Abstract 5069: Delivering docetaxel and curcumin via a nano-combination-therapy for modulating the progression of neuroblastoma
Authors: Fragassi Agnese , Di Francesco Martina , Pastorino Fabio , Ferreira Miguel , Di Francesco Valentina , Palange Anna Lisa , Celia Christian , Di Marzio Luisa , Cilli Michele , Bensa Veronica , Ponzoni Mirco , Decuzzi Paolo 
Published: June 2022

Abstract
Introduction: Neuroblastoma (NB) is a form of extracranial tumor derived from the sympathetic nervous system that affects most often infants and young children. It is a very heterogeneous tumor with different levels of aggressiveness. Despite the multiple therapeutic strategies (i.e. aggressive chemotherapy, surgery, radiotherapy, immunotherapy), the outcome in advanced stages or recurrent diseases is negative. New strategies are needed to improve the therapeutic efficacy of existing drugs and reduce their toxicity. Nanotechnology represents a good tool for reaching this goal. Taken this in mind, the focus of this experimental work was to engineer polymeric biodegradable nanomedicines for co-delivering anti-inflammatory and chemotherapeutic molecules to NB malignant masses. More specifically, the work focused on the synthesis, physico-chemical and biopharmaceutical characterization, in vitro testing and in vivo validation of nanomedicines loaded with the cytotoxic drug Docetaxel (DTXL) and the natural anti-inflammatory compound, Curcumin (CURC).
Methods: Four configurations of Spherical Polymeric Nanoparticles (SPNs) - loaded with CURC (CURC-SPNs), loaded with DTXL (DTXL-SPNs), loaded with the combination thereof (CURC/DTXL-SPNs), and empty (SPNs) - were synthesized using an oil-in water emulsion/solvent evaporation technique. SPNs size, zeta potential, and polydispersity index (PDI) were measured by dynamic light scattering. The toxicity of SPNs was determined by an MTT assay on the human NB cell line SH-SY5Y. For in vivo efficacy and biodistribution experiments, homozygous CD1 nu/nu athymic female mice (4 to 6-weeks old) were orthotopically injected with SH-SY5Y cells in the left adrenal gland.
Results: Empty, DTXL-SPNs, CURC-SPNs, and CURC/DTXL-SPNs were characterized by a narrow size distribution (PdI &lt; 0.15) with an average hydrodynamic diameter of about 185 nm. All the formulations showed a negative surface ζ-potential, associated with the carboxylate groups in the DSPE-PEG coating. A biphasic release profile was observed for all the 3 formulations, with almost 90% of the total drug mass released within the first 24 hours. In vivo results indicated that mice treated with CURC/DTXL -SPNs had a significant increase in life span as compared to untreated mice (control) (p=0.0002), mice treated with CURC-SPNs (p=0.0205), DTXL-SPNs (p=0.0391), and free DTXL (p=0.0054). Biodistribution experiments showed a 2% ID/g accumulation of the injected dose per tumor mass, regardless of the tumor development stage. This behavior is in agreement with results from a longitudinal Magnetic Resonance Imaging analysis of the malignant masses.
Conclusion: The obtained results would suggest that nanomedicines could effectively delivery two therapeutic molecules within the malignant mass and modulate its progression leading to a significant increase in overall survival.
Citation Format: Agnese Fragassi, Martina Di Francesco, Fabio Pastorino, Miguel Ferreira, Valentina Di Francesco, Anna Lisa Palange, Christian Celia, Luisa Di Marzio, Michele Cilli, Veronica Bensa, Mirco Ponzoni, Paolo Decuzzi. Delivering docetaxel and curcumin via a nano-combination-therapy for modulating the progression of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5069.