Synergistic Induction of Apoptosis in Brain Cancer Cells by Targeted Co delivery of siRNA and Anti-cancer drugs
Published Date:Aug 05 2011
Source:Mol Pharm. 8(5):1955-1961.
Brain Tumor Cells
Cell Line, Tumor
Receptor, Epidermal Growth Factor
RNA, Small Interfering
Pubmed Central ID:PMC3185194
Funding:1DP20D006462-01/DP/NCCDPHP CDC HHS/United States
DP2 OD006462/OD/NIH HHS/United States
DP2 OD006462-01/OD/NIH HHS/United States
Description:Multiple dysregulated pathways in tumors necessitate targeting multiple oncogenic elements by combining orthogonal therapeutic moieties like short-interfering RNAs (siRNA) and drug molecules in order to achieve a synergistic therapeutic effect. In this manuscript, we describe the synthesis of cyclodextrin-modified dendritic polyamines (DexAMs) and their application as a multicomponent delivery vehicle for translocating siRNA and anticancer drugs. The presence of β-cyclodextrins in our DexAMs facilitated complexation and intracellular uptake of hydrophobic anticancer drugs, suberoylanilide hydroxamic acid (SAHA) and erlotinib, whereas the cationic polyamine backbone allowed for electrostatic interaction with the negatively charged siRNA. The DexAM complexes were found to have minimal cytotoxicity over a wide range of concentrations and were found to efficiently deliver siRNA, thereby silencing the expression of targeted genes. As a proof of concept, we demonstrated that upon appropriate modification with targeting ligands, we were able to simultaneously deliver multiple payloads--siRNA against oncogenic receptor, EGFRvIII and anticancer drugs (SAHA or erlotinib)--efficiently and selectively to glioblastoma cells. Codelivery of siRNA-EGFRvIII and SAHA/erlotinib in glioblastoma cells was found to significantly inhibit cell proliferation and induce apoptosis, as compared to the individual treatments.
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