| Budget Amount *help |
¥3,110,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
The aim of this study was to develop oral delivery system for peptide/protein drugs having high bioavailability by using the smart polymer(poly(methacrylic acid-g-ethylene glycol)[P(MAA-g-EG)]) and cell-penetrating peptide(CPP). The following results were obtained.
1) Coadministration of insulin with R8, penetratin, pVEC, and RRL helix significantly increased ileal insulin absorption compared with insulin administration alone. In the case of R8, the D-form of the peptide had stronger absorption enhancing ability than the L-form. In contrast, the other three peptides exerted a more significant effect when the L-forms were applied, and L-penetratin had the strongest ability to enhance intestinal insulin absorption.
2) Insulin and GLP-1 were highly incorporated into the smart polymer, the ratio were 90% and 55%, respectively. R6 and HIV-tat were also highly incorporated into the polymer and they were rapidly released from the polymer. Oral insulin bioavailability was increased by the polymer incorporating CPP.
3) Incubation at low temperature and coincubation with heparin reduced the tissue distribution and permeation of fluorescein-labeled oligoarginine(FL-D-R6) through the rat ileal membrane. These results suggest that the attachment of FL-D-R6 to cell-surface proteoglycans and energy-dependent endocytosis are involved in its permeation through the ileal epithelial membrane.
4) Intermolecular interaction between CPP and insulin was analyzed by the surface plasmon resonance. As a result, it was found that the intestinal absorption enhancement effects of CPP is significantly related with their binding affinity to insulin. In addition, it was clearly shown that the binding ratio between CPP and drugs is a factor for determining intensity of enhancement effect of CPP.
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