Combined Replenishment of miR-34a and let-7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models

Daniela Di Paolo, Fabio Pastorino, Chiara Brignole, Maria Valeria Corrias, Laura Emionite, Michele Cilli, Roberto Tamma, Leslie Priddy, Adriana Amaro, Davide Ferrari, Roberto Marotta, Elisa Ferretti, Ulrich Pfeffer, Domenico Ribatti, Angela Rita Sementa, David Brown, Naohiko Ikegaki, Hiroyuki Shimada, Mirco Ponzoni, Patrizia Perri

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalSmall
DOIs
Publication statusAccepted/In press - Jan 1 2020

Keywords

  • let-7b
  • miR-34a
  • miRNA mimics delivery
  • neuroblastoma
  • targeted nanoparticles

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Chemistry(all)
  • Materials Science(all)

Fingerprint Dive into the research topics of 'Combined Replenishment of miR-34a and let-7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models'. Together they form a unique fingerprint.

  • Cite this