Oral delivery of liraglutide-loaded Poly-N-(2-hydroxypropyl) methacrylamide/chitosan nanoparticles: Preparation, characterization, and pharmacokinetics.

The delivery of peptides or protein drugs via the oral route has always presented a significant challenge. Here, nanoparticles for the oral delivery of liraglutide are prepared. The nanoparticles are composed of the biodegradable carrier materials chitosan and poly-N-(2-hydroxypropyl) methacrylamide (pHPMA). In addition, CSKSSDYQC (CSK) and hemagglutinin-2 (HA2) are introduced into the particles to improve the in vivo bioavailability of liraglutide. The size of the nanoparticles is less than 200 nm, and the encapsulation efficiency is approximately 80%. Compared with the subcutaneously injected liraglutide solution group (100%), the relative bioavailability of the nanoparticle group modified with CSK and HA2 reached 10.12%, which is 2.53 times that of the oral liraglutide solution group. In vivo imaging results showed that pHPMA/HA2-CSK chitosan nanoparticles (pHPMA/HA-CCNPs) are retained in the gastrointestinal tract for up to 12 h, which is beneficial for oral absorption. CSK and HA2 modified pHPMA/chitosan nanoparticles significantly improved liraglutide oral bioavailability and therefore have the potential to be applied for oral administration of peptides and proteins.

Intelligent Escape System for the Oral Delivery of Liraglutide: A Perfect Match for Gastrointestinal Barriers.

Epithelial cells are known to impede the oral delivery of polypeptides, and the accumulation of mucus and regular dynamic renewal also significantly impede drug absorption. In this work, we prepared a core-shell (COS) nanosystem using poly-N-(2-hydroxypropyl)methacrylamide (pHPMA)/chitosan (CTS). Liraglutide (NN2211) was isolated from the gastrointestinal environment and smoothly passes through the mucous layer. CSKSSDYQC (CSK) peptide and hemagglutinin-2 (HA2) were introduced into the COS nanosystem to establish a complete path from the oral cavity to the epithelial basal side. The fate of nanocapsules in vivo was studied by fluorescence detection. The results showed that the nanocapsules escaped smoothly from the mucus. Taking into account the characteristics of CSK targeting goblet cells, we conducted cell-level studies, and the results showed that after the modification of CSK and pHPMA, more nanocapsules entered the cells. In vitro and in vivo evaluation results showed that the system successfully established a complete path from mucus to epithelial cells by responding to the gastrointestinal environment multiple times.

Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson's disease.

Efficient delivery of brain-targeted drugs is highly important for successful therapy in Parkinson's disease (PD). This study was designed to formulate borneol and lactoferrin co-modified nanoparticles (Lf-BNPs) encapsulated dopamine as a novel drug delivery system to achieve maximum therapeutic efficacy and reduce side effects for PD. Dopamine Lf-BNPs were prepared using the double emulsion solvent evaporation method and evaluated for physicochemical and pharmaceutical properties. In vitro cytotoxicity studies indicated that treatment with dopamine Lf-BNPs has relatively low cytotoxicity in SH-SY5Y and 16HBE cells. Qualitative and quantitative cellular uptake experiments indicated that Lf modification of NPs increased cellular uptake of SH-SY5Y cells and 16HBE cells, and borneol modification can promote the cellular uptake of 16HBE. In vivo pharmacokinetic studies indicated that AUC0-12 h in the rat brain for dopamine Lf-BNPs was significantly higher (p < .05) than that of dopamine nanoparticles. Intranasal administration of dopamine Lf-BNPs effectively alleviated the 6-hydroxydopamine-induced striatum lesion in rats as indicated by the contralateral rotation behavior test and results for striatal monoamine neurotransmitter content detection. Taken together, intranasal administration of dopamine Lf-BNPs may be an effective drug delivery system for Parkinson's disease.

Oral delivery system for low molecular weight protamine-dextran-poly(lactic-co-glycolic acid) carrying exenatide to overcome the mucus barrier and improve intestinal targeting efficiency.

Aim: This study aimed to explore the effect of nanoparticles loaded with exenatide in overcoming the mucus barrier and improving intestinal targeting efficiency, to improve the oral bioavailability. Materials & methods: Low molecular weight protamine (LMWP)-dextran-poly(lactic-co-glycolic acid) was used to create LMWP-dextran-poly(lactic-co-glycolic acid)-nanoparticles (LDPs) encapsulating exenatide-Zn2+ complex.Results & conclusion: LDPs showed improved penetration of the mucus barrier, and LMWP was helpful for mediating cell translocation through protein transduction domains. The absorption sites and distribution rates of LDPs were verified by intestinal localization experiments and in vivo distribution experiments. Cell uptake and transmembrane experiments confirmed the absorption efficiency in the intestinal epithelium. Furthermore, the relative bioavailability after oral administration of exenatide-Zn2+-LDPs was 8.4%, with a significant hypoglycemic effect on Type 2 diabetic mice.

Synthesis of CSK-DEX-PLGA Nanoparticles for the Oral Delivery of Exenatide to Improve Its Mucus Penetration and Intestinal Absorption.

The oral absorption of exenatide, a drug for type 2 diabetes treatment, can be improved by using nanoparticles (NPs) for its delivery. To improve the mucus penetration and intestinal absorption of exenatide, we designed a block copolymer, CSKSSDYQC-dextran-poly(lactic-co-glycolic acid) (CSK-DEX-PLGA), and used it for the preparation of exenatide-loaded NPs. The functionalized exenatide-loaded NPs composed of CSK-DEX-PLGA were able to target intestinal epithelial cells and reduce the mucus-blocking effect of the intestine. Moreover, the CSK modification of DEX-PLGA was found to significantly promote the absorption efficiency of NPs in the small intestine based on in vitro ligation of the intestinal rings and an examination of different intestinal absorption sites. Compared to DEX-PLGA-NPs (DPs), the absorption of CSK-DEX-PLGA-NPs (CDPs) was increased in the villi, allowing the drug to act on gobletlike Caco-2 cells through clathrin-, caveolin-, and gap-mediated endocytosis. Furthermore, the enhanced transport ability of CDPs was observed in a study on Caco-2/HT-29-MTX cocultured cells. CDPs exhibited a prolonged hypoglycemic response with a relative bioavailability of 9.2% in diabetic rats after oral administration. In conclusion, CDPs can target small intestinal goblet cells and have a beneficial effect on the oral administration of macromolecular peptides as a nanometer-sized carrier.

Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting.

Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.

The use of low molecular weight protamine to enhance oral absorption of exenatide.

Although oral delivery of exenatide has significant advantages, its poor permeability through intestinal epithelial membranes and rapid digestion by pepsin and ereptase in the gastrointestinal tract make effective oral delivery of exenatide a formidable challenge. In this study, we constructed a zinc ion (Zn2+) and exenatide complex functionalized nanoparticle (NP) oral delivery system to overcome the above-mentioned issue. Polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) was used as a drug carrier to escape enzymatic degradation in the gastrointestinal tract, and low molecular weight protamine (LMWP) was used as a functional group to increase penetration of NPs into the intestinal epithelium. The functionalized NPs exhibited significantly improved penetration across the intestinal epithelium, as shown by cell uptake and transmembrane transport experiments. Moreover, a significant hypoglycemic effect was observed in diabetic rats. The relative bioavailability of the orally administered functionalized NPs vs. subcutaneous injection was 7.44%, 29-fold that of the exenatide-Zn2+ solution group. These findings indicate that our modification could effectively improve exenatide treatment.

Tf ligand-receptor-mediated exenatide-Zn2+ complex oral-delivery system for penetration enhancement of exenatide.

Safe and effective oral delivery of peptide is a challenge. Here, we used exenatide and zinc ions (Zn2+) to form a complex to explore a meaningful oral-targeted drug-delivery system. Polyethylene glycol-poly(lactic acid-co-glycolic acid) (PEG-PLGA) was used to prepare nanoparticles (NPs) to escape the degradation caused by gastrointestinal enzymes. Transferrin (Tf) was used as a targeting group. PEG-PLGA-NPs and Tf-modified exenatide-Zn2+-loaded NPs (Tf-PEG-PLGA-NPs) were uniformly sized spheres according to transmission electron microscopy. The results of pharmacodynamic and pharmacokinetic investigations in vivo were consistent with in vitro studies using Caco-2 cells. Tf enhanced NPs transport in cell-uptake and transmembrane-transport experiments. Our results showed that the relative bioavailability of Tf-exenatide-Zn2+-NPs was higher than that of exenatide-Zn2+-NPs. The relative bioavailability of Tf-exenatide-Zn2+-NPs versus subcutaneous injection of exenatide was 6.45%. This was a preliminary exploration of the oral administration of exenatide, that data from which can be used for future investigations.