Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy

Intravesical chemotherapy is highly recommended after transurethral resection of bladder tumor for patients with bladder cancer (BCa). However, this localized adjuvant therapy has drawbacks of causing indiscriminate damage and inability to penetrate bladder mucosal. Fluorinated polylysine micelles (...

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Bibliographic Details
Published in:Theranostics 2024, Vol.14 (1), p.203-219
Main Authors: Tang, Dongdong, Yan, Yang, Li, Yangyang, Li, Yuqing, Tian, Junqiang, Yang, Li, Ding, Hui, Bashir, Ghassan, Zhou, Houhong, Ding, Qiuxia, Tao, Ran, Zhang, Shaohua, Wang, Zhiping, Wu, Song
Format: Article
Language:English
Subjects:
Apoptosis
Biocompatibility
Bladder cancer
Cancer therapies
Cell culture
Chemotherapy
CRISPR
Drug resistance
Gene therapy
Genomes
Medical prognosis
Molecular weight
Polymers
Proteins
Reagents
Research Paper
Tumors
Vectors (Biology)
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Summary:Intravesical chemotherapy is highly recommended after transurethral resection of bladder tumor for patients with bladder cancer (BCa). However, this localized adjuvant therapy has drawbacks of causing indiscriminate damage and inability to penetrate bladder mucosal. Fluorinated polylysine micelles (PLLF) were synthesized by reacting polylysine (PLL) with heptafluorobutyrate anhydride. Anti-apoptotic gene defender against cell death 1 (DAD1) was selected by different gene expression analysis between BCa patients and healthy individuals and identified by several biological function assays. The gene transfection ability of PLLF was verified by multiple and assays. The therapeutic efficiency of PLLF nanoparticles (NPs) targeting DAD1 were confirmed by intravesical administration using an orthotopic BCa mouse model. Decorated with fluorinated chains, PLL can self-assemble to form NPs and condense plasmids with excellent gene transfection efficiency . Loading with the CRISPR-Cas9 system designed to target DAD1 (Cas9-sgDAD1), PLLF/Cas9-sgDAD1 NPs strongly inhibited the expression of DAD1 in BCa cells and induced BCa cell apoptosis through the MAPK signaling pathway. Furthermore, intravesical administration of PLLF/Cas9-sgDAD1 NPs resulted in significant therapeutic outcomes without systemic toxicity . The synthetized PLLF can transmucosally deliver the CRISPR-Cas9 system into orthotopic BCa tissues to improve intravesical instillation therapy for BCa. This work presents a new strategy for targeting DAD1 gene in the intravesical therapy for BCa with high potential for clinical applications.
ISSN:1838-7640
1838-7640
DOI:10.7150/thno.88550