A Nanocomposite Vehicle Based on Metal–Organic Framework Nanoparticle Incorporated Biodegradable Microspheres for Enhanced Oral Insulin Delivery

Abstract

Oral insulin delivery has revolutionized diabetes treatment, but challenges including degradation in the gastrointestinal environment and low permeation across the intestinal epithelium remain. Herein, to overcome these barriers, we developed a novel biodegradable nanocomposite microsphere embedded with metal−organic framework (MOF) nanoparticles. An iron-based MOF nanoparticle (NP) (MIL-100) was first synthesized as a carrier with an insulin loading capacity of 35%. The insulin-loaded MIL-100 nanoparticles modified with sodium dodecyl sulfate (Ins@MIL100/SDS) promoted insulin permeation across Caco-2 monolayer models in vitro. To improve resistance to the gastric acid environment, Ins@MIL100/SDS nanoparticles were embedded into a biodegradable microsphere to construct the nanocomposite delivery system (Ins@MIL100/SDS@MS). The microspheres effectively protected the MOF NPs from rapid degradation under acidic conditions and could release insulin-loaded MOF NPs in the simulated intestinal fluid. After the oral administration of Ins@MIL100/SDS@MS into BALB/c nude mice, increased intestinal absorption of the insulin was detected compared to the oral administration of free insulin or Ins@MIL100/SDS. Furthermore, significantly enhanced plasma insulin levels were obtained for over 6 h after oral administration of Ins@MIL100/SDS@MS into diabetic rats, leading to a remarkably enhanced effect in lowering blood glucose level with a relative pharmacological availability of 7.8%. Thus, the MOF-nanoparticle-incorporated microsphere may provide a new strategy for effective oral protein delivery.

Metal-organic frameworks for advanced drug delivery

“…What's more, Zhou et al. 273 studied insulin loaded microspheres named Ins@MIL100/SDS@MS, which showed resistance to the stomach acid environment while absorption and transportation at intestinal after oral administration in vivo. The distribution of insulin in major organs suggested that the microsphere potentially circulated through the portal veins to the liver then into the heart, finally metabolized via the kidneys ( Fig.…”

“…The distribution of insulin in major organs suggested that the microsphere potentially circulated through the portal veins to the liver then into the heart, finally metabolized via the kidneys ( Fig. 14 D) 273 . From pharmacokinetic parameter analysis, the peak level of BALB/c nude mice plasma insulin was emerged at 4 h and remained over 8 h. Moreover, contrast to the subcutaneous insulin injection, the relatively lagged absorption of oral system was likely due to the absorption process of GI tract.…”

Biological and environmental degradation of metal-organic frameworks and related mechanisms

“…MOFs可运载药物分子或造 影 剂 通 过 口 服 、 静 脉 注 射 和 吸 入 等 方 式 进 入 人 体 [5,36,37] . 例如, Zhou等 [39] 破坏 [48] . Li等 [49] 酸盐置换, 24 h内MIL-100降解率约为29.9%±2.1% [50] .…”

“…[97] . 除此之外, Leus等 [92] 、MIL-100 [39] 、Fe-BTC和Zn-BTC [77] [47,49,54,113] . MOFs中金属种类 会影响阴离子对MOFs的降解.…”

A Zr‐Based MOF with N‐heterocycle and its pH‐controlled drug release behavior

“…successfully synthesized a protective CMC/Cu‐MOF@IBU nanocomposite, which avoided the explosive release of IBU under acidic condition. Chen et al [36] . reported a MOF nanocrystalline modified with sodium dodecyl sulfate, designated as MIL100/SDS.…”