Development and Evaluation of Peptidic Ligands Targeting Tumor-associated Urokinase Plasminogen Activator Receptor (uPAR) for Use in Alpha-emitter Therapy of Disseminated Ovarian Cancer

http://www.springerlink.com/content/f4n86131k5895016/?p=86c3807e2c094db69f28dc721447fc2a&pi=8 Purpose: Among gynecologic malignancies, ovarian cancer has the highest mortality due to rapid peritoneal dissemination. Treatment failure particularly arises from failure to eliminate disseminated cells. Our aim was to develop peptidic radioligands targeting tumour cell-associated urokinase receptor (uPAR, CD87) for a-emitter therapy for advanced ovarian cancer. Methods DOTA-conjugated, uPAR-directed ligands were synthesised on solid-phase. Binding of peptides to human cells expressing uPAR was assayed by flow cytofluorometry or, in case of 213Bi-labelled peptides, by measuring cell-bound radioactivity. Bio-distribution of the 213Bi-labelled peptide P-P4D was analysed in nude mice 28 days after intraperitoneal inoculation of OV-MZ-6 ovarian cancer cells in the absence or presence of the plasma expander gelofusine. Results: uPAR-selective ligands were developed based on published high-affinity uPAR-binding peptides. For preparation of N-terminally cross-linked divalent ligands, a novel solid-phase procedure was developed. Specific binding of 213Bi-labelled peptides to monocytoid U937 and OV-MZ-6 cells was demonstrated using the natural ligand of uPAR, pro-uPA, or a soluble form of uPAR, suPAR, as competitors. The pseudo-symmetrical covalent dimer 213Bi-P-P4D displayed superior binding to OV-MZ-6 cells in vitro. Accumulation of 213Bi-P-P4D in tumour tissue was demonstrated by bio-distribution analysis in nude mice bearing intraperitoneal OV-MZ-6-derived tumours. Gelofusine reduced kidney uptake of 213Bi-P-P4D by half. Conclusion: Ovarian cancer cells overexpressing uPAR were specifically targeted in vitro and in vivo by 213Bi-P-P4D. Kidney uptake of 213Bi-P-P4D was distinctly reduced using gelofusine. Thus, this radiopeptide may represent a promising option for therapy for disseminated ovarian cancer.JRC.E.5-Nuclear chemistr

Harmonization of technology across an integrated delivery network

PURPOSE: A standardized blueprint for use when harmonizing or standardizing pharmacy automation and technology resources across individual institutions or an integrated delivery network (IDN) of institutions is described. SUMMARY: Whether to strive for standardization (use of the same vendors and equipment) versus harmonization (use of various technologies to meet patient-specific needs and organizational stability requirements) and how to coordinate activities across IDNs consisting of 3-30 or more hospitals are common questions due to consolidations in the healthcare industry. For most IDNs with legacy systems, harmonization may be the better option. Large-scale harmonization initiatives require significant planning and coordination involving all affected parties. Detailed project plans should include the compiling of all associated harmonization costs that involve human resources, information on ongoing services and equipment, and program schedules for multiple concurrent projects in order to provide a framework for planning and coordination. Part of the planning process for harmonization efforts should include an extensive current-state analysis that includes review of contracts and vendors. Final harmonization decisions should be based on a mix of vendor recommendations, best practices, and accommodation of current practices that result in the lowest complexity of system redesign with regard to existing systems. When harmonizing existing technologies, planning must also consider the impact of the change to both the organization and individual users. CONCLUSION: Harmonization is an evaluative process whereby process variation due to automation and technology variability can be reduced and organizational interoperability to meet patient-specific needs can be promoted