Biomolecules and Biomaterials

Leader: Ling Peng

Introduction

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

2020

Synthesis and use of an amphiphilic dendrimer for siRNA delivery into primary immune cells

Jiaxuan Chen, Aleksandra Ellert-Miklaszewska, Stefano Garofalo, Arindam Dey, Jingjie Tang, Yifan Jiang, Flora Clément, Patrice Marche, Xiaoxuan Liu, Bozena Kaminska, Angela Santoni, Cristina Limatola, John Rossi, Jiehua Zhou, Ling Peng

Nature Protocols (2020)10.1038/s41596-020-00418-9

An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile

Dinesh Dhumal, Wenjun Lan, Ling Ding, Yifan Jiang, Zhenbin Lyu, Erik Laurini, Domenico Marson, Aura Tintaru, Nelson Dusetti, Suzanne Giorgio, Juan Lucio Iovanna, Sabrina Pricl, Ling Peng

Nano Research (2020)10.1007/s12274-020-3216-8

A self-assembling amphiphilic dendrimer nanotracer for SPECT imaging

Ling Ding, Zhenbin Lyu, Aura Tintaru, Erik Laurini, Domenico Marson, Beatrice Louis, Ahlem Bouhlel, Laure Balasse, Samantha Fernandez, Philippe Garrigue, Eric Mas, Suzanne Giorgio, Sabrina Pricl, Benjamin Guillet, Ling Peng

Chemical Communications 56:301-304 (2020)10.1039/c9cc07750b

Surface Charge of Supramolecular Nanosystems for In Vivo Biodistribution: A MicroSPECT/CT Imaging Study

Ling Ding, Zhenbin Lyu, Beatrice Louis, Aura Tintaru, Erik Laurini, Domenico Marson, Mengjie Zhang, Wanxuan Shao, Yifan Jiang, Ahlem Bouhlel, Laure Balasse, Philippe Garrigue, Eric Mas, Suzanne Giorgio, Juan Iovanna, Yuanyu Huang, Sabrina Pricl, Benjamin Guillet, Ling Peng

Small 16:301-304 (2020)10.1002/smll.202003290

Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

Stefano Garofalo, Germana Cocozza, Alessandra Porzia, Maurizio Inghilleri, Marcello Raspa, Ferdinando Scavizzi, Eleonora Aronica, Giovanni Bernardini, Ling Peng, Richard Ransohoff, Angela Santoni, Cristina Limatola

Nature Communications 11:1773 (2020)10.1038/s41467-020-15644-8

Therapeutic siRNA: state of the art

Bo Hu, Liping Zhong, Yuhua Weng, Ling Peng, Yuanyu Huang, Yongxiang Zhao, Xing-Jie Liang

Signal Transduction and Targeted Therapy 5 (2020)10.1038/s41392-020-0207-x

Liver Activation of Hepatocellular Nuclear Factor-4α by Small Activating RNA Rescues Dyslipidemia and Improves Metabolic Profile

Kai-Wen Huang, Vikash Reebye, Katherine Czysz, Simona Ciriello, Stephanie Dorman, Isabella Reccia, Hong-Shiee Lai, Ling Peng, Nikos Kostomitsopoulos, Joanna Nicholls, Robert Habib, Donald Tomalia, Pål Sætrom, Edmund Wilkes, Pedro Cutillas, John Rossi, Nagy Habib

Molecular Therapy - Nucleic Acids 19:361-370 (2020)10.1016/j.omtn.2019.10.044

Targeting NUPR1 with the small compound ZZW-115 is an efficient strategy to treat hepatocellular carcinoma

Wenjun Lan, Patricia Santofimia-Castaño, Yi Xia, Zhengwei Zhou, Can Huang, Nicolas Fraunhoffer, Dolores Barea, Melchiore Cervello, Lydia Giannitrapani, Giuseppe Montalto, Ling Peng, Juan Iovanna

Cancer Letters 486:8-17 (2020)10.1016/j.canlet.2020.04.024

ZZW-115-dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents

Wenjun Lan, Patricia Santofimia-Castaño, Mirna Swayden, Yi Xia, Zhengwei Zhou, Stéphane Audebert, Luc Camoin, Can Huang, Ling Peng, Ana Jiménez-Alesanco, Adrián Velázquez-Campoy, Olga Abián, Gwen Lomberk, Raul Urrutia, Bruno Rizzuti, Vincent Geli, Philippe Soubeyran, José Neira, Juan Iovanna

JCI Insight 5 (2020)10.1172/jci.insight.138117

Novel Aryltriazole Acyclic C-Azanucleosides as Anticancer Candidates

Yanhua Zhang, Yun Lin, Qianqian Hou, Xi Liu, Sabrina Pricl, Ling Peng, Yi Xia

Organic and Biomolecular Chemistry (2020)10.1039/d0ob02164d

Novel triazole nucleoside analogues promote anticancer activity via both apoptosis and autophagy

Yanhua Zhang, Xi Liu, Yun Lin, Baoping Lian, Wenjun Lan, Juan Iovanna, Xiaoxuan Liu, Ling Peng, Yi Xia

Chemical Communications 56:10014-10017 (2020)10.1039/d0cc04660d

2019

Efficient and innocuous delivery of small interfering RNA 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 14:2441-2458 (2019)10.2217/nnm-2019-0176

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Can Huang, Wenjun Lan, Nicolas Fraunhoffer, Analía Meilerman, Juan Iovanna, Patricia Santofimia-Castaño

Cancers 11:1869 (2019)10.3390/cancers11121869

Poly(amidoamine) dendrimers: covalent and supramolecular synthesis

Z. Lyu, L. Ding, A.Y.T. Huang, L. Kao, Ling 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 129:2500-2513 (2019)10.1172/jci127223

Targeting intrinsically disordered proteins involved in cancer

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

Cellular and Molecular Life Sciences (2019)10.1007/s00018-019-03347-3

Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma

Patricia Santofimia-Castaño, Yi Xia, Ling Peng, Adrián Velázquez-Campoy, Olga Abián, Wenjun Lan, Gwen Lomberk, Raul Urrutia, Bruno Rizzuti, Philippe Soubeyran, José Luis Neira, Juan Iovanna

Cells 8:1453 (2019)10.3390/cells8111453

Flavonoid–alkylphospholipid conjugates elicit dual inhibition of cancer cell growth and lipid accumulation

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

Chemical Communications 55:8919-8922 (2019)10.1039/c9cc04084f

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)10.1007/s40843-018-9323-6

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

Yiwen Dong, Tianzhu Yu, Ling Ding, Erik Laurini, Yuanyu Huang, Mengjie Zhang, Yuhua Weng, Shuting Lin, Peng Chen, Domenico Marson, Yifan Jiang, Suzanne Giorgio, Sabrina Pricl, Xiaoxuan Liu, 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)10.1038/s41598-018-26613-z

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 Wong

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

Precise tuning of single molecule conductance in an electrochemical environment

Ling 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)10.1016/j.tplants.2018.09.008

Negative dendritic effect on enzymatic hydrolysis of dendrimer conjugates

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

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

2017

Potent drugless dendrimers

Zhenbin Lyu, Ling Peng

Nature Biomedical Engineering 1:686-688 (2017)10.1038/s41551-017-0136-3

Financement

Équipe Peng Équipe Peng 1

  • EU H2020 ERA-NET EuroNanoMed III project "iNanoGun"

    2021-2023: “Reactivation of antitumor immune responses in gliomas using nanotechnology based targeted delivery”

  • EU H2020 Marie-Curie ITN project "OLIGOMED"

    2021-2024: “Oligonucleotides for Medical Applications”

  • Equipe Labellisée Ligue Nationale Contre le Cancer,

    2021-2023: “Modular nanosystems for multimodal imaging and theranostics to fight against cancer”

 

  • 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"

  • EU H2020 ERA-Net EuroNanoMed III project "NAN-4-TUM"

2020-2023 "development of CXCR4 targeting-nanosystem-imaging probes for molecular imaging of cancer cells and tumor microenvironment"

Useful Links:

1) EU project "Safe-n-medtech":         https://safenmt.eu
2) EU COST Action CA17140 "nano2clinic" : https://www.nano2clinic.eu/cost-action-ca17140

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)

 

News

JANUARY 2021

  • Welcome Ms Kaiyue ZHANG

We welcome Ms. Kaiyue ZHANG to join our group for his PhD program. We wish her all the best with pleasant and productive stay in our group.

 

  • New projects in 2021

We start three new projects in 2021:

1) Equipe Labellisée Ligue Nationale Contre le Cancer,

“Modular nanosystems for multimodal imaging and theranostics to fight against cancer”

2) EU H2020 ERA-NET EuroNanoMed III

“Reactivation of antitumor immune responses in gliomas using nanotechnology based targeted delivery (iNanoGun)”

3) EU H2020 Marie-Curie ITN project 956070

“Oligonucleotides for Medical Applications (OLIGOMED)”

https://www.southampton.ac.uk/oligomed/index.page

 

  • A new article:

Self-Assembling Supramolecular Dendrimers for Biomedical Applications: Lessons Learned from Poly(amidoamine) Dendrimers

 Zhenbin Lyu, Ling Ding, Aura Tintaru, and Ling Peng

Acc. Chem. Res. 2020, DOI:10.1021/acs.accounts.0c00589

2020 AccChemRes LYU

Dendrimers, notable for their well-defined radial structures with numerous terminal functionalities, hold great promise for biomedical applications such as drug delivery, diagnostics, and therapeutics. However, their translation into clinical use has been greatly impeded by their challenging stepwise synthesis and difficult purification. In this paper, we provide out-of-box thinking about constructing non-covalent supramolecular dendrimers via self-assembling of small amphiphilic dendrimers, which are easy to synthesize. Using poly(amidoamine) (PAMAM) dendrimers as examples, the self-assembled supramolecular dendrimers mimic covalent dendrimers not only in the structure but also in their capacity for biomedical applications. Some of the reported supramolecular dendrimers exhibit outstanding performance, excelling the corresponding clinical anticancer therapeutics and imaging agents. This self-assembly approach to creating supramolecular dendrimers is completely novel in concept yet easy to implement in practice, offering a fresh perspective for exploiting the advantageous features of dendrimers in biomedical applications.

 

 

Figure: Cartoon representations of self-assembly supramolecular dendrimer for the delivery of hydrophobic and hydrophilic pharmaceutical agents as well as negatively charged nucleic acid

therapeutics.

Contact:

Dr. Ling Peng,

Email: ling.peng@univ-amu.fr

Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) UMR 7325, Equipe Labellisé par La Ligue, Marseille, France

 

DECEMBER 2020

  • A new article in Nature Protocol:

Synthesis and use of an amphiphilic dendrimer for siRNA delivery into primary immune cells

Jiaxuan Chen, Aleksandra Ellert-Miklaszewska, Stefano Garofalo, Arindam K Dey, Jingjie Tang, Yifan Jiang, Flora Clément, Patrice N Marche, Xiaoxuan Liu, Bozena Kaminska, Angela Santoni, Cristina Limatola, John Rossi, Jiehua Zhou, Ling Peng

Nat. Protocols. 2020, DOI: 10.1038/s41596-020-00418-9

Genetically manipulating immune cells using siRNAs is important for both basic immunological studies and therapeutic applications. However, the siRNA delivery is challenging because primary immune cells are often sensitive to the standard transfection reagents and generate immune responses. To circumvent these problems, we have developed an innovative amphiphilic dendrimer, which exhibits particularly high performance for siRNA delivery to a wide range of cell types, including highly challenging primary immune cells, such as human peripheral blood mononuclear cells (PBMCs), human B- and T-lymphocytes, NK cells (human and mouse), primary monocyte-derived macrophages and primary microglial cells (rat and mouse). Notably, this dendrimer is able to form small and stable nanoparticles with siRNA, thus protecting the siRNA from degradation and facilitating cellular uptake of siRNA. The subsequent siRNA-mediated gene silencing is specific and effective at both the mRNA and protein levels, leading to consequential biological effects. Remarkably, this dendrimer does not induce apparent cellular toxicity or non-specific immune responses under experimental conditions. Consequently, it constitutes the long-searched-for transfection reagent for siRNA delivery into primary immune cells and offers a new outlook for functional and therapeutic studies of the immune system.

This is a collaborative work between Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) at Aix-Marseille University, Institute for Advanced Biosciences at Grenoble-Alpes University (INSERM U1209, CNRS UMR5309), Sapienza University of Rome and IRCCS Neuromed in Italy, Nencki Institute of Experimental Biology in Poland, China Pharmaceutical University in China and Beckman Research Institute in USA.

Figure: (A) Cartoon illustration of the amphiphilic dendrimer-mediated siRNA delivery into various immune cells such T cells, monocytes/microglia, and NK cells. (B) Chemical structure of AD.

Contact:

Dr. Ling Peng,

Email: ling.peng@univ-amu.fr

Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) UMR 7325, Equipe Labellisé par La Ligue, Marseille, France

 

  • Congratulations to Zhenbin Lyu and Ling DING for their PhD defense.

Congratulation to Zhenbin Lyu and Ling DING for their PhD thesis defense on 27/11/2020 and 30/11/2020. We wish both of them all the best for future endeavor and successful career ahead.

 

  •  Welcome Mr. Akshay Hande

We welcome Mr. Akshay Hande in our group, he has joined as Ph.D. on 1 December 2020. We wish him all the best with pleasant and productive stay in our group.

 

NOVEMBER 2020

  • New article: An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile

Dinesh Dhumal, Wenjun Lan, Ling Ding, Yifan Jiang, Zhenbin Lyu, Erik Laurini, Domenico Marson, Aura Tintaru, Nelson Dusetti, Suzanne Giorgio, Juan Lucio Iovanna, Sabrina Pricl, and Ling Peng

Nano Research, https://doi.org/10.1007/s12274-020-3216-8

http://www.thenanoresearch.com/upload/justPDF/3216.pdf

Gene therapy using small interfering RNA (siRNA) is emerging as a novel therapeutic approach to treat various diseases. However, safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics. Here we report an ionizable supramolecular dendrimer vector, formed via self-assembly of a small amphiphilic dendrimer, as an effective siRNA delivery system with a favorable safety profile. By virtue of the ionizable tertiary amine terminals, the supramolecular dendrimer has a low positively charged surface potential and no notable cytotoxicity at physiological pH. Nonetheless, this ionizable feature imparted sufficient surface charge to the supramolecular dendrimer to enable formation of a stable complex with siRNA via electrostatic interactions. The resulting siRNA/dendrimer delivery system had a surface charge for favorable cellular uptake and endosomal release of the siRNA. When tested in different cancer cell lines and patient-derived cancer organoids, this dendrimer-mediated siRNA delivery system effectively silenced the oncogenes Myc and Akt2 with a potent antiproliferative effect, outperforming the gold standard vector, Lipofectamine 2000. Therefore, this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery. The concept of supramolecular dendrimer nanovectors via self-assembly is new, yet easy to implement in practice, offering a new perspective for supramolecular chemistry in biomedical applications.

 

This is a collaborative study among Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Centre de Recherche en Cancerologie de Marseille (CRCM), Institut de Chimie Radicalaire (ICR) at Aix-Marseille University in France, and University of Trieste, Trieste, Italy.

Figure: Schematic illustration of the supramolecular dendrimer formed via self-assembly of an ionizable amphiphilic dendrimer for siRNA delivery. (A) A representative transmission electron microscopy (TEM) image of the supramolecular dendrimer nanomicelles formed by ionizable tertiary amine terminated dendrimer, (B) complex formation between siRNA and the ionizable supramolecular dendrimer, (C) Cellular uptake of the (Cy3)-labeled siRNA/dendrimer complexes in human pancreatic cancer (Panc-1) cells revealed using confocal microscopic imaging, (D) siRNA release upon endosomal escape, siRNA-mediated gene silencing of the oncogenes Akt2 (E) at mRNA level assessed using qRT-PCR and at (F) protein level using western blotting, and (G)  the resulting antiproliferative effect on Panc-1 cells determined using MTT assay.

 

  • Congratulations to Wenjun LAN for her PhD defense.

Congratulation to Wenjun LAN for successfully defending her PhD thesis on 9/11/2020. We wish her all the best for future endeavor and successful career ahead.

 

  • Congratulations! The project “Reactivation of antitumor immune responses in gliomas using nanotechnology based targeted delivery (iNanoGUN)” in which our group is a partner, has been accepted for funding under the Frame of EU H2020 ERA-NET EuroNanoMed III!
  • Welcome Ms Xi LIU to join our group for her PhD program!

We wish her a pleasant stay in our group and all the best for her PhD.

 

  • Congratulations to Dr. Dinesh Dhumal, Wenjun Lan, Ling Ding, Dr. Yifan Jiang and Zhenbin Lyu for their manuscript being accepted!

The manuscript entitled “An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile” and co-authored by Dr. Dinesh Dhumal, Wenjun Lan, Ling Ding, Dr. Yifan Jiang and Zhenbin Lyu, has been accepted by the journal of “Nano Research”.

 

OCTOBER, 2020

  • Congratulations to Dr. Dinesh Dhumal for the best award of oral presentation at MatSAN!

Dinesh Dhumal won the prix Jeune Chercheur IMBL for the best oral communication at MatSAN 2020 by presenting his post-doctoral work on supramolecular dendrimer nanosystem for siRNA delivery in cancer therapy.  We congratulate him for his achievement.

 

  • Congratulations to Wenjun Lan for her marriage!

 

We congratulate Wenjun for her marriage with Jeremy on 17 October 2020, and wish them the beautiful journey of their life with the all happiness in the world.

 

 

 

January, 20th, 2020

A new article published in Nanomedecine :

De nombreuses pathologies cérébrales, telles que la maladie d’Alzheimer, de Parkinson ou certaines scléroses, sont associées à des altérations aigues ou chroniques des microglies, la principale défense immunitaire du cerveau. L’utilisation de petits ARN interférants (siRNA) pourrait permettre une manipulation génétique des fonctions microgliales, afin de soigner ces maladies, mais est actuellement entravée par l'absence de méthodes efficaces et inoffensives de livraison de siRNA dans les microglies. En particulier, les vecteurs actuellement disponibles affectent souvent les fonctions et les réponses basales des microglies. Une équipe du CINaM (CNRS/Université Aix-Marseille) a développé et validé un nanovecteur, sous la forme d’une molécule dendrimère (à branches), qui répond à ce défi. En se complexant aux siRNA pour former de petites nanoparticules robustes, ce dendrimère amphiphile cationique facilite l’entrée des siRNA dans les microglies primaires. Dans ces travaux publiés dans la revue Nanomedicine, cette méthode a permis d’interrompre la production d’ARN messager et de protéines des certains gènes, avec des effets biologiques importants : elle a par exemple empêché des cellules tumorales de stimuler les microglies à leur avantage, sans altération non désirée ou toxique pour les microglies. Il s’agit donc du premier vecteur qui livre des siRNA fonctionnels sans affecter les fonctions et réponses microgliales basales. Un outil prometteur pour les études génomiques fonctionnelles et thérapeutiques de divers modèles de maladies du système nerveux central.

Références:

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

Efficient and innocuous delivery of small interfering RNA to microglia using an amphiphilic dendrimer nanovector

DOI : 10.2217/nnm-2019-0176

Formation du complexe siRNA/dendrimère, son entrée dans la cellule via l'endocytose et sa libération de l'endosome dans le cytosol pour le silençage génique © Ling DING

 

  • December, 12th, 2019

A new article published in Chemical Communications:

A self-assembling amphiphilic dendrimer nanotracer for SPECT imaging

Ling Ding, Zhenbin Lyu, Aura Tintaru, Erik Laurini, Domenico Marson, Beatrice Louis, Ahlem Bouhlel, Laure Balasse, Samantha Fernandez, Philippe Garrigue, Eric Mas, Suzanne Giorgio, Sabrina Pricl, Benjamin Guillet, Ling Peng

Chem. Commun. 2019, doi: 10.1039/c9cc07750b

Bioimaging plays an important role in cancer diagnosis and treatment, and single photon emission computed tomography (SPECT) is the most prevalent imaging modality in clinic. Nanotechnology-based imaging is particularly promising for tumor imaging because nanosized imaging agents can specifically home in on tumors via the “Enhanced Permeability and Retention (EPR)” effect, thus resulting in enhanced imaging sensitivity and specificity. In this work, we report an original supramolecular nanosystem for SPECT imaging based on an amphiphilic dendrimer which bears multiple SPECT reporting units at the terminals (see Figure below). This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective SPECT imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. The work present in this paper alongside our previous studies on positron emission tomography (PET) and drug delivery, highlight that the supramolecular nanosystems formed from self-assembling dendrimers have great potential as novel and robust platforms for various biomedical applications.

This is a collaborative work between Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) and Centre Européen de Recherche en Imagerie Médicale (CERIMED) at Aix-Marseille University together with Institute de Chemie Radicale (ICR), Centre de Recherche en Cancérologie de Marseille (CRCM) and Triest University in Italy.

 

Figure 1: Schematic illustration of the supramolecular dendrimer nanosystem, based on a self-assembling amphiphilic dendrimer bearing radionuclide terminals, for single photon emission computed tomographic (SPECT) imaging of tumors.

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  • July, 4th, 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

Link here; 2019 ChemCommun XIA

Cancer constitutes a major global health burden, and cancer development is impacted by not only genetic factors but also environmental concerns such as obesity, smoking, infections etc. Individuals who are obese or overweight often have high risk of developing carcinoma. This is because elevated lipid levels, caused by enhanced lipid synthesis and aberrant lipid accumulation, are able to induce carcinogenesis and accelerate cancer metastasis. Here, we report a series of novel dual-functional compounds with both anticancer activity and the ability to lower lipid accumulation.

These compounds are hybrid conjugates of the natural product quercetin and synthetic alkylphospholipids (APLs). Quercetin is a flavonoid antioxidant, and affects the heat shock pathway and lipid metabolism, whereas APLs have proven anticancer activity. Indeed, the identifed active compounds outperformed the parent compounds (quercetin and APLs) in terms of their anticancer activity, while also significantly suppressed lipid accumulation and down-regulated heat-shock proteins and antiapoptotic proteins. Consequently, these conjugates constitute a novel promising structural paradigm in the discovery of new anticancer candidates. This study may also open new avenues for developing therapeutic agents to treat other lipid accumulation-related diseases, such as cardiovascular diseases, obesity and diabetes 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:This is a collaborative work among Chongqing University in China, Centre de Recherche en Cancerologie de Marseille (CRCM) and Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) in France under the frame of the French-Chinese cooperation program XUGUANGQI.

  • 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)

Jobs

  • May 2021, a new PhD position is available in our group

 

Functional dendrimer nanosystems for oligonucleotides delivery

Host institution : Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Centre National de la Recherche Scientifique (CNRS), Aix-Marseille University, Marseille, FRANCE

Supervisor : Dr. Ling PENG, Centre National de la Recherche Scientifique (CNRS)

Co-Supervisors: Dr. Carlo Vascotto, University of Udine (UNIUD), Udine, Italy (Academic); Dr. Shalini Andersson, AstraZeneca (AZ), Sweden (Industrial).

Project description

The Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), a joint laboratory of Aix-Marseille University and Centre National de la Recherche Scientifique (CNRS) in France is seeking to recruit an Early Stage Research (ESR) Fellow as part of the H2020 MSCA Innovative Training Network “Oligonucleotides for Medical Applications - OLIGOMED”. The successful candidate will join an international cohort of 15 ESR PhD student fellows researching key topics in the use of synthetic oligonucleotides (ONs) for medical applications leading to submission of their PhD thesis. A successful thesis will receive the PhD degree in Chemistry from Aix-Marseille University.

The use of synthetic oligonucleotides (ONs) in the treatment of genetic diseases is a rapidly growing field, and the most promising alternative to gene therapy using small molecules. This multicentre project is structured in four research work packages (WPs). WP1: Design and synthesis of ONs; WP2: Regulation of mRNA expression; WP3: ONs and non-canonical DNA structures in regulation of gene expression; WP4: Delivery of ONs.

The aim of this ESR PhD project will be the design, synthesis and evaluation of dendrimer nanovectors for ON delivery. In this project, various functional amphiphilic dendrimers for ON delivery will be designed and synthesized. These dendrimers will be then studied for their self-assembling and complexing with ONs to form nanosized complexes in the view to protecting ONs from degradation and promoting cellular uptake of ONs. The resulting biological effects of the delivered ONs will be evaluated in vitro using cell-based experiments and in vivo using animal models of cardiovascular diseases, Huntington disease and cancers in collaboration with AstraZenaca (AZ) and Stockholms Laens Landsting (SLL) through secondments in partner organizations.

Host laboratory

Research activities in the group of Dr. Ling PENG in CINaM-CNRS are focused on developing dendrimer nanotechnology-based delivery systems for nucleic acid therapeutics. The laboratory has all the key facilities and expertise in synthesizing, characterizing and evaluating the dendrimer molecules and nanosystems for ON delivery. The host institute has full access to NMR, MS, HPLC, DLS, TEM, cell culture and all the necessary infrastructure and arrangement in place to host the ESR fellow.

Secondments

This project is carried out in strong collaboration with the following groups, and visits to their laboratories is expected during the project. A willingness to travel and spend time abroad is therefore essential:

  • Carlo Vascotto, University of Udine, Italy;
  • Shalini Andersson, AstraZeneca (AZ), Sweden;
  • Edvard Smith and Prof Rula Zain, Stockholms Laens Landsting (SLL), Sweden.

Eligibility conditions

  • Early-Stage Researchers must, at the time of recruitment, hold a Master’s degree and be in the first four years (full-time equivalent research experience) of their research careers and have not yet been awarded a doctoral degree.
  • The Master’s degree must be in chemistry, biology, biotechnology or related field.
  • At the time of recruitment researchers must not have resided or carried out their main activity (work, studies, etc) in France for more than 12 months in the 3 years immediately prior to the reference date.

Required Skills

  • Research experience (e.g. through Master thesis work or research internships) in chemistry and/or biology/biomedical research are required.
  • Proficiency in the English language is required, as well as good communication skills, both oral and written.
  • Successful candidates will need to provide an English test (e.g. IELTS, TOEFL, Cambridge English); see [website] for details of accepted English Language Proficiency tests.

Benefits

  • A thorough scientific education in the frame of a doctoral training program.
  • The possibility to participate in specific international courses, workshops and conferences.
  • A strong involvement in a European research project with high international visibility.
  • The possibility to perform research visits to internationally renowned research labs in Europe.
  • A prestigious three-year MSCA Fellowship.
  • A competitive salary including mobility and family allowances.

Enquire

For general information about Oligomed project visit the web page:

https://www.southampton.ac.uk/oligomed/index.page

For additional information on this project please contact Dr. Ling PENG (ling.peng@univ-amu.fr)

How to apply

To complete your application, you need to send the following documents within ONE pdf file:

  1. Curriculum vitae et studiorum.
  2. A certificate of University examinations taken (with marks).
  3. A final degree certificate translated in English. If, at the time of application, candidates should not be yet in possession of a degree certificate, they can submit it at the time of the examination.
  4. Your statement of interest (limit of 2,500 characters) explaining why you wish to be considered for the fellowship and which qualities and experience you will bring to the role.
  5. Up to two recommendation letters.

 

  • January 2021, A new PhD position available  in our group:

Functional dendrimer nanosystems for oligonucleotides delivery

We are seeking to recruit an Early Stage Research (ESR) Fellow as part of the H2020 MSCA Innovative Training Network “Oligonucleotides for Medical Applications - OLIGOMED”.

The use of synthetic oligonucleotides (ONs) in the treatment of genetic diseases is a rapidly growing field. The aim of this ESR PhD project will be the development and optimization of dendrimer vectors for ON delivery. In this project, various amphiphilic dendrimers for ON delivery will be designed and synthesized. These dendrimers will be then studied for their self-assembling and complexing with ONs to form nanosized complexes in the view to protecting ONs from degradation and promoting cellular uptake of ONs. The resulting biological effects of the delivered ONs will be evaluated in vitro using cell-based experiments and in vivo using animal models of cardiovascular diseases, Huntington disease and cancers in collaboration with AstraZenaca (AZ) and Stockholms Laens Landsting (SLL) through secondments in partner organizations.

Host laboratory

Research activities in the group of Dr. Ling PENG in CINaM-CNRS are focused on developing dendrimer nanotechnology-based delivery systems for nucleic acid therapeutics, natural product drugs and imaging agents. The laboratory has all the key facilities and expertise in synthesizing, characterizing and evaluating the dendrimer molecules and nanosystems for ON delivery. The host institute has full access to NMR, MS, HPLC, DLS, TEM, cell culture and all the necessary infrastructure and arrangement in place to host the ESR fellow.

Eligibility conditions

  • Early-Stage Researchers must, at the time of recruitment, hold a Master’s degree and be in the first four years (full-time equivalent research experience) of their research careers and have not yet been awarded a doctoral degree.
  • The Master’s degree must be in chemistry, biology, biotechnology or related field.
  • At the time of recruitment researchers must not have resided or carried out their main activity (work, studies, etc) in France for more than 12 months in the 3 years immediately prior to the reference date.

Required Skills

  • Research experience (e.g. through Master thesis work or research internships) in chemistry and/or biology/biomedical research are required.
  • Proficiency in the English language is required, as well as good communication skills, both oral and written.
  • Successful candidates will need to provide an English test (e.g. IELTS, TOEFL, Cambridge English).

How to apply

To complete your on-line application, you need to upload on the CNRS recruitment web page (https://emploi.cnrs.fr/Offres/Doctorant/UMR7325-VALSEV-041/Default.aspx?lang=EN) the following documents in PDF format:

  1. Curriculum vitae including certificates of University examinations taken (with marks), a final degree certificate translated in English and up to two recommendation letters. If, at the time of application, candidates should not be yet in possession of a degree certificate, they can submit it at the time of the examination.
  2. Your statement of interest (limit of 2,500 characters) explaining why you wish to be considered for the fellowship and which qualities and experience you will bring to the role.

Application deadline

The closing date for applications is 28 Febuary 2021, with interviews expected to take place in March.

 

Patents

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.