Ultrasound-responsive nutlin-loaded nanoparticles for combined chemotherapy and piezoelectric treatment of glioblastoma cells

Abstract

Glioblastoma multiforme (GBM), also known as grade IV astrocytoma, represents the most aggressive primary brain tumor. The complex genetic heterogeneity, the acquired drug resistance, and the presence of the blood-brain barrier (BBB) limit the efficacy of the current therapies, with effectiveness demonstrated only in a small subset of patients. To overcome these issues, here we propose an anticancer approach based on ultrasound-responsive drug-loaded organic piezoelectric nanoparticles. This anticancer nanoplatform consists of nutlin-3a-loaded ApoE-functionalized P(VDF-TrFE) nanoparticles, that can be remotely activated with ultrasound-based mechanical stimulations to induce drug release and to locally deliver anticancer electric cues. The combination of chemotherapy treatment with chronic piezoelectric stimulation resulted in activation of cell apoptosis and anti-proliferation pathways, induction of cell necrosis, inhibition of cancer migration, and reduction of cell invasiveness in drug-resistant GBM cells. Obtained results pave the way for the use of innovative multifunctional nanomaterials in less invasive and more focused anticancer treatments, able to reduce drug resistance in GBM.

Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme

“…Interestingly, we confirmed our hypothesis through TCGA and validated them in CGGA and experiments. At the same time, the mechanisms behind RCN1 were also explored and the identified pathways were consistent with previous studies (Fukasawa et al, 2021;Pucci et al, 2021;Sighel et al, 2021;Xue et al, 2021). The convenient access to the public database allows us for the application of large-scale gene expression profiling and database mining for potential correlation between genes and overall survival of a variety of malignancies including GBM (Aldape et al, 2015;Zhou et al, 2021).…”

“…Interestingly, we confirmed our hypothesis through TCGA and validated them in CGGA and experiments. At the same time, the mechanisms behind RCN1 were also explored and the identified pathways were consistent with previous studies ( Fukasawa et al, 2021 ; Pucci et al, 2021 ; Sighel et al, 2021 ; Xue et al, 2021 ).…”

Modulation of anti-angiogenic activity using ultrasound-activated nutlin-loaded piezoelectric nanovectors

“…Nutlin-3a loaded P(VDF-TrFE) nanoparticles (Nut-PNPs) were synthesized and surface-functionalized with a peptide that corresponds to a fragment of apolipoprotein E (ApoE; GenScript), as previously described in a work of our group [ 15 ]. Briefly, 2 ​mL of 5 ​mg/mL P(VDF-TrFE) (45:65; Piezotech) and 200 ​μL of 5 ​mg/mL nutlin-3a (Sigma-Aldrich) in acetone (Sigma-Aldrich) were placed into 4.5 ​mL of a 1 ​mg/mL 1,2-distearoyl- sn -glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG; Nanocs) dispersion in water under stirring.…”

“…To assess the particle effect on the tube formation, cells (2·10 4 ​cells/cm 2 ) were treated for 24 ​h with Nut 21.5 ​μM (corresponding to Nut loaded in 500 ​μg/mL of ApoE-Nut-PNPs), ApoE-PNPs (500 ​μg/mL), or ApoE-Nut-PNPs (500 ​μg/mL). A previously described protocol was followed for chronic US stimulation [ 15 ]. Briefly, the US was delivered at 1 ​MHz frequency and 1 ​W/cm 2 intensity.…”

“…The literature reports that P(VDF-TrFE)-based scaffolds or films induce cell differentiation and controlled release of drugs upon appropriate US stimulation [ 13 , 14 ]. Furthermore, our recent study showed that P(VDF-TrFE) nanoparticles can be used to inhibit cancer progression upon US stimulation by activating anti-proliferation and apoptosis pathways, inducing necrosis, inhibiting cell migration, and decreasing invasion in drug-resistant glioblastoma cells [ 15 ].…”