Ultrasound enhanced release of therapeutics from drug-releasing implants based on titania nanotube arrays.

A non-invasive and external stimulus-driven local drug delivery system (DDS) based on titania nanotube (TNT) arrays loaded with drug encapsulated polymeric micelles as drug carriers and ultrasound generator is described. Ultrasound waves (USW) generated by a pulsating sonication probe (Sonotrode) in phosphate buffered saline (PBS) at pH 7.2 as the medium for transmitting pressure waves, were used to release drug-loaded nano-carriers from the TNT arrays. It was demonstrated that a very rapid release in pulsatile mode can be achieved, controlled by several parameters on the ultrasonic generator. This includes pulse length, time, amplitude and power intensity. By optimization of these parameters, an immediate drug-micelles release of 100% that spans a desirable time of 5-50 min was achieved. It was shown that stimulated release can be generated and reproduced at any time throughout the TNT-Ti implant life, suggesting considerable potential of this approach as a feasible and tunable ultrasound-mediated drug delivery system in situ via drug-releasing implants. It is expected that this concept can be translated from an in vitro to in vivo regime for therapeutic applications using drug-releasing implants in orthopedic and coronary stents.

[1]  Dusan Losic,et al.  Controlled drug release from porous materials by plasma polymer deposition. , 2010, Chemical communications.

[2]  Junru Wu,et al.  Ultrasound, cavitation bubbles and their interaction with cells. , 2008, Advanced drug delivery reviews.

[3]  W. Friess,et al.  Collagen as a carrier for on-site delivery of antibacterial drugs. , 2003, Advanced drug delivery reviews.

[4]  P. Sriamornsak,et al.  Drug-Loaded Pectin Microparticles Prepared by Emulsion-Solvent Evaporation , 2012 .

[5]  Dusan Losic,et al.  Drug-eluting Ti wires with titania nanotube arrays for bone fixation and reduced bone infection , 2011, Nanoscale research letters.

[6]  C. M. Li,et al.  Charged drug delivery by ultrafast exponentially grown weak polyelectrolyte multilayers: amphoteric properties, ultrahigh loading capacity and pH-responsiveness , 2012 .

[7]  T. Desai,et al.  Fabrication of mechanically robust, large area, polycrystalline nanotubular/porous TiO2 membranes , 2008 .

[8]  Jeffrey C Bamber,et al.  Physical parameters affecting ultrasound/microbubble-mediated gene delivery efficiency in vitro. , 2006, Ultrasound in medicine & biology.

[9]  Dusan Losic,et al.  Biocompatible polymer coating of titania nanotube arrays for improved drug elution and osteoblast adhesion. , 2012, Acta biomaterialia.

[10]  P. Cullis,et al.  Drug Delivery Systems: Entering the Mainstream , 2004, Science.

[11]  J. Addai-Mensah,et al.  Polymeric micelles in porous and nanotubular implants as a new system for extended delivery of poorly soluble drugs , 2011 .

[12]  Ghaleb A Husseini,et al.  Micelles and nanoparticles for ultrasonic drug and gene delivery. , 2008, Advanced drug delivery reviews.

[13]  A. Szent-Györgyi,et al.  Chemical and Biological Effects of Ultra-Sonic Radiation , 1933, Nature.

[14]  Roel Deckers,et al.  The role of ultrasound and magnetic resonance in local drug delivery , 2008, Journal of magnetic resonance imaging : JMRI.

[15]  J. Addai-Mensah,et al.  Polymer micelles for delayed release of therapeutics from drug-releasing surfaces with nanotubular structures. , 2012, Macromolecular bioscience.

[16]  T. Kumabe,et al.  Intraoperative radiation therapy (IORT) for previously untreated malignant gliomas , 2002, BMC Cancer.

[17]  Katherine W Ferrara,et al.  Driving delivery vehicles with ultrasound. , 2008, Advanced drug delivery reviews.

[18]  N. Rapoport.  Ultrasound-mediated micellar drug delivery , 2012, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[19]  W. Pitt,et al.  Investigating the mechanism of acoustically activated uptake of drugs from Pluronic micelles , 2002, BMC Cancer.

[20]  Thomas J Webster,et al.  Nanotechnology for bone materials. , 2009, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[21]  Robert Langer,et al.  Drugs on Target , 2001, Science.

[22]  A. Riga,et al.  Evaluation of the drug-polymer interaction in calcium alginate beads containing diflunisal. , 2010, Die Pharmazie.

[23]  R. Macdonald,et al.  Acoustically active liposomes for drug encapsulation and ultrasound-triggered release. , 2004, Biochimica et biophysica acta.

[24]  Jonas Addai-Mensah,et al.  Magnetic-responsive delivery of drug-carriers using titania nanotube arrays , 2012 .

[25]  K. Gulati,et al.  Controlling Drug Release from Titania Nanotube Arrays Using Polymer Nanocarriers and Biopolymer Coating , 2011 .

[26]  Dusan Losic,et al.  Self-ordered nanopore and nanotube platforms for drug delivery applications , 2009, Expert opinion on drug delivery.

[27]  E. Unger,et al.  Therapeutic applications of lipid-coated microbubbles. , 2004, Advanced drug delivery reviews.

[28]  W. Pitt,et al.  Sequestration and Ultrasound-Induced Release of Doxorubicin from Stabilized Pluronic P105 Micelles , 2002, Drug delivery.

[29]  J. Addai-Mensah,et al.  A multi-drug delivery system with sequential release using titania nanotube arrays. , 2012, Chemical communications.

[30]  Jesse B. Hall,et al.  Principles of Critical Care , 1992 .

[31]  Itaru Honma,et al.  Ultrasound‐Triggered Smart Drug Release from a Poly(dimethylsiloxane)– Mesoporous Silica Composite , 2006 .

[32]  P. Marmottant,et al.  Controlled vesicle deformation and lysis by single oscillating bubbles , 2003, Nature.

[33]  D. Cranston,et al.  High intensity focused ultrasound: surgery of the future? , 2003, The British journal of radiology.

[34]  W. Pitt,et al.  Ultrasonic drug delivery – a general review , 2004, Expert opinion on drug delivery.

[35]  D. Losic,et al.  A simple approach for synthesis of TiO2 nanotubes with through‐hole morphology , 2009 .

[36]  Tejal A Desai,et al.  Titania nanotubes: a novel platform for drug-eluting coatings for medical implants? , 2007, Small.

[37]  Mark R Prausnitz,et al.  Mechanism of intracellular delivery by acoustic cavitation. , 2006, Ultrasound in medicine & biology.

[38]  Joseph G. Shapter,et al.  Self-ordering Electrochemistry: A Simple Approach for Engineering Nanopore and Nanotube Arrays for Emerging Applications* , 2011 .

[39]  T. Webster,et al.  A Review of Nanotechnology for the Development of Better Orthopedic Implants , 2005 .

[40]  A. Fahr,et al.  Drug delivery strategies for poorly water-soluble drugs , 2007, Expert opinion on drug delivery.

[41]  Themistoklēs P. Chatzēiōannou,et al.  Quantitative calculations in pharmaceutical practice and research , 1993 .

[42]  H. Fain,et al.  Controlled and targeted tumor chemotherapy by micellar-encapsulated drug and ultrasound. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[43]  Si-Shen Feng,et al.  Vitamin E TPGS as a molecular biomaterial for drug delivery. , 2012, Biomaterials.