Enzyme-Triggered Intestine-Specific Targeting Adhesive Platform for Universal Oral Drug Delivery.

Patient adherence to chronic therapies can be suboptimal, leading to poor therapeutic outcomes. Dosage forms that enable reduction in dosing frequency stand to improve patient adherence. Variation in gastrointestinal transit time, inter-individual differences in gastrointestinal physiology and differences in physicochemical properties of drugs represent challenges to the development of such systems. To this end, a small intestine-targeted drug delivery system is developed, where prolonged gastrointestinal retention and sustained release are achieved through tissue adhesion of drug pills mediated by an essential intestinal enzyme catalase. Here proof-of-concept pharmacokinetics is demonstrated in the swine model for two drugs, hydrophilic amoxicillin and hydrophobic levodopa. It is anticipated that this system can be applicable for many drugs with a diverse of physicochemical characteristics.

Influence of PLA-PEG nanoparticles manufacturing process on intestinal transporter PepT1 targeting and oxytocin transport.

Oral administration of peptides still remains a challenging issue. We previously pointed out the possibility to target intestinal PepT1 transporter with functionalized PLA-PEG nanoparticles (NPs) formulated by nanoprecipitation, and to improve drug-loaded intestinal permeability. Nevertheless, alternative manufacturing processes exist and the impact on the intestinal transporter targeting could be interesting to study. Our objective is consequently to assess the ability of functionalized NPs to target PepT1 according to the manufacturing process, and the possibility to improve peptide absorption. PLA-PEG-Valine NPs were formulated by nanoprecipitation, double and simple emulsion with median particle size <200 nm. Using Caco-2 cells, the competition between PLA-PEG-Val NPs formulated by the different manufacturing processes, and [3H]Glycylsarcosine, a well-known substrate of PepT1, was observed to evaluate the impact of the process on the intestinal transporter PepT1 targeting. Simultaneously, PLA-PEG-Val NPs were labeled with fluorescein (FITC) to evaluate PepT1 targeting and to observe the behavior of the NPs close to the cell according to the manufacturing process by confocal imaging. Finally, oxytocin peptide (OXY) was encapsulated in Val-NPs according to the most relevant process and the transport of the drug was assessed in vitro and in vivo, and compared to free drug. It was possible to observe by TEM imaging a better organization and expression of the ligand at the surface for NPs formulated by emulsion processes. Furthermore, the competition between functionalized NPs and [3H]Glycylsarcosine revealed a better transport inhibition of [3H]Glycylsarcosine for NPs formulated by double emulsion (≈ 67%). These results were confirmed by fluorescence measurements, comparing the amount of fluorescence linked to the cells after incubation with fluorescent Val-NPs for the 3 processes (≈ 39% for double emulsion). Additionally, confocal microscopy confirmed the ability of Val-NPs prepared by double emulsion to target the cell membrane and even to reach the intracellular space. OXY was then encapsulated by double emulsion in Val-NPs with a drug load of ≈ 4%. It was thus shown in vitro that drug transport was doubled compared to free drug. In vivo, OXY plasma concentration after oral administration were significantly increased when encapsulated in Val-NPS obtained by double emulsion compared to free drug. These results demonstrated that NPs prepared by double emulsion allowed a better PepT1 targeting and is a promising approach for oral peptide delivery.

Targeted modulation of cell differentiation in distinct regions of the gastrointestinal tract via oral administration of differently PEG-PEI functionalized mesoporous silica nanoparticles.

Targeted delivery of drugs is required to efficiently treat intestinal diseases such as colon cancer and inflammation. Nanoparticles could overcome challenges in oral administration caused by drug degradation at low pH and poor permeability through mucus layers, and offer targeted delivery to diseased cells in order to avoid adverse effects. Here, we demonstrate that functionalization of mesoporous silica nanoparticles (MSNs) by polymeric surface grafts facilitates transport through the mucosal barrier and enhances cellular internalization. MSNs functionalized with poly(ethylene glycol) (PEG), poly(ethylene imine) (PEI), and the targeting ligand folic acid in different combinations are internalized by epithelial cells in vitro and in vivo after oral gavage. Functionalized MSNs loaded with γ-secretase inhibitors of the Notch pathway, a key regulator of intestinal progenitor cells, colon cancer, and inflammation, demonstrated enhanced intestinal goblet cell differentiation as compared to free drug. Drug-loaded MSNs thus remained intact in vivo, further confirmed by exposure to simulated gastric and intestinal fluids in vitro. Drug targeting and efficacy in different parts of the intestine could be tuned by MSN surface modifications, with PEI coating exhibiting higher affinity for the small intestine and PEI-PEG coating for the colon. The data highlight the potential of nanomedicines for targeted delivery to distinct regions of the tissue for strict therapeutic control.