Biomolecules and Biomaterials

Responsable : Ling Peng

Présentation

Notre groupe travaille à l’interface de la chimie et de la biologie et se consacre principalement au développement de sondes chimiques pour comprendre les événements biologiques, la découverte de molécules bioactives et les applications biomédicales basées sur la nanotechnologie dendrimère.
Molecular engineering of dendrimer nanosystems for biomedical applications

The application of nanotechnology to engineer nanovectors for drug delivery is widely expected to provide new breakthrough in medicine and create entirely novel nanotherapeutics. Dendrimers are ideal nanocarriers for drug delivery by virtue of their uniquely well-defined and precisely controlled structure with multivalent cooperativity all confined within a nanosized volume. We have established bio-inspired structurally-flexible dendrimers and self-assembling supramolecular dendrimers as excellent nanocarriers for drug and gene delivery. In particular, self-assembling amphiphilic dendrimers are able to form adaptive supramolecular nanostructures, which encapsulate anticancer therapeutics with high loading efficiency and ensure their effective delivery thus combating drug resistance. Our current research is focused on developing innovative functional dendrimer nanosystems for stimuli-responsive on-demand delivery and nanotheranostics for personalized medicine.

Chemistry and biology of nucleoside analogues

Nucleoside mimics are of considerable importance in the search for antiviral, anticancer and antibacterial drug candidates. One noteworthy example is ribavirin, the first synthetic triazole nucleoside showing antiviral activity against a broad spectrum of viruses yet with immunomodulatory activity as well. Recently, ribavirin was also reported to demonstrate apoptosis-related anticancer effects. On the back of this new evidence, we have developed novel triazole nucleoside derivatives with dual anticancer and immunomodulatory activity. Some of them have shown excellent potency against drug-resistant cancer forms using yet unexplored modes of action such as the targeting of the heat shock response pathway, inducing autophagy and eliciting an immunomodulation effect. Our current focus is studying their potential to inhibit cancer-initiating cells and the related novel mechanisms of action.

Molecular probes and chemical biology

Molecular probes are useful tools to study and understand biological events. We have designed and synthesized various molecular probes of phospholipids and of 2-oxoglutarate, an important intermediate of the Kreb’s cycle, with a view to studying biomembranes and the signaling roles and pathways of Kreb’s cycle intermediates in cancer

Publications

2019

Efficient and Innocuous Delivery of siRNA to Microglia using an Amphiphilic Dendrimer Nanovector

Aleksandra Ellert-Miklaszewska, Natalia Ochocka, Marta Maleszewska, Ling Ding, Erik Laurini, Yifan Jiang, Adria-Jaume Roura, Suzanne Giorgio, Bartlomiej Gielniewski, Sabrina Pricl, Ling Peng, Bozena Kaminska

Nanomedicine (2019)

Poly(amidoamine) dendrimers: covalent and supramolecular synthesis

Z. Lyu, L. Ding, A.Y.T. Huang, L. Kao, L. Peng

Materials Today Chemistry 13:34-48 (2019)10.1016/j.mtchem.2019.04.004

Designing and repurposing drugs to target intrinsically disordered proteins for cancer treatment: using NUPR1 as a paradigm

Patricia Santofimia-Castaño, Bruno Rizzuti, Yi Xia, Olga Abián, Ling Peng, Adrián Velázquez-Campoy, Juan Iovanna, José Neira

Molecular & Cellular Oncology 1-3 (2019)10.1080/23723556.2019.1612678

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Patricia Santofimia-Castaño, Yi Xia, Wenjun Lan, Zhengwei Zhou, Can Huang, Ling Peng, Philippe Soubeyran, Adrián Velázquez-Campoy, Olga Abián, Bruno Rizzuti, José Neira, Juan Iovanna

Journal of Clinical Investigation (2019)10.1172/JCI127223

Flavonoid-Alkylphospholipid Conjugates Elicit Dual Inhibition of Cancer Cell Growth and Lipid Accumulation

Zhengwei Zhou, Biyao Luo, Xi Liu, Mimi Chen, Wenjun Lan, Juan L Iovanna, Ling Peng, Yi Xia

Journal of the Chemical Society, Chemical Communications (2019)

2018

Dendrimer-based magnetic resonance imaging agents for brain cancer

Ling Ding, Zhenbin Lyu, Dinesh Dhumal, Chai-Lin Kao, Monique Bernard, Ling Peng

Science China Materials 61:1420-1443 (2018)

A Dual Targeting Dendrimer-Mediated siRNA Delivery System for Effective Gene Silencing in Cancer Therapy

Yiwen Dong, Tianzhu Yu, Ling Ding, Erik Laurini, Yuanyu Yu, Mengjie Zhang, Yuhua Yu, Shuting Lin, Peng Chen, Domenico Marson, Yifan Jiang, Suzanne Giorgio, Sabrina Pricl, Xiaoxuan Jiang, Palma Rocchi, Ling Peng

Journal of the American Chemical Society 140:16264-16274 (2018)10.1021/jacs.8b10021

Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors

Philippe Garrigue, Jingjie Tang, Ling Ding, Ahlem Bouhlel, Aura Tintaru, Erik Laurini, Yuanyuan Huang, Zhenbin Lyu, Mengjie Zhang, Samantha Fernandez, Laure Balasse, Wenjun Lan, Eric Mas, Domenico Marson, Yuhuang Weng, Xiaoxuan Liu, Suzanne Giorgio, Juan Iovanna, Sabrina Pricl, Benjamin Guillet, Ling Peng

Proceedings of the National Academy of Sciences of the United States of America 115:11454-11459 (2018)10.1073/pnas.1812938115

E2F signature is predictive for the pancreatic adenocarcinoma clinical outcome and sensitivity to E2F inhibitors, but not for the response to cytotoxic-based treatments

Wenjun Lan, Benjamin Bian, Yi Xia, Samir Dou, Odile Gayet, Martin Bigonnet, Patricia Santofimia-Castaño, Mei Cong, Ling Peng, Nelson Dusetti, Juan Iovanna

Scientific Reports 8:8330 (2018)

Blocking Stemness and Metastatic Properties of Ovarian Cancer Cells by Targeting p70S6K with Dendrimer Nanovector-Based siRNA Delivery

Jing Ma, Shashwati Kala, Susan Yung, Tak Mao Chan, Yu Cao, Yifan Jiang, Xiaoxuan Liu, Suzanne Giorgio, Ling Peng, Alice S.T. Wong

Molecular Therapy 26:70-83 (2018)10.1016/j.ymthe.2017.11.006

Precise tuning of single molecule conductance in an electrochemical environment

L. Peng, F. Chen, Z.-W. Hong, J.-F. Zheng, Laure Fillaud, Y. Yuan, M.-L. Huang, Y. Shao, X.-S. Zhou, J.-Z. Chen, Emmanuel Maisonhaute

Nanoscale 10:7026-7032 (2018)10.1039/c8nr00625c

Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis

Patricia Santofimia-Castaño, Wenjun Lan, Jennifer Bintz, Odile Gayet, Alice Carrier, Gwen Lomberk, José Luis Neira, Antonio Gonzalez, Raul Urrutia, Philippe Soubeyran, Juan Iovanna

Scientific Reports 8 (2018)10.1038/s41598-018-35020-3

Carbon/Nitrogen Metabolic Balance: Lessons from Cyanobacteria

Cheng-Cai Zhang, Cong-Zhao Zhou, Robert Burnap, Ling Peng

Trends in Plant Science 23:1116-1130 (2018)

Negative dendritic effect on enzymatic hydrolysis of dendrimer conjugates

Zhengwei Zhou, Mei Cong, Mengyao Li, Aura Tintaru, Jia Li, Jia Yao, Yi Xia, Ling Peng

Chemical Communications 54:5956-5959 (2018)10.1039/c8cc01221k

2017

Acyclonucleosides bearing coplanar arylethynyltriazole nucleobases: synthesis, structural analysis, and biological evaluation

Mimi Chen, Zhengwei Zhou, Yaxiong Suo, Mengyao Li, Jianhua Yao, Ling Peng, Yi Xia

New Journal of Chemistry 41:8509-8519 (2017)

Mix and Match: Coassembly of Amphiphilic Dendrimers and Phospholipids Creates Robust, Modular, and Controllable Interfaces

Samuel Hinman, Charles Ruiz, Yu Cao, Meghann Ma, Jingjie Tang, Erik Laurini, Paola Posocco, Suzanne Giorgio, Sabrina Pricl, Ling Peng, Quan Cheng

ACS Applied Materials & Interfaces 9:1029-1035 (2017)

Potent drugless dendrimers

Zhenbin Lyu, Ling Peng

Nature Biomedical Engineering 1:686-688 (2017)

2016

Mastering Dendrimer Self-Assembly for Efficient siRNA Delivery: From Conceptual Design to In Vivo Efficient Gene Silencing

Chao Chen, Paola Posocco, Xiaoxuan Liu, Qiang Cheng, Erik Laurini, Jiehua Zhou, Cheng Liu, Yang Wang, Jingjie Tang, Valentina Dal Col, Tianzhu Yu, Suzanne Giorgio, Maurizio Fermeglia, Fanqi Qu, Zicai Liang, John J. Rossi, Minghua Liu, Palma Rocchi, Sabrina Pricl, Ling Peng

Small 12:3667-3676 (2016)10.1002/smll.201503866

Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis

Qi Cui, Su Yang, Peng Ye, E. Tian, Guoqiang Sun, Jiehua Zhou, Guihua Sun, Xiaoxuan Liu, Chao Chen, Kiyohito Murai, Chunnian Zhao, Krist T. Azizian, Lu Yang, Charles Warden, Xiwei Wu, Massimo d'Apuzzo, Christine Brown, Behnam Badie, Ling Peng, Arthur D. Riggs, John J. Rossi, Yanhong Shi

Nature Communications 7:10637 (2016)10.1038/ncomms10637

A Fluorinated Bola-Amphiphilic Dendrimer for On-Demand Delivery of siRNA, via Specific Response to Reactive Oxygen Species

Xiaoxuan Liu, Yang Wang, Chao Chen, Aura Tintaru, Yu Cao, Juan Liu, Fabio Ziarelli, Jingjie Tang, Hongbo Guo, Roseline Rosas, Suzanne Giorgio, Laurence Charles, Palma Rocchi, Ling Peng

Advanced Functional Materials 26:8594-8603 (2016)10.1002/adfm.201604192

Hepatocellular Nuclear Factor 4 alpha (HNF-4 alpha) activation by saRNA rescues dyslipidemia and promotes favorable metabolic profile in a high fat diet (HFD) fed rat model.

Vikash Reebye, Kai-Wen Huang, Katherine Czysz, Simona Ciriello, Stehpanie Dorman, Isabella Reccia, H. S. Lai, Ling Peng, Nikos Kostomitsopoulos, Joanna Nicholls, Robert Habib, Donald Tomalia, Pal Saetrom, Edmund Wilkes, Pedro Cutillas, John Rossi, Nagy Habib

Hepatology 63:794A (2016)10.1002/hep.28799

Financement

Équipe Peng Équipe Peng 1

  • Equipe Labellisé par La Ligue

2016-2020: “Innovative dendrimer nanotechnology based theranostics for cancer therapy”

  • ERA-Net EuroNanoMed project “Target4Cancer”

2016-2019: “(Nano)systems with active targeting to sensitize colorectal cancer stem cells to anti-tumoral treatment”

  • ERA-Net EuroNanoMed project “NANOGLIO”

2017-2020: “Nanotechnology based immunotherapy for glioblastoma”

  • ERA-Net EuroNanoMed III project “TARBRAINFECT”

2019-2022: "Nanosystems conjugated with antibody fragments for treating brain infections"

  • EU H2020 NMBP project “SAFE-N-MEDTECH”

2019-2023: "Safety testing in the life cycle of nanotechnology-enabled medical technologies for health"

Collaborations

Dr. Monique Bernard (Aix-Marseille University, CRMBM, Marseille, France)

Prof. Benjamin Guillet (Aix-Marseille University, CERIMED, Marseille, France)

Prof. Yuanyu Huang (Beijing University of Technology, Beijing, China)

Dr. Juan Iovanna (INSERM CRCM, Marseille, France)

Prof. Chai-Lin Kao (Kaohsiung Medical University, Kaohsiung, Taiwan)

Prof. Bozena Kaminska (Nencki Institute of Experimental Biology, Warsaw, Poland)

Prof. Xiaoxuan Liu (China Pharmaceutical University, Nanjing, China)

Prof. Sabrina Pricl (Trieste University, Trieste, Italy)

Dr. Aura Tintaru (Aix-Marseille University, ICR, Marseille, France)

Prof. Alice Wong, (Hong Kong University, Hong Kong)

Prof. Yi Xia (Chongqing University, Chongqing, China)

 

Actualité

4 juillet 2019:

Flavonoid-Alkylphospholipid Conjugates Elicit Dual Inhibition of Cancer Cell Growth and Lipid Accumulation, Zhengwei Zhou, Biyao Luo, Xi Liu, Mimi Chen, Wenjun Lan, Juan L. Iovanna, Ling Peng*, and Yi Xia*

Chemical Communications, 2019, DOI: 10.1039/C9CC04084F

L'article ici: 2019 ChemCommun XIA

Le cancer est un problème majeur de santé publique. Le développement du cancer est impacté non seulement par des facteurs génétiques, mais également par des facteurs environnementaux et sociétaux tels que l'obésité, le tabagisme, les infections, etc. En effet, les personnes obèses ou en surpoids ont souvent un risque plus élevé de développer une tumeur. Cela s’explique par des taux de lipides élevés, provoqués par une synthèse accrue et une accumulation aberrante de lipides, capables d’induire la tumorigénèse et d’accélérer l’apparition de métastases.

Nous decrivons ici, une série de nouveaux composés à double fonction ayant à la fois une activité anticancéreuse et la capacité de réduire l’accumulation de lipides. Ces composés sont des composés hybrides d’un produit naturel la quercétine et d’alkylphospholipides synthétiques (APL). La quercétine est un antioxydant flavonoïde qui affecte le métabolisme des lipides, alors que les APL ont une activité anticancéreuse prouvée. En effet, ces composés hybrides surpassent l’efficacité des composés modèles (la quercétine et les APL) en termes d’activité anticancéreuse, tout en supprimant de manière significative l’accumulation de lipides. Ils induisent également la diminution de la voie du choc thermique et des proteines anti-apoptotiques. Par conséquent, ces composés constituent un nouveau paradigme structurel prometteur dans la découverte de nouveaux candidats anticancéreux. Cette étude pourrait également ouvrir de nouvelles perspectives pour la mise au point d’agents thérapeutiques permettant de traiter d’autres maladies liées à l’accumulation de lipides, telles que les maladies cardiovasculaires, l’obésité, le diabète etc.

Figure 1. (A) Chemical structures of the natural product quercetin, the synthetic alkylphospholipid drugs miltefosine and edelfosine, and their conjugates Id and IIc developed in this work; (B) their antiproliferative activity against cancer cells; and (C) their inhibition on lipid accumulation in cancer cells.

A:B:C:Il s'agit d'un travail collaboratif entre l'Université de Chongqing en Chine, le Centre de Recherche en Cancérologie de Marseille (CRCM) et le Centre Interdisciplinaire de Nanosciences de Marseille (CINaM) en France dans le cadre du programme de coopération franco-chinois XU GUANGQI.

  • May 2-3, 2019: Kick-off meeting of the H2020 project SAFE-N-MEDTECH in Bilbao, Spain
  • April 1, 2019:  We started the H2020 NMBP project, “Safety testing in the life cycle of nanotechnology-enabled medical technologies for health (SAFE-N-MEDTECH)”
  •  March 1, 2019: We started the H2020 Era-Net EuroNanoMed project “Nanosystems conjugated with antibody fragments for treating brain infections” (TARBRAINFEC)
Press Release: SAFE-N-MEDTECH kicks off in Bilbao

The SAFE-N-MEDTECH initiative just kicked off last week in Bilbao, in a meeting hosted by Osteba, the HTA Unit of the Health Ministry of the Basque Country (Spain) in collaboration with BIOPRAXIS-BIOKERALTY. The project is coordinated by TECNAN (an SME from Navarra, with great experience in Nano products), together with BIOPRAXIS-BIOKERALTY (the research branch of the global health companies Keralty and Praxis).

The Project is part of the Open Innovation Test Bed(OITB) initiative from the European Commission, a new and challenging approach towards upscaling the use of nanotechnologies in Europe and abroad. It represents an investment of 18M€ for 4 years, concretely receiving 15M€ from the European Commission.

More than 50 people gathered in Bilbao, coming from 28 entities, from 13 countries to refine the basis of the collaboration, and set the scene for the first years of the Project.

Ambition and strategy

Society and clinical practice pose a growing demand on novel biomaterials, ICT, micro and nanotechnologies for innovative medical devices and in vitro diagnostics (Medical Technologies-MTs). In addition to the challenge of time, the new technologies are subjected to other pressing factors such as qualification, regulation, cost, biocompatibility and the need to be applicable worldwide. In the most recent years it is obvious that nano-enabled MTs can be applied in nearly every medical area, with a major presence and increased importance in cancer, regenerative medicine, advanced therapies, neurology, cardiology, orthopaedics, and dentistry.

SAFE-N-MEDTECH will build an innovative open access platform to offer to companies and reference laboratories, the capabilities, knowhow, networks and services required for the development, testing, assessment, upscaling and market exploitation of nanotechnology-based Medical and Diagnosis Devices.

SAFE-N-MEDTECH will offer a multidisciplinary and market oriented innovation approach to SME´s, Healthcare providers and Industries for the translation to the market of MTs, based on a deep understanding and knowledge of the material nanoproperties, their advance use and applications in MTs and other aspects involved in MTs safety (electric compatibility, electromagnetic properties, etc).

Who's in?

There are 28 partners in SAFE-N-MEDTECH, a great challenge for management, but a huge opportunity to address all the key challenges to come ahead. Research Institutes, Small and larger companies, Associations, Health Technology Assessment experts, Hospitals and Care centres are amongst the partners, and ensure the project can cover all the relevant aspects of the translation of nano-enabled medical technologies.

What's next?

SAFE-N-MEDTECH starts its journey by ensuring its validity with four test cases. During the first years of the initiative, the partners will develop their services and test them, so that in four years from now, it will become a self-sustainable and competitive services platform for companies to test and ensure their nano enabled MTs are safe to use!

For more info on the project:

Coordinator: Tamara Oroz, TECNAN (tamara.oroz@tecnan-nanomat.es) Scientific Lead: Angel del Pozo, Biopraxis –Keralty (angel.delpozo@keralty.com) Communication: Anaïs Le Corvec, Aura Costa (info@cebr.net)

Brevets

1.
Juan Iovanna, Jose Luis Neira, Yi Xia, Patricia Santofimia-Castaño, Bruno Rizzuti, Olga Abian, Adrian Velazquez Campoy, Ling Peng, "NUPR1 INHIBITION FOR TREATING CANCER", European patent application date: May 31, 2018; Application N°: EP18305672.0.
2.
Alice Sze Tsai Wong, Jing Ma, Kwok Wai Lo, Ling Peng, "BCL3 siRNA amphiphilic dendriplexes for effective and potent nasopharyngeal carcinoma treatment", Application date: March 15, 2017; Application number: 15/459,806; US Patent Non-Provisional No. 15/459,806; Publication No. US2018/0265872A1.
3.
Ling Peng, Yi Xia, Palma Rocchi, Jinqiao Wan, Yang Liu, Menghua Wang, Fanqi Qu, Juan Iovanna, "Novel triazole nucleoside derivatives, their preparation and their application in therapeutics", 2008, EU 08 155481.8; 2009, PCT/EP2009/055213.; 2009, WO/2009/133147A1; US 2011/0136754A1.
4.
Ling Peng, Fanqi Qu, Ruizhi Zhu, Johan Neyt, "Novel Viral Replication Inhibitors", 2007, GB0714649.1; 2008, PCT/BE2008/000059; 2009, WO/2009/015446.