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Multifunctional temozolomide-loaded lipid superparamagnetic nanovectors: dual targeting and disintegration of glioblastoma spheroids by synergic chemotherapy and hyperthermia treatment

ABSTRACT: The recent develop of nanotechnology promises to revolutionize the delivery of chemotherapeutic agents across the blood-brain barrier and against cancer cells. Superparamagnetic iron oxide nanoparticles have been successfully exploited in many different clinical trials for the remote hyperthermal treatment of cancer cells in response to alternated magnetic fields (AMF) and as nontargeted contrast agents for magnetic resonance imaging (MRI). In this work, the functionalization of SPIONs- and TMZ-loaded lipid magnetic nanovectors (LMNVs) with the antibody against the transferrin receptor (TfR) for the dual targeting of the endothelial cells of BBB and GBM cells is reported. The targeting efficiency of the functionalized nanovectors (AbLMNVs) has been demonstrated on a multicellular organoid system modeling the BBB and the microscopic GBM foci. Transcytosis through endothelial cells and penetration in GBM spheroids of functionalized nanovectors have been verified and quantified through flow cytometry analysis and different imaging techniques. Moreover, the lipid component of the functionalized nanovectors has been modified with a lipophilic temperature sensitive fluorescent dye to monitor the intraparticle temperature in response to AMF Chronic AMF treatments of microscopic GBM spheroids targeted with the functionalized nanovectors, plain or loaded with TMZ drug, were carried out and their elevated potential to induce spheroid disintegration, cell necrosis and apoptosis was revealed. Finally, magnetothermal ability of nanovectors was successfully tested on a post-mortem brain tissue.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Andrea Petretto

LAB HEAD: Andrea Petretto

PROVIDER: PXD014652 | Pride | 2019-11-25

REPOSITORIES: Pride

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			Action	DRS
	Ciofani1.7z	Other
	DeglInnocenti_0519_1_CTR_15_02_75.raw	Raw
	DeglInnocenti_0519_1_CTR_15_03_77.raw	Raw
	DeglInnocenti_0519_1_CTR_22_02_76.raw	Raw
	DeglInnocenti_0519_2_AMF_15_02_69.raw	Raw

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Project description:Glioblastoma (GBM) carries a dismal prognosis largely due to acquired resistance to the standard treatment, which incorporates the chemotherapy temozolomide (TMZ). Inhibiting the proteasomal pathway is an emerging strategy, where combination treatments are under clinical investigation. We hypothesized that pre-treatment of GBM with bortezomib (BTZ) might sensitize glioblastoma to TMZ by abolishing autophagy survival signals to augment DNA damage and apoptosis. P3 patient-derived GBM cells as well as the tumor cell lines U87, HF66, A172 and T98G were investigated for clonogenic survival after single or combined treatment with TMZ and BTZ in vitro. Change in autophagic flux was examined after experimental treatments in conjunction with inhibitors of autophagy or downregulation of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in TMZ-resistant P3 and T98G cells as indicated by diminished levels of the autophagy markers LC3A/B-II and increased STX17, higher protein degradation and no formation of p62 bodies nor induction of apoptosis. In contrast, BTZ treatment attenuated ULK1 mRNA, total and phosphorylated protein, and accumulated LC3A/B-II, p62 and autophagosomes analogously to Baf1 and chloroquine autophagy inhibitors. These autophagosomes did not fuse with lysosomes, indicated by attenuated STX17 expression and reduced degradation of long-lived proteins, which culminated in enhanced caspase-3/8 dependent apoptosis. BTZ synergistically enhanced TMZ efficacy, attenuated tumor cell proliferation, triggered ATM/Chk2 DNA damage signalling to further augment caspase-3/8 mediated apoptosis in the TMZ resistant P3 and T98G GBM cells. Genetic or chemical inhibition of autophagy (with CRISPR-CAs9 ATG5, ATG7 shRNA, MRT68921 or VPS34-IN1) abrogated BTZ efficacy and rescued BTZ+ TMZ treated GBM cells from death. We conclude that Bortezomib ameliorates temozolomide resistance through ATG5/7-dependent abrogated autophagic flux and may be amenable in combination treatment regimens for TMZ refractory GBM patients.

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Multifunctional temozolomide-loaded lipid superparamagnetic nanovectors: dual targeting and disintegration of glioblastoma spheroids by synergic chemotherapy and hyperthermia treatment

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