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

Bibliographische Detailangaben
Veröffentlicht in:	Advanced materials (Deerfield Beach, Fla.). - 1998. - 36(2024), 41 vom: 05. Okt., Seite e2404784
1. Verfasser:	Schneider, Paul (VerfasserIn)
Weitere Verfasser:	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
Format:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2024
Zugriff auf das übergeordnete Werk:	Advanced materials (Deerfield Beach, Fla.)
Schlagworte:	Journal Article desloratadine endosomal escape hepatocellular carcinoma polyion complex micelles polypept(o)ides siRNA co‐delivery RNA, Small Interfering Micelles

Beschreibung
Zusammenfassung:	© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH. 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
Beschreibung:	Date Completed 10.10.2024 Date Revised 10.10.2024 published: Print-Electronic Citation Status MEDLINE
ISSN:	1521-4095
DOI:	10.1002/adma.202404784