TPP-Based Nanovesicles Kill MDR Neuroblastoma Cells and Induce Moderate ROS Increase, While Exerting Low Toxicity...

Area of Science:

• Nanomedicine
• Pediatric Oncology
• Cancer Biology

Background:

• Neuroblastoma (NB) is a common childhood cancer with poor survival rates for high-risk (HR-NB) forms due to drug resistance.
• Existing treatments for HR-NB often lead to secondary cancers and limited efficacy against multi-drug-resistant (MDR) neuroblastoma.
• Novel therapeutic strategies are urgently needed to improve outcomes for children with HR-NB.

Purpose of the Study:

• To evaluate the in vitro efficacy and safety of triphenyl phosphonium (TPP)-based bola amphiphilic nanovesicles (BPPBs) against drug-sensitive and MDR neuroblastoma (NB) cell lines.
• To investigate the mechanism of BPPB's cytotoxic action, including the role of reactive oxygen species (ROS).
• To assess the potential clinical applicability of BPPBs by evaluating their toxicity in primary neuron and astrocyte cultures.

Main Methods:

• In vitro testing of BPPBs against drug-sensitive (HTLA 230) and MDR (HTLA ER) neuroblastoma cell lines to determine IC50 values.
• Apoptosis assays to confirm BPPB-induced cell death.
• Reactive oxygen species (ROS) monitoring and advanced analytical modeling to elucidate the cytotoxic mechanism.
• Assessment of BPPB toxicity on primary neuron and astrocyte cultures to calculate selectivity indices.

Main Results:

• BPPBs exhibited potent sub-micromolar IC50 values against drug-sensitive NB cells (0.4-0.9 µM) and low micromolar IC50 values against MDR NB cells (1.20-1.35 µM).
• BPPBs were confirmed to induce apoptosis in both sensitive and resistant NB cell populations.
• A ROS-dependent cytotoxic mechanism was identified for BPPB treatments.
• BPPBs demonstrated significant selectivity, with high selectivity index values (up to 23.7) in primary neuron and astrocyte cultures, alongside low haemolytic activity.

Conclusions:

• BPPBs represent a promising novel therapeutic agent for high-risk neuroblastoma, particularly against multi-drug-resistant forms.
• The observed ROS-dependent apoptosis induction and favorable safety profile in neural cells support further investigation of BPPBs.
• These findings lay the groundwork for potential clinical development of BPPBs as a new treatment option for pediatric neuroblastoma.