Aptamer-Mediated Codelivery of Doxorubicin and NF-κB Decoy Enhances Chemosensitivity of Pancreatic Tumor Cells

Abstract

Aptamers able to bind efficiently cell-surface receptors differentially expressed in tumor and in healthy cells are emerging as powerful tools to perform targeted anticancer therapy. Here, we present a novel oligonucleotide chimera, composed by an RNA aptamer and a DNA decoy. Our assembly is able to (i) target tumor cells via an antitransferrin receptor RNA aptamer and (ii) perform selective codelivery of a chemotherapeutic drug (Doxorubicin) and of an inhibitor of a cell-survival factor, the nuclear factor κB decoy oligonucleotide. Both payloads are released under conditions found in endolysosomal compartments (low pH and reductive environment). Targeting and cytotoxicity of the oligonucleotidic chimera were assessed by confocal microscopy, cell viability, and Western blot analysis. These data indicated that the nuclear factor κB decoy does inhibit nuclear factor κB activity and ultimately leads to an increased therapeutic efficacy of Doxorubicin selectively in tumor cells.

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

“…Doxorubicin, an antibiotic anthracycline, is commonly considered to exert its anti-tumor activity at two fundamental levels, altering DNA and producing free radicals to trigger apoptosis of cancer cells through DNA damage. Doxorubicin-induced G2/M checkpoint arrest is attributed to elevated cyclin G2 (CycG2) expression and phospho-modification of proteins in the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) signaling pathways 42, 43, 44. In addition, compared with the controls of no treatment and siNC 50 nM, cells treated with siRRM2 (50 and 25 nM) displayed a remarkable and dose-dependent increase in S-phase populations; and the G2/M-phase population decreased significantly (Figures 4E and 4F).…”

Suppression of FOXM1 Transcriptional Activities via a Single-Stranded DNA Aptamer Generated by SELEX

“…A number of aptamer-based therapeutics are currently undergoing clinical trials, including therapeutic aptamers for cancer treatment such as AS1411 targeting nucleolin26 and NOX-A12 targeting stroma cell-derived factor-1 (SDF-1)27. An aptamer specific for modulating the function of intracellular transcription factor NF-κB has been developed and shows effective inhibition of NF-κB in vitro and in vivo 2829, suppressing non-small cell lung cancer resistance to Doxorubicin30. An aptamer that inhibits the function of the E2F family of transcription factors has also been obtained and can be potentially used for preventing tumor development31.…”

Multivalent Aptamer–RNA Conjugates for Simple and Efficient Delivery of Doxorubicin/siRNA into Multidrug‐Resistant Cells

“…Because aptamer–siRNA chimeras (Apt–siRNA) efficiently silence genes in target cells both in vitro and in vivo, they might be an alternative tool for the targeted delivery of Dox and nucleic acid drugs. Recent studies suggest that treatment with Dox‐intercalated aptamer–nucleic acid chimeras or cotreatment with aptamer–nucleic acid and Dox exerts increased anticancer effects . However, a single type of monovalent aptamer has weak binding affinity toward target cells and is required to be administered at high doses to obtain desirable therapeutic outcomes.…”