Research Article: Nanoparticles: Oral Delivery for Protein and Peptide Drugs

Date Published: May 20, 2019

Publisher: Springer International Publishing

Author(s): Shu-jun Cao, Shuo Xu, Hui-ming Wang, Yong Ling, Jiahua Dong, Rui-dong Xia, Xiang-hong Sun.


Protein and peptide drugs have many advantages, such as high bioactivity and specificity, strong solubility, and low toxicity. Therefore, the strategies for improving the bioavailability of protein peptides are reviewed, including chemical modification of nanocarriers, absorption enhancers, and mucous adhesion systems. The status, advantages, and disadvantages of various strategies are systematically analyzed. The systematic and personalized design of various factors affecting the release and absorption of drugs based on nanoparticles is pointed out. It is expected to design a protein peptide oral delivery system that can be applied in the clinic.

Partial Text

Since the first bioactive peptide was synthesized in 1953 by Robert Bruce Merrifield, the research of protein and peptide drugs has been developing rapidly, and the research of protein and peptide drugs targeting multiple receptors has been carried out in the world. Protein and peptide drugs have many valuable applications in the clinic to treat or prevent diseases by modulating physiological or pathological processes. And protein and peptide drugs play an indispensable role in cancer, autoimmune diseases, and cardiovascular diseases; especially in the field of tumor and diabetes treatment, many protein and peptide drugs have been listed, and great economic benefits have been achieved (1). However, their widespread application is restricted due to chemical and physical instabilities, such as low pH value, enzymatic degradation in the gastrointestinal tract, and rapid elimination from circulation in contrast to small-molecule drugs (2).

Generally speaking, protein and peptide drug–loading nanoparticles have four ways through the gastrointestinal membrane, which are transmembrane transport, receptor-mediated transport, vector-mediated transport and M cell(membranous/microfold cell) transport (6).

Most of the protein and peptide drugs are macromolecular hydrophilic, in the extreme environment of gastrointestinal stability, susceptible to gastric acid and pepsin degradation; at the same time, because of its hydrophilicity, it cannot effectively penetrate the physiological barrier of the small intestinal mucous layer and epithelial layers such as the intercellular tight junction (Fig. 1). Most of the strategies for oral administration of protein and peptide drugs are the same, that is, to avoid enzymatic degradation in the digestive system, and to improve the drug oral bioavailability (23).Fig. 1Major barriers to oral delivery of peptide and protein-based drugs

Although it has been proved that the nanoparticles can be absorbed by the GT after oral administration, low absorption is the biggest obstacle to the development of oral nanoscale drug delivery systems. With the further research of absorption mechanism, many methods to promote the absorption of nanoparticle gastrointestinal tract are mainly focused on the modification of intestinal epithelial cells with adhesion and targeting on M cells. And there are four distinct mechanisms for molecules to cross the cell membrane including paracellular, transcellular, carrier-mediated, and receptor-mediated transport (Fig. 2). The strategies reported for improving the bioavailability of protein include a chemical modification, absorption enhancers, mucous adhesion systems, and nanoparticle list in Table II. This section reviews the strategies for improving the oral bioavailability of protein and polypeptide drugs.Fig. 2Schematic representation of the transport mechanisms: (I) receptor-mediated transport; (II) carrier-mediated transport; (III) paracellular transport; (IV) phagocytosis by M cellsTable IIAdvantages and Disadvantages of Approaches for Enhancing Oral Bioavailability of Proteins and PeptidesMethodAdvantagesDisadvantagesAbsorption enhancersEnhancing oral bioavailabilityNo protein specific and risk of toxin or allergen import along with the proteinsEnzyme inhibitorsPreventing the enzymatic degradation of protein and peptide drugsHigh toxicityMucoadhesive systemsProlonging retention time and improving oral bioavailabilityNo avoiding rapid mucus clearance and penetrating the mucus layerColon-specific drug deliveryProtecting the activity of protein and peptide drugsHaving technical difficulties

The chemical modification of protein polypeptide can improve the stability of protein polypeptide drugs, increase the permeability of the membrane, reduce the immunogenicity, and reduce its bioactivity, and the absorption enhancer can promote the absorption of the small intestine to the protein polypeptide. But it has no protein specificity, while promoting the absorption of drugs; it may also promote the gastrointestinal toxicity. The mucosal adhesion system can prolong the retention time of protein and polypeptide drugs in the gastrointestinal tract and improve its bioavailability, but it cannot increase the oral permeability of drugs and avoid the cleaning of the small intestinal mucosa.




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