basal drug release from nanoparticles before they could reach the tumor. Despite the advances in pH-triggered release, undesirable basal drug release has been a constant challenge under in vivo conditions. In this study, functionalized single walled carbon nanohorn supported immunoliposomes were assembled for paclitaxel delivery. The immunoliposomes were formulated with polyethylene glycol, thermal stable and pH sensitive phospholipids. Each nanohorn was found to be encapsulated within one immunoliposome. Results showed a highly pH dependent release of paclitaxel in the presence of serum at body temperature with minimal basal release under physiological conditions. Upon acidification, paclitaxel was released at a steady rate over 30 days with a cumulative release of 90% of the loaded drug. The drug release results proved our hypothesized double controlled release mechanism from the nanoparticles. Other results showed the nanoparticles have doubled loading capacity compared to that of traditional liposomes and higher affinity to breast cancer cells overexpressing Her2 receptors. Internalized nanoparticles were found in lysosomes.


Assuntos
Portadores de Fármacos , Nanocompostos/química , Nanopartículas/química , Linhagem Celular , Preparações de Ação Retardada , Humanos , Concentração de Íons de Hidrogênio , Lipossomos/química , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Paclitaxel/administração & dosagem , Tamanho da Partícula , Polietilenoglicóis/química , Receptor ErbB-2/metabolismo , Soro , Solubilidade
12.
Nat Chem ; 5(10): 880-5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24056346

RESUMO

Although fullerenes were discovered nearly three decades ago, the mechanism of their formation remains a mystery. Many versions of the classic 'bottom-up' formation mechanism have been advanced, starting with C2 units that build up to form chains and rings of carbon atoms and ultimately form those well-known isolated fullerenes (for example, I(h)-C60). In recent years, evidence from laboratory and interstellar observations has emerged to suggest a 'top-down' mechanism, whereby small isolated fullerenes are formed via shrinkage of giant fullerenes generated from graphene sheets. Here, we present molecular structural evidence for this top-down mechanism based on metal carbide metallofullerenes M2C2@C1(51383)-C84 (M = Y, Gd). We propose that the unique asymmetric C1(51383)-C84 cage with destabilizing fused pentagons is a preserved 'missing link' in the top-down mechanism, and in well-established rearrangement steps can form many well-known, high-symmetry fullerene structures that account for the majority of solvent-extractable metallofullerenes.


Assuntos
Fulerenos/química , Gadolínio/química , Ítrio/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Solventes/química
13.
Acc Chem Res ; 46(7): 1548-57, 2013 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-23489255

RESUMO

Shortly after the discovery of the carbon fullerene allotrope, C60, researchers recognized that the hollow spheroidal shape could accommodate metal atoms, or clusters, which quickly led to the discovery of endohedral metallofullerenes (EMFs). In the past 2 decades, the unique features of EMFs have attracted broad interest in many fields, including inorganic chemistry, organic chemistry, materials chemistry, and biomedical chemistry. Some EMFs produce new metallic clusters that do not exist outside of a fullerene cage, and some other EMFs can boost the efficiency of magnetic resonance (MR) imaging 10-50-fold, in comparison with commercial contrast agents. In 1999, the Dorn laboratory discovered the trimetallic nitride template (TNT) EMFs, which consist of a trimetallic nitride cluster and a host fullerene cage. The TNT-EMFs (A3N@C2n, n = 34-55, A = Sc, Y, or lanthanides) are typically formed in relatively high yields (sometimes only exceeded by empty-cage C60 and C70, but yields may decrease with increasing TNT cluster size), and exhibit high chemical and thermal stability. In this Account, we give an overview of TNT-EMF research, starting with the discovery of these structures and then describing their synthesis and applications. First, we describe our serendipitous discovery of the first member of this class, Sc3N@Ih-C80. Second, we discuss the methodology for the synthesis of several TNT-EMFs. These results emphasize the importance of chemically adjusting plasma temperature, energy, and reactivity (CAPTEAR) to optimize the type and yield of TNT-EMFs produced. Third, we review the approaches that are used to separate and purify pristine TNT-EMF molecules from their corresponding product mixtures. Although we used high-performance liquid chromatography (HPLC) to separate TNT-EMFs in early studies, we have more recently achieved facile separation based on the reduced chemical reactivity of the TNT-EMFs. These improved production yields and separation protocols have allowed industrial researchers to scale up the production of TNT-EMFs for commercial use. Fourth, we summarize the structural features of individual members of the TNT-EMF class, including cage structures, cluster arrangement, and dynamics. Fifth, we illustrate typical functionalization reactions of the TNT-EMFs, particularly cycloadditions and radical reactions, and describe the characterization of their derivatives. Finally, we illustrate the unique magnetic and electronic properties of specific TNT-EMFs for biomedicine and molecular device applications.


Assuntos
Descoberta de Drogas/métodos , Fulerenos/química , Metais/química , Nitrogênio/química , Compostos Organometálicos/química , Conformação Molecular
14.
J Am Chem Soc ; 135(9): 3351-4, 2013 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-23342951

RESUMO

Although not found to date in empty-cage fullerenes, the fused pentagon motifs (pentalenes) are allowed in endohedral metallofullerenes (EMFs). We have found that members of the trimetallic nitride template (TNT) EMF Y3N@C2n (n = 39-44) family that contain pentalene motifs exhibit significant dipole moments. This finding is predicted to be significant for other EMFs with a metal atom orientated toward the pentalene motif. Chromatographic retention data and computational results for Y3N@C2-C78, Y3N@Cs-C82, and Y3N@Cs-C84 are examples that pentalene groups lead to a significant induced dipole moment (∼1D). A special case is the Y3N@C2-C78 that contains two pentalenes in a relatively small cage. The (13)C NMR spectrum for Y3N@C2-C78 exhibits strongly deshielded signals for the fullerene cage (155-170 ppm) supporting the presence of the pentalene motif. In addition, a lengthening of the covalent M-N bond in the internal M3N cluster is found for all reported TNT EMFs that contain one or two pentalene motifs.

15.
Bioconjug Chem ; 23(9): 1873-80, 2012 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-22881865

RESUMO

Fullerenes are used across scientific disciplines because of their diverse properties gained by altering encapsulated or surface-bound components. In this study, the recently developed theranostic agent based on a radiolabeled functionalized metallofullerene ((177)Lu-DOTA-f-Gd(3)N@C(80)) was synthesized with high radiochemical yield and purity. The efficacy of this agent was demonstrated in two orthotopic xenograft brain tumor models of glioblastoma multiforme (GBM). A dose-dependent improvement in survival was also shown. The in vivo stability of the agent was verified through dual label measurements of biological elimination from the tumor. Overall, these results provide evidence that nanomaterial platforms can be used to deliver effective interstitial brachytherapy.


Assuntos
Braquiterapia , Neoplasias Encefálicas/radioterapia , Fulerenos/química , Glioblastoma/radioterapia , Nanotecnologia , Animais , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Feminino , Glioblastoma/patologia , Camundongos , Camundongos Nus
16.
J Am Chem Soc ; 134(20): 8487-93, 2012 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-22497289

RESUMO

The nanoscale parameters of metal clusters and lattices have a crucial influence on the macroscopic properties of materials. Herein, we provide a detailed study on the size and shape of isolated yttrium carbide clusters in different fullerene cages. A family of diyttrium endohedral metallofullerenes with the general formula of Y(2)C(2n) (n = 40-59) are reported. The high field (13)C nuclear magnetic resonance (NMR) and density functional theory (DFT) methods are employed to examine this yttrium carbide cluster in certain family members, Y(2)C(2)@D(5)(450)-C(100), Y(2)C(2)@D(3)(85)-C(92), Y(2)C(2)@C(84), Y(2)C(2)@C(3v)(8)-C(82), and Y(2)C(2)@C(s)(6)-C(82). The results of this study suggest that decreasing the size of a fullerene cage with the same (Y(2)C(2))(4+) cluster results in nanoscale fullerene compression (NFC) from a nearly linear stretched geometry to a constrained "butterfly" structure. The (13)C NMR chemical shift and scalar (1)J(YC) coupling parameters provide a very sensitive measure of this NFC effect for the (Y(2)C(2))(4+) cluster. The crystal structural parameters of a previously reported metal carbide, Y(2)C(3) are directly compared to the (Y(2)C(2))(4+) cluster in the current metallofullerene study.

17.
Radiology ; 261(1): 136-43, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21813738

RESUMO

PURPOSE: To demonstrate in an orthotopic xenograft brain tumor model that a functionalized metallofullerene (f-Gd3N@C80) can enable longitudinal tumor imaging and, when radiolabeled with lutetium 177 (¹77Lu) and tetraazacyclododecane tetraacetic acid (DOTA) (¹77Lu-DOTA-f-Gd3N@C80), provide an anchor to deliver effective brachytherapy. MATERIALS AND METHODS: All experiments involving the use of mice were carried out in accordance with protocols approved by the institutional animal care and use committee. Human glioblastoma U87MG cells were implanted by using stereotactic procedures into the brains of 37 female athymic nude-Foxn1nu mice and allowed to develop into a tumor for 8 days. T1- and T2-weighted magnetic resonance (MR) imaging was performed in five mice. Biodistribution studies were performed in 12 mice at four time points over 7 days to evaluate gadolinium content. Survival studies involved 20 mice that received infusion of a nanoplatform by means of convection-enhanced delivery (CED) 8 days after tumor implantation. Mice in survival studies were divided into two groups: one comprised untreated mice that received f-Gd3N@CC80 alone and the other comprised mice treated with brachytherapy that received 1.11 MBq of ¹77Lu-DOTA-f-Gd3N@CC80. Survival data were evaluated by using Kaplan-Meier statistical methods. RESULTS: MR imaging showed extended tumor retention (25.6% ± 1.2 of the infused dose at 52 days, confirmed with biodistribution studies) of the f-Gd3N@CC80 nanoplatform, which enabled longitudinal imaging. Successful coupling of ¹77Lu to the f-Gd3N@CC80 surface was achieved by using a bifunctional macrocyclic chelator. The extended tumor retention allowed for effective brachytherapy, as indicated by extended survival time (> 2.5 times that of the untreated group) and histologic signs of radiation-induced tumor damage. CONCLUSION: The authors have developed a multimodal nanoplatform and have demonstrated longitudinal tumor imaging, prolonged intratumoral probe retention, biodistribution, and extended survival in an orthotopic xenograft brain tumor model.


Assuntos
Braquiterapia/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Complexos de Coordenação , Fulerenos , Glioblastoma/diagnóstico por imagem , Glioblastoma/radioterapia , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Lutécio/uso terapêutico , Radioisótopos/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Nus , Nanotecnologia , Transplante de Neoplasias , Cintilografia
18.
Bioconjug Chem ; 22(6): 1012-6, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21528932

RESUMO

Nanoparticle-supported liposomes can be a promising platform for drug delivery, vaccine development, and biomedical imaging. Single-walled carbon nanohorns are a relatively new carbon nanomaterial, and they could be used as carriers of drug and imaging reagents. Assembling lipids around carbon nanohorns would confer this nanomaterial much broader applications such as vaccine development and targeted drug delivery by embedding a target protein or immunogenic protein into the lipid bilayer structure. Here, we show the assembly of functionalized single-walled carbon nanohorns (-CH(2)-CH(2)-COOH(x), ~100 nm) with positively charged lipids through a freeze and thaw cycle. The assembled complex particles can be readily separated from individual nanohorns or liposomes under specific centrifugation conditions. The results from transmission electronic microscopy, flow cytometry through nitrobenzoxadiazole labeled lipids, and zeta potential analysis clearly show that the nanohorns are encapsulated by liposomes with a median size of ca. 120 nm.


Assuntos
Lipossomos/química , Lipossomos/síntese química , Nanotubos de Carbono/química , Sistemas de Liberação de Medicamentos , Tamanho da Partícula , Propriedades de Superfície
19.
Nanomedicine (Lond) ; 6(3): 449-58, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21542684

RESUMO

BACKGROUND: Glioblastoma multiforme is the most common and most lethal primary brain tumor in humans, with median survival of approximately 1 year. Owing to the ability of glioma cells to aggressively infiltrate normal brain tissue and survive exposure to current adjuvant therapies, there is a great need for specific targeted nanoplatforms capable of delivering both therapeutic and imaging agents directly to invasive tumor cells. METHOD: Gadolinium-containing endohedral fullerenes, highly efficient contrast agents for MRI, were functionalized and conjugated with a tumor-specific peptide and assessed for their ability to bind to glioma cells in vitro. RESULTS: We report the successful conjugation of the carboxyl functionalized metallofullerene Gd(3)N@C(80)(OH)(-26)(CH(2)CH(2)COOH)(-16) to IL-13 peptides and the successful targeting ability towards brain tumor cells that overexpress the IL-13 receptor (IL-13Rα2). CONCLUSION: These studies demonstrate that IL-13 peptide-conjugated gadolinium metallofullerenes could serve as a platform to deliver imaging and therapeutic agents to tumor cells.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Complexos de Coordenação/uso terapêutico , Fulerenos/uso terapêutico , Glioblastoma/diagnóstico , Glioblastoma/tratamento farmacológico , Interleucina-13/metabolismo , Nanoconchas , Sequência de Aminoácidos , Animais , Meios de Contraste , Complexos de Coordenação/química , Sistemas de Liberação de Medicamentos , Fulerenos/química , Humanos , Interleucina-13/química , Imagem por Ressonância Magnética , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/metabolismo , Receptores de Interleucina-13/metabolismo , Rodaminas/química
20.
J Am Chem Soc ; 133(25): 9741-50, 2011 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-21548647

RESUMO

The dimetallic endohedral heterofullerene (EHF), Gd(2)@C(79)N, was prepared and isolated in a relatively high yield when compared with the earlier reported heterofullerene, Y(2)@C(79)N. Computational (DFT), chemical reactivity, Raman, and electrochemical studies all suggest that the purified Gd(2)@C(79)N, with the heterofullerene cage, (C(79)N)(5-) has comparable stability with other better known isoelectronic metallofullerene (C(80))(6-) cage species (e.g., Gd(3)N@C(80)). These results describe an exceptionally stable paramagnetic molecule with low chemical reactivity with the unpaired electron spin density localized on the internal diatomic gadolinium cluster and not on the heterofullerene cage. EPR studies confirm that the spin state of Gd(2)@C(79)N is characterized by a half-integer spin quantum number of S = 15/2. The spin (S = ½) on the N atom of the fullerene cage and two octet spins (S = 7/2) of two encapsulated gadoliniums are coupled with each other in a ferromagnetic manner with a small zero-field splitting parameter D. Because the central line of Gd(2)@C(79)N is due to the Kramer's doublet with a half-integer spin quantum number of S = 15/2, this relatively sharp line is prominent and the anisotropic nature of the line is weak. Interestingly, in contrast with most Gd(3+) ion environments, the central EPR line (g = 1.978) is observable even at room temperature in a toluene solution. Finally, we report the first EHF derivative, a diethyl bromomalonate monoadduct of Gd(2)@C(79)N, which was prepared and isolated via a modified Bingel-Hirsch reaction.


Assuntos
Fulerenos/química , Gadolínio , Magnetismo , Espectroscopia de Ressonância de Spin Eletrônica
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