title: Synergistic induction of apoptosis in brain cancer cells by targeted codelivery of siRNA and anticancer drugs.
abstract: 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.
authors.forename: Cheoljin
authors.initials: C
authors.lastname: Kim
authors.forename: Birju P
authors.initials: BP
authors.lastname: Shah
authors.forename: Prasad
authors.initials: P
authors.lastname: Subramaniam
authors.forename: Ki-Bum
authors.initials: KB
authors.lastname: Lee
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D004339:Drug Compounding; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D020868:Gene Silencing; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D016716:PC12 Cells; D010316:Particle Size; D011799:Quinazolines / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism*; D051381:Rats; D000077337:Vorinostat
chemical_list: D000277:Adjuvants, Pharmaceutic; D000970:Antineoplastic Agents; D004337:Drug Carriers; D006877:Hydroxamic Acids; D008024:Ligands; D009363:Neoplasm Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; C410723:epidermal growth factor receptor VIII; D000077337:Vorinostat; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors