RESUMEN
Cytoreductive surgery (CRS) has emerged as a survival-extending treatment of peritoneal metastasis (PM); recent advances include using intraperitoneal chemotherapy (IPC) at normothermic or hyperthermic temperatures, or under pressure (CRS + IPC). Clinical CRS + IPC research has established its highly variable efficacy and suggested tumor size, tumor locations and presence of ascites as potential determinants. On the other hand, there is limited knowledge on the effects of pharmaceutical properties on treatment outcomes. The present study investigated the inter-subject variability of paclitaxel binding to proteins in patient ascites because some PM patients show accumulation of ascites and because activity and transport of highly protein-bound drugs such as paclitaxel are affected by protein binding. Ascites samples were collected from 26 patients and investigated for their protein contents using LC/MS/MS proteomics analysis and for the concentrations of total proteins and two major paclitaxel-binding proteins (human serum albumin or HSA and α-1-acid glycoprotein or AAG). The association constants of paclitaxel to HSA and AAG and the extent of protein binding of paclitaxel in patient ascites were studied using equilibrium dialysis. Proteomic analysis of four randomly selected samples revealed 288 proteins, >90% of which are also present in human plasma. Between 72% - 94% of paclitaxel was bound to proteins in patient ascites. The concentrations of HSA and AAG in ascites showed substantial inter-subject variations, ranging from 14.7 - 46.3 mg/mL and 0.13-2.56 mg/mL, respectively. The respective paclitaxel association constants to commercially available HSA and AAG were â¼ 3.5 and â¼ 120 mM. Calculation using these constants and the HSA and AAG concentrations in individual patient ascites indicated that these two proteins accounted for >85% of the total protein-binding of paclitaxel in ascites. The extensive drug binding to ascites proteins, by reducing the pharmacologically active free fraction, may lead to the diminished CRS efficacy in PM patients with ascites. Clinical advances in CRS + IPC have outpaced current knowledge of pharmaceutical properties in this setting. IPC, as a locally acting therapy, is subjected to processes different from those governing systemic treatments. This study, to our knowledge, is the first to illustrate the implications of drug properties in the CRS + IPC efficacy against PM. While drugs are now an integral part of PM patient management, there is limited pharmaceutical research in this treatment setting (e.g., effects of hyperthermia or pressure on drug transport or release from delivery systems, pharmacokinetics, pharmacodynamics). Hence, CRS + IPC of PM represents an area where additional pharmaceutical research can assist further development and optimization.
Asunto(s)
Neoplasias Colorrectales , Hipertermia Inducida , Neoplasias Peritoneales , Investigación Farmacéutica , Humanos , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Ascitis/tratamiento farmacológico , Proteómica , Espectrometría de Masas en Tándem , Paclitaxel/uso terapéutico , Preparaciones Farmacéuticas , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
Advances in molecular medicine have led to identification of worthy cellular and molecular targets located in extracellular and intracellular compartments. Effectiveness of cancer therapeutics is limited in part by inadequate delivery and transport in tumor interstitium. Parts I and II of this report give an overview on the kinetic processes in delivering therapeutics to their intended targets, the transport barriers in tumor microenvironment and extracellular matrix (TME/ECM), and the experimental approaches to overcome such barriers. Part III discusses new concepts and findings concerning nanoparticle-biocorona complex, including the effects of TME/ECM. Part IV outlines the challenges in animal-to-human translation of cancer nanotherapeutics. Part V provides an overview of the background, current status, and the roles of TME/ECM in immune checkpoint inhibition therapy, the newest cancer treatment modality. Part VI outlines the development and use of multiscale computational modeling to capture the unavoidable tumor heterogeneities, the multiple nonlinear kinetic processes including interstitial and transvascular transport and interactions between cancer therapeutics and TME/ECM, in order to predict the in vivo tumor spatiokinetics of a therapeutic based on experimental in vitro biointerfacial interaction data. Part VII provides perspectives on translational research using quantitative systems pharmacology approaches.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Matriz Extracelular/metabolismo , Humanos , Nanopartículas/administración & dosificación , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Microambiente TumoralRESUMEN
Nanotechnology is widely used in cancer research. Models that predict nanoparticle transport and delivery in tumors (including subcellular compartments) would be useful tools. This study tested the hypothesis that diffusive transport of cationic liposomes in 3-dimensional (3D) systems can be predicted based on liposome-cell biointerface parameters (binding, uptake, retention) and liposome diffusivity. Liposomes comprising different amounts of cationic and fusogenic lipids (10-30mol% DOTAP or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1-20mol% DOPE or 1,2-dioleoyl-3-trimethylammonium-propane, +25 to +44mV zeta potential) were studied. We (a) measured liposome-cell biointerface parameters in monolayer cultures, and (b) calculated effective diffusivity based on liposome size and spheroid composition. The resulting parameters were used to simulate the liposome concentration-depth profiles in 3D spheroids. The simulated results agreed with the experimental results for liposomes comprising 10-30mol% DOTAP and ≤10mol% DOPE, but not for liposomes with higher DOPE content. For the latter, model modifications to account for time-dependent extracellular concentration decrease and liposome size increase did not improve the predictions. The difference among low- and high-DOPE liposomes suggests concentration-dependent DOPE properties in 3D systems that were not captured in monolayers. Taken together, our earlier and present studies indicate the diffusive transport of neutral, anionic and cationic nanoparticles (polystyrene beads and liposomes, 20-135nm diameter, -49 to +44mV) in 3D spheroids, with the exception of liposomes comprising >10mol% DOPE, can be predicted based on the nanoparticle-cell biointerface and nanoparticle diffusivity. Applying the model to low-DOPE liposomes showed that changes in surface charge affected the liposome localization in intratumoral subcompartments within spheroids.
Asunto(s)
Liposomas/metabolismo , Neoplasias/metabolismo , Transporte Biológico , Simulación por Computador , Difusión , Ácidos Grasos Monoinsaturados/química , Ácidos Grasos Monoinsaturados/metabolismo , Humanos , Liposomas/química , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/metabolismo , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/metabolismo , Esferoides Celulares , Células Tumorales CultivadasRESUMEN
This study established a multiscale computational model for intraperitoneal (IP) chemotherapy, to depict the time-dependent and spatial-dependent drug concentrations in peritoneal tumors as functions of drug properties (size, binding, diffusivity, permeability), transport mechanisms (diffusion, convection), spatial-dependent tumor heterogeneities (vessel density, cell density, pressure gradient), and physiological properties (peritoneal pressure, peritoneal fluid volume). Equations linked drug transport and clearance on three scales (tumor, IP cavity, whole organism). Paclitaxel was the test compound. The required model parameters (tumor diffusivity, tumor hydraulic conductivity, vessel permeability and surface area, microvascular hydrostatic pressure, drug association with cells) were obtained from literature reports, calculation, and/or experimental measurements. Drug concentration-time profiles in peritoneal fluid and plasma were the boundary conditions for tumor domain and blood vessels, respectively. The finite element method was used to numerically solve the nonlinear partial differential equations for fluid and solute transport. The resulting multiscale model accounted for intratumoral spatial heterogeneity, depicted diffusive and convective drug transport in tumor interstitium and across blood vessels, and provided drug flux and concentration as a function of time and spatial position in the tumor. Comparison of model-predicted tumor spatiokinetics with experimental results (autoradiographic data of 3H-paclitaxel in IP ovarian tumors in mice, 6 h posttreatment) showed good agreement (1% deviation for area under curve and 23% deviations for individual data points, which were several-fold lower compared to the experimental intertumor variations). The computational multiscale model provides a tool to quantify the effects of drug-, tumor-, and host-dependent variables on the concentrations and residence time of IP therapeutics in tumors.