The use of absorption enhancers is an effective strategy to achieve transmucosal delivery of poorly absorbed drugs. Many preclinical studies for developing delivery systems using absorption enhancers have been conducted since 1980s, and recently several such delivery systems have been evaluated in clinical trials. In 2019, Novo Nordisk A/S succeeded in developing the world’s first oral GLP-1 (glucagon-like peptide-1) analog formulation in the United States. The new oral formulation contains salcaprozate sodium (SNAC) as an absorption enhancer. The absorption enhancement technologies are quite effective for developing formulation options other than injections to improve patient convenience. The biopharmaceutical industry is expected to expand further in the future, and now the development of oral formulation of biopharmaceuticals is receiving increased attention. In this review, we describe the current status, safety and future prospects of the oral delivery system of biopharmaceuticals, especially focusing on absorption enhancers.

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The great philosopher Hegel proposed a concept of spiral progression of things. In the other word, nothing is lost or destroyed but elevated and preserved as in a spiral. The past will re-emerge with progress. Epithelium covers the body and separates the inner body from the outside environment. Passage of drugs across epithelium is inevitable step for drug absorption. Thus, permeation of drugs across epithelium is a basic strategy for drug absorption. A concept for permeation-enhancement by modulating intercellular seals in epithelium was proposed over 50 years ago. Recently, progress in understanding the biology of the epithelial seals has provided us new insight into drug absorption. In this review, we overview spiral progression of the permeation enhancers.

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mRNA therapeutics is defined as a new type of nucleic acid medicine by direct administration of synthesized mRNA into the body for therapeutic and prophylactic purposes. Since mRNA is extremely unstable outside the cells, DDS plays a crucial role for delivering the mRNA into the target cells in the body. LNPs have been most frequently used for mRNA delivery, however, it is still difficult to target various tissues and organs other than the liver. We are developing an original DDS, polyplex nanomicelle, which is advantageous in its excellent capacity of tissue penetration after local administration, as well as the low toxicity due to the biodegradability of the nanomicelle. In this article, I would like to introduce the system of polyplex nanomicelle, and the recent studies using the nanomicelles for administering mRNA therapeutics for disease treatment.

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Drug delivery system (DDS) is one of the key technologies to achieve safe treatment, as without DDS, drug molecules can easily diffuse throughout body and affect non-diseased sites. Exosomes serve as versatile intercellular communication vehicles and transfer their cargo to recipient cells. Therefore, increasing attention has been focused on exosome for the delivery of biomolecules and synthetic drugs to various target tissues. Although exosomes have been shown to harbor great promise in therapeutic delivery, substantial improvements regarding developing standardized isolation techniques with high efficiency and robust yield, scalable production methods, standard procedures for exosome storage, efficient loading methods that do not damage exosome integrity, and novel exosome-based nanocarriers and understanding their in vivo trafficking are still required before their clinical translation. In this chapter, we discuss the potential of exosome to be utilized as natural nanocarriers of functional small RNA, proteins, and synthetic drugs and compare their advantages and disadvantages to other delivery mechanisms.

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Extracellular vesicles (exosomes, EVs) (30-200 nm) that encapsulate biofunctional molecules (e.g., microRNAs and enzymes) are highly expected to be useful as next-generation therapeutic carriers because of their pharmaceutical advantages such as controlled immunogenicity, effective usage of cell-to-cell communication routes, absence of cytotoxicity, constitutive secretion, encapsulation of additional biofunctional molecules, and expression of functional proteins in membranes. However, methods for increasing the cellular uptake efficacy of EVs must be developed to achieve effective intracellular delivery of EV contents. In this review, I introduce and discuss novel techniques to enhance cellular EV uptake by modification of arginine-rich peptides on EV membranes for macropinocytosis induction and effective cellular uptake. Our research group previously found that macropinocytosis (accompanied by actin reorganization, ruffling of the plasma membrane, and engulfment of large volumes of extracellular fluid) is very important route for the cellular uptake of EVs. Therefore, we developed macropinocytosis induction techniques by modification of biofunctional peptides on EV membranes to enhance their cellular uptake. Arginine-rich cell-penetrating peptides have been shown to induce macropinocytosis via proteoglycans on plasma membranes, and we developed arginine-rich cell-penetrating peptide-modified EVs that can actively induce macropinocytotic uptake by cells. In addition, I discuss effects of lyophilization of arginine-rich cell-penetrating peptide-modified EVs on their biological activity. Our findings may contribute to the development of EV-based intracellular delivery systems via macropinocytosis.

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DDS nanocarriers are used to provide spatiotemporal control in the body of therapeutic agents. Specifically, they should have multi-stage delivery functions, such as （1）encapsulating therapeutic drugs, （2）escaping from capture by the immune system, （3）reaching the affected area （organ/cell）, and （4）releasing appropriate amount of the therapeutic drugs at the target site inside and outside the cell at appropriate timing. DDS nanocarriers that have been developed so far are roughly classified into chemical products and biologics, but the former does not have any of the above functions. On the other hand, there is a virus as the latter model having all the above functions. In this paper, we will outline the DDS nanocarrier “Bio-nanocapsule” that mimics the early infection machinery of hepatitis B virus that specifically infects the human liver.

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In therapeutic cancer vaccine, it is important that vaccine antigen should be efficiently delivered at the appropriate time to antigen-presenting cells (dendritic cells and macrophages) located in lymphoid organs (lymph nodes and spleen) in order to induce higher anti-tumor immune response. We have developed novel cancer vaccines using cholesterol-substituted pullulan (CHP) nanogel as an antigen delivery system for targeted antigen delivery. In addition, recently we have proposed a new technology using CHP nanogel to regulate the functions of tumor-associated macrophages leading to the improvement of tumor microenvironment. When combined with other immunotherapies, modulation of macrophage function using CHP nanogel brings potent inhibitory effect on immune checkpoint inhibition-resistant cancer.

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In March 2019, the first chimeric antigen receptor-T cell （CAR-T cell） therapy, tisagenlecleucel （Kymriah^®, Novartis）, was approved in Japan. Tisagenlecleucel is indicated for relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia （B-ALL） and relapsed or refractory CD19-positive diffuse large B-cell lymphoma （DLBCL）. Tisagenlecleucel is a living drug generated from patient’s own T cells. Leukapheresis is an important step, which in turn, T cells are genetically reprogrammed by a lentivirus vector encodes chimeric antigen receptor （CAR） gene. The approval of tisagenlecleucel is based on the results of an international multicenter phase II study （ELIANA, JULIET） for relapsed or refractory CD19-positive B-ALL and DLBCL. This CAR-T cell therapy requires not only advanced manufacturing but also a quality management system.

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