Oral Delivery of Protein Drugs Bioencapsulated in Plant Cells

Kwang-Chul Kwon, Henry Daniell, Kwang-Chul Kwon, Henry Daniell

Abstract

Plants cells are now approved by the FDA for cost-effective production of protein drugs (PDs) in large-scale current Good Manufacturing Practice (cGMP) hydroponic growth facilities. In lyophilized plant cells, PDs are stable at ambient temperature for several years, maintaining their folding and efficacy. Upon oral delivery, PDs bioencapsulated in plant cells are protected in the stomach from acids and enzymes but are subsequently released into the gut lumen by microbes that digest the plant cell wall. The large mucosal area of the human intestine offers an ideal system for oral drug delivery. When tags (receptor-binding proteins or cell-penetrating peptides) are fused to PDs, they efficiently cross the intestinal epithelium and are delivered to the circulatory or immune system. Unique tags to deliver PDs to human immune or nonimmune cells have been developed recently. After crossing the epithelium, ubiquitous proteases cleave off tags at engineered sites. PDs are also delivered to the brain or retina by crossing the blood-brain or retinal barriers. This review highlights recent advances in PD delivery to treat Alzheimer's disease, diabetes, hypertension, Gaucher's or ocular diseases, as well as the development of affordable drugs by eliminating prohibitively expensive purification, cold chain and sterile delivery.

Figures

Figure 1
Figure 1
Mechanism of protein drug (PD) delivery to target cells. (a) Oral delivery of bioencapsulated protein drugs: Step 1, The plant cell wall protects PDs from acids and enzymes in the stomach; Step 2, Digestion of the plant cell wall by gut microbes and release of PDs into the gut lumen (b) Intestines of mice fed with lyophilized cells expressing cholera toxin B subunit (CTB)-GFP stained with anti-GFP (green signal; Alexa Fluor 488), UEA-1 (microfold cells (M cells), red signal, rhodamine), and DAPI (nuclear stain, blue). DAPI, 4',6-diamidino-2-phenylindole. Solid arrow, GFP+ M cells; EC, epithelial cells; PC, plant cells. (c) Interaction of CTB-GFP with GM1 and predicted 3D structure of protein transduction domain (PTD) and DCpep. Amino acid sequences of PTD and dendritic cell peptide (DCpep) are indicated below 3D structures. (d) Uptake of GFP-fused tags by human immune and nonimmune cells. Purified GFP fusion proteins were incubated with human cell lines and cells were stained with DAPI. Images were captured at 100× magnification under a confocal microscope. (b), (c), and (d) are modified from a previous publication.

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