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- Title
Sulfonated Amphiphilic Poly(α)glutamate Amine—A Potential siRNA Nanocarrier for the Treatment of Both Chemo-Sensitive and Chemo-Resistant Glioblastoma Tumors.
- 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
- Abstract
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 O6-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.
- Subjects
METHYLGUANINE; SMALL interfering RNA; GLUTAMIC acid; GLIOBLASTOMA multiforme; GENETIC overexpression; GENE silencing
- Publication
Pharmaceutics, 2021, Vol 13, Issue 12, p2199
- ISSN
1999-4923
- Publication type
Article
- DOI
10.3390/pharmaceutics13122199