Neuroblastoma (NB) is a children malignant tumour having an incidence of about 15,000 new cases per year worldwide and a survival rate < 50%, due to therapy-induced secondary tumorigenesis and emerging multidrug-resistant (MDR) NB cells, in the high-risk (HR-NB) forms. Recently, we were testing in vitro the effects of triphenyl phosphonium (TPP)-based bola amphiphilic nanovesicles, towards various drug-sensitive and MDR cancer cell lines1,2,3. Such vesicles self-form by dispersing in water the sterically hindered quaternary phosphonium salt, 1,1-(1,12-dodecanediyl)-bis-[1,1,1]-triphenyl phosphonium di-bromide (BPPB). It was obtained as hygroscopic low-melting white foam by reacting 1,12-dibromo-dodecane with triphenylphosphine in ethanol (EtOH), at reflux for 48 h4 according to Scheme 1. Scheme 1. Synthetic route to achieve BPPB. ATR-FTIR, NMR, UV, FIA-MS (ESI) and elemental analysis confirmed its structure, while DLS analyses showed spherical vesicles of 45 nm in solution, having positive ζ of +18 mV4. Here, BPPB vesicles (BPPBVs) were tested in vitro against both drug-sensitive HTLA 230 human stage-IV and MDR HTLA ER, HR-NB cells, observing IC50 values of 0.4-0.9 and 1.20-1.35 µM, respectively. We have demonstrated that BPPBVs kill both cell populations by an apoptotic mechanism without necrosis, sustained by reactive oxygen species (ROS) overproduction. As a novelty, by an analytical approach, a correlation study was carried out to verify if BPPBVs cytotoxic effects could depend on their concentrations, exposure times and/or ROS overproduction and if ROS increase could depend on BPPBV concentrations and/or time exposure. To better support the potential clinical development of BPPBVs as a new therapeutic option to treat MDR HR-NB, their effects were tested on primary astrocytes and neurons, observing appreciable and good tolerability in neurons and astrocytes respectively, allowing selectivity index values up to 23.7. These in vitro results associated to the low haemolytic activity of BPPB, previously reported1,2,3,4 pave the way for future in vivo investigations and, upon confirmation, for the possible development of BPPB as a novel therapeutic strategy to treat MDR HR-NB. References: [1] S. Alfei, B. Marengo, et al. Nanomaterials 2024, 14, 1505. https://doi.org/10.3390/nano14181505. [2] S. Alfei, B. Marengo, et al. Int. J. Mol. Sci. 2024, 25, 10071. https://doi.org/10.3390/ijms251810071. [3] S. Alfei, B. Marengo, et al. Int. J. Mol. Sci. 2025, 26, 3227. https://doi.org/10.3390/ijms26073227 [4] S. Alfei, A.M. Schito, et al. Nanomaterials 2024, 14, 1351. https://doi.org/10.3390/nano14161351
Synthesized Triphenyl-phosphonium-Based Nanovesicles Induce Apoptotic Death in MDR Neuroblastoma Cells, While Exert Low Toxicity Towards Primary Cell Cultures
Silvana Alfei;Barbara Marengo;Marco Milanese;Cinzia Domenicotti
2025-01-01
Abstract
Neuroblastoma (NB) is a children malignant tumour having an incidence of about 15,000 new cases per year worldwide and a survival rate < 50%, due to therapy-induced secondary tumorigenesis and emerging multidrug-resistant (MDR) NB cells, in the high-risk (HR-NB) forms. Recently, we were testing in vitro the effects of triphenyl phosphonium (TPP)-based bola amphiphilic nanovesicles, towards various drug-sensitive and MDR cancer cell lines1,2,3. Such vesicles self-form by dispersing in water the sterically hindered quaternary phosphonium salt, 1,1-(1,12-dodecanediyl)-bis-[1,1,1]-triphenyl phosphonium di-bromide (BPPB). It was obtained as hygroscopic low-melting white foam by reacting 1,12-dibromo-dodecane with triphenylphosphine in ethanol (EtOH), at reflux for 48 h4 according to Scheme 1. Scheme 1. Synthetic route to achieve BPPB. ATR-FTIR, NMR, UV, FIA-MS (ESI) and elemental analysis confirmed its structure, while DLS analyses showed spherical vesicles of 45 nm in solution, having positive ζ of +18 mV4. Here, BPPB vesicles (BPPBVs) were tested in vitro against both drug-sensitive HTLA 230 human stage-IV and MDR HTLA ER, HR-NB cells, observing IC50 values of 0.4-0.9 and 1.20-1.35 µM, respectively. We have demonstrated that BPPBVs kill both cell populations by an apoptotic mechanism without necrosis, sustained by reactive oxygen species (ROS) overproduction. As a novelty, by an analytical approach, a correlation study was carried out to verify if BPPBVs cytotoxic effects could depend on their concentrations, exposure times and/or ROS overproduction and if ROS increase could depend on BPPBV concentrations and/or time exposure. To better support the potential clinical development of BPPBVs as a new therapeutic option to treat MDR HR-NB, their effects were tested on primary astrocytes and neurons, observing appreciable and good tolerability in neurons and astrocytes respectively, allowing selectivity index values up to 23.7. These in vitro results associated to the low haemolytic activity of BPPB, previously reported1,2,3,4 pave the way for future in vivo investigations and, upon confirmation, for the possible development of BPPB as a novel therapeutic strategy to treat MDR HR-NB. References: [1] S. Alfei, B. Marengo, et al. Nanomaterials 2024, 14, 1505. https://doi.org/10.3390/nano14181505. [2] S. Alfei, B. Marengo, et al. Int. J. Mol. Sci. 2024, 25, 10071. https://doi.org/10.3390/ijms251810071. [3] S. Alfei, B. Marengo, et al. Int. J. Mol. Sci. 2025, 26, 3227. https://doi.org/10.3390/ijms26073227 [4] S. Alfei, A.M. Schito, et al. Nanomaterials 2024, 14, 1351. https://doi.org/10.3390/nano14161351
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