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1.
J Control Release ; 371: 288-297, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38705519

RESUMEN

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes.


Asunto(s)
Antineoplásicos , Liposomas , Neoplasias Ováricas , Oxaliplatino , Polietilenglicoles , Receptor ErbB-2 , Trastuzumab , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Animales , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/inmunología , Oxaliplatino/administración & dosificación , Línea Celular Tumoral , Polietilenglicoles/química , Polietilenglicoles/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/química , Trastuzumab/administración & dosificación , Trastuzumab/química , Ratones Desnudos , Sistemas de Liberación de Medicamentos , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C
2.
J Immunol Methods ; 500: 113177, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34756881

RESUMEN

Quantification of cytokines in cancerous tissue is important for understanding basic tumor biology and for deciphering anti-cancer mechanisms in drug development. Cytokine measurements on protein-level are often done by immunoassays such as enzyme-linked immunosorbent assay (ELISAs) and multiplex assays. However, immunoassays are prone to interference due to the presence of perturbing factors. The sum of these factors is known as the matrix effect, which results in a deviation of the measured cytokine concentration from the actual concentration. In this study, we demonstrated that matrix effects are present in tumor lysates from 11 different syngeneic murine tumors and that it can greatly affect cytokine measurements in ELISAs and multiplex assays. Dilution of tumor lysates and careful selection of lysis buffer components may decrease matrix effects. However, matrix effects are still present, and care should be taken when analyzing cytokine measurements of tumor lysates.


Asunto(s)
Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Neoplasias/metabolismo , Animales , Línea Celular Tumoral , Errores Diagnósticos , Femenino , Ratones , Ratones Endogámicos BALB C , Microambiente Tumoral
3.
BMC Cancer ; 20(1): 134, 2020 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-32075610

RESUMEN

BACKGROUND: Diffusion weighted magnetic resonance imaging (DW-MRI) holds great potential for monitoring treatment response in cancer patients shortly after initiation of radiotherapy. It is hypothesized that a decrease in cellular density of irradiated cancerous tissue will lead to an increase in quantitative apparent diffusion coefficient (ADC) values. DW-MRI can therefore serve as a non-invasive marker of cell death and apoptosis in response to treatment. In the present study, we aimed to investigate the applicability of DW-MRI in preclinical models to monitor radiation-induced treatment response. In addition, we compared DW-MRI with ex vivo measures of cell density, cell death and apoptosis. METHODS: DW-MRI was tested in two different syngeneic mouse models, a colorectal cancer (CT26) and a breast cancer (4 T1). ADC values were compared with quantitative determinations of apoptosis and cell death by flow cytometry. Furthermore, ADC-values were also compared to histological measurement of cell density on tumor sections. RESULTS: We found a significant correlation between ADC-values and apoptotic state in the CT26 model (P = 0.0031). A strong correlation between the two measurements of ADC-value and apoptotic state was found in both models, which were also present when comparing ADC-values to cell densities. CONCLUSIONS: Our findings demonstrate that DW-MRI can be used for non-invasive monitoring of radiation-induced changes in cell state during cancer therapy. ADC values reflect ex vivo cell density and correlates well with apoptotic state, and can hereby be described as a marker for the cell state after therapy and used as a non-invasive response marker.


Asunto(s)
Biomarcadores/análisis , Imagen de Difusión por Resonancia Magnética/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos BALB C , Neoplasias/radioterapia , Resultado del Tratamiento
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