Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an MYCN Amplified Neuroblastoma Tumor
Received 13 May 2020
Accepted for publication 18 August 2020
Published 16 September 2020 Volume 2020:15 Pages 6873—6886
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo
Isabella Orienti,1 Giovanna Farruggia,1 Ferro Nguyen,2 Peng Guan,2 Natalia Calonghi,1 Venkatadri Kolla,2 Michael Chorny,2 Garrett M Brodeur2
1Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40127, Italy; 2Divisions of Oncology and Cardiology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Correspondence: Isabella Orienti Email firstname.lastname@example.org
Purpose: In a previous study, we demonstrated that the combination of fenretinide with lenalidomide, administered by a novel nanomicellar formulation (FLM), provided a strong antitumor effect in a neuroblastoma TrkB-expressing tumor. In this study, we tested the nanomicellar combination in an MYCN amplified neuroblastoma xenograft to assess its efficacy in different tumor genotypes and evaluate the interactions of the nanomicelles with the tumor cells.
Experimental Design: FLM was administered to mice bearing human NLF xenografts to evaluate its efficacy in comparison with the nanomicelles containing fenretinide alone (FM). Confocal laser-scanning fluorescence microscopy images of the NLF cells treated with FLM and FM allowed us to estimate the nanomicelle ability to transport the encapsulated drugs inside the tumor cells. Flow cytometric analysis of the cells from treated tumors was performed to assess the effect of treatment on GD2 expression and NK cell infiltration.
Results: FLM and FM decreased the growth of NLF xenografts at comparable extents during the treatment period. Afterwards, FLM induced a progressive tumor regression without regrowth, while FM treatment was followed by regrowth within 15– 20 days after the end of treatment. Both FLM and FM were able to penetrate the tumor cells transporting the encapsulated drugs. FLM transported higher amount of fenretinide inside the cells. Also, FLM treatment strongly increased GD2 expression in treated tumors and slightly decreased the NK infiltration compared to FM.
Conclusion: FLM treatment induced a superior antitumor response than FM in NLF xenografts, presumably due to the combined effects of fenretinide cytotoxicity and lenalidomide antiangiogenic activity. The ability of FLM to penetrate tumor cells, transporting the encapsulated drugs, substantially improved the therapeutic efficiency of this system. Moreover, the enhancement of GD2 expression in FLM treated tumors offers the possibility to further increase the antitumor effect by the use of anti-GD2 CAR-T cells and anti-GD2 antibodies in combination with FLM in multimodal therapies.
Keywords: nanomicelles, fenretinide–lenalidomide combination, neuroblastoma, antitumor activity, nanomicelle penetration in tumor cells, GD2 increased expression.