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Combined Replenishment of miR-34a and let-7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma
Daniela Di Paolo1, Fabio Pastorino1, Chiara Brignole1
1Laboratory of Experimental Therapies in Oncology, IRCCS Istituto Giannina Gaslini, Genoa, 16147, Italy.
Abstract:
Neuroblastoma (NB) tumor substantially contributes to childhood cancer mortality. The design of novel drugs targeted to specific molecular alterations becomes mandatory, especially for high-risk patients burdened by chemoresistant relapse. The dysregulated expression of MYCN, ALK, and LIN28B and the diminished levels of miR-34a and let-7b are oncogenic in NB. Due to the ability of miRNA-mimics to recover the tumor suppression functions of miRNAs underexpressed into cancer cells, safe and efficient nanocarriers selectively targeted to NB cells and tested in clinically relevant mouse models are developed. The technology exploits the nucleic acids negative charges to build coated-cationic liposomes, then functionalized with antibodies against GD2 receptor. The replenishment of miR-34a and let-7b by NB-targeted nanoparticles, individually and more powerfully in combination, significantly reduces cell division, proliferation, neoangiogenesis, tumor growth and burden, and induces apoptosis in orthotopic xenografts and improves mice survival in pseudometastatic models. These functional effects highlight a cooperative down-modulation of MYCN and its down-stream targets, ALK and LIN28B, exerted by miR-34a and let-7b that reactivate regulatory networks leading to a favorable therapeutic response. These findings demonstrate a promising therapeutic efficacy of miR-34a and let-7b combined replacement and support its clinical application as adjuvant therapy for high-risk NB patients.
Insights
Novel nanoparticles deliver miR-34a and let-7b to neuroblastoma (NB) cells, reducing tumor growth and improving survival. This miRNA replacement therapy shows promise for high-risk neuroblastoma patients.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Neuroblastoma (NB) is a significant cause of childhood cancer mortality, particularly in high-risk patients with chemoresistant relapse.
- Oncogenic factors in NB include dysregulated MYCN, ALK, LIN28B expression, and diminished miR-34a and let-7b levels.
Purpose of the Study:
- To develop safe and efficient nanocarriers for targeted delivery of miRNA mimics (miR-34a and let-7b) to neuroblastoma cells.
- To evaluate the therapeutic efficacy of miRNA replacement therapy in preclinical neuroblastoma models.
Main Methods:
- Development of cationic liposomes coated with antibodies against the GD2 receptor for selective NB cell targeting.
- Functionalization of nanocarriers to deliver miR-34a and let-7b mimics.
- Testing in orthotopic xenograft and pseudometastatic mouse models of neuroblastoma.
Main Results:
- Nanoparticle-mediated delivery of miR-34a and let-7b significantly reduced cell proliferation, neoangiogenesis, tumor growth, and induced apoptosis.
- Combined delivery of both miRNAs demonstrated enhanced therapeutic effects and improved survival in mouse models.
- Therapeutic effects correlated with cooperative down-modulation of MYCN, ALK, and LIN28B.
Conclusions:
- Combined replacement of miR-34a and let-7b using targeted nanoparticles demonstrates significant therapeutic efficacy against neuroblastoma.
- This approach reactivates regulatory networks, leading to a favorable therapeutic response and supporting clinical application as adjuvant therapy for high-risk NB.
