The use of low molecular weight protamine chemical chimera to enhance monomeric insulin intestinal absorption

doi:10.1016/j.biomaterials.2013.06.047

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物制剂研究中心

	The use of low molecular weight protamine chemical chimera to enhance monomeric insulin intestinal absorption
	He, Huining 8,9; Sheng, Jianyong 1,7; David, Allan E.6; Kwon, Young Min 5; Zhang, Jian 4; Huang, Yongzhuo1,3,7 ; Wang, Jianxin 1,7; Yang, Victor C.2,4,9
刊名	BIOMATERIALS
	2013-10
卷号	34 期号:31 页码:7733-7743
关键词	Cell-penetrating peptide Intestinal absorption Low molecular weight protamine Insulin Monomeric conjugation Permeation enhancement
ISSN号	0142-9612
DOI	10.1016/j.biomaterials.2013.06.047
文献子类	Article
英文摘要	Although oral delivery of insulin offers a number of unmatched advantages, it nevertheless is beset by the poor permeability of insulin molecules through the epithelial cell membranes of the intestinal mucosal layer. We previously reported the development of low molecular weight protamine (LMWP) as a non-toxic yet potent cell-penetrating peptide, of which via covalent linkage was capable of translocating protein cargos through the membranes of almost all cell types. It is therefore hypothesized that LMWP could be practically employed as a safe and effective tool to deliver insulin across the intestinal mucosal membrane, thereby augmenting its absorption through the GI tract. However, formulating 1:1 monomeric insulin/LMWP conjugate presents a tall order of challenge, as the acidic insulin and basic LMWP would automatically form tight aggregates through electrostatic interactions. In this paper, we developed an innovative conjugation strategy to solve this problem, by using succinimidyl[(N-maleimidopropionamido)-polyethyleneglycol] ester (NHS-PEG-MAL) as an intermediate crosslinker during the coupling process. Both SDS-PAGE and MALDI-TOF mass spectroscopy confirmed the formation of a homogenous, monomeric (1:1 ratio) insulin/LMWP conjugate without encountering the conventional problem of substrate aggregation. Cell culture studies demonstrated that transport of the Insulin-PEG-LMWP conjugate across the intestinal mucosal monolayer was augmented by almost five-folds compared to native insulin. Furthermore, results from the in situ loop absorption tests in rats showed that systemic pharmacological bioavailability of insulin was significantly enhanced after its conjugation with LMWP. Overall, the presented chemical conjugation with LMWP could offer a reliable and safe means to improve the intestinal permeability of therapeutic peptides/proteins, shedding light of the possibility for their effective oral delivery. Published by Elsevier Ltd.
资助项目	NIH[CA114612] ; NSFC, China[91029743] ; NSFC, China[81172996] ; Shanghai Pu-jiang Scholar Program[11PJ1411800] ; National Science and Technology Major Project[2012ZX09304004] ; Key Lab of Smart Drug Delivery (Fudan University), MOE PLA[SDD2011-02] ; World Class University (WCU) project of the MEST[R31-2008-000-10103-01] ; NRF of South Korea[00000000]
WOS关键词	VIVO PROTEIN TRANSDUCTION ; HIV-1 TAT PROTEIN ; ORAL INSULIN ; IN-VIVO ; PENETRATING PEPTIDES ; MAMMALIAN-CELLS ; CELLULAR UPTAKE ; DRUG-DELIVERY ; CACO-2 CELLS ; PLASMID DNA
WOS研究方向	Engineering ; Materials Science
语种	英语
出版者	ELSEVIER SCI LTD
WOS记录号	WOS:000323459100018
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277454]
专题	药物制剂研究中心
通讯作者	Yang, Victor C.
作者单位	1.Fudan Univ, Minist Educ, Key Lab Smart Drug Delivery, Shanghai 201203, Peoples R China; 2.Seoul Natl Univ, Dept Mol Med & Biopharmaceut, Seoul, South Korea 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 4.Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA; 5.Nova SE Univ, Coll Pharm, Dept Pharmaceut Sci, Ft Lauderdale, FL 33328 USA; 6.Auburn Univ, Dept Chem Engn, Auburn, AL 36849 USA; 7.Fudan Univ, Sch Pharm, Dept Pharmaceut, PLA, Shanghai 201203, Peoples R China; 8.Tianjin Univ, Sch Chem Engn & Technol, Tianjin 300072, Peoples R China; 9.Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therape, Tianjin 300070, Peoples R China;
推荐引用方式 GB/T 7714	He, Huining,Sheng, Jianyong,David, Allan E.,et al. The use of low molecular weight protamine chemical chimera to enhance monomeric insulin intestinal absorption[J]. BIOMATERIALS,2013,34(31):7733-7743.
APA	He, Huining.,Sheng, Jianyong.,David, Allan E..,Kwon, Young Min.,Zhang, Jian.,...&Yang, Victor C..(2013).The use of low molecular weight protamine chemical chimera to enhance monomeric insulin intestinal absorption.BIOMATERIALS,34(31),7733-7743.
MLA	He, Huining,et al."The use of low molecular weight protamine chemical chimera to enhance monomeric insulin intestinal absorption".BIOMATERIALS 34.31(2013):7733-7743.