Press Release
Polymeric Nanomicelles Improve Internalization ofLipid Metabolism Modulators in Brain Cells
Summary:
Fatty acid (FA) metabolism is the critical link between obesity and cancer progression,
making it an attractive target for the central appetite regulation for obesity and glioblastoma
therapy. (±)-C75-CoA and its enantiomers are effective modulators of FA metabolism but areanionic and have low cellular permeability. We thus developed charge-neutralizing poly-ion
complex (PIC) nanomicelles to efficiently deliver such molecules into glioma cells andneurons in 2D and 3D cultures.
https://pubs.rsc.org/en/Content/ArticleLanding/2021/BM/D1BM00689D
August 3, 2021, Kawasaki (Japan) and Barcelona (Spain): Innovation Center ofNanoMedicine (Director General: Prof. Kazunori Kataoka, Abbreviation: iCONM) and theBasic Sciences Department, Faculty of Medicine and Health Sciences of the International
University of Catalunya (Abbreviation: UIC Barcelona) jointly announced that a research
paper “Poly-ion complex micelle effectively delivers CoA-conjugated CPT1A inhibitors tomodulate lipid metabolism in brain cells” was published on July 27 in Biomaterials Science(Impact Factor: 6.843 in 2021). This paper was accomplished by the joint project between
iCONM and UIC Barcelona led by Dr. Sabina Quader (Senior Research Scientist, iCONM)
and Dr. Rosalía Rodríguez (Associate Professor, Department of Basic Sciences, Faculty ofMedicine and Health Sciences, UIC Barcelona) to report that PIC micelles carrying CPT1A
inhibitors can effectively ferry their drug cargoes inside brain cells such as neurons andglioma cells, leading to reduced fatty acid oxidation (FAO). Several researchers from theUniversity of Barcelona (Barcelona, Spain) also participated in this research project.
Recent evidences suggest that FA metabolism serves as the critical link between obesityand cancer progression. FAs are important substrates for energy metabolism and are thebuilding blocks for lipids. It is becoming increasingly apparent that intermediary lipid
metabolism within the brain is a major contributor to the regulation of systemic metabolism.
Lipid metabolism within the brain is tightly regulated to maintain neuronal structure andfunction to modulate peripheral tissues. Central levels of malonyl-CoA act as a molecularmessenger of nutritional status. Therefore, pharmacological manipulation of malonyl-CoA
levels in the brain, results in changes in food intake and energy expenditure. In addition,
many types of tumor cells, including glioma cells, show alterations in FA metabolism.
Glioblastoma (GBM), in particular, has been connected with increased expression of CPT1.
While tumor molecular heterogeneity is emerging as a critical concern in oncology,
homogeneous elevated expression of CPT1 in GBM is indeed an attractive molecular target
for therapy. Accordingly, FA metabolism in the brain is an attractive target for the central
regulation of obesity and glioblastoma therapy.
In this paper, poly-ion complex (PIC) nanomicelles loaded with the CPT1A inhibitors (±)-,(+)-, and (–)-C75-CoA have been developed. The CoA adducts’ chemical structure presents
challenges to cellular entry, being small, polar, and charged metabolites. They have low
permeability across the cell membrane, and as a consequence, need a delivery system for
intracellular transport. The anionic state of CoA, together with its long aliphatic side-chain
enables CoA to interact with cation-conjugated polymers through a combination ofelectrostatic and hydrophobic interactions. Therefore, forming a poly-ion complex (PIC)
micelle with racemic C75-CoA or its enantiomers is a sound approach in designing a delivery
system since this neutralizes the overall negative charge that would hinder its cellular entry.
The cationic block-copolymer PEG-PAsp (DET) provided a platform by neutralizing thenegative charge of the cargo molecules, generating micelles with optimal physicochemical
properties (55-65 nm size range). Through targeting CPT1A, fatty acid oxidation (FAO) was
effectively inhibited in both U87MG glioma cells and GT1-7 hypothalamic neurons, which
led to overall decreased metabolism of radioactively-labeled palmitate into CO2 and acidsoluble products. The final product of FA metabolism, ATP, was also effectually reduced by
the micelles up to 5-fold, in comparison with the free drug counterparts.
The dye-loaded model particle, Fluor-CoA micelle, showed a statistically increased
internalization in both brain cells. This higher cellular internalization corroborated the FAO
inhibition results, that delivery through PIC micelle resulted in increased cellularconcentration of the cargo, which further led to increased biological activity. Effective cellular
entry of Fluor-CoA micelle was further confirmed in 3D spheroids, especially in neurons
where uptake reached up to 3-fold over the free dye, inferring the superior activity of CoA
adducts when loaded in micelles in a biological model that is transitional in complexity
between standard 2D in vitro and diseased tissue in vivo. The size range of these PIC
micelles, combined with their efficient penetration in 3D spheroids, imply that this platformis ideal in navigating through the brain parenchyma. This justifies additional exploration of
its in vivo properties in subsequent works and further development into effective brain
therapeutics, especially those that involve the delivery of CPT1A inhibitors and othernegatively-charged molecules for management of diseases where modulating lipid
metabolism is a key emerging strategy.

Key points of this press release:
1. Carnitine palmitoyltransferase 1A (CPT1A) is a central player in lipid metabolism,
catalyzing the first committed step to fatty acid oxidation (FAO). Inhibiting CPT1A,especially in the brain, can have several pharmacological benefits, such as in obesityand brain cancer.
2. C75-CoA is a strong competitive inhibitor to CPT1A. However, due to its negativelycharged nature, it has low cellular permeability.
3. PIC nanomicelles were formed through charge-neutralization of C75-CoA with thecationic side chain of PEG-Pasp (DET), forming particles with 55 to 65-nm diameter
4. Nanomicelle-entrapped CPT1A inhibitors resulted in up to 5-fold reduction of ATPsynthesis compared to the free drug. Nanomicelle treatment showed a marked decreasein 14C-palmitate oxidation into CO2 and acid-soluble metabolites.
5. To measure cellular uptake of these CoA-adduct loaded PIC nanomicelles, we
synthesized a fluorescent CoA derivative and prepared Fluor-CoA nanomicelle, whichshowed efficient internalization in brain cells, both in 2D and 3D culture models,
especially in neurons where uptake reached up to 3-fold over the free dye.
6. This press release is about the first academic paper by the CPT Obesity Cancer Drug
Delivery (COnCorD) project for the treatment of obesity and cancer, which is being jointlypromoted by iCONM and UIC Barcelona. See the following site to find this original paper:
W. K. D. Paraiso, J. Garcia-Chica, X. Ariza, S. Zagmutt, S. Fukushima, J. Garcia Gomez,
Y. Mochida, D. Serra, L. Herrero, H. Kinoh, N. Casals, K. Kataoka, R. RodriguezRodriguez and S. Quader, Biomater. Sci., 2021.
DOI: 10.1039/D1BM00689D.

Kawasaki Institute of Industrial Promotion (KIIP)
Kawasaki Institute of Industrial Promotion was established in 1988 funded 100% from Kawasaki Cityfor the purpose of coping with the hollowing out of industry and changes in the demand structure. In
order to realize a higher level of market development, transforming R&D type companies, training
technological capabilities to support it, human resources development, understanding market needs,etc., by utilizing the functions of the Kawasaki, KIIP has been contributing to revitalize the local
economy by promoting exchanges of local industry information, advancing technology and corporate
exchanges with establishment of a R&D institutions, developing creative human resources throughworkshops and promoting businesses such as expanding sales channels through exhibitionbusiness.
https://www.kawasaki-net.ne.jp/
Innovation Center of NanoMedicine (iCONM)
Innovation Center of NanoMedicine (iCONM) started its operation in April 2015 as a core research
center in life science field at King SkyFront on the request of Kawasaki city that KIIP utilized nationalpolicies as a business operator and proposer. It is a unique research center that the world has everseen which is designed for the purpose of promoting open innovation through industry-academiagovernment/medical-engineering collaboration, prepared with state-of-the-art facilities andexperimental equipment, that enables comprehensive research and development from organic
synthesis / microfabrication to preclinical testing.
iCONM: https://iconm.kawasaki-net.ne.jp/en/index.html
Kataoka-Kinoh Lab: https://iconm.kawasaki-net.ne.jp/en/laboratory_kataoka.html
The International University of Catalunya (UIC Barcelona)
The International University of Catalunya (UIC Barcelona: The Universitat Internacional deCatalunya) was founded in 1997 with the aim of offering outstanding university education andpromoting research that benefits society. With strong ties to the world of health, business and ahighly international profile, the institution offers 16 bachelor's degrees, 8 double degrees, around 30
international double degrees and a wide range of postgraduate programs across both campuses,
located in Barcelona and Sant Cugat del Vallès.
UIC Barcelona: https://www.uic.es/enR. Rodríguez’s Lab: https://www.uic.es/en/research/research/research-groups/health-sciences/grc-

research-group-regulation-lipid-metabolism-0
CPT Obesity Cancer Drug Delivery (COnCorD)
COnCorD was one of the three bilateral projects awarded by the Spanish State Agency for Research(AEI) and the Japan Agency for Medical Research and Development (AMED) as a result of invitation
for joint project proposals from early-stage researchers in Japan and Spain in the "Nanomedicine"research area in 2018. The main objective of this project is the development and use of novel
nanomedicine-based therapeutic approaches directed to specific cells of the brain and to fightagainst obesity and brain tumors focusing on the brain lipid metabolism's key enzyme CPT1. This
project signifies a tremendous biomedical challenge, principally in the field of nanomedicine, sincedrug delivery into specific brain cells has not yet been thoroughly investigated. This bilateralendeavor enables boosting collaboration between institutions in the two countries and significantly
strengthens the international nature of research at the Innovation Center of Nanomedicine (iCONM),
Japan and UIC Barcelona, Spain.