Delivery of Orally Administered Digestible Antibodies Using Nanoparticles

Abstract

Oral administration of medications is highly preferred in healthcare owing to its simplicity and convenience; however, problems of drug membrane permeability can arise with any administration method in drug discovery and development. In particular, commonly used monoclonal antibody (mAb) drugs are directly injected through intravenous or subcutaneous routes across physical barriers such as the cell membrane, including the epithelium and endothelium. However, intravenous administration has disadvantages such as pain, discomfort, and stress. Oral administration is an ideal route for mAbs. Nonetheless, proteolysis and denaturation, in addition to membrane impermeability, pose serious challenges in delivering peroral mAbs to the systemic circulation, biologically, through enzymatic and acidic blocks and, physically, through the small intestinal epithelium barrier. A number of clinical trials have been performed using oral mAbs for the local treatment of gastrointestinal diseases, some of which have adopted capsules or tablets as formulations. Surprisingly, no oral mAbs have been approved clinically. An enteric nanodelivery system can protect cargos from proteolysis and denaturation. Moreover, mAb cargos released in the small intestine may be delivered to the systemic circulation across the intestinal epithelium through receptor-mediated transcytosis. Oral Abs in milk are transported by neonatal Fc receptors to the systemic circulation in neonates. Thus, well-designed approaches can establish oral mAb delivery. In this review, I will introduce the implementation and possibility of delivering orally administered mAbs with or without nanoparticles not only to the local gastrointestinal tract but also to the systemic circulation.

The Promise of Nanotechnology in Personalized Medicine

“…When a drug is encapsulated in nanoparticles, all these issues are overcome, and the absorption process strictly depends on the nanoparticle’s physicochemical properties. When nanoparticles are orally administered, they could be absorbed through the gastrointestinal tract by different processes, such as paracellular pathway transport, transcytosis mediated by the carrier, passive cross-cell diffusion, or microfold cells (M cells) absorption [ 16 , 17 ]. Thus, nanoparticles are able to enter the systemic blood circulation by intestinal lymph node or through the portal vein; moreover, nanoparticles absorption by M cells improves the drug bioavailability because of the bypass of cytochrome P450 metabolism, hepatic first-pass, and P-glycoprotein (P-gp)-mediated efflux [ 18 ].…”

“…The remainder can cross the mucus and lung epithelium, being absorbed [ 21 ]. In addition, it is known that positively charged nanodrugs have an enhanced absorption process through the lung mucosa [ 17 ], because of the interaction with the negatively charged sulphate sialic acid and sugar moieties of mucin [ 14 ].…”

Delivery of Intravenously Administered Antibodies Targeting Alzheimer’s Disease-Relevant Tau Species into the Brain Based on Receptor-Mediated Transcytosis

“…Role of FcRn of the Endothelium at the BBB FcRn [11] plays a vital role in transferring Abs across enterocytes in the small intestine, podocytes, renal proximal tubular cells of the kidney, and syncytiotrophoblasts of the placenta. In contrast, FcRn endocytoses Abs and recycle them back, via a process known as salvation, in the vascular endothelial cells and hepatocytes of the liver.…”

“…Nonetheless, strategies that enable the delivery of substances into the brain across the BBB, based on solute carrier (SLC) transporter-mediated transport or receptor-mediated transcytosis, depending on molecular size and hydrophilicity, have been developed. Several methods for membrane substance permeation exist, including substances that (i) are subject to SLC transporter-mediated transport across the membrane [6], (ii) are transported into cells using cell penetrating peptides (CPPs) [7], (iii) specifically enter cancer cells through receptor-mediated endocytosis based on the enhanced permeability and retention (EPR) effect using nanoparticles [8], (iv) are delivered into the brain based on receptor-mediated transcytosis across the BBB after intravenous administration [9] or (v) across the olfactory epithelium after intranasal administration using insulin as a carrier [10], and (vi) deliver orally administered mAbs as cargo through neonatal Fc receptor (FcRn)-mediated transcytosis across the intestinal epithelium into systemic circulation using enteric nanoparticles [11]. These pharmacokinetic findings are also useful for the design and development of AD drugs.…”

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

“…Therapeutic proteins and peptides are poorly resistant to the acidic and proteolytic content of the stomach, thus protection strategies have been envisioned to overcome these barriers and include enteric coating ( Crowe et al, 2019 ) and encapsulation in nanoparticles ( Tashima, 2021 ). Interestingly, formulations based on coated mini capsules were engineered for the local treatment of inflammatory bowel disease with anti-TNFα antibody and led to high intestinal and colon concentrations with limited systemic exposure ( Crowe et al, 2019 ).…”