Combating Glioblastoma by Codelivering the Small-Molecule Inhibitor of STAT3 and STAT3siRNA with α5β1 Integrin Receptor-Selective Liposomes

Abstract

Glioblastoma multiforme (GBM) is one of the most aggressive tumors with a median survival of only 15 months. Effective therapeutics need to overcome the formidable challenge of crossing the blood–brain barrier (BBB). Receptors and transporters overexpressed on BCECs are being used for designing liposomes, polymers, polymeric micelles, peptides, and dendrimer-based drug carriers for combating brain tumors. Herein, using the orthotopic mouse glioblastoma model, we show that codelivering a small-molecule inhibitor of the JAK/STAT pathway (WP1066) and STAT3siRNA with nanometric (100–150 nm) α5β1 integrin receptor-selective liposomes of RGDK-lipopeptide holds therapeutic promise in combating glioblastoma. Rh-PE (red)-labeled liposomes of RGDK-lipopeptide were found to be internalized in GL261 cells via integrin α5β1 receptors. Intravenously administered near-infrared (NIR)-dye-labeled α5β1 integrin receptor-selective liposomes of RGDK-lipopeptide were found to be accumulated preferentially in the mouse brain tumor tissue. Importantly, we show that iv injection of WP1066 (a commercially sold small-molecule inhibitor of the JAK/STAT pathway) and STAT3siRNA cosolubilized within the liposomes of RGDK-lipopeptide leads to significant inhibition (>350% compared to the untreated mice group) of orthotopically growing mouse glioblastoma. The present strategy may find future use in combating GBM.

Targeted Liposomes Encapsulating miR-603 Complexes Enhance Radiation Sensitivity of Patient-Derived Glioblastoma Stem-Like Cells

“…α 5 β 1 is highly expressed on glioblastomas [ 12 , 13 ]. We confirmed the expression of the α 5 β 1 integrin in three independent patient-derived glioblastoma lines, GBM-CCC-001, GBM-CCC-002 and GBM-CCC-003, cultured in conditions that induce cancer-stem cell phenotypes [ 16 ] ( Figure S2 ).…”

“…In this context, we generated liposomes that encapsulated miR-603/PEI complexes in their aqueous core and decorated the liposomes with the PR_b peptide, a fibronectin-mimetic peptide that binds to integrin α 5 β 1 with high affinity and specificity [ 11 ]. PR_b was selected because α 5 β 1 is highly over-expressed in multidrug-resistant glioblastoma cells [ 12 , 13 ]. We also chose to work with patient-derived glioblastoma stem-like cells, as serum cultured, adherent glioblastoma lines poorly recapitulate cancer heterogeneity and therapeutic resistance [ 14 , 15 ].…”

Recent Advancements in the Design of Nanodelivery Systems of siRNA for Cancer Therapy

“…The RNAi mechanism works better in animal experiments when combined with lipid NCs. Tables and summarize recently used lipid-mediated NCs, bioavailable siRNA, and anticancer drugs related to cancer type and cell line for tumor targeting in the years 2020 and 2021. ,,,,,− …”

Targeting steroid hormone receptors for anti‐cancer therapy—A review on small molecules and nanotherapeutic approaches

“…Besides the discovery of various tumor penetrating peptides, targeting membrane bound integrin receptors (IRs) of several subtypes expressed on tumor-associated cells, especially on vascular endothelial cells is a well-known strategy for treating cancer (Ruoslahti, 2017;Weis & Cheresh, 2011). In contrast to the use of RGD peptide as a well-established ligand to nonselectively target IR of multiple subtypes on vascular endothelial cells Arabinda Chaudhuri et al critically emphasized the importance of an extra lysine (K) to RGD-peptide (as RGDK or RGDGWK) hooked to the liposomal nanodelivery systems, which could indeed target α5β1, a subtype that is the highly expressed subtype of IR in tumorassociated cells (Barui et al, 2014(Barui et al, , 2016Majumder et al, 2014;Mondal, Barui, Saha, et al, 2013;Pramanik et al, 2008;Samanta et al, 2010;Vangala et al, 2020). This concept was also extended for single walled nanotube (SWNT)-based delivery systems for targeting tumor cells (Das et al, 2017).…”