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Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.
Schneider, Paul; Zhang, Heyang; Simic, Leon; Dai, Zhuqing; Schrörs, Barbara; Akilli-Öztürk, Özlem; Lin, Jian; Durak, Feyza; Schunke, Jenny; Bolduan, Vanessa; Bogaert, Bram; Schwiertz, David; Schäfer, Gabriela; Bros, Matthias; Grabbe, Stephan; Schattenberg, Jörn Markus; Raemdonck, Koen; Koynov, Kaloian; Diken, Mustafa; Kaps, Leonard; Barz, Matthias.
Afiliação
  • Schneider P; Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, 55128, Mainz, Germany.
  • Zhang H; Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, 2333CC, Netherlands.
  • Simic L; Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, 55128, Mainz, Germany.
  • Dai Z; Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, 2333CC, Netherlands.
  • Schrörs B; Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, 2333CC, Netherlands.
  • Akilli-Öztürk Ö; Biosampling Unit, TRON gGmbH - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Freiligrathstr. 12, 55131, Mainz, Germany.
  • Lin J; Biosampling Unit, TRON gGmbH - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Freiligrathstr. 12, 55131, Mainz, Germany.
  • Durak F; Max Planck Institute for Polymer Research, Physics at Interphases, Ackermannweg 10, 55128, Mainz, Germany.
  • Schunke J; Biosampling Unit, TRON gGmbH - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Freiligrathstr. 12, 55131, Mainz, Germany.
  • Bolduan V; Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, 55128, Mainz, Germany.
  • Bogaert B; Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, 55128, Mainz, Germany.
  • Schwiertz D; Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, 9000, Belgium.
  • Schäfer G; Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, 55128, Mainz, Germany.
  • Bros M; Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, 2333CC, Netherlands.
  • Grabbe S; Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, 55128, Mainz, Germany.
  • Schattenberg JM; Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, 2333CC, Netherlands.
  • Raemdonck K; Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, 55128, Mainz, Germany.
  • Koynov K; Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, 55128, Mainz, Germany.
  • Diken M; Department of Medicine II, Saarland University Medical Center, Saarland University, 66421, Homburg, Germany.
  • Kaps L; Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, 9000, Belgium.
  • Barz M; Max Planck Institute for Polymer Research, Physics at Interphases, Ackermannweg 10, 55128, Mainz, Germany.
Adv Mater ; : e2404784, 2024 Jun 21.
Article em En | MEDLINE | ID: mdl-38958110
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Adv Mater Assunto da revista: BIOFISICA / QUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Alemanha
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Adv Mater Assunto da revista: BIOFISICA / QUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Alemanha