Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer‐Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma

Advanced Materials, vol. 36, pp. e2404784

Abstract

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-π interaction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model.

Authors 20

1. Paul M. Schneider

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

2. Heyang Zhang corresponding Aachen

   Leiden University

   Affiliation as printed

   Division of BioTherapeutics Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden 2333CC Netherlands

3. Leon Simić Aachen

   Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

   Division of BioTherapeutics Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden 2333CC Netherlands

4. Barbara Schrörs

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz

   Affiliation as printed

   Biosampling Unit TRON gGmbH ‐ Translational Oncology at the University Medical Center of the Johannes Gutenberg University Freiligrathstr. 12 55131 Mainz Germany

5. Özlem Akilli‐Öztürk

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz

   Affiliation as printed

   Biosampling Unit TRON gGmbH ‐ Translational Oncology at the University Medical Center of the Johannes Gutenberg University Freiligrathstr. 12 55131 Mainz Germany

6. Lin Jian

   Max Planck Institute for Polymer Research

   Affiliation as printed

   Max Planck Institute for Polymer Research, Physics at Interphases Ackermannweg 10 55128 Mainz Germany

7. Feyza Durak

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz

   Affiliation as printed

   Biosampling Unit TRON gGmbH ‐ Translational Oncology at the University Medical Center of the Johannes Gutenberg University Freiligrathstr. 12 55131 Mainz Germany

8. Jenny Schunke

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

9. Vanessa Bolduan

   Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

10. Bram Bogaert

    Ghent University

    Affiliation as printed

    Ghent Research Group on Nanomedicines Laboratory of General Biochemistry and Physical Pharmacy Faculty of Pharmaceutical Sciences Ghent University Ghent 9000 Belgium

11. David Schwiertz Aachen

    Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

    Division of BioTherapeutics Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden 2333CC Netherlands

12. Gabriela Giannina Schäfer Aachen

    Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

    Division of BioTherapeutics Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden 2333CC Netherlands

13. Matthias Bros

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

14. Stephan Grabbe

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

15. Jörn Markus Schattenberg

    Universitätsklinikum des Saarlandes · Saarland University

    Affiliation as printed

    Department of Medicine II Saarland University Medical Center Saarland University 66421 Homburg Germany

16. Koen Raemdonck

    Ghent University

    Affiliation as printed

    Ghent Research Group on Nanomedicines Laboratory of General Biochemistry and Physical Pharmacy Faculty of Pharmaceutical Sciences Ghent University Ghent 9000 Belgium

17. Kaloian Koynov

    Max Planck Institute for Polymer Research

    Affiliation as printed

    Max Planck Institute for Polymer Research, Physics at Interphases Ackermannweg 10 55128 Mainz Germany

18. Mustafa Diken

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz

    Affiliation as printed

    Biosampling Unit TRON gGmbH ‐ Translational Oncology at the University Medical Center of the Johannes Gutenberg University Freiligrathstr. 12 55131 Mainz Germany

19. Leonard Kaps corresponding

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz · Universitätsklinikum des Saarlandes · Saarland University

    Affiliation as printed

    Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

    Department of Medicine II Saarland University Medical Center Saarland University 66421 Homburg Germany

20. Matthias Barz corresponding Aachen

    Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Department of Dermatology University Medical Center of the Johannes Gutenberg‐University 55128 Mainz Germany

    Division of BioTherapeutics Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden 2333CC Netherlands