DDS Fusion of regenerative medicine with DDS, RIST, TUS Japanese

Introduction to “Fusion of regenerative medicine with DDS”

■ Established April 2015
■ Research Content : R&D on regenerative medicine with DDS.

【Process of the establishment】

A base of the “Fusion of regenerative medicine with DDS” is the “Center for Drug Delivery Research” which was adopted by “High-Tech Research Center Project” for the private university academic research upgrading project conducted by the Ministry of Education, Culture, Sports, Science and Technology Japan (MEXT) at April, 2004.

This section was established at April, 2015, after five years project activity of “Center for Physical Pharmaceutics” (purpose of study: development of nano-DDS technology for efficient drug delivery) which was adopted by Program for Development of Strategic Research Center in Private Universities supported by MEXT 2010.

We have associated with pharmaceutical industries and medical researchers. Collaborative study with Bulgarian, Canadian and Indian researchers are also improved in this project.

【The project of fusion of regenerative medicine with DDS】

“Create a novel research foundation for efficient treatment based on regenerative medicine”

Molecular signals have a crucial role in this project, however, DDS having sufficient activation of a molecular signaling pathway will be developed.

【Relationship between the regenerative medicine and DDS】

The regeneration medicine is a study of regenerate normal cells and organs by inducting cell growth and differentiation adequately, and close cooperation among the regions of biomaterial, basic medicine and clinical medicine are required.
DDS is the system of drug targeting and controlled release.
Scaffold structures appropriated to cell growth and differentiation are required in regeneration medicine.
“Fusion of regenerative medicine with DDS” has great significance because DDS is needed to deliver growth factor with controlled release to target site.

【Research theme】

Nanomedicine is medical treatment at the “nano” scale of about 100 nm or less. From 1980’s, progress in developing nanosized hybrid therapeutics and drug delivery system has been remarkable and products have been approved for clinical use. Most are anticancer therapies, polymer-coated liposomes (Doxil®/Caelyx®), antibodies (Herceptin®, Avastin™), a nanoparticle containing paclitaxel (Abraxane™). The concepts of antibody-conjugates, liposomes, nanoparticles, polymer micelles stem from the 1970s. Liposomes are biocompatible drug carriers, but easily release drugs quickly or do not release drugs and sometimes captured by the reticuloendothelial system (RES), even when the liposome surfaces are coated by hydrophilic polymer layers. Particles with the diameters larger than 200 nm are easily recognized by RES and digested by macrophages after intravenously administered. To escape from the recognition by RES, many studies have been reported. For this purpose, synthetic biocompatible polymers have been developed.
Preclinical and clinical evidence of this formulation (Doxil®/Caelyx®), Fig. 1, has demonstrated that the nanoparticle, especially pegylated liposome, delivery system leads to greater localization of doxorubicin to tumor site and consequent improved efficacy, as well as, reduced toxicity. For vascularized tumors, the selective accumulation and retention of liposomes is a result of the combination of ‘leaky’ tumor neovasculature and malfunctioning lymphatics, integrated in enhanced permeability and retention (EPR) effect, as shown in Fig. 2.
Nanosized particles have high surface-to-volume ratio, could be especially dangerous, although they are less effectively taken up by macrophages and can reach brain passing through blood brain barrier (BBB). Any toxicity of nanoparticles depends on the route and frequency of administration, and polymer used to prepare the particles.

Fig. 1 Pegylated liposomal doxorubicin
Fig. 1 Pegylated liposomal doxorubicin
Fig. 2 Pegylated liposomal doxorubicin in normal (left) and tumor vessels.
Fig. 2 Pegylated liposomal doxorubicin
in normal (left) and tumor vessels.

Regenerative medicine
Angiogenesis, the formulation of new blood vessels, is fundamental to development and post-injury tissue repair. Vascular endothelial growth factor (VEGF)-A guides and enhances actin filament formation and endothelial cell migration. Treatment of limb ischemia is improved by nano-DDS systems. Furthermore, nano-DDS systems can contribute to treatment of Chronic Obstructive Pulmonary Disease (COPD).

Pulmonary drug delivery system
The lung (adjectival form: pulmonary) is the essential respiration organ, and two lungs are located in the chest on either side of the heart. Their principal function is exchange of oxygen and carbon dioxide, transporting oxygen from the atmosphere into bloodstream and releasing carbon dioxide from the bloodstream to atmosphere, by the passage of air through the mouth to the alveoli. The air progresses through the mouth or nose, it travels through the oropharynx, nasopharynx, the larynx, the trachea, the primary bronchiole, the secondary bronchiole, the terminal bronchiole, the respiratory bronchiole, and finally reaches the alveolar duct where the gas exchange of CO2 and O2 takes place. Recently, there have been many attempts to improve systemic delivery of peptide and protein drugs by routs of administration other than injection. The drug delivery in these studies have included nasal, rectal, buccal, and respiratory rout of administration. Because of the unique physiological characteristics, lung is an attractive port of entry to the systemic circulation for the administration of drugs. That is, the alveoli present a large surface area for adsorption of about 100 m2, a very thin diffusion path separates the airspace form the blood stream, i.e., the alveolar epithelium, the vascular endothelium and their respective basal membranes are less than 0.5 µm thick. Also, the high blood flow of about 5 ℓ / min of the pulmonary circulation rapidly distributes molecules throughout the body without first-pass hepatic metabolism, and the metabolic activity locally in the lungs is relatively low. Together with the success of design of new inhalers, pulmonary delivery of small drugs and proteins has reached clinical trials of drugs such as insulin, calcitonin, interferon, and hormone.

Fig. 3 Deposittioned particle size in respiratory tract.
Fig. 3 Deposittioned particle size in respiratory tract.

The environment in the lungs is very moist, and the humidity in the respiratory tract is almost 100 %. To reach alveolar through the respiratory tract, the medicine should have the proper size and density, shown as an aerodynamic diameter. As shown in Fig, 3, the particles with the aerodynamic diameters between 2 and 5 µm can efficiently reach alveoli. The particles smaller than 1 µm are easily inhaled by respiration but exhausted from lungs without deposition in alveoli, like tabacco smoke. The aerodynamic diameter of the particle, daer, is defined as equation (1) which is simply derived from Stokes’ equation,


where dp is the diameter of the particle which is usually measured using laser diffraction, ρp the density of the particle, ρ0 the density of water at the same temperature.
As mentioned before, the environment in the lungs is very moist, which makes it hospital for bacteria and it causes infectious diseases in the lungs. For the treatment of these infectious diseases, direct delivery of antimicrobe agents to the lungs through respiratory tract has been considered to be effective. This is included in local injection of medicine to the lungs. Also, this concept has been applied to the treatment of lung carcinoma.

【Research organization】

[Research group]
We establish four research groups.

○ Tissue regeneration
○ Novel drug carrier design
○ Novel dosage form design
○ Application of new DDS tools to experimental disease models

[Corresponding member of the project]
Thirteen researchers are delegated in the section as corresponding members to promote the project multidirectionally and effectively. Clinician and researchers of universities, pharmaceutical industries and medical institutions are belonged. They will give a hand to make this project succeed.

[Advisory Committee]
Three researchers on DDS study are advisory board in this section, and support us with specialist advices.

Prof. Kazunori Kataoka
(Innovation Center of NanoMedicine (iCONM))
Dr. Hiroshi Kikuchi
(Eisai Co., Ltd.)
Prof. Mitsuru Hashida
(Kyoto University Institute for Advanced Study.)

【Research facility】

The main research facility is the Center for Drug Delivery Research. In addition, we study in laboratories of each member.

[Introduction in facilities]

[1F] Common machine room
[1F] Common machine room
[1F] Electronic microscope room
[1F] Electronic microscope room
[2F] Darkroom
[2F] Darkroom
[2F] Common machine room
[2F] Common machine room