RIST Outline

Fusion of Regenerative Medicine with DDS

Director  Director Kimiko Makino Professor, Department of Pharmacy, Faculty of Pharmaceutical Sciences 
Research Content R&D on regenerative medicine with DDS.
Objetcitves With a view to promoting commercially viable regenerative medicine, our aim is to learn the structure of human body and to deliver medicine to the target organ when the medicine is needed.

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-The Research Highlight, 2016-

DDS

For the effective regenerative therapy, we have studied targeting of medicine.

Nanomedicine

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®, AvastinTM), a nanoparticle containing paclitaxel (AbraxaneTM). 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.

Regenerative medicine

Angiogenesis, the formulation of new blood vessels, is fundamental to development and post-injury tissue repair. Vascular endotherial growth factor (VEGF)-A guides and enhances actin filament formation and endotherial cell migration. Ischemic limb treatment will be improved by nano-DDS systems. Also, nano-DDS systems will be useful for the 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 mm 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.

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 mm can efficiently reach alveoli. The particles smaller than 1 mm 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,

(1)

where dp is the diameter of the particle which is usually measured using laser diffraction, rp the density of the particle, r0 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.

Future Development Goals

To research and develop more efficient drug delivery systems with lower side effects of drugs.

Message

DDS is an indispensable means of making drugs work more efficiently. We have develop biocompatible and biodegradable particles with nano- or micro-size to deliver bioactive materials to the target organs, such as skin, brain, lungs. For this purpose, new drug molecules and polymers are also developed. Intelligent tablets including oral disintegration system will be developed.

Angiogenesis, the formulation of new blood vessels, is fundamental to development and post-injury tissue repair. Vascular endotherial growth factor (VEGF)-A guides and enhances actin filament formation and endotherial cell migration. Ischemic limb treatment will be improved by nano-DDS systems. Also, nano-DDS systems will be useful for the treatment of Chronic Obstructive Pulmonary Disease (COPD).

Angiogenesis, the formulation of new blood vessels, is fundamental to development and post-injury tissue repair. Vascular endotherial growth factor (VEGF)-A guides and enhances actin filament formation and endotherial cell migration. Ischemic limb treatment will be improved by nano-DDS systems. Also, nano-DDS systems will be useful for the treatment of Chronic Obstructive Pulmonary Disease (COPD).

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