RESUMEN
The aim of this first-time-in-human non-randomized dose-escalating prospective phase I clinical trial was to analyze safety of two doses of fluorescent rhodamine-labeled cationic liposomes (LDF01) in head and neck squamous cell carcinoma (HNSCC). Patients had resectable UICC stadium I-IV A HNSCCs. LDF01 was administered before tumor resection under general anesthesia as an intravenous infusion with effective lipid doses of 0.5 or 2 mg/kg b.w., respectively. In addition to clinical monitoring for safety assessment, tumor biopsies were taken during the surgical procedure for fluorescence histological analysis. Eight patients were assigned to the two dose groups. During safety follow-up no clinically relevant adverse events occurred. Fluorescence histology revealed some evidence of favorable selectivity of LDF01 for tumor microvessels in the high-dose group. LDF01 is safe applied as infusion at both tested dose levels. Furthermore, LDF01 can be detected in the vicinity of tumor cells and could be assigned to the microvessel target in individual HNSSC cases. Detailed analysis of targeting properties of LDF01 has to be performed in upcoming clinical phase II trials.
Asunto(s)
Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/cirugía , Sistemas de Liberación de Medicamentos/métodos , Colorantes Fluorescentes/administración & dosificación , Liposomas/administración & dosificación , Microvasos/patología , Neoplasias de Oído, Nariz y Garganta/irrigación sanguínea , Neoplasias de Oído, Nariz y Garganta/cirugía , Rodaminas/administración & dosificación , Anciano , Biopsia , Carcinoma de Células Escamosas/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de Oído, Nariz y Garganta/patología , Estudios ProspectivosRESUMEN
Exposure to static magnetic fields (SMFs) results in a reduced blood flow in tumor vessels as well as in activation and adherence of platelets. Whether this phenomenon may have a significant functional impact on tumors has not been investigated as yet. The aim of our study was to evaluate the effects of prolonged exposure to SMFs on tumor angiogenesis and growth. Experiments were performed in dorsal skinfold chamber preparations of Syrian Golden hamsters bearing syngenic A-Mel-3 melanomas. On 3 d following tumor cell implantation one group of animals was immobilized and exposed to a SMF of 586 mT for three h. Control animals were immobilized for the same duration without SMF exposure. Using in vivo-fluorescence microscopy the field effects on tumor angiogenesis and microcirculation were analyzed for seven days. Tumor growth was assessed by repeated planimetry of the tumor area during the observation period. Exposure to SMFs resulted in a significant retardation of tumor growth ( approximately 30%). Furthermore, histological analysis showed an increased peri- and intratumoral edema in tumors exposed to SMFs. Analysis of microcirculatory parameters revealed a significant reduction of functional vessel density, vessel diameters and red blood cell velocity in tumors after exposure to SMFs compared to control tumors. These changes reflect retarded vessel maturation by antiangiogenesis. The increased edema after SMF exposure indicates an increased tumor microvessel leakiness possibly enhancing drug-uptake. Hence, SMF therapy appears as a promising new anticancer strategy-as an inhibitor of tumor growth and angiogenesis and as a potential sensitizer to chemotherapy.
Asunto(s)
Magnetoterapia/métodos , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/terapia , Neovascularización Patológica/prevención & control , Animales , Células Cultivadas , Cricetinae , Melanoma Experimental/patología , Mesocricetus , Microcirculación , Microscopía Fluorescente , Carga TumoralRESUMEN
Red blood cell flow in capillaries is reduced during exposure to strong static magnetic fields (SMFs). Intratumoral microcirculation is characterized by tortuous microvessels with chaotic architecture and by irregular, sluggish blood flow with unstable rheology. It was the aim of this study to analyze SMF exposure effects on tumor microcirculation with regard to interactions of corpuscular blood components with tumor microvessel walls. In vivo fluorescence microscopy was performed in A-Mel-3 tumors growing in dorsal skinfold chamber preparations of Syrian Golden hamsters. SMFs with varying field strength (< 600 mT) were generated by changing the distance between a strong NdFeB rod magnet and the tissue region of interest. Short-time exposure above a magnetic flux density of about 150 mT resulted in a significant reduction of red blood cell velocity (vRBC) and segmental blood flow in tumor microvessels. At the maximum strength of 587 mT, a reversible reduction of vRBC (approximately 40%) and of functional vessel densitiy (approximately 15%) was observed. Prolongation of the exposure time from 1 min to up to 3 h resulted in comparable reductions. Microvessel diameters and leukocyte-endothelial cell interactions remained unaffected by SMF exposure. However, in contrast to tumor-free striated muscle controls, exposure at the maximum flux density induced a significant increase in platelet-endothelial cell adherence in a time-dependent manner that was reversible after reducing SMF strength. These reversible changes may have implications for functional measurements of tumor microcirculation by MRI and new therapeutic strategies using strong SMFs.
Asunto(s)
Campos Electromagnéticos , Microcirculación , Neoplasias/metabolismo , Neoplasias/terapia , Adhesividad Plaquetaria , Inhibidores de la Angiogénesis/farmacología , Animales , Capilares/metabolismo , Cricetinae , Leucocitos/citología , Imagen por Resonancia Magnética/métodos , Masculino , Mesocricetus , Músculos/irrigación sanguínea , Neovascularización Patológica , ReologíaRESUMEN
Blood flowing in microvessels is one possible site of action of static magnetic fields (SMFs). We evaluated SMF effects on capillary flow of red blood cells (RBCs) in unanesthetized hamsters, using a skinfold chamber technique for intravital fluorescence microscopy. By this approach, capillary RBC velocities (v(RBC)), capillary diameters (D), arteriolar diameters (D(art)), and functional vessel densities (FVD) were measured in striated skin muscle at different magnetic flux densities. Exposure above a threshold level of about 500 mT resulted in a significant (P < 0.001) reduction of v(RBC) in capillaries as compared to the baseline value. At the maximum field strength of 587 mT, v(RBC) was reduced by more than 40%. Flow reduction was reversible when the field strength was decreased below the threshold level. In contrast, mean values determined at different exposure levels for the parameters D, D(art), and FVD did not vary by more than 5%. Blood flow through capillary networks is affected by strong SMFs directed perpendicular to the vessels. Since the influence of SMFs on blood flow in microvessels directed parallel to the field as well as on collateral blood supply could not be studied, our findings should be carefully interpreted with respect to the setting of safety guidelines.