KAWASAKI, Japan, Dec. 9, 2020 /PRNewswire/ -- The December 2020 issue of Kawasaki SkyFront i-Newsletter includes a video interview on developing a novel cell therapy for heart failure patients with the co-founders of Metcela Inc. and highlights of research being conducted by scientists affiliated with Kawasaki INnovation Gateway at SKYFRONT (KING SKYFRONT) — the City's flagship science and technology innovation hub focused on the life sciences and environment.
December 2020 issue of Kawasaki SkyFront iNewsletter
The KING SKYFRONT was launched by Kawasaki City in 2013 as a base for scholars, industrialists and government administrators to work together to devise real life solutions to global issues in the life sciences and environment.
KING SKYFRONT is a 40 hectare area located in the Tonomachi area of the Keihin Industrial Region that spans Tokyo and Kanagawa Prefecture and Tokyo International Airport (Haneda Airport) and an important initiative in establishing the Tonomachi area of Kawasaki City as Asia's Silicon Valley.
Contents of the 19th issue of Kawasaki SkyFront i-Newsletter
Liver blood vessel stealth coating assists the successful delivery of nanomedicines
A biologically safe organic polymer coating applied to liver scavenger blood vessels (sinusoids) to inhibit the unwanted capture of nanomedicines by the liver resulted in redirecting to specific target tissues in the human body — an important advancement in nanotechnological drug delivery.
The concept of nanomedicines involves the use of nanoparticles for transporting pharmaceutical substances to intended tissues. Nanomedicines have successfully been applied to deliver a wide range of therapeutic and diagnostic agents to specific target tissues. However, nanomedicines are subject to biological processes referred to as 'clearance mechanisms' that act against nanoparticles, which are seen as 'foreign particles' by the human body.
One such mechanism is found in liver scavenger endothelial cells (LSECs), which line the wall of liver blood vessels, abundantly expressing 'scavenger receptors' that can capture foreign particles including nanomedicines, and remove them from the blood circulation.
Now, Kazunori Kataoka, Director General of the Innovation Center of NanoMedicine (iCONM) administered by Kawasaki Institute of Industrial Promotion, and his team from iCONM, and collaborators at the National Institute of Quantum and Radiological Science and Technology (QST) and Department of Bioengineering, School of Engineering, The University of Tokyo, report on the successful suppression of the clearing mechanisms of LSECs by applying a stealth coating agent to liver blood vessels that inhibits the scavenger receptor activity, as a result, nanomedicines are no longer captured by the liver before being delivered to specific organs (Figure 1).
The idea of 'stealth coating' of nanomedicines has been widely used to suppress LSEC-mediated clearance. However, depending on the formulation and drug type, it is often difficult to obtain sufficient stealthiness of nanomedicines to completely inhibit LSEC clearance. To address this issue of LSEC-mediated capture, previous studies have attempted to saturate scavenging functions of LSECs by preinjecting empty nanoparticles and scavenger receptor inhibitors such as polyinosinic acid. However, receptor saturation strategies often induce inflammatory responses, hence they are not clinically viable. Furthermore, scavenger receptor inhibitors block only the specific receptor that they target even though LSECs have different types of scavenger receptors, which often recognize the same nanomedicine, implying that various clearing mechanisms need to be inhibited simultaneously. To overcome these issues, Kataoka and his team developed an approach to block the diverse clearance pathways of liver sinusoidal scavenger walls by coating them with polyethylene glycol (PEG), the first -of-its-kind strategy in the world.
The PEG coating must satisfy two primary requirements. First, the coating must be selective to the liver sinusoidal wall because coating to extra-liver blood vessels not only causes adverse toxicity but also decreases the amount of nanomedicines delivered to target organs. Second, the coating must be temporary as long-term coating affects normal liver functions. To meet these prerequisites, the team precisely designed a coating agent with two-armed PEG conjugated to positively charged oligolysine (two-arm PEG−OligoLys) (Figure 1A), which demonstrated selective coating to the liver sinusoidal wall, leaving other tissue endothelium uncoated, thus accessible to the delivery of nanomedicines. Interestingly, the two-arm PEG−OligoLys coating is gradually removed from the wall and is excreted to the bile within six hours, while its counter variant one-armed PEG−OligoLys do not de-coat the wall. Therefore, the precise molecular design of the two-arm PEG−OligoLys satisfied both selective and transient stealth coating.
The selective and transient liver scavenger wall stealth coating by the two-arm PEG−OligoLys efficiently prevents the sinusoidal clearance of both viral and nonviral gene vectors, representatives of nature-derived and artificially-engineered nanomedicines, respectively, thereby boosting their gene delivery efficiency in the target tissues (Figure 1B). Despite the clinical success of viral vectors, liver sinusoidal capture drastically hinders the ability of viruses to reach their target organs, thus resulting in the use of high viral dose—often leading to death humans—to obtain a therapeutic level of protein expression.
Two-arm PEG−OligoLys coating successfully suppressed the liver sinusoidal capture of adeno-associated virus serotype 8 (AAV8), and as a result, dramatically improved the gene transfer efficiency to their intrinsic target organs, heart, and skeletal muscle. Also, the researchers extended their strategy to a plasmid DNA encapsulated smart nanomachine (polyplex micelle; PM), a model nonviral gene delivery system, which allows economically feasible and safe gene therapy. Two-arm PEG−OligoLys precoating suppressed the adsorption of DNA nanomachine to the liver sinusoidal wall thus resulting in a 10-fold improvement in gene delivery efficiency to the cancer site.
Quoting the scientists: "Our approach is versatile for combinational use with various nanomedicines, including synthetic and nature-derived nanomedicines, opening avenues for future nanotherapy and nanodiagnosis."
Dirisala, A. et al. Transient stealth coating of liver sinusoidal wall by anchoring two-armed PEG for retargeting nanomedicines
Sci. Adv. 2020; 6 : eabb8133
Figure 1. In situ stealth coating of liver sinusoidal wall. (A) OligoLys with 20 Lys units conjugated with two linear chains of 40-kDa PEG at its carboxyl end (two-arm-PEG-OligoLys). (B) Schematic illustration of stealth coating of the liver sinusoidal wall with two-arm PEG−OligoLys and its gradual excretion to the bile. This transient PEG coating inhibits the capture of nanomedicines, such as polyplex micelle (PM) and adeno-associated virus (AAV), by the liver blood vessel walls and thus retarget the nanomedicines to their intrinsically targeted organs. (Credit Science Advances)
A new potential approach for treating post-infarct heart failure
A particular type of human cardiac fibroblast is found to improve the heart function in post-infarct heart failure rats.
Cardiovascular diseases — involving the heart or blood vessels — are a major global cause of death. Specifically, injuries causing restricted blood supply to organ tissue lead to drastically degraded organ function, which can be followed by heart failure. There is plenty of evidence that cardiac fibroblasts (CFs) are particularly critical for maintaining heart function in times of both health and disease. But detailed understanding is lacking, partly because CFs have various origins, and so exist as a heterogeneous population. Now, Takahiro Iwamiya from Metcela Inc. and colleagues have analyzed the CF population, and have identified a subpopulation that improves heart systolic function by triggering lymphangiogenesis.
Takahiro Iwamiya, Bertrand-David Segard, Yuimi Matsuoka, and Tomomi Imamura, Human cardiac fibroblasts expressing VCAM1 improve heart function in postinfarct heart failure rat models by stimulating lymphangiogenesis.
PLoS ONE 15(9): e0237810 (2020)
Takahiro Iwamiya and Kenichi Nogami
Co-Founders & CEOs, Metcela Inc.
Metcela is a venture company developing new regenerative medicine products for patients with heart failure. Once afflicted with heart failure, the disease gets increasingly worse and it is difficult to treat it with current medical procedures.
Therefore, we aim to cure patients with heart failure using special cells based on special heart fibroblasts. I discovered them when I was at Tokyo Women's Medical University between 2010-2014. These cells cannot only protect and proliferate heart muscle cells but also develop lymphatic vessels of the heart. This will improve the systolic function of the heart with restored mechanical properties of ventricular walls due to heart failure.
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About KING SKYFRONT
The Kawasaki INnovation Gateway (KING) SKYFRONT is the flagship science and technology innovation hub of Kawasaki City. KING SKYFRONT is a 40 hectare area located in the Tonomachi area of the Keihin Industrial Region that spans Tokyo and Kanagawa Prefecture and Tokyo International Airport (also often referred to as Haneda Airport).
KING SKYFRONT was launched in 2013 as a base for scholars, industrialists and government administrators to work together to devise real life solutions to global issues in the life sciences and environment.
KING-SKYFRONT iNewsletter Publishing Team
TONOMACHI LifeScience Cluster Division, Kawasaki Institute of Industrial Promotion Life Science & Environment research center (LiSE) 1F,
3-25-10, Tonomachi, Kawasaki-ku, Kawasaki-shi,
Kanagawa Prefecture, Japan, 210-0821
SOURCE KING SKYFRONT