Sulfonated Amphiphilic Poly(α)glutamate Amine-A Potential siRNA Nanocarrier for the Treatment of Both Chemo-Sensitive and Chemo-Resistant Glioblastoma Tumors.
Adva KrivitskySabina PozziEilam YeiniSahar Israeli DangoorTal ZurSapir GolanVadim KrivitskyNitzan AlbeckEvgeny PisarevskyPaula OfekAsaf MadiRonit Satchi-FainaroPublished in: Pharmaceutics (2021)
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 6 -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.
Keyphrases
- cancer therapy
- drug delivery
- photodynamic therapy
- induced apoptosis
- combination therapy
- dna repair
- cell proliferation
- cell cycle arrest
- locally advanced
- endothelial cells
- dna damage
- white matter
- oxidative stress
- cell death
- endoplasmic reticulum stress
- signaling pathway
- genome wide
- squamous cell carcinoma
- rectal cancer
- pi k akt
- gene expression
- radiation therapy
- dna methylation
- dna damage response
- transcription factor
- replacement therapy
- ionic liquid