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• W2188049168 abstract "E. E. Uzgiris, B. Moasser, M. Amaratunga, D. E. Meyer, A. Narendran, J. F. Smith GE Global Research Center, Niskayuna, NY, United States, GE Global Research Center, Niskayuna, Ny, United States Synopsis The imaging effectiveness of Gd-polymeric agents relies on polymer conformation. We test the dependence of polymer conformation on Gd-chelator charge by measuring polymer hydrodynamic properties that include gel permeation chromatography, gel electrophoresis, and T1 relaxivity and correlate these to tumor imaging efficacy in a rat mammary tumor model. As predicted by molecular modeling, charge interactions between neighboring residues are decisive factors in whether polymer is extended or collapsed. However, charged DOTA-isothyocyanate derivatives, although producing a correct polymer conformation, appear to cause the polymer agent not to be transported across the tumor endothelium. Introduction Extended linear polymeric agents have been shown to give high signal enhancement in comprised neovasculature that is associated with tumor angiogenesis. Compared to other macromolecular and nanoparticle agents, these signals are some 10 times larger indicating a higher degree of transport across the tumor endothelium. The imaging efficacy of the agent Gd-DTPA-polylysine is dependent on conformation: If the DTPA conjugation is 90% or higher the conformation is of extended form and the imaging efficacy is high; If the conjugation is lower the polymer is coiled. This critical conformation change is driven by electrostatic and steric interactions between the adjacent charged DTPA groups as indicated by a molecular modeling calculation. To validate this view we replaced DTPA with DOTA (lys-Gd-DOTA is neutral) and eliminated charge interactions in the polymer conformation. To recover the charge interactions between neighboring residues, we conjugated polylysine with an isothiocyanate -DOTA derivative. The central question of this investigation is whether conformation recovery is sufficient to regain imaging efficacy. Materials and Methods Synthesis of highly conjugated DTPA or DOTA -polylysine was done by a modified mixed anhydride method. The modifications enabled conjugation levels in the 95% range. Detailed synthesis procedures will be published elsewhere. Purified constructs gave a single peak on gel permeation chromatography or in gel electrophoresis. The polylysine backbone had a mean polymerization monomer number of 402. A DOTA-isothyocyanate derivative was coupled to the polylysine backbone by a standard coupling reaction. Female Fisher 344 rats where implanted with 10 MatB cells (ATCC 13762) subcutaneously and tumors grew up in about 8 days to a 5mm to 10mm size. These tumors were well vascularized on the periphery but not excessively leaky, i.e., albumin Gd-DTPA gave small signal enhancements. Imaging efficacy was thus related to a well studied macromolecular agent, albumin-Gd-DTPA. Polymeric agents and the control agent were injected at 0.025mmole Gd/kG, and signals changes at 24 hours were obtained (the clearance rate from the blood was such that at 24 hours the blood plasma levels were only ~10% of initial values). T1 weighted tumor signal changes were noted in the periphery of the tumors on a GE Signa scanner at 1.5T utilizing a solenoid receive coil. Gel permeation chromatography was done on a TSK-GEL G-DNA –PW (Tosho Biosep) column using a Dionex HPLC sytem. The pattern of elution times is dependent on hydrodynamic size and the extended polymers were well displaced (1.4minutes longer) from the pattern of globular protein standards. The full displacement for a particular monomer number gives and index of conformation change. As the polymer is made to collapse the displacement is smaller and smaller and in the fully collapsed state (conjugation <80%) it falls on the elution pattern of globular proteins. Relaxivity is also dependent on conformation: In an extended conformation, the relaxivity is lower than in the collapsed state. Relaxivity was measured at 1.5 T using a multi-well plate and an inversion recovery sequence on a GE Signa scanner and an internally developed analysis program for multi-well data sets. Results Table 1. Comparison of DTPA and DOTA polylysine constructs Constructs (polylysine,PL) HPLC elution Index R1 ** Imaging efficacy Free lysines,%" @default.
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• W2188049168 date "2003-01-01" @default.
• W2188049168 modified "2023-09-27" @default.
• W2188049168 title "Chelator charge and structure and their effects on polymeric agent conformation and imaging efficacy" @default.
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