Gemcitabine-Incorporated G-Quadruplex Aptamer for Targeted Drug Delivery into Pancreas Cancer

Gemcitabine has been considered a first-line chemotherapy agent for the treatment of pancreatic cancer. However, the initial response rate of gemcitabine is low and chemoresistance occurs frequently. Aptamers can be effectively internalized into cancer cells via binding to target molecules with high affinity and specificity. In the current study, we constructed an aptamer-based gemcitabine delivery system, APTA-12, and assessed its therapeutic effects on pancreatic cancer cells in vitro and in vivo. APTA-12 was effective in vitro and in vivo in pancreatic cancer cells with high expression of nucleolin. The results of in vitro cytotoxicity assays indicated that APTA-12 inhibited the growth of pancreatic cancer cell lines. In vivo evaluation showed that APTA-12 effectively inhibited the growth of pancreatic cancer in Capan-1 tumor-bearing mice compared to mice that received gemcitabine alone or vehicle. These results suggest that the gemcitabine-incorporated APTA-12 aptamer may be a promising targeted therapeutic strategy for pancreatic cancer.

[1]  R. Chari,et al.  Targeted cancer therapy: conferring specificity to cytotoxic drugs. , 2008, Accounts of chemical research.

[2]  John O Trent,et al.  Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. , 2009, Experimental and molecular pathology.

[3]  Zhenjun Yang,et al.  Bioactivity of 2′-deoxyinosine-incorporated aptamer AS1411 , 2016, Scientific Reports.

[4]  Seong-Wook Lee,et al.  An RNA aptamer that binds carcinoembryonic antigen inhibits hepatic metastasis of colon cancer cells in mice. , 2012, Gastroenterology.

[5]  W Cai,et al.  Molecular imaging with nucleic acid aptamers. , 2011, Current medicinal chemistry.

[6]  F. Cappuzzo,et al.  Role of gemcitabine in cancer therapy. , 2005, Future oncology.

[7]  Jean-Pierre Benoit,et al.  Strategies for the nanoencapsulation of hydrophilic molecules in polymer-based nanoparticles. , 2011, Biomaterials.

[8]  D. Patel,et al.  Structural basis of DNA folding and recognition in an AMP-DNA aptamer complex: distinct architectures but common recognition motifs for DNA and RNA aptamers complexed to AMP. , 1997, Chemistry & biology.

[9]  Sang Moo Lim,et al.  RGD Peptide–Conjugated Multimodal NaGdF4:Yb3+/Er3+ Nanophosphors for Upconversion Luminescence, MR, and PET Imaging of Tumor Angiogenesis , 2013, The Journal of Nuclear Medicine.

[10]  P. Bates,et al.  Antiproliferative activity of G-quartet-forming oligonucleotides with backbone and sugar modifications. , 2002, Biochemistry.

[11]  Xiaoling Zhang,et al.  Molecular Assembly of an Aptamer–Drug Conjugate for Targeted Drug Delivery to Tumor Cells , 2009, Chembiochem : a European journal of chemical biology.

[12]  P. Bates,et al.  Antiproliferative Activity of G-rich Oligonucleotides Correlates with Protein Binding* , 1999, The Journal of Biological Chemistry.

[13]  E. Fishman,et al.  Recent progress in pancreatic cancer , 2013, CA: a cancer journal for clinicians.

[14]  W. Duan,et al.  Clinical applications of aptamers and nucleic acid therapeutics in haematological malignancies , 2011, British journal of haematology.

[15]  Y. Yarden,et al.  Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth , 2013, Proceedings of the National Academy of Sciences.

[16]  H. Lipps,et al.  G-quadruplexes and their regulatory roles in biology , 2015, Nucleic acids research.

[17]  Carsten Denkert,et al.  Standardized Ki67 Diagnostics Using Automated Scoring—Clinical Validation in the GeparTrio Breast Cancer Study , 2014, Clinical Cancer Research.

[18]  Volker Heinemann,et al.  Gemcitabine: Progress in the Treatment of Pancreatic Cancer , 2000, Oncology.

[19]  Maria C. DeRosa,et al.  Small-Molecule Binding Aptamers: Selection Strategies, Characterization, and Applications , 2016, Front. Chem..

[20]  I. Gladhaug,et al.  Pancreatic Cancer Chemoresistance to Gemcitabine , 2017, Cancers.

[21]  M. Stephenson,et al.  Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Mu,et al.  Self-aggregation of DNA oligomers with XGG trinucleotide repeats: kinetic and atomic force microscopy measurements. , 1999, Biophysical journal.

[23]  Jinhui Wu,et al.  Nucleolin targeting AS1411 modified protein nanoparticle for antitumor drugs delivery. , 2013, Molecular pharmaceutics.

[24]  M. Caruthers,et al.  An investigation of several deoxynucleoside phosphoramidites useful for synthesizing deoxyoligonucleotides , 1983 .

[25]  T. Przytycka,et al.  Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth , 2016, Molecular therapy. Nucleic acids.

[26]  M. Gleave,et al.  Antisense therapy for cancer , 2005, Nature Reviews Cancer.

[27]  L. Garraway,et al.  A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma , 2014, Investigational New Drugs.

[28]  L. Qiu,et al.  Targeted delivery of anticancer drugs by aptamer AS1411 mediated Pluronic F127/cyclodextrin-linked polymer composite micelles. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[29]  P. Bates,et al.  G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms. , 2017, Biochimica et biophysica acta. General subjects.

[30]  M. Hogan,et al.  Intramolecular G-quartet Motifs Confer Nuclease Resistance to a Potent Anti-HIV Oligonucleotide (*) , 1996, The Journal of Biological Chemistry.

[31]  P. Bouvet,et al.  AS-1411, a guanosine-rich oligonucleotide aptamer targeting nucleolin for the potential treatment of cancer, including acute myeloid leukemia. , 2010, Current opinion in molecular therapeutics.

[32]  Y. Zu,et al.  Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy , 2014, Molecular therapy. Nucleic acids.

[33]  E. Spicer,et al.  The nucleolin targeting aptamer AS1411 destabilizes Bcl-2 messenger RNA in human breast cancer cells. , 2008, Cancer research.

[34]  J. Y. Park,et al.  Hybridization-based aptamer labeling using complementary oligonucleotide platform for PET and optical imaging. , 2016, Biomaterials.

[35]  E. Seyedjafari,et al.  Nanotechnology for delivery of gemcitabine to treat pancreatic cancer. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[36]  B. Sullenger,et al.  Aptamer-mediated delivery of chemotherapy to pancreatic cancer cells. , 2012, Nucleic acid therapeutics.

[37]  Xiaoyuan Chen,et al.  PET Imaging of Tenascin-C with a Radiolabeled Single-Stranded DNA Aptamer , 2015, The Journal of Nuclear Medicine.

[38]  B. Sullenger,et al.  Aptamer-mediated delivery of splice-switching oligonucleotides to the nuclei of cancer cells. , 2012, Nucleic acid therapeutics.

[39]  Mark W. Ball,et al.  AGRO100 inhibits activation of nuclear factor-kappaB (NF-kappaB) by forming a complex with NF-kappaB essential modulator (NEMO) and nucleolin. , 2006, Molecular cancer therapeutics.

[40]  M. Stephenson,et al.  Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  J. Rossi,et al.  Aptamers as targeted therapeutics: current potential and challenges , 2016, Nature Reviews Drug Discovery.

[43]  Robert Langer,et al.  An aptamer-doxorubicin physical conjugate as a novel targeted drug-delivery platform. , 2006, Angewandte Chemie.

[44]  Xiaoyuan Chen,et al.  Aptamer-Drug Conjugates. , 2015, Bioconjugate chemistry.

[45]  L. J. Lee,et al.  Targeted Delivery Systems for Oligonucleotide Therapeutics , 2009, The AAPS Journal.

[46]  R. Chari.  Targeted cancer therapy: conferring specificity to cytotoxic drugs. , 2008, Accounts of chemical research.

[47]  Ying-Fon Chang,et al.  Tumor targeting by an aptamer. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[48]  Silvia Catuogno,et al.  Aptamer-Mediated Targeted Delivery of Therapeutics: An Update , 2016, Pharmaceuticals.

[49]  H. Ueno,et al.  Pharmacogenomics of Gemcitabine: Can Genetic Studies Lead to Tailor-made Therapy? Gemcitabine Metabolism and Mechanism of Action Nucleoside Transporters , 2022 .

[50]  Paula J. Bates,et al.  AGRO100 inhibits activation of nuclear factor-κB (NF-κB) by forming a complex with NF-κB essential modulator (NEMO) and nucleolin , 2006, Molecular Cancer Therapeutics.

[51]  P. Blackshear,et al.  Transforming Growth Factor β Regulates P-Body Formation through Induction of the mRNA Decay Factor Tristetraprolin , 2013, Molecular and Cellular Biology.

[52]  J. Palau,et al.  DNA and histone H1 interact with different domains of HMG 1 and 2 proteins. , 1983, The EMBO journal.

[53]  Jung-Hwan Yoon,et al.  Modified AS1411 Aptamer Suppresses Hepatocellular Carcinoma by Up-Regulating Galectin-14 , 2016, PloS one.

[54]  C. R. Crawford,et al.  Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. , 1998, Cancer research.

[55]  F. Richardson,et al.  Synthesis and restriction enzyme analysis of oligodeoxyribonucleotides containing the anti-cancer drug 2',2'-difluoro-2'-deoxycytidine. , 1992, Nucleic Acids Research.

[56]  John R. Mackey,et al.  Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma , 2009, Clinical Cancer Research.

[57]  Xi‐lin Xiao,et al.  A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy , 2015, PloS one.