Neonatal Fc Receptor-Targeted Nanoparticles for Oral Delivery of Anti-Diabetic Drugs

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Title: Neonatal Fc Receptor-Targeted Nanoparticles for Oral Delivery of Anti-Diabetic Drugs
Author: Oliveira Martins, João Pedro
Contributor: University of Helsinki, Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology
Doctoral Programme in Drug Research
Publisher: Helsingin yliopisto
Date: 2021-12-17
Language: en
Thesis level: Doctoral dissertation (article-based)
Abstract: Managing a chronic disease throughout the lifetime is an enormous challenge, and diabetes mellitus (DM) is no exception. For the time being, DM cannot be cured but only managed, if and when appropriately diagnosed. However, the vast majority of the currently available glucose-lowering interventions provide diabetic patients with only invasive and distressing treatment opportunities, and an undeniably poor compliance to the therapy. Therefore, it is of utmost importance to develop alternative treatment modalities. Success in the oral delivery of anti-diabetic proteins and peptides could represent a paradigm shift in the management of DM and improve the quality of life of millions of patients. Over the years, nanoparticles (NPs) emerged with great potential to carry and deliver drugs in a precisely tuned and controllable manner. Moreover, nanocarrier systems aimed at oral drug delivery have demonstrated the ability to overcome a variety of biochemical, physical, and mechanical barriers that are intrinsic to the physiological functioning of gastrointestinal tract (GIT). Yet, drug absorption at the intestinal microenvironment is still severely mitigated due to the presence of the tightly organized and restrictive cellular barrier of the intestinal epithelium. The exploration of the mechanisms by which molecules presented in the lumen can be naturally transported into the blood circulation has recently drawn attention to the neonatal Fc receptor (FcRn). FcRn is a membrane receptor responsible for maintaining the homeostasis of immunoglobulin G (IgG) and albumin, via mechanisms of recycling and transcytosis. Hence, NPs functionalized with FcRn-targeting ligands could hijack the FcRn transport pathway to promote the transport of drugs across the intestinal cell wall. Therefore, the main aim of this dissertation was to design and develop different FcRn-targeted NPs for efficient oral anti-diabetic drug delivery. Porous silicon (PSi) NPs were used as core drug carriers due to the unprecedented advantages shown as drug nanocarriers. Recombinant human insulin and GLP-1 were loaded into the PSi NPs as model anti-diabetic peptides. Drug-loaded PSi NPs were further encapsulated into different pH-responsive polymers (hypromellose acetate succinate and lignin), via different preparation techniques (emulsification-evaporation, microfluidics and desolvation). The surface of the NPs was functionalized with either albumin or the Fc portion of IgG, to investigate the underexplored potential of the FcRn in increasing the intestinal absorption of orally administered drug-loaded NPs. Overall, the developed NP formulations showed a small size and narrow size distribution. Microscopy images showed the successful encapsulation of the NPs into the pH-sensitive polymeric matrices. Moreover, these pH-responsive matrices remained intact in acidic conditions, dissolving only at specific pH conditions, thereby enabling the controlled release of the drugs. When functionalized with FcRn-targeting ligands, the NPs presented high cytocompatibility and increased levels of interaction with intestinal cells, in which the FcRn expression was also confirmed. Also importantly, the targeted NPs showed augmented drug permeability across in vitro intestinal models. Hence, this dissertation provides new insights on the design and development of FcRn-targeted NPs, which emerge as a toolbox to explore the potential of the FcRn transcytotic capacity for oral anti-diabetic drug delivery.
Subject: Pharmaceutical Technology
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