RESUMEN
CEND-1 (iRGD) is a bifunctional cyclic peptide that can modulate the solid tumour microenvironment, enhancing the delivery and therapeutic index of co-administered anti-cancer agents. This study explored CEND-1's pharmacokinetic (PK) properties pre-clinically and clinically, and assessed CEND-1 distribution, tumour selectivity and duration of action in pre-clinical tumour models. Its PK properties were assessed after intravenous infusion of CEND-1 at various doses in animals (mice, rats, dogs and monkeys) and patients with metastatic pancreatic cancer. To assess tissue disposition, [3H]-CEND-1 radioligand was administered intravenously to mice bearing orthotopic 4T1 mammary carcinoma, followed by tissue measurement using quantitative whole-body autoradiography or quantitative radioactivity analysis. The duration of the tumour-penetrating effect of CEND-1 was evaluated by assessing tumour accumulation of Evans blue and gadolinium-based contrast agents in hepatocellular carcinoma (HCC) mouse models. The plasma half-life was approximately 25 min in mice and 2 h in patients following intravenous administration of CEND-1. [3H]-CEND-1 localised to the tumour and several healthy tissues shortly after administration but was cleared from most healthy tissues by 3 h. Despite the rapid systemic clearance, tumours retained significant [3H]-CEND-1 several hours post-administration. In mice with HCC, the tumour penetration activity remained elevated for at least 24 h after the injection of a single dose of CEND-1. These results indicate a favourable in vivo PK profile of CEND-1 and a specific and sustained tumour homing and tumour penetrability. Taken together, these data suggest that even single injections of CEND-1 may elicit long-lasting tumour PK improvements for co-administered anti-cancer agents.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratas , Ratones , Animales , Perros , Infusiones Intravenosas , Péptidos , Microambiente TumoralRESUMEN
Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time-of-day dependent changes of proliferation and DNA damage in HCC. Using transgenic c-myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ-H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev-erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ-H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time-of-day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.
Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Experimentales/genética , Proteínas Circadianas Period/genética , Animales , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Proliferación Celular/genética , Cloruros/administración & dosificación , Cloruros/toxicidad , Cronoterapia , Daño del ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Ratones , Ratones Transgénicos , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/terapia , Fotoperiodo , Proteínas Proto-Oncogénicas c-myc/genética , Factor de Crecimiento Transformador alfa/genética , Células Tumorales Cultivadas , Compuestos de Zinc/administración & dosificación , Compuestos de Zinc/toxicidadRESUMEN
BACKGROUND: The accuracy of blood-based early tumour recognition is compromised by signal production at non-tumoral sites, low amount of signal produced by small tumours, and variable tumour production. Here we examined whether tumour-specific enhancement of vascular permeability by the particular tumour homing peptide, iRGD, which carries dual function of binding to integrin receptors overexpressed in the tumour vasculature and is known to promote extravasation via neuropilin-1 receptor upon site-specific cleavage, might be useful to improve blood-based tumour detection by inducing a yet unrecognised vice versa tumour-to-blood transport. METHODS: To detect an iRGD-induced tumour-to-blood transport, we examined the effect of intravenously injected iRGD on blood levels of α-fetoprotein (AFP) and autotaxin in several mouse models of hepatocellular carcinoma (HCC) or in mice with chronic liver injury without HCC, and on prostate-specific antigen (PSA) levels in mice with prostate cancer. FINDINGS: Intravenously injected iRGD rapidly and robustly elevated the blood levels of AFP in several mouse models of HCC, but not in mice with chronic liver injury. The effect was primarily seen in mice with small tumours and normal basal blood AFP levels, was attenuated by an anti-neuropilin-1 antibody, and depended on the concentration gradient between tumour and blood. iRGD treatment was also able to increase blood levels of autotaxin in HCC mice, and of PSA in mice with prostate cancer. INTERPRETATION: We conclude that iRGD induces a tumour-to-blood transport in a tumour-specific fashion that has potential of improving diagnosis of early stage cancer. FUNDING: Deutsche Krebshilfe, DKTK, LOEWE-Frankfurt Cancer Institute.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Hepatocelular , Modelos Animales de Enfermedad , Neoplasias Hepáticas , Hidrolasas Diéster Fosfóricas , Animales , Ratones , Biomarcadores de Tumor/sangre , Hidrolasas Diéster Fosfóricas/sangre , Hidrolasas Diéster Fosfóricas/metabolismo , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , alfa-Fetoproteínas/metabolismo , Masculino , Humanos , Línea Celular Tumoral , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Oligopéptidos/administración & dosificaciónRESUMEN
INTRODUCTION: In parts of Europe and North America, cycling volumes decrease in winter due to a reduction in subjective safety. To counter this, high-quality winter maintenance is required on cycle paths. At the moment, grit and sodium chloride are considered state-of-the-art gritting/de-icing materials in Germany. However, grit has to be removed after winter because it poses a serious injury risk on dry streets, and, in various German cities, using sodium chloride is prohibited on segregated bike paths due to the harmful impact on surrounding trees. Therefore, there is a need for alternative gritting/de-icing materials. METHOD: We used a mixed-methods approach consisting of qualitative and quantitative surveys together with laboratory investigations and a life cycle assessment to find suitable alternatives to sodium chloride and grit for use on segregated bike paths, and tested four de-icing materials (sodium chloride as a reference, sodium formate, calcium magnesium acetate or CMA, and potassium acetate) at two sites in Hamburg, Germany. The tests were accompanied by on-site cyclist surveys. RESULTS: The results show that the use of alternative (non-sodium chloride) de-icing materials either reduces or eliminates negative impacts on the environment at a local level, for example on trees along the cycle path. However, this reduction goes hand in hand with increasing negative environmental impacts at a global level due to higher overall emissions associated with the tested alternative de-icing materials. Regarding cyclists' safety, sodium formate was the only de-icing material which delivered comparable results to sodium chloride and should therefore be tested in extended conditions. CONCLUSIONS: Further research is needed on the large-scale application of the investigated de-icing agents on cycle paths in different cities, along with a survey of a larger number of cyclists. A final evaluation of the environmental aspects can only be made when the supply and production conditions for large-scale use are clear. PRACTICAL APPLICATIONS: Basically there are two options for the practical application of de-icing materials: The usage of the costlier alternatives with better properties at a local level in the hope of fast development towards a better global GHG footprint in their manufacturing processes, or sticking to the use of grit and sodium chloride (where it is possible) while committing to improving clean-up after the snow and ice melt to prevent unsafe road conditions in spring.