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A gene delivery system with autophagy blockade for enhanced anti-angiogenic therapy against Fusobacterium nucleatum-associated colorectal cancer.
- Source :
-
Acta biomaterialia [Acta Biomater] 2024 Jul 15; Vol. 183, pp. 278-291. Date of Electronic Publication: 2024 Jun 03. - Publication Year :
- 2024
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Abstract
- Anti-angiogenesis has emerged a promising strategy against colorectal cancer (CRC). However, the efficacy of anti-angiogenic therapy is greatly compromised by the up-regulated autophagy levels resulting from the evolutionary resistance mechanism and the presence of Fusobacterium nucleatum (F. nucleatum) in CRC. Herein, we report a cationic polymer capable of blocking autophagic flux to deliver plasmid DNA (pDNA) encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) for enhanced anti-angiogenic therapy against F. nucleatum-associated CRC. The autophagy-inhibiting cationic polymer, referred to as PNHCQ, is synthesized by conjugating hydroxychloroquine (HCQ) into 3,3'-diaminodipropylamine-pendant poly(β-benzyl-L-aspartate) (PAsp(Nors)), which can be assembled and electrostatically interacted with sFlt-1 plasmid to form PNHCQ/sFlt-1 polyplexes. Hydrophobic HCQ modification not only boosts transfection efficiency but confers autophagy inhibition activity to the polymer. Hyaluronic acid (HA) coating is further introduced to afford PNHCQ/sFlt-1@HA for improved tumor targeting without compromising on transfection. Consequently, PNHCQ/sFlt-1@HA demonstrates significant anti-tumor efficacy in F. nucleatum-colocalized HT29 mouse xenograft model by simultaneously exerting anti-angiogenic effects through sFlt-1 expression and down-regulating autophagy levels exacerbated by F. nucleatum challenge. The combination of anti-angiogenic gene delivery and overall autophagy blockade effectively sensitizes CRC tumors to anti-angiogenesis, providing an innovative approach for enhanced anti-angiogenic therapy against F. nucleatum-resident CRC. STATEMENT OF SIGNIFICANCE: Up-regulated autophagy level within tumors is considered responsible for the impaired efficacy of clinic antiangiogenic therapy against CRC colonized with pathogenic F. nucleatum. To tackle this problem, an autophagy-inhibiting cationic polymer is developed to enable efficient intracellular delivery of plasmid DNA encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) and enhance anti-angiogenic therapy against F. nucleatum-associated CRC. HA coating that can be degraded by tumor-enriching hyaluronidase is further introduced for improved tumor targeting without compromising transfection efficiency. The well-orchestrated polyplexes achieve considerable tumor accumulation, efficient in vivo transfection, and effectively reinforce the sensitivity of CRC to the sFlt-1-derived anti-angiogenic effects by significantly blocking overall autophagy flux exacerbated by F. nucleatum challenge, thus harvesting robust antitumor outcomes against F. nucleatum-resident CRC.<br />Competing Interests: Declaration of competing interest The authors declare no competing financial interest.<br /> (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Humans
Gene Transfer Techniques
Mice, Nude
Mice
Vascular Endothelial Growth Factor Receptor-1 metabolism
Genetic Therapy methods
Mice, Inbred BALB C
Neovascularization, Pathologic drug therapy
Neovascularization, Pathologic pathology
Plasmids
Angiogenesis Inhibitors pharmacology
Hydroxychloroquine pharmacology
Fusobacterium Infections drug therapy
Fusobacterium Infections complications
Fusobacterium nucleatum drug effects
Colorectal Neoplasms pathology
Colorectal Neoplasms drug therapy
Autophagy drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1878-7568
- Volume :
- 183
- Database :
- MEDLINE
- Journal :
- Acta biomaterialia
- Publication Type :
- Academic Journal
- Accession number :
- 38838905
- Full Text :
- https://doi.org/10.1016/j.actbio.2024.05.051