Neuroblastoma is an embryonal tumour originating from the simpatico-adrenal lineage of the neural crest. It approximately accounts for about 15% of all paediatric oncology deaths. Metastatic Neuroblastoma tumours at diagnosis remains a clinical challenge, despite advances in multimodal therapy. Retinoids are a class of compounds known to induce both terminal differentiation and apoptosis/necrosis of neuroblastoma cells. Among them, fenretinide (4-HPR), has been considered one of the most promising chemopreventive agent but it is partially efficacious due to both a low water solubility and a rapid metabolism. Here, we have developed a novel micellar HPR formulation by which the drug was encapsulated into mixed micelles formed by 1,2-distearoyl-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG) and Vitamin E D‑α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) in 1:2 molar ratio. These amphiphilic molecules, able to self-assemble above the critical micellar concentration (CMC) in nanometric aggregates of about 13 nm (Figure 1), are characterized by a hydrophilic corona and a hydrophobic core which can host poorly soluble drugs. The loaded micelles were prepared according to the solvent casting method by dissolving 4-HPR in chloroform at different drug: micelle forming material w:w ratios (from 1:10 to 1:50) [1]. Then the film was rehydrated with Milli-Q water and the drug content in solution was assessed after filtration (0.22 µm) to remove the excess non-encapsulated drug and used for further characterizations. Aliquots of each sample were diluted in methanol to disrupt the micelles and release the drug. The organic solutions were then spectrophotometrically analyzed to asses 4-HPR total solubility and drug entrapment efficiency (EE %). The particle sizes as well as polydispersion indexes and zeta potential of the preparations were measured by a Malvern Nano ZS90 light scattering apparatus. Size analysis was performed on both fresh dispersions and on rehydrated freeze-dried powders. The thermal properties of lyophilized 4-HPR micelles, free 4-HPR and TPGS-DSPE-PEG, and of physical mixtures of the raw materials were studied. The obtained results showed the considerable effect of TPGS-DSPE-PEG on 4-HPR total solubility. At the maximum ratio tested, total drug solubility reached the value of about 1.35 mM, establishing an improvement by 314 folds.
Preparation of Vitamin E D--Tocopheryl Polyethylene Glycol Succinate (TPGS)-based mixed micelles for the enhancement of Fenretinide solubility
Guendalina Zuccari;Alice Balboni;Giorgia Ailuno;Sara Baldassari;Gabriele Caviglioli
2021-01-01
Abstract
Neuroblastoma is an embryonal tumour originating from the simpatico-adrenal lineage of the neural crest. It approximately accounts for about 15% of all paediatric oncology deaths. Metastatic Neuroblastoma tumours at diagnosis remains a clinical challenge, despite advances in multimodal therapy. Retinoids are a class of compounds known to induce both terminal differentiation and apoptosis/necrosis of neuroblastoma cells. Among them, fenretinide (4-HPR), has been considered one of the most promising chemopreventive agent but it is partially efficacious due to both a low water solubility and a rapid metabolism. Here, we have developed a novel micellar HPR formulation by which the drug was encapsulated into mixed micelles formed by 1,2-distearoyl-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG) and Vitamin E D‑α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) in 1:2 molar ratio. These amphiphilic molecules, able to self-assemble above the critical micellar concentration (CMC) in nanometric aggregates of about 13 nm (Figure 1), are characterized by a hydrophilic corona and a hydrophobic core which can host poorly soluble drugs. The loaded micelles were prepared according to the solvent casting method by dissolving 4-HPR in chloroform at different drug: micelle forming material w:w ratios (from 1:10 to 1:50) [1]. Then the film was rehydrated with Milli-Q water and the drug content in solution was assessed after filtration (0.22 µm) to remove the excess non-encapsulated drug and used for further characterizations. Aliquots of each sample were diluted in methanol to disrupt the micelles and release the drug. The organic solutions were then spectrophotometrically analyzed to asses 4-HPR total solubility and drug entrapment efficiency (EE %). The particle sizes as well as polydispersion indexes and zeta potential of the preparations were measured by a Malvern Nano ZS90 light scattering apparatus. Size analysis was performed on both fresh dispersions and on rehydrated freeze-dried powders. The thermal properties of lyophilized 4-HPR micelles, free 4-HPR and TPGS-DSPE-PEG, and of physical mixtures of the raw materials were studied. The obtained results showed the considerable effect of TPGS-DSPE-PEG on 4-HPR total solubility. At the maximum ratio tested, total drug solubility reached the value of about 1.35 mM, establishing an improvement by 314 folds.
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