Oral gene delivery:: Strategies to improve stability of pDNA towards intestinal digestion

被引：33

作者：

Loretz, Brigitta ^{[1
]}

Foeger, Florian ^{[1
]}

Werle, Martin ^{[1
]}

Bernkop-Schnuerch, Andreas ^{[1
]}

机构：

[1] Leopold Franzens Univ, Dept Pharmaceut Technol, Inst Pharm, A-6020 Innsbruck, Austria

来源：

JOURNAL OF DRUG TARGETING | 2006年 / 14卷 / 05期

关键词：

enzymatic degradation; DNase inhibitors; chitosan; gene therapy; DNA vaccines;

D O I：

10.1080/10611860600823766

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Purpose : Gastrointestinal (GI) nucleases are responsible for a rapid presystemic degradation of orally administered transgenes. Within the current study, the activity of these degrading enzymes as well as the effect of various nuclease inhibitors on the degradation process were evaluated in order to assess their potential as auxiliary agents in oral gene delivery. Methods : Digestion assays of pDNA with DNaseI and in GI juices were performed in absence and presence of inhibitors. Consequently, a chitosan conjugate with covalently bound ethylendiaminetetraacetic acid disodium salt dihydrat (EDTA) was synthesized and its nuclease inhibitory properties were evaluated. Results : Small intestinal juice was shown to possess a nuclease activity per millilitre corresponding to 0.02 Kunitz units of DNaseI. Inhibition studies revealed that inhibitory activity followed the ranking: EDTA > sodium dodecyl sulfate (SDS) > aurintricarboxylic acid (ATA) > poly (acrylic acid) > cysteine. The chitosan-EDTA conjugate offered good nuclease inhibiting properties. Conclusion : This study determined the nuclease activity of native porcine small intestinal juice as well as enterocytes homogenate. Moreover, several promising strategies to overcome this enzymatic barrier were identified.

引用

页码：311 / 319

页数：9

共 20 条

[1] Mucoadhesive polymers as platforms for peroral peptide delivery and absorption: synthesis and evaluation of different chitosan-EDTA conjugates [J].