TAT-modified nanosilver for combating multidrug-resistant cancer.

A nanopharmaceutical system using TAT-enhanced cell/tissue penetration strategy was developed for multidrug-resistant (MDR) cancer treatment, in which nanocrystalline silver with mean size of 8 nm modified with TAT cell-penetrating peptide (termed AgNP-TAT) displayed extraordinary antitumor activity in both MDR cells and non-resistant cells at an indiscriminating manner. Such anti-MDR effect is presumably due to the size-exclusion effect, by which the nanoparticles are too large to be pumped out. Of note, AgNP-TAT showed significant enhancement in killing tumor cells, e.g. up to 24 fold higher compared to its counterpart without TAT-modification. The animal studies further confirmed the success of our strategy that AgNP-TAT was able to effectively inhibit the tumor growth in the mice bearing malignant melanoma at a dose of 1 nmol/kg, compared with the effective dose (4.3 μmol/kg) of doxorubicin. AgNP-TAT also showed significantly reduced adverse toxicity in vivo. It indicates AgNP-TAT could be a class of nano drug for MDR cancer treatment.

[1]  Beatriz Pelaz,et al.  The effect of static magnetic fields and tat peptides on cellular and nuclear uptake of magnetic nanoparticles. , 2010, Biomaterials.

[2]  S. Unnikrishnan,et al.  The antithrombotic and antimicrobial properties of PEG-protected silver nanoparticle coated surfaces. , 2012, Biomaterials.

[3]  W. Frey,et al.  Delivery of Neurotrophic Factors to the Central Nervous System , 2001, Clinical pharmacokinetics.

[4]  Kurt Ballmer-Hofer,et al.  Antennapedia and HIV Transactivator of Transcription (TAT) “Protein Transduction Domains” Promote Endocytosis of High Molecular Weight Cargo upon Binding to Cell Surface Glycosaminoglycans* , 2003, Journal of Biological Chemistry.

[5]  H. Verheul,et al.  Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib. , 2009, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[6]  S. Gurunathan,et al.  Antitumor activity of silver nanoparticles in Dalton’s lymphoma ascites tumor model , 2010, International journal of nanomedicine.

[7]  P. Gentile,et al.  Nanocrystalline Silver: A Systematic Review of Randomized Trials Conducted on Burned Patients and an Evidence-Based Assessment of Potential Advantages Over Older Silver Formulations , 2009, Annals of plastic surgery.

[8]  Seung-Hae Kwon,et al.  Quantification of cellular uptake and in vivo tracking of transduction using real-time monitoring. , 2010, Biochemical and biophysical research communications.

[9]  M. Gottesman,et al.  Targeting multidrug resistance in cancer , 2006, Nature Reviews Drug Discovery.

[10]  A. Marcus,et al.  Imaging and tracking of tat peptide-conjugated quantum dots in living cells: new insights into nanoparticle uptake, intracellular transport, and vesicle shedding. , 2007, Journal of the American Chemical Society.

[11]  G. Wong,et al.  HIV TAT forms pores in membranes by inducing saddle-splay curvature: potential role of bidentate hydrogen bonding. , 2008, Angewandte Chemie.

[12]  Zhi Yuan,et al.  Doxorubicin-loaded glycyrrhetinic acid-modified alginate nanoparticles for liver tumor chemotherapy. , 2012, Biomaterials.

[13]  Cheol Moon,et al.  Synthetic skin-permeable proteins enabling needleless immunization. , 2010, Angewandte Chemie.

[14]  Mark E. Davis,et al.  Nanoparticle therapeutics: an emerging treatment modality for cancer , 2008, Nature Reviews Drug Discovery.

[15]  P. Johnston,et al.  Molecular mechanisms of drug resistance , 2005, The Journal of pathology.

[16]  C. Higgins,et al.  Three-dimensional Structure of P-glycoprotein , 2005, Journal of Biological Chemistry.

[17]  S. Ghosh,et al.  Induction of apoptosis in cancer cells at low silver nanoparticle concentrations using chitosan nanocarrier. , 2011, ACS applied materials & interfaces.

[18]  M. Dean,et al.  Multidrug Efflux Pumps and Cancer Stem Cells: Insights Into Multidrug Resistance and Therapeutic Development , 2011, Clinical pharmacology and therapeutics.

[19]  D. Clarke,et al.  Determining the Dimensions of the Drug-binding Domain of Human P-glycoprotein Using Thiol Cross-linking Compounds as Molecular Rulers* , 2001, The Journal of Biological Chemistry.

[20]  L. Liotta,et al.  Mechanism of Cell Adaptation: When and How Do Cancer Cells Develop Chemoresistance? , 2011, Cancer journal.

[21]  Vladimir P Torchilin,et al.  Tat peptide-mediated intracellular delivery of pharmaceutical nanocarriers. , 2008, Advanced drug delivery reviews.

[22]  Yue Weng,et al.  Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding , 2009, Science.

[23]  H. Autrup,et al.  Cytotoxicity and genotoxicity of silver nanoparticles in the human lung cancer cell line, A549 , 2011, Archives of Toxicology.

[24]  S. Schwarze,et al.  In vivo protein transduction: delivery of a biologically active protein into the mouse. , 1999, Science.

[25]  S. Batra,et al.  Penetratin improves tumor retention of single-chain antibodies: a novel step toward optimization of radioimmunotherapy of solid tumors. , 2005, Cancer research.

[26]  R. Marais,et al.  Melanoma biology and new targeted therapy , 2007, Nature.

[27]  K. Berg,et al.  Photochemical Internalization of Therapeutic Macromolecular Agents: A Novel Strategy to Kill Multidrug-Resistant Cancer Cells , 2006, Journal of Pharmacology and Experimental Therapeutics.

[28]  Peng Zhang,et al.  Multifunctional nanoassemblies for vincristine sulfate delivery to overcome multidrug resistance by escaping P-glycoprotein mediated efflux. , 2011, Biomaterials.

[29]  A. Seelig.  How does P-glycoprotein recognize its substrates? , 1998, International journal of clinical pharmacology and therapeutics.

[30]  Fiona Wood,et al.  Nanocrystalline silver dressings in wound management: a review , 2006, International journal of nanomedicine.