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Aptamer sgc8-Modified PAMAM Nanoparticles for Targeted siRNA Delivery to Inhibit BCL11B in T-Cell Acute Lymphoblastic
Xiangbo Zeng1,2, Dingrui Nie1,3, Zhen Liu2
1Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, People's Republic of China.
Introduction:
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disease with limited targeted therapy options. Overexpression of B-cell lymphoma/leukemia 11B is frequently observed in T-ALL and contributes to leukemogenesis. Knockdown of BCL11B inhibits T-ALL cell proliferation and induces apoptosis, making it a potential therapeutic target. However, the clinical application of siRNA therapies is hindered by challenges such as poor delivery efficiency and limited clinical outcomes.
Methods:
We developed a targeted delivery system for BCL11B siRNA (siBCL11B) using generation 5 polyamidoamine (G5-PAMAM) dendrimers conjugated with the sgc8 aptamer, which specifically binds to the T-ALL cell membrane protein PTK7. This nanoparticle, designated G5-sgc8-siBCL11B, was designed to selectively deliver siRNA to T-ALL cells. In vitro and in vivo experiments were conducted to evaluate its therapeutic efficacy and safety.
Results:
We demonstrate that sgc8-conjugated siBCL11B nanoparticles selectively and efficiently target BCL11B-overexpressing T-ALL cells, significantly inhibiting cell viability and promoting apoptosis while exhibiting minimal impact on the viability of normal T cells. In T-ALL mouse model studies, G5-sgc8-siBCL11B and G5-siBCL11B significantly inhibited the progression of T-ALL in vivo, extending the survival of mice compared to the control (CTR), G5, and G5-sgc8 groups. Although there was no significant difference in survival between the G5-sgc8-siBCL11B and G5-siBCL11B groups, a trend towards improved survival was observed (p = 0.0993).
Conclusion:
The G5-sgc8-siBCL11B nanoparticle system demonstrated efficient delivery and significant therapeutic efficacy, highlighting its potential as a promising novel approach for the treatment of T-ALL.
