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Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy.
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.
Afiliación
  • Tang D; Department of Urology, Lanzhou University Second Hospital, Lanzhou 730030, China.
  • Yan Y; Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen University, Shenzhen 518000, China.
  • Li Y; Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • Li Y; Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen University, Shenzhen 518000, China.
  • Tian J; Songshan Lake Materials Laboratory, Dongguan, 523808, China.
  • Yang L; Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen University, Shenzhen 518000, China.
  • Ding H; Department of Urology, South China Hospital, Medical School, Shenzhen University, Shenzhen 518000, China.
  • Bashir G; Department of Urology, Lanzhou University Second Hospital, Lanzhou 730030, China.
  • Zhou H; Department of Urology, Lanzhou University Second Hospital, Lanzhou 730030, China.
  • Ding Q; Department of Urology, Lanzhou University Second Hospital, Lanzhou 730030, China.
  • Tao R; Department of Urology, South China Hospital, Medical School, Shenzhen University, Shenzhen 518000, China.
  • Zhang S; Department of Urology, South China Hospital, Medical School, Shenzhen University, Shenzhen 518000, China.
  • Wang Z; Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen University, Shenzhen 518000, China.
  • Wu S; Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen University, Shenzhen 518000, China.
Theranostics ; 14(1): 203-219, 2024.
Article en En | MEDLINE | ID: mdl-38164146
ABSTRACT

Background:

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.

Methods:

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 in vitro and in vivo assays. The therapeutic efficiency of PLLF nanoparticles (NPs) targeting DAD1 were confirmed by intravesical administration using an orthotopic BCa mouse model.

Results:

Decorated with fluorinated chains, PLL can self-assemble to form NPs and condense plasmids with excellent gene transfection efficiency in vitro. 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 in vivo.

Conclusion:

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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Vejiga Urinaria / Nanopartículas Límite: Animals / Humans Idioma: En Revista: Theranostics Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Vejiga Urinaria / Nanopartículas Límite: Animals / Humans Idioma: En Revista: Theranostics Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia