Dual Stimuli-Responsive Nanoparticle-Incorporated Hydrogels as an Oral Insulin Carrier for Intestine-Targeted Delivery and Enhanced Paracellular Permeation,ACS Biomaterials Science & Engineering

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Dual Stimuli-Responsive Nanoparticle-Incorporated Hydrogels as an Oral Insulin Carrier for Intestine-Targeted Delivery and Enhanced Paracellular Permeation
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2018-06-29 00:00:00 , DOI: 10.1021/acsbiomaterials.8b00646
Liang Liu _{1,

2} , Ying Zhang _{1,

2} , Shuangjiang Yu ₁ , Zhiming Yang ₃ , Chaoliang He _{1,

2} , Xuesi Chen _{1,

2}

Affiliation

For enhanced oral insulin delivery, a strategy of acid-resistant and enteric hydrogels encapsulating insulin-loaded nanoparticles was developed. The nanoparticles were prepared by the formation of an anionic insulin/heparin sodium (Ins/HS) aggregate, followed by coating of chitosan (CS) on the surface. The nanoparticles, tagged as CS/Ins/HS NPs, exhibited excellent mucosa affinity, effective protease inhibition, and marked paracellular permeation enhancement. Moreover, to improve the acid-stability of CS/Ins/HS NPs and impart the capacity of intestine-targeted delivery, a pH- and amylase-responsive hydrogel was synthesized via free radical copolymerization, using methacrylic acid as the monomer and acrylate-grafted-carboxymethyl starch as the cross-linker. The resulting hydrogel exhibited sharp pH-sensitivity in the gastrointestinal tract and rapid enteric behavior under intestinal amylase. The additional protection for insulin in artificial gastric fluid was confirmed by packaging CS/Ins/HS NPs into the hydrogel. The obtained nanoparticle-incorporated hydrogel was named as [email protected] The release of insulin from [email protected] was evidently accelerated in artificial intestinal fluid containing α-amylase. Furthermore, the hypoglycemic effects were evaluated with type-1 diabetic rats. Compared to subcutaneous injection of insulin solution, the relative pharmacological availability (rPA) for oral intake of [email protected] (30 IU/kg) was determined to be 8.6%, along with rPA of 4.6% for oral administration of unpackaged CS/Ins/HS NPs (30 IU/kg). Finally, the two-week therapeutic outcomes in diabetic rats were displayed after twice-daily treatments by oral intake of [email protected], showing the relief of diabetic symptoms and suppression of weight loss in the rats. Therefore, this dual stimuli-responsive nanoparticle-incorporated hydrogel system could be a promising platform for oral insulin delivery.

中文翻译：

双重刺激响应的纳米粒子结合水凝胶作为口服胰岛素载体的肠道靶向递送和增强的细胞旁渗透。

为了增强口服胰岛素的递送，开发了一种抗酸和肠溶性水凝胶封装载有胰岛素的纳米颗粒的策略。通过形成阴离子胰岛素/肝素钠（Ins / HS）聚集体，然后在表面涂覆壳聚糖（CS）来制备纳米颗粒。标记为CS / Ins / HS NP的纳米颗粒表现出优异的粘膜亲和力，有效的蛋白酶抑制作用和明显的细胞旁渗透增强作用。此外，为了提高CS / Ins / HS NP的酸稳定性并赋予肠道靶向递送能力，使用甲基丙烯酸作为单体并丙烯酸接枝丙烯酸，通过自由基共聚合成了pH和淀粉酶反应性水凝胶。-羧甲基淀粉作为交联剂。所得的水凝胶在胃肠道中表现出尖锐的pH敏感性，在肠淀粉酶作用下表现出快速的肠道行为。通过将CS / Ins / HS NP包装到水凝胶中，证实了对人工胃液中胰岛素的额外保护。将获得的掺有纳米颗粒的水凝胶称为[电子邮件保护的]。在含有α-淀粉酶的人工肠液中，胰岛素从[电子邮件保护的]中的释放明显加速。此外，还对1型糖尿病大鼠的降血糖作用进行了评估。与皮下注射胰岛素溶液相比，口服[受电子邮件保护的]（30 IU / kg）的相对药理学有效性（rPA）被确定为8.6％，而口服未包装的CS / Ins的rPA为4.6％ / HS NP（30 IU / kg）。最终，通过每天两次口服[email protected]的治疗，显示了糖尿病大鼠的两周治疗结果，显示出糖尿病症状的减轻和大鼠体重的减轻。因此，这种双重刺激响应纳米粒子结合水凝胶系统可能是口服胰岛素输送的有前途的平台。

更新日期：2018-06-29

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