pH-Responsive Polypropylene Sulfide Magnetic Nanocarrier-Mediated Chemo-Hyperthermia Kills Breast Cancer Stem Cells by Long-Term Reversal of Multidrug Resistance and Chemotherapy Resensitization.

Cancer stem cells (CSCs) present a formidable challenge in cancer treatment due to their inherent resistance to chemotherapy, primarily driven by the overexpression of ABC transporters and multidrug resistance (MDR). Despite extensive research on pharmacological small-molecule inhibitors, effectively managing MDR and improving chemotherapeutic outcomes remain elusive. On the other hand, magnetic hyperthermia (MHT) holds great promise as a cancer therapeutic, but there is limited research on its potential to reverse MDR in breast CSCs and effectively eliminate CSCs through combined chemo-hyperthermia. To address these gaps, we developed tumor microenvironment-sensitive, drug-loaded poly(propylene sulfide) (PPS)-coated magnetic nanoparticles (PPS-MnFe). These nanoparticles were employed to investigate hyperthermia sensitivity and MDR reversion in breast CSCs, comparing their performance to that of small-molecule inhibitors. Additionally, we explored the efficacy of combined chemo-hyperthermia in killing CSCs. CSC-enriched breast cancer cells were subjected to low-dose MHT at 42 °C for 30 min and then treated with the chemical MDR inhibitor salinomycin (SAL). The effectiveness of each treatment in inhibiting MDR was assessed by measuring the efflux of the MDR substrate, rhodamine 123 (R123) dye. Notably, MHT induced a prolonged reversal of MDR activity compared with SAL treatment alone. After successfully inhibiting MDR, the breast CSCs were exposed to chemotherapy using paclitaxel to trigger synergistic cell death. The combination of MHT and chemotherapy demonstrated remarkable reductions in stemness properties, MDR reversal, and the effective eradication of breast CSCs in this innovative dual-modality approach.

Polypropylene sulphide coating on magnetic nanoparticles as a novel platform for excellent biocompatible, stimuli-responsive smart magnetic nanocarriers for cancer therapeutics.

Magnetic nanoparticle (MNP) delivery systems are promising for targeted drug delivery, imaging, and chemo-hyperthermia of cancer; however, their uses remain limited primarily due to their toxicity associated with reactive oxygen species (ROS) generation, targeted delivery, and biodegradation. Attempts employing polymer coatings to minimize the toxicity, along with other challenges, have had limited success. We designed a novel yet generic 'one-for-all' polypropylene sulphide (PPS) coated magnetic nano-delivery system (80 ± 15 nm) as a multi-faceted approach for significant biocompatibility improvement, loading of multiple drugs, ROS-responsive delivery, and combined chemo-hyperthermia therapy for biomedical applications. Three distinct MNP systems (15 ± 1 nm) were fabricated, coated with PPS polymer, and investigated to validate our hypothesis and design. Simultaneous degradation of MNPs and PPS coatings with ROS-scavenging characteristics boosted the biocompatibility of MNPs 2-3 times towards non-cancerous fibroblasts (NIH3T3) and human epithelial cells (HEK293). In an alternating magnetic field, PPS-MNPs (MnFe) had the strongest heating characteristics (SAR value of 240 W g-1). PPS-MNP drug-loaded NPs were efficiently internalised into cells and released 80% of the drugs under tumor microenvironment-mimicking (pH 5-7, ROS) conditions, and demonstrated effective chemo-hyperthermia (45 °C) application for breast cancer cells with 95% cell death in combined treatment vs. 55% and 30% cell death in only hyperthermia and chemotherapy respectively.