RESUMEN
Accumulation of nanoparticles in solid tumors depends on their extravasation. However, vascular permeability is very heterogeneous within a tumor and among different tumor types, hampering efficient delivery. Local hyperthermia at a tumor can improve nanoparticle delivery by increasing tumor vasculature permeability, perfusion and interstitial fluid flow. The aim of this study is to investigate hyperthermia conditions required to improve tumor vasculature permeability, subsequent liposome extravasation and interstitial penetration in 4 tumor models. Tumors are implanted in dorsal skin flap window chambers and observed for liposome (~85 nm) accumulation by intravital confocal microscopy. Local hyperthermia at 41°C for 30 min initiates liposome extravasation through permeable tumor vasculature in all 4 tumor models. A further increase in nanoparticle extravasation occurs while continuing heating to 1h, which is a clinically relevant duration. After hyperthermia, the tumor vasculature remains permeable for 8h. We visualize gaps in the endothelial lining of up to 10 µm induced by HT. Liposomes extravasate through these gaps and penetrate into the interstitial space to at least 27.5 µm in radius from the vessel walls. Whole body optical imaging confirms HT induced extravasation while liposome extravasation was absent at normothermia. In conclusion, a thermal dose of 41°C for 1h is effective to induce long-lasting permeable tumor vasculature for liposome extravasation and interstitial penetration. These findings hold promise for improved intratumoral drug delivery upon application of local mild hyperthermia prior to administration of nanoparticle-based drug delivery systems.
Asunto(s)
Carcinoma Pulmonar de Lewis/terapia , Hipertermia Inducida/métodos , Liposomas/administración & dosificación , Melanoma Experimental/terapia , Nanopartículas/administración & dosificación , Neoplasias Cutáneas/terapia , Animales , Permeabilidad Capilar , Carcinoma Pulmonar de Lewis/metabolismo , Línea Celular Tumoral , Humanos , Lípidos/química , Liposomas/química , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Nanopartículas/química , Neoplasias Cutáneas/metabolismoRESUMEN
Various liposomal drug carriers have been developed to overcome short plasma half-life and toxicity related side effects of chemotherapeutic agents. We developed a mathematical model to compare different liposome formulations of doxorubicin (DOX): conventional chemotherapy (Free-DOX), Stealth liposomes (Stealth-DOX), temperature sensitive liposomes (TSL) with intra-vascular triggered release (TSL-i), and TSL with extra-vascular triggered release (TSL-e). All formulations were administered as bolus at a dose of 9 mg/kg. For TSL, we assumed locally triggered release due to hyperthermia for 30 min. Drug concentrations were determined in systemic plasma, aggregate body tissue, cardiac tissue, tumor plasma, tumor interstitial space, and tumor cells. All compartments were assumed perfectly mixed, and represented by ordinary differential equations. Contribution of liposomal extravasation was negligible in the case of TSL-i, but was the major delivery mechanism for Stealth-DOX and for TSL-e. The dominant delivery mechanism for TSL-i was release within the tumor plasma compartment with subsequent tissue- and cell uptake of released DOX. Maximum intracellular tumor drug concentrations for Free-DOX, Stealth-DOX, TSL-i, and TSL-e were 3.4, 0.4, 100.6, and 15.9 µg/g, respectively. TSL-i and TSL-e allowed for high local tumor drug concentrations with reduced systemic exposure compared to Free-DOX. While Stealth-DOX resulted in high tumor tissue concentrations compared to Free-DOX, only a small fraction was bioavailable, resulting in little cellular uptake. Consistent with clinical data, Stealth-DOX resulted in similar tumor intracellular concentrations as Free-DOX, but with reduced systemic exposure. Optimal release time constants for maximum cellular uptake for Stealth-DOX, TSL-e, and TSL-i were 45 min, 11 min, and <3 s, respectively. Optimal release time constants were shorter for MDR cells, with â¼4 min for Stealth-DOX and for TSL-e. Tissue concentrations correlated well quantitatively with a prior in-vivo study. Mathematical models may thus allow optimization of drug delivery systems to achieve a better therapeutic index.
Asunto(s)
Antineoplásicos/farmacología , Doxorrubicina/farmacología , Liposomas/química , Modelos Biológicos , Temperatura , Animales , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Transporte Biológico/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Línea Celular Tumoral , Doxorrubicina/farmacocinética , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Ratones , Factores de TiempoRESUMEN
PURPOSE: To develop and validate a computational model that simulates (1) tissue heating with high intensity focused ultrasound (HIFU), and (2) resulting hyperthermia-mediated drug delivery from temperature-sensitive liposomes (TSL). MATERIALS AND METHODS: HIFU heating in tissue was simulated using a heat transfer model based on the bioheat equation, including heat-induced cessation of perfusion. A spatio-temporal multi-compartment pharmacokinetic model simulated intravascular release of doxorubicin from TSL, its transport into interstitium, and cell uptake. Two heating schedules were simulated, each lasting 30 min: (1) hyperthermia at 43 °C (HT) and (2) hyperthermia followed by a high temperature (50 °C for 20 s) pulse (HT+). As preliminary model validation, in vivo studies were performed in thigh muscle of a New Zealand White rabbit, where local hyperthermia with a clinical magnetic resonance-guided HIFU system was applied following TSL administration. RESULTS: HT produced a defined region of high doxorubicin concentration (cellular concentration â¼15-23 µg/g) in the target region. Cellular drug uptake was directly related to HT duration, with increasing doxorubicin uptake up to â¼2 h. HT+ enhanced drug delivery by â¼40% compared to HT alone. Temperature difference between model and experiment within the hyperthermia zone was on average 0.54 °C. Doxorubicin concentration profile agreed qualitatively with in vivo fluorescence profile. CONCLUSIONS: Computational models can predict temperature and delivered drug from combination of HIFU with TSL. Drug delivery using TSL may be enhanced by prolonged hyperthermia up to 2 h or by local cessation of vascular perfusion with a high temperature pulse following hyperthermia.
Asunto(s)
Simulación por Computador , Sistemas de Liberación de Medicamentos/métodos , Ultrasonido Enfocado de Alta Intensidad de Ablación , Hipertermia Inducida/métodos , Animales , Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Liposomas , Neoplasias/metabolismo , Neoplasias/terapia , Conejos , TemperaturaRESUMEN
PURPOSE: Studies have demonstrated a synergistic effect between hyperthermia and chemotherapy, and clinical trials in image-guided drug delivery combine high-temperature thermal therapy (ablation) with chemotherapy agents released in the heating zone via low temperature sensitive liposomes (LTSL). The complex interplay between heat-based cancer treatments such as thermal ablation and chemotherapy may require computational models to identify the relationship between heat exposure and pharmacokinetics in order to optimise drug delivery. MATERIALS AND METHODS: Spatio-temporal data on tissue temperature and perfusion from heat-transfer models of radiofrequency ablation were used as input data. A spatio-temporal multi-compartmental pharmacokinetic model was built to describe the release of doxorubicin (DOX) from LTSL into the tumour plasma space, and subsequent transport into the extracellular space, and the cells. Systemic plasma and tissue compartments were also included. We compared standard chemotherapy (free-DOX) to LTSL-DOX administered as bolus at a dose of 0.7 mg/kg body weight. RESULTS: Modelling LTSL-DOX treatment resulted in tumour tissue drug concentration of approximately 9.3 microg/g with highest values within 1 cm outside the ablation zone boundary. Free-DOX treatment produced comparably uniform tissue drug concentrations of approximately 3.0 microg/g. Administration of free-DOX resulted in a considerably higher peak level of drug concentration in the systemic plasma compartment (16.1 microg/g) compared to LTSL-DOX (4.4 microg/g). These results correlate well with a prior in vivo study. CONCLUSIONS: Combination of LTSL-DOX with thermal ablation allows localised drug delivery with higher tumour tissue concentrations than conventional chemotherapy. Our model may facilitate drug delivery optimisation via investigation of the interplays among liposome properties, tumour perfusion, and heating regimen.