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

Published on Apr 22, 2020in Small11.459
· DOI :10.1002/SMLL.201906426
Daniela Di Paolo22
Estimated H-index: 22
(Istituto Giannina Gaslini),
D. Di Paolo5
Estimated H-index: 5
(Istituto Giannina Gaslini)
+ 17 AuthorsPatrizia Perri22
Estimated H-index: 22
(Istituto Giannina Gaslini)
Sources
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.
📖 Papers frequently viewed together
2015
1 Author (Farzaneh Moshiri)
66 Citations
References70
Newest
#1Fabio Pastorino (Istituto Giannina Gaslini)H-Index: 34
#2Chiara Brignole (Istituto Giannina Gaslini)H-Index: 29
Last. Mirco Ponzoni (Istituto Giannina Gaslini)H-Index: 55
view all 7 authors...
: Neuroblastoma is a rare pediatric cancer characterized by a wide clinical behavior and adverse outcome despite aggressive therapies. New approaches based on targeted drug delivery may improve efficacy and decrease toxicity of cancer therapy. Furthermore, nanotechnology offers additional potential developments for cancer imaging, diagnosis, and treatment. Following these lines, in the past years, innovative therapies based on the use of liposomes loaded with anticancer agents and functionalized...
18 CitationsSource
#1Ruth Ladenstein (Boston Children's Hospital)H-Index: 53
#2Ulrike PötschgerH-Index: 43
Last. Holger N. LodeH-Index: 39
view all 24 authors...
Background Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. Methods We did an international,...
107 CitationsSource
#1Mirco Ponzoni (Istituto Giannina Gaslini)H-Index: 55
#2Flavio Curnis (UniSR: Vita-Salute San Raffaele University)H-Index: 32
Last. Fabio Pastorino (Istituto Giannina Gaslini)H-Index: 34
view all 24 authors...
: Targeted delivery of anticancer drugs with nanocarriers can reduce side effects and ameliorate therapeutic efficacy. However, poorly perfused and dysfunctional tumor vessels limit the transport of the payload into solid tumors. The use of tumor-penetrating nanocarriers might enhance tumor uptake and antitumor effects. A peptide containing a tissue-penetrating (TP) consensus motif, capable of recognizing neuropilin-1, is here fused to a neuroblastoma-targeting peptide (pep) previously developed...
13 CitationsSource
#1Sara Nizzero (Rice University)H-Index: 8
#2Arturas Ziemys (Houston Methodist Hospital)H-Index: 17
Last. Mauro Ferrari (Cornell University)H-Index: 90
view all 3 authors...
Transport processes in cancer are the focus of transport oncophysics (TOP). In the TOP approach, the sequential negotiation of transport barriers is critical to both drug delivery and metastasis development. New and creative therapeutic opportunities are currently emerging, stimulated by the study of cancer hallmarks with the TOP approach.
21 CitationsSource
#1Rhamy Zeid (Harvard University)H-Index: 11
#2Matthew A. Lawlor (Harvard University)H-Index: 11
Last. James E. Bradner (Harvard University)H-Index: 108
view all 19 authors...
Amplification of the locus encoding the oncogenic transcription factor MYCN is a defining feature of high-risk neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of MYCN perturbation in neuroblastoma. At oncogenic levels, MYCN associates with E-box binding motifs in an affinity-dependent manner, binding to strong canonical E-boxes at promoters and invading abundant weaker non-canonical E-boxes clustered at enhancers. Loss of MYCN leads to a global reduction ...
88 CitationsSource
#1Yongbo Yu (Capital Medical University)H-Index: 5
#2Jie Zhang (Capital Medical University)H-Index: 10
Last. Xin Ni (Capital Medical University)H-Index: 15
view all 12 authors...
Background Neuroblastoma (NB) is the most common malignant tumor originating from the extracranial sympathetic nervous system in children. The molecular mechanisms underlying this disease are complex, and not completely understood.
22 CitationsSource
#1Rajen Mody (UM: University of Michigan)H-Index: 24
#2Arlene Naranjo (UF: University of Florida)H-Index: 28
Last. Rochelle Bagatell (Children's Hospital of Philadelphia)H-Index: 26
view all 14 authors...
Summary Background Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide has activity in these patients, and its acceptable toxicity profile makes it an excellent backbone for study of new agents. We aimed to test the addition of temsirolimus or dinutuximab to irinotecan–temozolomide in patients with relapsed or refractory neuroblastoma. Methods For this open-label, randomised, phase 2 selection design trial of the Children's ...
106 CitationsSource
#1Muhammad Shaalan Beg (UTSW: University of Texas Southwestern Medical Center)H-Index: 19
#2Andrew Brenner (University of Texas Health Science Center at San Antonio)H-Index: 28
Last. David S. Hong (University of Texas MD Anderson Cancer Center)H-Index: 79
view all 10 authors...
Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with so...
403 CitationsSource
#1Rajesha Rupaimoole (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 34
#2Frank J. Slack (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 87
MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic.
1,808 CitationsSource
#1Changshan Song (JNU: Jinan University)H-Index: 2
#2Pingfang LuH-Index: 3
Last. Zheng Wang (JNU: Jinan University)H-Index: 2
view all 6 authors...
Abstract Cisplatin is the most potent and widespread used chemotherapy drug for lung cancer treatment. However, a large proportion of NSCLC patients were insensitive to chemotherapy. This study explored the role of miR-34a in regulating sensitivity of NSCLC cells to cisplatin and its downstream targets. The quantitative PCR result showed that miR-34a expression was upregulated in cisplatin sensitive NSCLC patients compared cisplatin insensitive NSCLC controls. By applying loss-and-gain function ...
26 CitationsSource
Cited By7
Newest
#1William LiuH-Index: 7
#2Salida MirzoevaH-Index: 16
Last. Gayle E. WoloschakH-Index: 41
view all 22 authors...
Neuroblastoma is the most common extracranial solid malignancy in childhood which, despite the current progress in radiotherapy and chemotherapy protocols, still has a high mortality rate in high risk tumors. Nanomedicine offers exciting and unexploited opportunities to overcome the shortcomings of conventional medicine. The photocatalytic properties of Fe3O4 core-TiO2 shell nanocomposites and their potential for cell specific targeting suggest that nanoconstructs produced using Fe3O4 core-TiO2 ...
1 CitationsSource
#1Fabio Morandi (Istituto Giannina Gaslini)H-Index: 30
#2Veronica Bensa (Istituto Giannina Gaslini)
Last. Chiara Brignole (Istituto Giannina Gaslini)H-Index: 29
view all 8 authors...
Neuroblastoma (NB) is the most common extra-cranial solid tumor of pediatric age. The prognosis for high-risk NB patients remains poor, and new treatment strategies are desirable. The olive leaf extract (OLE) is constituted by phenolic compounds, whose health beneficial effects were reported. Here, the anti-tumor effects of OLE were investigated in vitro on a panel of NB cell lines in terms of (i) reduction of cell viability; (ii) inhibition of cell proliferation through cell cycle arrest; (iii)...
Source
#1Daniela Di Paolo (Istituto Giannina Gaslini)H-Index: 22
Last. Cristina BorziH-Index: 8
view all 17 authors...
Lung cancer is the leading cause of cancer-related death worldwide. Late diagnosis and metastatic dissemination contribute to its low survival rate. Since microRNA (miRNA) deregulation triggers lung carcinogenesis, miRNAs might represent an interesting therapeutic tool for lung cancer management. We identified seven miRNAs, including miR-126-3p and miR-221-3p, that are deregulated in tumours compared with normal tissues in a series of 38 non-small-cell lung cancer patients. A negative correlatio...
Source
#1Irene Paraboschi (UCL: University College London)
Source
#1Chiara Brignole (Istituto Giannina Gaslini)H-Index: 29
#2Veronica Bensa (Istituto Giannina Gaslini)
Last. Fabio Pastorino (Istituto Giannina Gaslini)H-Index: 34
view all 24 authors...
BACKGROUND Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Nucleolin (NCL) is a protein overexpressed and partially localized on the cell surface of tumor cells of adult cancers. Little is known about NCL and pediatric tumors and nothing is reported about cell surface NCL and NB. METHODS NB cell lines, Schwannian stroma-poor NB tumors and bone marrow (BM)-infiltrating NB cells were evaluated for the expression of cell surface NCL by Flo...
1 CitationsSource
The functional involvement of microRNAs in human neoplasia has raised in the last years an increasing interest in the scientific community toward the potential application in clinics as therapeutic tools. Indeed, the possibility to modulate their expression to re-establish a lost equilibrium and counteract tumor growth and dissemination, and/or to improve responsiveness to standard therapies, is promising and fascinating. However, several issues need to be taken into account such as factors rela...
3 CitationsSource
#1Andrea LampisH-Index: 19
#2Jens C. Hahne (ICR: Institute of Cancer Research)H-Index: 23
Last. Nicola ValeriH-Index: 32
view all 4 authors...
MicroRNAs are small RNA transcripts involved in fine-tuning of several cellular mechanisms and pathways crucial for maintaining cells' homeostasis like apoptosis, differentiation, inflammation and cell-cycle regulation. They act by regulation of gene expression at post-transcriptional level through fine-tuning of target proteins expression. Expression of microRNAs is cell-type specific and since their discovery they have been proven to be deregulated in various disorders including cancer. Severa...
7 CitationsSource