ATP-triggered anticancer drug delivery

Stimuli-triggered drug delivery systems have been increasingly used to promote physiological specificity and on-demand therapeutic efficacy of anticancer drugs. Here we utilize adenosine-5'-triphosphate (ATP) as a trigger for the controlled release of anticancer drugs. We demonstrate that polymeric nanocarriers functionalized with an ATP-binding aptamer-incorporated DNA motif can selectively release the intercalating doxorubicin via a conformational switch when in an ATP-rich environment. The half-maximal inhibitory concentration of ATP-responsive nanovehicles is 0.24 μM in MDA-MB-231 cells, a 3.6-fold increase in the cytotoxicity compared with that of non-ATP-responsive nanovehicles. Equipped with an outer shell crosslinked by hyaluronic acid, a specific tumour-targeting ligand, the ATP-responsive nanocarriers present an improvement in the chemotherapeutic inhibition of tumour growth using xenograft MDA-MB-231 tumour-bearing mice. This ATP-triggered drug release system provides a more sophisticated drug delivery system, which can differentiate ATP levels to facilitate the selective release of drugs.

[1]  J. Knowles Enzyme-catalyzed phosphoryl transfer reactions. , 1980, Annual review of biochemistry.

[2]  Dean Ho,et al.  Cancer Nanomedicine: From Drug Delivery to Imaging , 2013, Science Translational Medicine.

[3]  C Haanen,et al.  A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. , 1995, Journal of immunological methods.

[4]  M. Götte,et al.  Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective. , 2006, Cancer research.

[5]  Zhen Gu,et al.  A novel intracellular protein delivery platform based on single-protein nanocapsules. , 2010, Nature nanotechnology.

[6]  N. Rapoport Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery , 2007 .

[7]  Ronghua Yang,et al.  A spherical nucleic acid platform based on self-assembled DNA biopolymer for high-performance cancer therapy. , 2013, ACS nano.

[8]  D. Loo,et al.  In situ detection of apoptosis by the TUNEL assay: an overview of techniques. , 2011, Methods in molecular biology.

[9]  C. Glorieux,et al.  Intracellular ATP levels determine cell death fate of cancer cells exposed to both standard and redox chemotherapeutic agents. , 2011, Biochemical pharmacology.

[10]  Robert Langer,et al.  Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile , 2012, Science Translational Medicine.

[11]  Alexander L. Klibanov,et al.  Microbubbles in ultrasound-triggered drug and gene delivery. , 2008, Advanced drug delivery reviews.

[12]  Bogdan Catargi,et al.  Chemically controlled closed-loop insulin delivery. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[13]  C. K. Smith,et al.  DNA-nogalamycin interactions: the crystal structure of d(TGATCA) complexed with nogalamycin. , 1994, Biochemistry.

[14]  T. Allen Ligand-targeted therapeutics in anticancer therapy , 2002, Nature Reviews Cancer.

[15]  R. Balhorn,et al.  Protamine-induced condensation and decondensation of the same DNA molecule. , 1999, Science.

[16]  Q. Ping,et al.  Multistage pH‐Responsive Liposomes for Mitochondrial‐Targeted Anticancer Drug Delivery , 2012, Advanced materials.

[17]  Charles W Buffington,et al.  Human plasma ATP concentration. , 2007, Clinical chemistry.

[18]  Omid C Farokhzad,et al.  DNA Self-Assembly of Targeted Near-Infrared-Responsive Gold Nanoparticles for Cancer Thermo-Chemotherapy , 2012, Angewandte Chemie.

[19]  H. Taguchi,et al.  Biomolecular robotics for chemomechanically driven guest delivery fuelled by intracellular ATP. , 2013, Nature chemistry.

[20]  M. Waring,et al.  Preferential binding of daunomycin to 5'ATCG and 5'ATGC sequences revealed by footprinting titration experiments. , 1990, Biochemistry.

[21]  Y. Jeong,et al.  A drug-loaded aptamer-gold nanoparticle bioconjugate for combined CT imaging and therapy of prostate cancer. , 2010, ACS nano.

[22]  G. Takemura,et al.  Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. , 2007, Progress in cardiovascular diseases.

[23]  Yi Lu,et al.  Smart Nanomaterials Responsive to Multiple Chemical Stimuli with Controllable Cooperativity , 2006 .

[24]  Zhen Gu,et al.  Degradable polymeric nanocapsule for efficient intracellular delivery of a high molecular weight tumor-selective protein complex , 2013 .

[25]  Sergiy Minko,et al.  Stimuli-responsive nanoparticles, nanogels and capsules for integrated multifunctional intelligent systems , 2010 .

[26]  P. Nicotera,et al.  Intracellular Adenosine Triphosphate (ATP) Concentration: A Switch in the Decision Between Apoptosis and Necrosis , 1997, The Journal of experimental medicine.

[27]  M. V. Vander Heiden Targeting cancer metabolism: a therapeutic window opens. , 2011, Nature reviews. Drug discovery.

[28]  Younan Xia,et al.  Smart multifunctional hollow microspheres for the quick release of drugs in intracellular lysosomal compartments. , 2011, Angewandte Chemie.

[29]  Li Tang,et al.  Chain-shattering polymeric therapeutics with on-demand drug-release capability. , 2013, Angewandte Chemie.

[30]  V. Torchilin Recent advances with liposomes as pharmaceutical carriers , 2005, Nature Reviews Drug Discovery.

[31]  Sébastien Lecommandoux,et al.  Magnetic field triggered drug release from polymersomes for cancer therapeutics. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[32]  S. Wise Nanocarriers as an emerging platform for cancer therapy , 2007 .

[33]  Targeting glucose metabolism for cancer therapy , 2012 .

[34]  L. Huang,et al.  Protamine sulfate enhances lipid-mediated gene transfer , 1997, Gene Therapy.

[35]  C. Huang,et al.  Graphene oxide as a nano-platform for ATP detection based on aptamer chemistry , 2012 .

[36]  Akira Matsumoto,et al.  A phenylboronate-functionalized polyion complex micelle for ATP-triggered release of siRNA. , 2012, Angewandte Chemie.

[37]  C. Chauzy,et al.  Increased hyaluronidase levels in breast tumor metastases , 1997, International journal of cancer.

[38]  Chunhai Fan,et al.  A target-responsive electrochemical aptamer switch (TREAS) for reagentless detection of nanomolar ATP. , 2007, Journal of the American Chemical Society.

[39]  Younan Xia,et al.  A temperature-sensitive drug release system based on phase-change materials. , 2010, Angewandte Chemie.

[40]  Angela C Cruciano,et al.  Redox-triggered contents release from liposomes. , 2008, Journal of the American Chemical Society.

[41]  W. Wilson,et al.  Targeting hypoxia in cancer therapy , 2011, Nature Reviews Cancer.

[42]  V. Torchilin,et al.  ATP-loaded liposomes effectively protect mechanical functions of the myocardium from global ischemia in an isolated rat heart model. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[43]  Zhen Gu,et al.  Endoprotease-mediated intracellular protein delivery using nanocapsules. , 2011, ACS nano.

[44]  Robert Langer,et al.  Nanotechnology in drug delivery and tissue engineering: from discovery to applications. , 2010, Nano letters.

[45]  Cuichen Wu,et al.  Engineering of switchable aptamer micelle flares for molecular imaging in living cells. , 2013, ACS nano.

[46]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[47]  Daniel G Anderson,et al.  Injectable nano-network for glucose-mediated insulin delivery. , 2013, ACS nano.

[48]  I Nicoletti,et al.  A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. , 1991, Journal of immunological methods.

[49]  T. Traut,et al.  Physiological concentrations of purines and pyrimidines , 1994, Molecular and Cellular Biochemistry.

[50]  Ming Yan,et al.  Protein nanocapsule weaved with enzymatically degradable polymeric network. , 2009, Nano letters.

[51]  K. Nicolaou,et al.  Chemistry and Biology of the Enediyne Anticancer Antibiotics , 1991 .

[52]  C. Reutelingsperger,et al.  Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. , 1998, Cytometry.

[53]  F. Ashcroft,et al.  A Novel Method for Measurement of Submembrane ATP Concentration* , 2000, The Journal of Biological Chemistry.

[54]  S. Nagata,et al.  A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD , 1998, Nature.

[55]  H. McMahon,et al.  Mechanisms of endocytosis. , 2009, Annual review of biochemistry.

[56]  Y. Bae,et al.  Electrically credible polymer gel for controlled release of drugs , 1991, Nature.

[57]  V. Torchilin,et al.  ATP-loaded liposomes for targeted treatment in models of myocardial ischemia. , 2010, Methods in molecular biology.

[58]  M. J. Jedrzejas,et al.  Hyaluronidases: their genomics, structures, and mechanisms of action. , 2006, Chemical reviews.