In an effort to develop new agents and molecular targets for the treatment of cancer, aspargine-glycine-arginine (NGR)-targeted liposomal doxorubicin (TVT-DOX) is being studied. The NGR peptide on the surface of liposomal doxorubicin (DOX) targets an aminopeptidase N (CD13) isoform, specific to the tumor neovasculature, making it a promising strategy. To further understand the molecular mechanisms of action, we investigated cell binding, kinetics of internalization as well as cytotoxicity of TVT-DOX in vitro. We demonstrate the specific binding of TVT-DOX to CD13-expressing endothelial [human umbilical vein endothelial cells (HUVEC) and Kaposi sarcoma-derived endothelial cells (SLK)] and tumor (fibrosarcoma, HT-1080) cells in vitro. Following binding, the drug was shown to internalize through the endosomal pathway, eventually leading to the localization of doxorubicin in cell nuclei. TVT-DOX showed selective toxicity toward CD13-expressing HUVEC, sparing the CD13-negative colon-cancer cells, HT-29. Additionally, the nontargeted counterpart of TVT-DOX, Caelyx, was less cytotoxic to the CD13-positive HUVECs demonstrating the advantages of NGR targeting in vitro. The antitumor activity of TVT-DOX was tested in nude mice bearing human prostate-cancer xenografts (PC3). A significant growth inhibition (up to 60%) of PC3 tumors in vivo was observed. Reduction of tumor vasculature following treatment with TVT-DOX was also apparent. We further compared the efficacies of TVT-DOX and free doxorubicin in the DOX-resistant colon-cancer model, HCT-116, and observed the more pronounced antitumor effects of the TVT-DOX formulation over free DOX. The potential utility of TVT-DOX in a variety of vascularized solid tumors is promising.

American Petroleum Institute (API) [2] recommendations for modeling the lateral soil resistancedisplacement (p-y) response were not developed for fatigue analysis of deepwater wells. The recently developed soil models [1] is aimed to fill this knowledge gap. Based on extensive physical testing in a geotechnical centrifuge and complementary numerical modelling, a more accurate approach was developed for soil modeling specific to well conductor fatigue analysis. The approach was presented at OTC2015 [1]. While the approach proposed in [1] performed very well in predicting the fatigue damage in the model tests, its performance is yet to be evaluated against actual field data obtained in the field. This paper evaluates the performance of the recently developed soil models in predicting field measurements and fatigue damage obtained from a monitored well in the Gulf of Mexico (GoM). Important considerations for modeling soil response (e.g., modeling of soil crust near mudline) are also discussed. The new approaches are applicable to fatigue analysis of conductors pertaining to subsea wells worldwide. The motion monitoring loggers collect acceleration and angular rate information at the point of installation. The objective was to investigate the fatigue performance of the wellhead and conductor system. Fatigue was estimated based on the motion data collected from the data loggers. The measured motions and fatigue damage obtained from the loggers were compared to those estimated from predictive methods using the proposed soil model. This paper demonstrates that the recently developed soil models perform satisfactorily in predicting the deformations (displacements and rotations) measured at the top of the lower marine riser package (LMRP); hence, providing a more accurate prediction of the system (LMRP, wellhead and casings) response and thereby, its fatigue damage.

Current subsea wellhead fatigue monitoring systems typically measure subsea BOP stack response and convert accelerations directly to the stress on various critical wellhead components using transfer functions. The veracity of this process relies on the accuracy of input data and the numerical modelling of the riser, subsea stack and wellhead conductor system. Poor representation of a real system could potentially yield an inaccurate calculation of transfer functions and consequently, imprecise estimation of the stress levels and predicted fatigue damage. The transfer function is strongly influenced by subsea stack system stiffness, which depends on dynamic soil response, stack hydrodynamic added mass and drag, location of the subsea stack fixity point, and stack-conductor system characteristic frequency. The latter two can be measured in the field and compared with predictions from numerical models. This paper evaluates the subsea wellhead fatigue monitoring algorithm and accuracy using verification and calibration techniques with field measurements. Important considerations for verification and calibration (e.g. soil property) are also discussed. The new approaches described are applicable to fatigue monitoring and analysis of subsea wellhead and conductor systems in both shallow and deep waters. The approaches presented herein could improve determination of the conductor fixity point and subsea stack characteristics, which in turn, would help in accurately determining wellhead fatigue and extracting displacements if needed. The good match between predicted and measured values of these parameters demonstrates that the numerical model and associated transfer functions are adequate for measured fatigue damage estimation. The transfer functions for fatigue monitoring systems and the associated subsea wellhead fatigue results could be significantly affected by the accuracy of the modelling methods and input data, particularly the soil properties. An inacccurate representation of the distance between the sensor and wellhead hot spot locations from which the transfer functions are derived could affect the accuracy of the fatigue results. For the case presented herein, the hydrodynamic properties drag loads and added mass have a less significant effect on the accuracy of transfer function and fatigue results.

A significant effort is made by the industry through analyses and field monitoring to ensure delivery of safe and reliable wells. Fatigue analysis is an important aspect of well integrity assurance. Structural fatigue damage arises from stress changes caused by environmental cyclic loads acting on the riser system. In practice, the conductor-soil interaction under cyclic loading is modeled using the soil resistance-displacement (P-y) springs. Use of an appropriate soil model is essential for accurate determination of the fatigue damage. The American Petroleum Institute recommendations (API 2011) for P-y curves, which are often used for conductor-soil interaction analysis, have originally been developed for piled foundation and are inappropriate for well fatigue analysis. To that end, a new approach was developed by Zakeri et al. (2015) to derive P-y curves specifically for well fatigue analysis. Ultimate performance of each soil model can be determined and verified with field monitoring. This paper presents results of a field monitoring campaign for a well drilled in 354 ft water depth within a complex seabed stratigraphy comprising sands (loose to dense) and clays (very soft to stiff). Design, calibration and verification of the riser/conductor structural model using field data are presented in a companion paper (Ge et al. 2017). Herein, the effect of soil modeling on wellhead fatigue is discussed and predictions made with the API (2011) and the Zakeri et al. (2015) soil P-y springs are compared to field monitoring data. For the case presented herein, the results indicate that the Blowout Preventer (BOP) stack motion response is significantly affected by the soil stiffness and modeling methods. The predictions made with the Zakeri et al. (2015) model provided BOP response similar to those observed in the field both above and below the mudline. Whereas, the analyses done with the API (2011) model significantly overestimated the 'measured' conductor fatigue life above the mudline and underestimated it below. The results of this monitoring program are a step forward in better understanding system behavior of offshore wells.

In support of its commitment to safe and reliable operations, BP has been continuously developing a program to assess and maintain structural integrity for offshore drilling risers and conductors. This paper presents recent efforts by BP, in conjunction with 2H Offshore, to develop a new fatigue monitoring methodology for drilling riser systems due to both wave and vortex-induced-vibration (VIV) damage. BP has been monitoring structural response, including the fatigue damage, of riser systems in the Gulf of Mexico over the past ten years. To date, the focus has predominantly been on determining the fatigue damage due to VIV, since VIV and its effects on structural response are considered a not well-understood phenomenon. In addition to VIV fatigue, direct wave loading and vessel motions also contribute to the total fatigue damage, and sometimes wave fatigue may have a larger contribution than VIV fatigue damage. Therefore, it is necessary to determine fatigue due to both wave and VIV effects to confirm the long-term fatigue integrity of the drilling risers. To take full advantage of the accumulated monitoring data, a new fatigue monitoring methodology was developed using an analytical solution to account for the damage due to both wave and VIV effects. With this method, the measured acceleration data are converted into curvature, and then fatigue damage along the length of riser and conductor are calculated. This new methodology has been validated with both finite element analysis (FEA) and field data, and sensitivities to various parameters have been considered.