RESUMO
PURPOSE: Melanoma is a lethal skin cancer with unmet clinical needs for targeted imaging and therapy. Nanoscale materials conjugated with targeting components have shown great potential to improve tumor delivery efficiency while minimizing undesirable side effects in vivo. Herein, we proposed to develop targeted nanoparticles for melanoma theranostics. METHOD: In this work, gold nanocages (AuNCs) were conjugated with α-melanocyte-stimulating hormone (α-MSH) peptide and radiolabeled with 64Cu for melanocortin 1 receptor-(MC1R) targeted positron emission tomography (PET) in a mouse B16/F10 melanoma model. RESULTS: Their controlled synthesis and surface chemistry enabled well-defined structure and radiolabeling efficiency. In vivo pharmacokinetic evaluation demonstrated comparable organ distribution between the targeted and nontargeted AuNCs. However, micro-PET/computed tomography (CT) imaging demonstrated specific and improved tumor accumulation via MC1R-mediated delivery. By increasing the coverage density of α-MSH peptide on AuNCs, the tumor delivery efficiency was improved. CONCLUSION: The controlled synthesis, sensitive PET imaging, and optimal tumor targeting suggested the potential of targeted AuNCs for melanoma theranostics.
Assuntos
Ouro/química , Melanoma Experimental/diagnóstico por imagem , Melanoma Experimental/patologia , Nanopartículas Metálicas/química , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons , Receptor Tipo 1 de Melanocortina/metabolismo , Animais , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos C57BL , Polietilenoglicóis/química , Distribuição Tecidual , Tomografia Computadorizada por Raios X , alfa-MSH/químicaRESUMO
Focused ultrasound (FUS) technology is reported to enhance the delivery of 64 Cu-integrated ultrasmall gold nanoclusters (64 Cu-AuNCs) across the blood-brain barrier (BBB) as measured by positron emission tomography (PET). To better define the optimal physical properties for brain delivery, 64 Cu-AuNCs with different surface charges are synthesized and characterized. In vivo biodistribution studies are performed to compare the individual organ uptake of each type of 64 Cu-AuNCs. Quantitative PET imaging post-FUS treatment shows site-targeted brain penetration, retention, and diffusion of the negative, neutral, and positive 64 Cu-AuNCs. Autoradiography is performed to compare the intrabrain distribution of these nanoclusters. PET Imaging demonstrates the effective BBB opening and successful delivery of 64 Cu-AuNCs into the brain. Of the three 64 Cu-AuNCs investigated, the neutrally charged nanostructure performs the best and is the candidate platform for future theranostic applications in neuro-oncology.
Assuntos
Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Ouro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Tomografia por Emissão de Pósitrons , Ultrassom/métodos , Animais , Nanopartículas Metálicas/ultraestrutura , Camundongos , Polietilenoglicóis/química , Propriedades de Superfície , Ácido Tióctico/química , Distribuição TecidualRESUMO
PURPOSE: To assess the physicochemical properties, pharmacokinetic profiles, and in vivo positron emission tomography (PET) imaging of natriuretic peptide clearance receptors (NPRC) expressed on atherosclerotic plaque of a series of targeted, polymeric nanoparticles. METHODS: To control their structure, non-targeted and targeted polymeric (comb) nanoparticles, conjugated with various amounts of c-atrial natriuretic peptide (CANF, 0, 5, 10 and 25%), were synthesized by controlled and modular chemistry. In vivo pharmacokinetic evaluation of these nanoparticles was performed in wildtype (WT) C57BL/6 mice after (64)Cu radiolabeling. PET imaging was performed on an apolipoprotein E-deficient (ApoE(-/-)) mouse atherosclerosis model to assess the NPRC targeting efficiency. For comparison, an in vivo blood metabolism study was carried out in WT mice. RESULTS: All three (64)Cu-CANF-comb nanoparticles showed improved biodistribution profiles, including significantly reduced accumulation in both liver and spleen, compared to the non-targeted (64)Cu-comb. Of the three nanoparticles, the 25% (64)Cu-CANF-comb demonstrated the best NPRC targeting specificity and sensitivity in ApoE(-/-) mice. Metabolism studies showed that the radiolabeled CANF-comb was stable in blood up to 9 days. Histopathological analyses confirmed the up-regulation of NPRC along the progression of atherosclerosis. CONCLUSION: The 25% (64)Cu-CANF-comb demonstrated its potential as a PET imaging agent to detect atherosclerosis progression and status.
Assuntos
Aterosclerose/metabolismo , Fator Natriurético Atrial/metabolismo , Radioisótopos de Cobre/metabolismo , Nanopartículas/metabolismo , Polímeros/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Aterosclerose/diagnóstico por imagem , Fator Natriurético Atrial/administração & dosagem , Fator Natriurético Atrial/química , Radioisótopos de Cobre/administração & dosagem , Radioisótopos de Cobre/química , Sistemas de Liberação de Medicamentos/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanopartículas/administração & dosagem , Nanopartículas/química , Polímeros/administração & dosagem , Polímeros/química , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologiaRESUMO
Gold nanoparticles have been labeled with various radionuclides and extensively explored for single photon emission computed tomography (SPECT) in the context of cancer diagnosis. The stability of most radiolabels, however, still needs to be improved for accurate detection of cancer biomarkers and thereby monitoring of tumor progression and metastasis. Here, the first synthesis of Au nanoparticles doped with (199)Au atoms for targeted SPECT tumor imaging in a mouse triple negative breast cancer (TNBC) model is reported. By directly incorporating (199)Au atoms into the crystal lattice of each Au nanoparticle, the stability of the radiolabel can be ensured. The synthetic procedure also allows for a precise control over both the radiochemistry and particle size. When conjugated with D-Ala1-peptide T-amide, the Au nanoparticles doped with (199)Au atoms can serve as a C-C chemokine receptor 5 (CCR5)-targeted nanoprobe for the sensitive and specific detection of both TNBC and its metastasis in a mouse tumor model.
Assuntos
Ouro/química , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Nanopartículas Metálicas/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Autorradiografia , Linhagem Celular Tumoral , Feminino , Imuno-Histoquímica , Neoplasias Pulmonares/secundário , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/farmacologia , Polietilenoglicóis/química , Distribuição Tecidual/efeitos dos fármacos , Tomografia Computadorizada por Raios XRESUMO
Gold nanoparticles have been widely used for oncological applications including diagnosis and therapy. However, the non-specific mononuclear phagocyte system accumulation and potential long-term toxicity have significantly limited clinical translation. One strategy to overcome these shortcomings is to reduce the size of gold nanoparticles to allow renal clearance. Herein, we report the preparation of (64)Cu alloyed gold nanoclusters ((64)CuAuNCs) for in vivo evaluation of pharmacokinetics, systemic clearance, and positron emission tomography (PET) imaging in a mouse prostate cancer model. The facile synthesis in acqueous solution allowed precisely controlled (64)Cu incorporation for high radiolabeling specific activity and stability for sensitive and accurate detection. Through surface pegylation with 350 Da polyethylene glycol (PEG), the (64)CuAuNCs-PEG350 afforded optimal biodistribution and significant renal and hepatobiliary excretion. PET imaging showed low non-specific tumor uptake, indicating its potential for active targeting of clinically relevant biomarkers in tumor and metastatic organs.