In vivo performance of "pH-responsive" dosage forms is complex and influenced by a multitude of factors other than just in situ pH.

SUMMARYBackground Current approaches to colonic drug delivery exploit one of two main physiological characteristics: the pH change or increase in bacterial numbers along the gastrointestinal tract. Here, we describe a new concept in targeted delivery, which combines these triggers to improve colonic delivery.

We report the safety, biodistribution, and internal radiation dosimetry of a new PET tracer, 18 F-AH111585, a peptide with a high affinity for the a v b 3 integrin receptor involved in angiogenesis. Methods: PET scans of 8 healthy volunteers were acquired at time points up to 4 h after a bolus injection of 18 F-AH111585. 18 F activity in whole blood and plasma and excreted urine were measured up to 4 h after injection. In vivo 18 F activities in up to 12 source regions were determined from quantitative analysis of the images. The cumulated activities subsequently calculated were then used to determine the internal radiation dosimetry, including the effective dose. Results: Injection of 18 F-AH111585 was well tolerated in all subjects, with no serious or drug-related adverse events reported. The main route of 18 F excretion was renal (37%), and the 3 highest initial uptakes were by liver (15%); combined walls of the small, upper large, and lower large intestines (11%); and kidneys (9%). The 3 highest absorbed doses were received by the urinary bladder wall (124 mGy/MBq), kidneys (102 mGy/MBq), and cardiac wall (59 mGy/MBq). The effective dose was 26 mGy/MBq. Conclusion: 18 F-AH111585 is a safe PET tracer with a dosimetry profile comparable to other common 18 F PET tracers. Int egrin receptors are heterodimeric transmembrane proteins, expressed on the surfaces of endothelial cells and by a variety of tumor types, that bind to neighboring cell membrane proteins and the extracellular matrix (1,2). In particular, a v b 3 integrin receptors are associated with the regulation of tumor growth and are expressed on activated endothelial cells. As a v b 3 receptor antagonists are being evaluated for antiangiogenic therapy (3), clear interest in developing means of in vivo monitoring of such therapy is evident. Several molecular imaging agents have been investigated for the provision of in vivo assessment of angiogenesis (4,5).AH111585 is a cyclic peptide containing an arginineglycine-aspartic acid (RGD) motif that binds to integrin receptors such as a v b 3 with high affinity. We are investigating 18 F-labeled AH111585 for the quantitative in vivo monitoring of antiangiogenic therapy using PET. Details of the 18 F-AH111585 agent and its feasibility in detecting primary and metastatic cancer have been described previously (6). The study described here determined the safety of 18 F-AH111585 in healthy adult volunteers, biodistribution of 18 F, and the associated radiation dosimetry calculated after the MIRD schema (7). MATERIALS AND METHODSUnless otherwise specified, numeric data are provided as the mean 6 1 SD. Radiopharmaceutical PreparationSynthesis of the agent has been described previously (6,8). SubjectsApproval for this study was received from the Hammersmith Hospitals NHS Trust Research Ethics Committee, the Administration of Radioactive Substances Advisory Committee, and the Medicines and Healthcare Products Regulatory Agency. Eight healthy volunteers (5 men, 3 women), with an age of 61 6 4 y and body mass index of ...

No abstract

No abstract