B&B

Biomolecules and Biomaterials

Leader: Ling Peng

Introduction

Our group works at the interface of chemistry and biology and is mainly dedicated to the development of chemical probes to understand biological events, the discovery of bioactive molecules and biomedical applications based on dendrimeric nanotechnology.
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

2024

Amphiphilic Dendrimer as Potent Antibacterial against Drug-Resistant Bacteria in Mouse Models of Human Infectious Diseases

Noah King, Dinesh Dhumal, Shi Qian Lew, Shanny Hsuan Kuo, Christina Galanakou, Myung Whan Oh, Sook Yin Chong, Nian Zhang, Leo Tsz On Lee, Zvi Hayouka, Ling Peng, Gee W Lau

ACS Infectious Diseases 10:453-466 (2024)10.1021/acsinfecdis.3c00425

Self-assembling dendrimer nanosystems for specific fluorine magnetic resonance imaging and effective theranostic treatment of tumors

Zhenbin Lyu, Brigino Ralahy, Teodora-Adriana Perles-Barbacaru, Ling Ding, Yifan Jiang, Baoping Lian, Tom Roussel, Xi Liu, Christina Galanakou, Erik Laurini, Aura Tintaru, Suzanne Giorgio, Sabrina Pricl, Xiaoxuan Liu, Monique Bernard, Juan Iovanna, Angèle Viola, Ling Peng

Proceedings of the National Academy of Sciences of the United States of America 121:e2322403121 (2024)10.1073/pnas.2322403121

Insight into the Internal Structure of High-Performance Multicore Magnetic Nanoparticles Used in Cancer Thermotherapy

Tom Roussel, Daniel Ferry, Artemis Kosta, Dalila Miele, Giuseppina Sandri, Felista Tansi-Lemnyui, Frank Steiniger, Paul Southern, Quentin Pankhurst, Ling Peng, Suzanne Giorgio

ACS Materials Au (2024)

Targeting the phosphatidylglycerol lipid: An amphiphilic dendrimer as a promising antibacterial candidate

Nian Zhang, Dinesh Dhumal, Shanny Hsuan Kuo, Shi Qian Lew, Pankaj Patil, Raleb Taher, Sanika Vaidya, Christina Galanakou, Abdechakour Elkihel, Myung Whan Oh, Sook Yin Chong, Domenico Marson, Jun Zheng, Oleg Rouvinski, Williams Abolarin, Sabrina Pricl, Gee Lau, Leo Tsz On Lee, Ling Peng

Science Advances 10:eadn8117 (2024)10.1126/sciadv.adn8117

Capture and flocculation of toxic cyanobacteria by amphiphilic peptide dendrimers for mitigating harmful blooms

Heng Zheng, Pier-Luc Tremblay, Wang Chen, Qi Wang, Danni Hu, Yuanzheng Huang, Xiaoxuan Liu, Cheng-Cai Zhang, Ling Peng, Tian Zhang

Chemical Engineering Journal (2024)10.1016/j.cej.2024.151382

2023

Progress and Harmonization of Gene Editing to Treat Human Diseases (Proceeding of COST Action CA21113 GenE-HumDi)

Alessia Cavazza, Ayal Hendel, Rasmus O Bak, Paula Rio, Marc Güell, Duško Lainšček, Virginia Arechavala-Gomeza, Ling Peng, Fatma Zehra Hapil, Joshua Harvey, Francisco G Ortega, Coral Gonzalez-Martinez, Carsten W Lederer, Kasper Mikkelsen, Giedrius Gasiunas, Nechama Kalter, Manuel a F V Gonçalves, Julie Petersen, Alejandro Garanto, Lluis Montoliu, Marcello Maresca, Stefan E Seemann, Jan Gorodkin, Loubna Mazini, Rosario Sanchez, Juan R Rodriguez-Madoz, Noelia Maldonado-Pérez, Torella Laura, Michael Schmueck-Henneresse, Cristina Maccalli, Julian Grünewald, Gloria Carmona, Neli Kachamakova-Trojanowska, Annarita Miccio, Francisco Martin, Giandomenico Turchiano, Toni Cathomen, Yonglun Luo, Shengdar Q Tsai, Karim Benabdellah

Molecular Therapy - Nucleic Acids (2023)10.1016/j.omtn.2023.102066

Cargo-selective and adaptive delivery of nucleic acid therapeutics by bola-amphiphilic dendrimers

Jiaxuan Chen, Dandan Zhu, Baoping Lian, Kangjie Shi, Peng Chen, Ying Li, Wenyi Lin, Ling Ding, Qiulin Long, Yang Wang, Erik Laurini, Wenjun Lan, Yun Li, Aura Tintaru, Caoyun Ju, Can Zhang, Sabrina Pricl, Juan Iovanna, Xiaoxuan Liu, Ling Peng

Proceedings of the National Academy of Sciences of the United States of America 120:e2220787120 (2023)10.1073/pnas.2220787120

Modular Self‐Assembling Dendrimer Nanosystems for Magnetic Resonance And Multimodality Imaging of Tumors

Ling Ding, Zhenbin Lyu, Teodora‐adriana Perles-Barbacaru, Adela Ya‐ting Huang, Baoping Lian, Yifan Jiang, Tom Roussel, Christina Galanakou, Suzanne Giorgio, Chai‐lin Kao, Xiaoxuan Liu, Juan Iovanna, Monique Bernard, Angèle Viola, Ling Peng

Advanced Materials (2023)10.1002/adma.202308262

Amphiphilic dendrimers against antibiotic resistance: light at the end of the tunnel?

Christina Galanakou, Dinesh Dhumal, Ling Peng

Biomaterials Science (2023)10.1039/D2BM01878K

Dendrimer nanosystems for adaptive tumor-assisted drug delivery via extracellular vesicle hijacking

Yifan Jiang, Zhenbin Lyu, Brigino Ralahy, Juan Liu, Tom Roussel, Ling Ding, Jingjie Tang, Artemis Kosta, Suzanne Giorgio, Richard Tomasini, Xing-Jie Liang, Nelson Dusetti, Juan Iovanna, Ling Peng

Proceedings of the National Academy of Sciences of the United States of America 120 (2023)10.1073/pnas.2215308120

2022

Amphiphilic Dendrimer Vectors for RNA Delivery: State-of-the-Art and Future Perspective

Jiaxuan Chen, Dandan Zhu, Xiaoxuan Liu, Ling Peng

Accounts of Materials Research (2022)10.1021/accountsmr.1c00272

Dynamic self-assembling supramolecular dendrimer nanosystems as potent antibacterial candidates against drug-resistant bacteria and biofilms

Dinesh Dhumal, Bar Maron, Einav Malach, Zhenbin Lyu, Ling Ding, Domenico Marson, Erik Laurini, Aura Tintaru, Brigino Ralahy, Suzanne Giorgio, Sabrina Pricl, Zvi Hayouka, Ling Peng

Nanoscale (2022)10.1039/d2nr02305a

Thermostable ionizable lipid-like nanoparticle (iLAND) for RNAi treatment of hyperlipidemia

Bo Hu, Bo Li, Kun Li, Yuanyuan Liu, Chunhui Li, Lulu Zheng, Mengjie Zhang, Tongren Yang, Shuai Guo, Xiyu Dong, Tian Zhang, Qing Liu, Abid Hussain, Yuhua Weng, Ling Peng, Yongxiang Zhao, Xing-Jie Liang, Yuanyu Huang

Science Advances 8 (2022)10.1126/sciadv.abm1418

Solid-phase dendrimer synthesis: a promising approach to transform dendrimer construction

Ya-Ting Huang, C.-L Kao, A Selvaraj, Ling Peng

Materials Today Chemistry (2022)10.1016/j.mtchem.2022.101285

A biodegradable amphiphilic poly(aminoester) dendrimer for safe and effective siRNA delivery

Chi Ma, Dandan Zhu, Wenyi Lin, Ying Li, Yuanzheng Huang, Huiling Zhu, Mengyun Ye, Yang Wang, Ling Peng, Xiaoxuan Liu

Chemical Communications (2022)10.1039/D1CC06655B

NUPR1 protects against hyperPARylation-dependent cell death

Patricia Santofimia-Castano, Can Huang, Xi Liu, Yi Xia, Stephane Audebert, Luc Camoin, Ling Peng, Gwen Lomberk, Raul Urrutia, Philippe Soubeyran, Jose Luis Neira, Juan Iovanna

Communications Biology 5 (2022)10.1038/s42003-022-03705-1

Small Activating RNA Modulation of the G Protein‐Coupled Receptor for Cancer Treatment

Yunfang Xiong, Ran Ke, Qingyu Zhang, Wenjun Lan, Wanjun Yuan, Karol Nga Ieng Chan, Tom Roussel, Yifan Jiang, Jing Wu, Shuai Liu, Alice Sze Tsai Wong, Joong Sup Shim, Xuanjun Zhang, Ruiyu Xie, Nelson Dusetti, Juan Iovanna, Nagy Habib, Ling Peng, Leo Tsz On Lee

Advanced Science 2200562 (2022)10.1002/advs.202200562

Bola‐Amphiphilic Glycodendrimers: New Carbohydrate Mimicking Scaffolds to Target Carbohydrate‐Binding Proteins

Wenzheng Zhang, Dinesh Dhumal, Xiaolei Zhu, Brigino Ralahy, Aleksandra Ellert-Miklaszewska, Jing Wu, Erik Laurini, Yi-Wen W Yao, Chai-Lin L Kao, Juan L Iovanna, Sabrina Pricl, Bozena Kaminska, Yi Xia, Ling Peng

Chemistry - A European Journal (2022)10.1002/chem.202201400

2021

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

Nature Protocols (2021)10.1038/s41596-020-00418-9

A self-assembling prodrug nanosystem to enhance metabolic stability and anticancer activity of gemcitabine

Mei Cong, Guangling Xu, Shaoyou Yang, Jing Zhang, Wenzheng Zhang, Dinesh Dhumal, Erik Laurini, Kaiyue Zhang, Yi Xia, Sabrina Pricl, Ling Peng, Weidong Zhao

Chinese Chemical Letters (2021)10.1016/j.cclet.2021.11.083

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 (2021)10.1007/s12274-020-3216-8

NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner

Can Huang, Patricia Santofimia-Castaño, Xi Liu, Yi Xia, Ling Peng, Célia Gotorbe, Jose Luis Neira, Daolin Tang, Jacques Pouyssegur, Juan Iovanna

Cell Death Discovery 7:269 (2021)10.1038/s41420-021-00662-2

Dendrimeric Nanosystem Consistently Circumvents Heterogeneous Drug Response and Resistance in Pancreatic Cancer

Juan Liu, Chao Chen, Tuo Wei, Odile Gayet, Céline Loncle, Laurence Borge, Nelson Dusetti, Xiaowei Ma, Domenico Marson, Erik Laurini, Sabrina Pricl, Zhongwei Gu, Juan Iovanna, Ling Peng, Xing‐jie Liang

Energy Exploration and Exploitation 1:21-34 (2021)10.1002/EXP.20210003

Design of Inhibitors of the Intrinsically Disordered Protein NUPR1: Balance between Drug Affinity and Target Function

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

Biomolecules 11:1453 (2021)10.3390/biom11101453

2020

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

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 S Habib, Donald A Tomalia, Pål Sætrom, Edmund Wilkes, Pedro Cutillas, John J Rossi, Nagy A 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

Novel Aryltriazole Acyclic C-Azanucleosides as Anticancer Candidates

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

Organic & Biomolecular Chemistry (2020)10.1039/d0ob02164d

Seminars

Webinar at 10h30 (CET) on Monday 17/01/2022

 

Small activating RNA therapeutics from concept to Phase 2 clinical trials

 

Prof. Nagy Habib

Imperial College of London, UK

 

Zoom Meeting linker :

https://univ-amu-fr.zoom.us/j/92847760892?pwd=eTZtbllYMVltZHRpV2JKdEZVVkxKdz09

 

 

Abstract:
Small activating RNA (saRNA) molecules are double stranded 21 nucleotide RNA that either target promoters or enhance genes leading to mRNA upregulation. saRNAs can be delivered with liposomes into the systemic circulation or subcutaneously by conjugation with aptamers or GalNAC. MTL-CEBPA is an investigative drug that resulted from the conjugation of saRNA CEBPA with NOV 340 lipsomes that targets tumour associated macrophages in order to alter favourably the tumour microenvironment. MTL-CEBPA has been administered safely in over 100 patients with advanced cancer and improved clinical outcome in a sub-set of patients when co-administered with TKI or check point inhibitor.

Reference:

https://clincancerres.aacrjournals.org/content/early/2021/08/24/1078-0432.CCR-21-0986.long

 

 

Biograph

Nagy is Lead Clinician and Head of the Department of HPB Surgery at Imperial College London. Nagy is also the founder and Head of R&D of MiNA Therapeutics. For over three decades Nagy has been at the forefront of clinical research and clinical practice in cancer. He pioneered the first clinical trial in the use of adenovirus and plasmid for the treatment of liver cancer, as well as the use of plasmid gene therapy in hydrodynamic gene delivery. Currently, he is driving the development of an saRNA drug (a new class of medicines) which is currently being trialed in patients with liver cancer in eight UK centres, and sites in Singapore and Taiwan (OUTREACH study, ClinicalTrials.gov ID NCT02716012) and in a second trial in patients with solid tumours (TIMEPOINT study, ClinicalTrials.gov ID NCT 04105335) in the UK, USA, Europe, Singapore and Taiwan. He has published widely in gene therapy, stem cell therapy, oligonucleotides, endoscopy and surgery. Previously Nagy was founder and Chairman of EMcision Limited (acquired by Boston Scientific Inc in 2018).

 

Financement

Équipe Peng Équipe Peng 1

  • EU Horizon Europe Research and Innovation program Cancer Mission “HIT-GLIO” (2023-2027) (grant agreement No. 101136835)

Link: https://hit-glio.eu/

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

2022-2025: "Developing Novel nanopharmaceutics against bacterial infections at center nervous system"

  • 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

  • May 2023

Cargo-selective and adaptive delivery of nucleic acid therapeutics by bola-amphiphilic dendrimers

Jiaxuan Chen, Dandan Zhu, Baoping Lian, Kangjie Shi, Peng Chen, Ying Li, Wenyi Lin, Ling Ding, Qiulin Long, Yang Wang, Erik Laurini, Wenjun Lan, Yun Li, Aura Tintaru, Caoyun Ju, Can Zhang, Sabrina Pric, Juan Iovanna, Xiaoxuan Liu, Ling Peng

May 15, 2023, 120 (21) e2220787120

DOI: www.pnas.org/doi/10.1073/pnas.2220787120

2023 PNAS CHEN

Tailor-made functional materials that meet specific requirements for different applications are of great importance in material and biomedical research. Dendrimers, by virtue of their well-defined structure and cooperative multivalence, represent precision materials. Recently, we synthesized and studied bipolar (bola) amphiphilic dendrimers for selective and on-demand delivery of DNA and small interfering RNA (siRNA), both are important nucleic acid therapeutics (Figure 1). Nucleic acid therapeutics are becoming a new drug modality, offering the unique opportunity to target "undruggable" targets, respond rapidly to evolving pathogens, and treat diseases at the genetic level for precision medicine. However, nucleic acid therapeutics suffer from poor bioavailability and are susceptible to chemical and enzymatic degradation, necessitating the use of delivery vectors.

By employing bola-amphiphilic dendrimers, we achieved superior performance in siRNA delivery with the second-generation dendrimer, whereas the third-generation dendrimer showed excellent DNA delivery. We systematically investigated these dendrimers in terms of cargo binding, cellular uptake, endosomal release, and in vivo delivery. The differences in size between the dendrimers and their nucleic acid cargos affected the cooperative multivalent interactions for cargo/vector binding and release, resulting in adaptive and selective cargo delivery (Figure 2). Furthermore, both dendrimers capitalized on the advantages of lipid and polymer vectors, while also providing tumor-targeting capabilities based on nanotechnology and redox-responsive cargo release. Notably, they enabled tumor- and cancer cell-specific delivery of siRNA and DNA therapeutics, leading to effective treatment in various cancer models, including aggressive and metastatic malignancies. These dendrimers outperformed currently available vectors (Figure 3). This study will inspire further exploitation of tailor-made dendrimer platforms for the cargo-selective delivery of various therapeutics in precision medicine.

This collaborative study involved the Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), China Pharmaceutical University, Trieste University and the Centre de Recherche en Cancérologie de Marseille (CRCM).

 

Fig. 1. Bola-amphiphilic dendrimers for cargo-specific nucleic acid delivery. (A) Chemical structures of the bola-amphiphilic dendrimers bola2A, bola4A, and bola8A studied in this work. (B) Cartoon illustration of bola-amphiphilic dendrimers bola4A and bola8A for cargo-selective and adaptive delivery of the two distinct nucleic acid types, DNA and siRNA.

Fig. 2. Physicochemical characterization of and rationale behind the cargo-selective delivery performance of bola4A and bola8A. (A) The sizes and the ζ-potentials of the DNA/dendrimer complex and the siRNA/dendrimer complex obtained with DNA (24 ng/μL) at an N/P ratio of 2 and siRNA (1.0 μM) at an N/P ratio of 10. (B, C) Cellular uptake and intracellular trafficking of DNA and siRNA delivered by the bola-amphiphilic dendrimers bola4A and bola8A. Confocal imaging of the cellular uptake of (B) the DNA/dendrimer complexes (12 ng/μL YOYO-1-labeled DNA, N/P ratio of 1.0) and (C) the siRNA/dendrimer complexes (50 nM Cy5-labeled siRNA, N/P ratio of 10) in SKOV-3 cells, evaluated using confocal microscopy. The green channel image shows the YOYO-1-labeled DNA (green), the red channel image shows the Cy5-labeled siRNA (red), and the blue channel image shows the nuclei of the SKOV-3 cells stained by Hoechst33342 (blue). (D) The siRNA release from the siRNA/dendrimer complexes assessed using heparin-coupled ethidium bromide (EB) fluorescence assays. ***p < 0.001 versus siRNA/bola4A or siRNA/bola8A, and significance was determined using two-way ANOVA (mean ± SD, n = 3). Atomistic MD simulations of bola4A and bola8A in the presence of siRNA (E and F) and DNA (G and H), respectively. Bola4A atoms are shown as “firebrick spheres”, with the terminal charged amine groups highlighted in deep sky-blue, while bola8A atoms are depicted as dark red spheres with the terminal charged amines colored in navy blue. The siRNA (“orchid” light purple) and the DNA (dark purple) are portrayed as their van der Waals surface and the oxygen atoms in water are shown as cyan transparent spheres. Hydrogen atoms, ions and counterions (Na+ and Cl-) are omitted for clarity. (I) Binding data of bola4A and bola8A with siRNA and DNA as derived from atomistic MD simulations: free energy of effective binding (ΔGbind,eff), number of effective charges (Neff), and effective-charge-normalized free energy of binding (ΔGbind,eff/Neff) for the nucleic acid/dendrimer complexes are listed.

 

Fig. 3. Effective inhibition of tumor metastasis using DNA and siRNA therapeutics delivered by bola8A and bola4A respectively in lung metastatic cancer model. (A-E) 4T1-luc metastatic tumor-bearing mice received intravenous injections of PBS buffer (control), p53 alone, p53/bola8A complex, p53/Lipo complex (2.0 mg/kg DNA, 1.5 mg/kg bola8A, N/P ratio of 1.0), siAKT2 alone, siAKT2/bola4A complex, or siAKT2/MC3 complex (1.0 mg/kg siRNA, 3.9 mg/kg bola4A, N/P ratio of 5.0) (n=5): (A) In vivo bioluminescence imaging of 4T1-luc tumor metastases in the mice. (B) Ex vivo bioluminescence imaging of 4T1-luc tumor metastases in the lung at the experimental end point post treatment. (C) Histological analysis of lung tissues from 4T1-luc metastatic tumor-bearing mice at the experimental end point post treatment. The metastatic lesions (red solid outlines) were identified as cell clusters with darkly stained nuclei. Scale bars, 1 m. (D) p53 and (E) AKT2 protein expression revealed by immunohistochemistry staining after treatments. Scale bar, 200 μm. (F-J) B16-F10-luc metastatic tumor-bearing mice received intravenous injections of PBS buffer (control), p53 alone, p53/bola8A complex, p53/JetPEI complex (2.0 mg/kg DNA, 1.5 mg/kg bola8A, N/P ratio of 1.0), siAKT2 alone, siAKT2/bola4A complex, or siAKT2/MC3 complex (1.0 mg/kg siRNA, 3.9 mg/kg bola4A, N/P ratio of 5.0) (n=5): (F) in vivo bioluminescence imaging of B16-F10-luc tumor metastases in the mice. (G) Ex vivo bioluminescence imaging of B16-F10-luc tumor metastases in the lung tissue or images of excised lung tissues at the experimental end point post treatment. (H) Histological analysis of lung tissues from B16-F10-luc metastatic tumor-bearing mice at the experimental end point post treatment. The metastatic lesions (red solid outline) were identified as cell clusters with darkly stained nuclei. Scale bars, 1.0 m. (I) p53 and (J) AKT2 protein expression revealed by immunohistochemistry staining after treatments. Scale bar, 200 μm. p53: plasmid DNA expressing tumor suppressor protein p53, siAKT2: siRNA targeting AKT2.

 

 

  • May 2023

http://xlink.rsc.org/?DOI=D2BM01878K

  • February 2023: new article

Dendrimer nanosystems for adaptive tumor-assisted drug delivery via extracellular vesicle hijacking

Yifan Jiang, Zhenbin Lyu, Brigino Ralahy, Juan Liu, Tom Roussel, Ling Ding, Jingjie Tang, Artemis Kosta, Suzanne Giorgio, Richard Tomasini, Xing-Jie Liang, Nelson Dusetti, Juan Iovanna, Ling Peng

PNAS,  2023,  Vol. 120, No. 7,  e2215308120; https://doi.org/10.1073/pnas.2215308120 

Cancer is one of the leading causes of death in the world, and remains a difficult disease to treat because of its intrinsic heterogeneity and dynamic evolution. Nanosystems (DDSs) that can overcome tumor heterogeneity and dynamic evolution, yet delivering anticancer drug deep in tumor tissue are desperately demanded for cancer treatment. However, such systems are difficult and challenging to develop. We report a drug delivery nanosystem based on self-assembling dendrimer nanomicelles (ADNMs) for deep tumor penetration and effective drug delivery via in situ tumor-secreted extracellular vesicles (EVs), an endogenous transport system that evolves with the parental cells in the tumor microenvironment, hence overcoming tumor heterogeneity and dynamic evolution, leading to excellent anticancer activity. Specifically, these dendrimer nanomicelles, upon arrival at a tumor, had their drug payload repackaged by the cells into EVs. Those were further transported and internalized by other cells for delivery “in relay”, deep into the tumor tissue improving drug delivery efficacy and cancer cell killing (Figure 1). Using pancreatic and colorectal cancer-derived 2D, 3D, and xenograft models, we demonstrated that the in situ-generated EVs mediated intercellular delivery (Figure 2), propagating drug delivery from cell to cell deep into the tumor, leading to excellent anticancer potency yet reducing adverse effects (Figure 3). These promising results highlight the remarkable potential of this drug delivery system for cancer treatment and provide a proof of concept for the development of new therapeutic modalities for adaptive drug delivery. This study also provides a new perspective on exploiting the intrinsic features of tumor alongside dendrimer supramolecular chemistry to develop smart and effective DDSs to overcome intra-tumoral microenvironment and heterogeneity as their evolutive nature, thereby improving cancer therapy.

Figure 1: Amphiphilic dendrimer nanomicelles (ADNMs) encapsulate the anticancer drug and induce tumor-assisted drug delivery via extracellular vesicle (EV)-mediated intercellular transport. The amphiphilic dendrimer (AD) encapsulates the anticancer drug and forms nanomicelles (ADNMs) which reach the tumor lesion via the enhanced permeability and retention (EPR) effect. There they induce in situ tumor-assisted drug delivery for deep tumor penetration via EV-mediated intercellular transport. This EV-mediated delivery process involves: (1) internalization of ADNMs inside cells within the tumor tissue; (2) repackaging of ADNM payload into EVs; (3) intercellular transport of the generated EVs; (4) internalization of the generated EVs by the recipient cell.

Figure 2. ADNM induced EV payload-packaging and cellular uptake. EVs, generated by cells upon treatment with ADNMs (R/AD, Cy3/R/AD and Dil/R/AD), were characterized using TEM (a), cryogenic electron microscopy (Cryo-EM) (b), fluorescent microscopy (c) and EV using western blotting (d). e, Confocal images of cryo-sectioned tumor tissues from HCT-8GFP xenograft mice treated with ADNM (DiI/R/AD) show the process of EV-mediated delivery in the tumor. The DiI fluorescence appeared in EVs derived from HCT-8GFP tumor (arrows). The hollow-donut shape of red DiI signal with green GFP filling highlights the HCT-8GFP-derived EVs with the DiI-labelled phospholipid bilayer and the HCT-8GFP-derived contents inside. Box 1, a DiI-loaded EV (arrow) located within the intercellular space; Box 24, the DiI-loaded EVs mediated intercellular transport within the tumor. Box 2, DiI-loaded EVs adhered onto the cell surface; Box 3, a DiI-loaded EV entering into a cell; Box 4, a DiI-loaded EV inside a cell. The tumor tissues were collected 24 hours after intravenous injection of DiI/R/AD in HCT-8GFP xenografts. AD: amphiphilic dendrimer; C: Cy3; Dil: fluorescent dye; R: rapamycin.

 

Figure 3. ADNMs were effective for inhibiting tumor growth, reducing drug toxicity and preventing tumor metastasis via specific accumulation and deep penetration through EVs in tumor. a, Tumor growth curves of the patient-derived pancreatic cancer xenografts PDAC087T and PDAC074T, and the colorectal cancer HCT-8 xenografts in mice upon treatment with ADNM carrying either doxorubicin (DOX) or rapamycin R, respectively. Mice treated with PBS buffer, drug alone or dendrimer alone were used as the controls. Data are presented as the mean ± s.e.m. The statistical significance was calculated by two-way ANOVA with a Tukey's multiple comparisons test. n = 6 mice for all groups. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. b, Accumulation of R/AD in tumors in the PDAC074T and HCT-8 xenograft mice was analyzed using fluorescent imaging with ADNM carrying both rapamycin and the near-infrared fluorescent dye DiR (DiR/R/AD). The in vivo fluorescence images were acquired 48 hours after intravenous administration of DiR/R/AD in PDAC074T (upper panel) and HCT-8 (lower panel) xenografts. Mice treated with PBS, free DiR, and a simple mixture of DiR, rapamycin and AD (DiR+R+AD), were used as controls. Arrows point to the tumor locations. c, Confocal images of tumor tissues show a deep intratumoral penetration of R/AD, using ADNM loaded with both rapamycin and the fluorescent dye DiI (DiI/R/AD). Mice treated with PBS, DiI alone, or a simple mixture of DiI, rapamycin and AD (DiI+R+AD), were used as controls. Tumors were harvested from PDAC074T (left) and HCT-8 (right) xenografts 24 hours post-intravenous administration, then cryosectioned and imaged by tracing DiI fluorescence (red). Blood vessels were labelled with DyLight488-labelled Lycopersicon esculentum lectin (green), and nuclei with DAPI (blue). d, HE stain of heart tissue issued from PDAC087T xenografts treated with PBS, AD, DOX and DOX/AD (n = 6). Treatment with DOX/AD prevented DOX-induced hyperemia and myocardial fiber breakage (arrows) in heart. e, HPS stain of lung tissues issued from HCT-8 xenografts treated with PBS, AD, R and R/AD (n = 6). Treatment with R/AD prevented the rapamycin-induced lung metastasis (T represents the tumor). Lung metastases were observed in mice treated with R, but not in those treated with PBS, dendrimer alone (AD) or the R/AD. Lung tissue was collected from mice at the end of treatment.

 

 

 

 

  • August 2022: 3  new articles published

Dynamic self-assembling supramolecular dendrimer nanosystems as potent antibacterial candidates against drug-resistant bacteria and biofilms

Dinesh Dhumal, Bar Maron, Einav Malach, Zhenbin Lyu, Ling Ding, Domenico Marson, Erik Laurini, Aura Tintaru, Brigino Ralahy, Suzanne Giorgio, Sabrina Pricl, Zvi Hayouka and Ling Peng

Nanoscale, 2022, 14, 9286-9296. DOI:10.1039/d2nr02305a

The alarming and prevailing antibiotic resistance crisis urgently calls for innovative “outside of the box” antibacterial agents, which will differ substantially from conventional antibiotics. In this context, we have established antibacterial candidates based on dynamic supramolecular dendrimer nanosystems self-assembled with amphiphilic dendrimers composed of a long hydrophobic alkyl chain and a small hydrophilic poly(amidoamine) dendron bearing distinct terminal functionalities. Remarkably, the amphiphilic dendrimer with amine terminals exhibited strong antibacterial activity against both Gram-positive and Gram-negative as well as drug-resistant bacteria, and prevented biofilm formation. Multidisciplinary studies combining experimental approaches and computer modelling together demonstrate that the dendrimer interacts and binds via electrostatic interactions with the bacterial membrane, where it becomes enriched and then dynamically self-assembles into supramolecular nanoassemblies for stronger and multivalent interactions. These, in turn, rapidly promote the insertion of the hydrophobic dendrimer tail into the bacterial membrane thereby inducing bacterial cell lysis and constituting powerful antibacterial activity. Our study presents a novel concept for creating nanotechnology-based antibacterial candidates via dynamic self-assembly and offers a new perspective for combatting recalcitrant bacterial infection.

This is a collaborative study among Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) at Aix-Marseille University in France, The Hebrew University of Jerusalem in Israel, and University of Trieste in Italy.

 

Figure: Amphiphilic dendrimers studied for antibacterial activity in this work. (A) Chemical structures of amphiphilic PAMAM dendrimers 1a–d bearing different terminal groups; (B) Cartoon illustration of the antibacterial activity shown by these amphiphilic dendrimers via membrane adsorption, self-assembling, interaction, insertion, disintegration and disruption.

 

 

  • Bola-Amphiphilic Glycodendrimers: New Carbohydrate Mimicking Scaffolds to Target Carbohydrate-Binding Proteins

Wenzheng Zhang, Dinesh Dhumal, Xiaolei Zhu, Brigino Ralahy, Aleksandra Ellert- Miklaszewska, Jing Wu, Erik Laurini, Yi-Wen Yao, Chai-Lin Kao, Juan L. Iovanna, Sabrina Pricl, Bozena Kaminska, Yi Xia* and Ling Peng*

Chemistry – A European Journal, DOI: 10.1002/chem.202201400

Carbohydrates, the most abundant biomacromolecules, are important not only for energy production, but also as structural materials and as signaling moieties. They regulate many biological processes, such as cell differentiation, proliferation and adhesion, inflammation, cancer metastasis and immune responses etc. Carbohydrates mediate cell-cell and cell-matrix interactions via carbohydrate-carbohydrate and carbohydrate-protein binding by harnessing the glycoside cluster effect, which exploits the cooperative interactions issued from the branched and multivalent structure of carbohydrates for improved binding strength and specificity.

Dendrimers, by virtue of their unique ramified structure and multivalent cooperativity, are particularly appealing scaffolds for constructing carbohydrate mimics and targeting carbohydrate-binding proteins. In this study, we report novel bola-amphiphilic dendrimers bearing carbohydrate units for binding and targeting carbohydrate-binding proteins. Different from traditional amphiphilic molecules, the dumbbell-like shape of bola-amphiphiles has a unique bipolar amphiphilic structure, which is able to reinforce molecular recognition, binding and stability towards carbohydrate-binding proteins. In addition, the mannose- and glucose-terminated bola-amphiphilic dendrimers are able to target respectively mannose receptors and glucose transporters expressed on cell surface for effective and specific cellular uptake, hence holding great promise for targeted delivery.

This is a collaborative study among Aix-Marseille University in France, Chongqing University in China, Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Poland and University of Trieste in Italy.

 

Figure 1. (A) Chemical structures of bola-amphiphilic glycodendrimers bearing mannose (Ia) and glucose (Ib) terminals studied in this work, with the amphiphilic dendrimer II bearing mannose terminals as the reference dendrimer; (B) Binding of Ia and II towards ConA using turbidimetric assay. Turbidity curves recorded at 450 nm for the precipitation of ConA with Ia and II, respectively, at 0.10 μM, in HEPES buffer at room temperature. (C) Imaging on the cellular uptake of fluorescent probe-labelled glycodendrimers Ia and Ib in primary microglia cultures, primary astrocyte cultures, human pancreatic cancer Panc-1 cells and mouse glioblastoma GL261 cells.

 

 

  • Small Activating RNA Modulation of the G Protein-Coupled Receptor for Cancer TreatmentYunfang Xiong, Ran Ke, Qingyu Zhang, Wenjun Lan, Wanjun Yuan, Karol Nga Ieng Chan, Tom Roussel, Yifan Jiang, Jing Wu, Shuai Liu, Alice Sze Tsai Wong, Joong Sup Shim, Xuanjun Zhang, Ruiyu Xie, Nelson Dusetti, Juan Iovanna, Nagy Habib, Ling Peng*, Leo Tsz On Lee*

Advanced Science, DOI: 10.1002/advs.202200562

G protein-coupled receptors (GPCRs) are the most common and important drug targets, and more than 30% of approved drugs target GPCRs. However, over 70% of GPCRs are undruggable or difficult to target using conventional small molecular agonists/antagonists, because of the various subtypes and splice variants as well as the high similarity of GPCRs within the same subfamily and target selectivity. Therefore, a new strategy is urgently needed to develop effective and specific drug candidates to expand the druggable “GPCRome”.

Small nucleic acid molecules, which can sequence-specifically modulate any gene, offer a unique opportunity to address “undruggable” targets such as GPCRs and at the same time provide precision medicine. In this study, scientists demonstrated for the first time that saRNA molecules are able to effectively modulate a GPCR, Mas receptor (MAS1), for cancer treatment. Specifically, the identified saRNAs promoted the expression of MAS1, a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration of multiple cancer cells. The MAS1 saRNAs (saMAS1s), delivered by an amphiphilic dendrimer vector, significantly suppressed tumorigenesis and inhibited tumor progression of multiple cancers in tumor-xenograft mouse models and patient tumor-derived organoids. This study provides not only a new strategy for cancer therapy by targeting the renin-angiotensin system, but also a new avenue to address undruggable GPCRs or any other target. Additionally, because of the pleiotropic role of the renin-angiotensin system in multiple physiological processes, the saRNAs developed in this study may also be extended to treat other diseases, such as cardiovascular or COVID-19-associated diseases.

This is a collaborative study among Macao University in China, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) and Centre de Recherche en Cancerologie de Marseille (CRCM) in France, and Imperial College of London in UK.

Figure:

Schematic diagram summarizing the molecular mechanism by which saMAS1 delivered by the amphiphilic dendrimer AD enhances MAS1 gene expression and suppresses cancer progression and metastasis.

 

 

  • New article

Amphiphilic dendrimer vectors for RNA delivery: state-of-the-art and future perspective

Jiaxuan Chen, Dandan Zhu, Xiaoxuan Liu, Ling Peng,

Acc. Mater. Res. 2022, 3, 5, 484-497.

DOI:10.1021/accountsmr.1c00272

Dendrimers, a special family of polymers, are particularly promising materials for various biomedical applications by virtue of their well-defined dendritic structure and cooperative multivalency. Specifically, in this account, we present state-of-the-art amphiphilic dendrimers for nucleic acid delivery.

Ribonucleic acid (RNA) molecules are fast becoming an important drug modality, particularly since the recent success of mRNA vaccines against COVID-19. However, RNA therapeutics are not stable and have poor bioavailability, imposing the need for their protection and safe delivery by vectors to the sites-of-action to allow the desired therapeutic effects. Currently, the two most advanced non-viral vectors are based on lipids and polymers, with lipid vectors primarily exploiting the membrane-fusion mechanism and polymer vectors mainly endocytosis-mediated delivery. Notably, only lipid vectors have been advanced through to their clinical use in the delivery of, for example, the first siRNA drug and the first mRNA vaccine.

The success of lipid vectors for RNA delivery has motivated research for further innovative materials as delivery vectors. Specifically, we have pioneered lipid/dendrimer conjugates, referred to as amphiphilic dendrimers, for siRNA delivery with the view to harnessing the delivery advantages of both lipid and polymer vectors while enjoying the unique structural features of dendrimers. These amphiphilic dendrimer vectors are lipid/dendrimer hybrids, and are thus able to mimic lipid vectors and exploit membrane-fusion-mediated delivery, while simultaneously retaining the multivalent properties of polymer vectors that allow endocytosis-based delivery. In addition, they have precisely controllable and stable nanosized chemical structures, and offer nanotechnology-based delivery.

In this short account, we provide a conceptual overview of this exciting field with the latest breakthroughs and key advances in the design of amphiphilic dendrimers for the delivery of siRNA and mRNA. Specifically, we start with a short introduction to siRNA- and mRNA-based therapeutics and their delivery challenges. We then outline the pioneering and representative studies on amphiphilic dendrimer vectors to highlight their historical development and promising features that offer to facilitate the once challenging RNA delivery. We conclude by offering perspectives for the future of amphiphilic dendrimer vectors for nucleic acid delivery in general.

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.

                                           ________________________________________________________________________

  • 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

  • February 2023:  Job opportunities

We are looking for motivated candidates with team-work spirit and strong background in chemistry, biology and/or biomedical science to join our group. The candidates will work on the design, synthesis, characterization and/or biomedical evaluation of innovative dendrimer nanosystems for the delivery of drugs, nucleic acid therapeutics and imaging agents, in the view to detecting and treating diseases such as life-threatening cancers, infectious diseases and neurodegenerative dementia. PhD and post-doc fellowship will be made available via Horizon Europe, French National Research Agency (ANR), Marie-Curie mobility program, Ligue contre le Cancer, Fondation de Recherche Médicale (FRM) and Fondation etc.

Interested and motivated candidates are welcome to contact us, and submit ONE single PDF file with CV including education and work experience, abstract of PhD thesis (< 1 page) or/and post-doc research (< 1 page) and three reference letters of the supervisors.

  • 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

  • Ling Peng, Zvi Hayouka, Dinesh Dhumal, Einav Cohen, Zhenbin Lyu, "SELF-ASSEMBLING DENDRIMERS AND ANTIBACTERIAL USES THEREOF", US patent application date: May 18, 2022; Application N°: 63/343,121. Applicant: The Hebrew University of Jerusalem; Filing country: Israel

 

  • Juan Iovanna, Jose Luis Neira, Yi Xia, Patricia Santofimia-Castaño, Wenjun Lan, Ling Peng, "NEW COMBINATION TO TREAT CANCER", European patent application date: Nov 27, 2019; Applicant: Inserm-Transfert; Filing country: France; Application N°: 2019, EP19306528.1.

 

  • 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.
  • 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.
  • 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.
  • Ling Peng, Fanqi Qu, Ruizhi Zhu, Johan Neyt, "Novel Viral Replication Inhibitors", 2007, GB0714649.1; 2008, PCT/BE2008/000059; 2009, WO/2009/015446.