Sulfonated Amphiphilic Poly(α)glutamate Amine-A Potential siRNA Nanocarrier for the Treatment of Both Chemo-Sensitive and Chemo-Resistant Glioblastoma Tumors

Sulfonated Amphiphilic Poly(α)glutamate Amine-A Potential siRNA Nanocarrier for the Treatment of Both Chemo-Sensitive and Chemo-Resistant Glioblastoma Tumors

Development of chemo-resistance is a major challenge in glioblastoma (GB) treatment. This phenomenon is often driven by increased activation of genes associated with DNA repair, such as the alkyl-removing enzyme O -methylguanine-DNA methyltransferase (MGMT) in combination with overexpression of cano...

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Published in:Pharmaceutics Vol. 13; no. 12; p. 2199
Main Authors: Krivitsky, Adva, Pozzi, Sabina, Yeini, Eilam, Israeli Dangoor, Sahar, Zur, Tal, Golan, Sapir, Krivitsky, Vadim, Albeck, Nitzan, Pisarevsky, Evgeny, Ofek, Paula, Madi, Asaf, Satchi-Fainaro, Ronit
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 20-12-2021
MDPI
Subjects:
amphiphilic poly(α)glutamate
Brain cancer
Cancer therapies
Cell cycle
Chemotherapy
DNA damage
DNA methylation
Drug dosages
Endothelium
Enzymes
Genes
glioblastoma therapy
Glycoproteins
Kinases
Ligands
Medical prognosis
nanocarrier
Nanoparticles
P-selectin
Permeability
polyplexes
siRNA delivery
Tumors
St Louis Missouri
United States > US
Israel
siRNA delivery
nanocarrier
amphiphilic poly(α)glutamate
glioblastoma therapy
P-selectin
polyplexes
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Summary:Development of chemo-resistance is a major challenge in glioblastoma (GB) treatment. This phenomenon is often driven by increased activation of genes associated with DNA repair, such as the alkyl-removing enzyme O -methylguanine-DNA methyltransferase (MGMT) in combination with overexpression of canonical genes related to cell proliferation and tumor progression, such as Polo-like kinase 1 (Plk1). Hereby, we attempt to sensitize resistant GB cells using our established amphiphilic poly(α)glutamate (APA): small interfering RNA (siRNA) polyplexes, targeting Plk1. Furthermore, we improved brain-targeting by decorating our nanocarrier with sulfonate groups. Our sulfonated nanocarrier showed superior selectivity towards P-selectin (SELP), a transmembrane glycoprotein overexpressed in GB and angiogenic brain endothelial cells. Self-assembled polyplexes of sulfonated APA and siPlk1 internalized into GB cells and into our unique 3-dimensional (3D) GB spheroids inducing specific gene silencing. Moreover, our RNAi nanotherapy efficiently reduced the cell viability of both chemo-sensitive and chemo-resistant GB cells. Our developed sulfonated amphiphilic poly(α)glutamate nanocarrier has the potential to target siRNA to GB brain tumors. Our findings may strengthen the therapeutic applications of siRNA for chemo-resistant GB tumors, or as a combination therapy for chemo-sensitive GB tumors.
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ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics13122199