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

• Published in: Acta biomaterialia 2022-02, Vol.139, p.218-236
• Main Authors: Pucci, Carlotta, Marino, Attilio, Şen, Özlem, De Pasquale, Daniele, Bartolucci, Martina, Iturrioz-Rodríguez, Nerea, di Leo, Nicoletta, de Vito, Giuseppe, Debellis, Doriana, Petretto, Andrea, Ciofani, Gianni
• Format: Article
• Language: English
• Subjects: Actin; Apolipoprotein E; Apoptosis; Astrocytoma; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain cancer; Brain Neoplasms - drug therapy; Brain tumors; Cell activation; Cell Line, Tumor; Cell migration; Chemotherapy; Drug resistance; Genotoxicity; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma cells; Glioblastoma multiforme; Glioma cells; Heterogeneity; Humans; Invasiveness; Lipids; Nanomaterials; Nanoparticles; Nanotechnology; Necrosis; Nutlin-3a; Piezoelectric nanoparticles; Piezoelectricity; Stimulation; Ultrasonic imaging; Ultrasound
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2021.04.005

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. Piezoelectric hybrid lipid-polymeric nanoparticles, efficiently encapsulating a non-genotoxic drug (nutlin-3a) and functionalized with a peptide (ApoE) that enhances their passage through the BBB, are proposed. Upon ultrasound stimulation, nanovectors resulted able to reduce cell migration, actin polymerization, and invasion ability of glioma cells, while fostering apoptotic and necrotic events. This wireless activation of anticancer action paves the way to a less invasive, more focused and efficient therapeutic strategy. [Display omitted]