Cargando…
A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model
PURPOSE: Currently >50% of high-risk neuroblastoma (NB) patients, despite intensive therapy and initial partial or complete response, develop recurrent NB due to the persistence of minimal residual disease (MRD) that is resistant to conventional antitumor drugs. Indeed, their low therapeutic inde...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930389/ https://www.ncbi.nlm.nih.gov/pubmed/31908416 http://dx.doi.org/10.2147/DDDT.S221909 |
_version_ | 1783482880305922048 |
---|---|
author | Orienti, Isabella Nguyen, Ferro Guan, Peng Kolla, Venkatadri Calonghi, Natalia Farruggia, Giovanna Chorny, Michael Brodeur, Garrett M |
author_facet | Orienti, Isabella Nguyen, Ferro Guan, Peng Kolla, Venkatadri Calonghi, Natalia Farruggia, Giovanna Chorny, Michael Brodeur, Garrett M |
author_sort | Orienti, Isabella |
collection | PubMed |
description | PURPOSE: Currently >50% of high-risk neuroblastoma (NB) patients, despite intensive therapy and initial partial or complete response, develop recurrent NB due to the persistence of minimal residual disease (MRD) that is resistant to conventional antitumor drugs. Indeed, their low therapeutic index prevents drug-dose escalation and protracted administration schedules, as would be required for MRD treatment. Thus, more effective and less toxic therapies are urgently needed for the management of MRD. To address this aim, we evaluated a new combination of fenretinide and lenalidomide, both endowed with antitumor activity and low-toxicity profiles. New nanomicelles were prepared as carriers for this combination to maximize bioavailability and accumulation at the tumor site because of the enhanced permeability and retention (EPR) effect. EXPERIMENTAL DESIGN: New nanomicelles containing the fenretinide–lenalidomide combination (FLnMs) were prepared by a one-step method, providing high drug encapsulation and micelle dimensions suitable for tumor accumulation. Their administration to mice bearing human NB xenografts allowed us to evaluate their efficacy in comparison with the nanomicelles containing fenretinide alone (FnMs). RESULTS: Treatment by FLnMs significantly decreased the tumor growth of NB xenografts. FLnMs were more active than FnMs despite comparable fenretinide concentrations in tumors, and lenalidomide alone did not show cytotoxic activity in vitro against NB cells. The tumor mass at the end of treatment with FLnMs was predominantly necrotic, with a decreased Ki-67 proliferation index. CONCLUSION: FLnMs provided superior antitumor efficacy in NB xenografts compared to FnMs. The enhanced efficacy of the combination was likely due to the antiangiogenic effect of lenalidomide added to the cytotoxic effect of fenretinide. This new nanomicellar combination is characterized by a low-toxicity profile and offers a novel therapeutic option for the treatment of high-risk tumors where the persistence of MRD requires repeated administrations of therapeutic agents over long periods of time to avoid recurrent disease. |
format | Online Article Text |
id | pubmed-6930389 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-69303892020-01-06 A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model Orienti, Isabella Nguyen, Ferro Guan, Peng Kolla, Venkatadri Calonghi, Natalia Farruggia, Giovanna Chorny, Michael Brodeur, Garrett M Drug Des Devel Ther Original Research PURPOSE: Currently >50% of high-risk neuroblastoma (NB) patients, despite intensive therapy and initial partial or complete response, develop recurrent NB due to the persistence of minimal residual disease (MRD) that is resistant to conventional antitumor drugs. Indeed, their low therapeutic index prevents drug-dose escalation and protracted administration schedules, as would be required for MRD treatment. Thus, more effective and less toxic therapies are urgently needed for the management of MRD. To address this aim, we evaluated a new combination of fenretinide and lenalidomide, both endowed with antitumor activity and low-toxicity profiles. New nanomicelles were prepared as carriers for this combination to maximize bioavailability and accumulation at the tumor site because of the enhanced permeability and retention (EPR) effect. EXPERIMENTAL DESIGN: New nanomicelles containing the fenretinide–lenalidomide combination (FLnMs) were prepared by a one-step method, providing high drug encapsulation and micelle dimensions suitable for tumor accumulation. Their administration to mice bearing human NB xenografts allowed us to evaluate their efficacy in comparison with the nanomicelles containing fenretinide alone (FnMs). RESULTS: Treatment by FLnMs significantly decreased the tumor growth of NB xenografts. FLnMs were more active than FnMs despite comparable fenretinide concentrations in tumors, and lenalidomide alone did not show cytotoxic activity in vitro against NB cells. The tumor mass at the end of treatment with FLnMs was predominantly necrotic, with a decreased Ki-67 proliferation index. CONCLUSION: FLnMs provided superior antitumor efficacy in NB xenografts compared to FnMs. The enhanced efficacy of the combination was likely due to the antiangiogenic effect of lenalidomide added to the cytotoxic effect of fenretinide. This new nanomicellar combination is characterized by a low-toxicity profile and offers a novel therapeutic option for the treatment of high-risk tumors where the persistence of MRD requires repeated administrations of therapeutic agents over long periods of time to avoid recurrent disease. Dove 2019-12-19 /pmc/articles/PMC6930389/ /pubmed/31908416 http://dx.doi.org/10.2147/DDDT.S221909 Text en © 2019 Orienti et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Orienti, Isabella Nguyen, Ferro Guan, Peng Kolla, Venkatadri Calonghi, Natalia Farruggia, Giovanna Chorny, Michael Brodeur, Garrett M A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model |
title | A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model |
title_full | A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model |
title_fullStr | A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model |
title_full_unstemmed | A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model |
title_short | A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model |
title_sort | novel nanomicellar combination of fenretinide and lenalidomide shows marked antitumor activity in a neuroblastoma xenograft model |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930389/ https://www.ncbi.nlm.nih.gov/pubmed/31908416 http://dx.doi.org/10.2147/DDDT.S221909 |
work_keys_str_mv | AT orientiisabella anovelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT nguyenferro anovelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT guanpeng anovelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT kollavenkatadri anovelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT calonghinatalia anovelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT farruggiagiovanna anovelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT chornymichael anovelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT brodeurgarrettm anovelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT orientiisabella novelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT nguyenferro novelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT guanpeng novelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT kollavenkatadri novelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT calonghinatalia novelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT farruggiagiovanna novelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT chornymichael novelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel AT brodeurgarrettm novelnanomicellarcombinationoffenretinideandlenalidomideshowsmarkedantitumoractivityinaneuroblastomaxenograftmodel |