Regulation of cell proliferation by multi-layered phospholipid polymer hydrogel coatings through controlled release of paclitaxel.

We fabricated multi-layered hydrogels on titanium alloy (Ti) surfaces by applying alternating layers of a water-soluble phospholipid polymer (PMBV) and polyvinyl alcohol (PVA). This was accomplished by a layer-by-layer (LbL) process that is based on the formation of reversible covalent bonds between the boronic acid subunits in the PMBV and the hydroxyl groups in the PVA. When placed in an aqueous medium, PMBV acquires a polymeric aggregate structure with hydrophobic domains that can effectively solubilize hydrophobic molecules such as the anticancer drug paclitaxel (PTX) used in this study. The PTX-containing PMBV layer acted as a reservoir in the multi-layered hydrogels. To obtain diverse release profiles, the PTX was loaded in either the top layer (top-type) or the bottom layer (bottom-type) of the hydrogels; additional layers of PMBV and PVA, without PTX, functioned as a diffusion-barrier. In cell culture experiments, top-type hydrogels demonstrated excessive suppression of human epidermal carcinoma A431 cell proliferation over 5 days due to the initial high concentration of released PTX. However, bottom-type hydrogels were able to maintain a constant cell number profile. The release of PTX from multi-layered hydrogels was governed by both diffusion through the diffusion-barrier and dissociation of the hydrogel through an exchange reaction of phenylboronic acid subunits with the low-molecular weight D-glucose in the cell culture medium. In the cell culture experiments, the cell cycle was arrested in S and G2/M phases, as expected following PTX-mediated growth inhibition; control hydrogels did not demonstrate any appreciable cell cycle arrest. We concluded that cell proliferation could be controlled by the concentration of PTX released from the multi-layered hydrogels prepared through the LbL process. This system when used to solubilize bioactive agents at an appropriate layer within the hydrogel has potential for localized and surface-mediated delivery of bioactive molecules from biomedical devices.

[1]  James M. Anderson,et al.  Biological Responses to Materials , 2001 .

[2]  J. Watanabe,et al.  Enhanced solubility of paclitaxel using water-soluble and biocompatible 2-methacryloyloxyethyl phosphorylcholine polymers. , 2003, Journal of biomedical materials research. Part A.

[3]  Barry O'Brien,et al.  The evolution of cardiovascular stent materials and surfaces in response to clinical drivers: a review. , 2009, Acta biomaterialia.

[4]  Jun Zhang,et al.  Natural polyelectrolyte films based on layer-by layer deposition of collagen and hyaluronic acid. , 2005, Biomaterials.

[5]  K. Ishihara,et al.  Controlled drug release from multilayered phospholipid polymer hydrogel on titanium alloy surface. , 2009, Biomaterials.

[6]  A. Metters,et al.  Hydrogels in controlled release formulations: network design and mathematical modeling. , 2006, Advanced drug delivery reviews.

[7]  R. Kuntz,et al.  Zotarolimus (ABT-578) eluting stents. , 2006, Advanced drug delivery reviews.

[8]  J. Watanabe,et al.  Efficacy of an MPC-BMA co-polymer as a nanotransporter for paclitaxel. , 2007, Anticancer research.

[9]  T. Okano,et al.  Amine containing phenylboronic acid gel for glucose-responsive insulin release under physiological pH , 1995 .

[10]  Kenji Yamazaki,et al.  Preclinical biocompatibility assessment of the EVAHEART ventricular assist device: coating comparison and platelet activation. , 2007, Journal of biomedical materials research. Part A.

[11]  D. M. Lynn,et al.  Controlling interlayer diffusion to achieve sustained, multiagent delivery from layer-by-layer thin films , 2006, Proceedings of the National Academy of Sciences.

[12]  T. H. Wang,et al.  Paclitaxel‐induced cell death , 2000, Cancer.

[13]  F. Moussy,et al.  Implantable glucose sensor: progress and problems , 2002, Proceedings of IEEE Sensors.

[14]  M. Rubner,et al.  Molecular-Level Processing of Conjugated Polymers. 4. Layer-by-Layer Manipulation of Polyaniline via Hydrogen-Bonding Interactions , 1997 .

[15]  R. Donehower,et al.  Drug therapy : paclitaxel (Taxol) , 1995 .

[16]  G. Viale,et al.  The microtubule-affecting drug paclitaxel has antiangiogenic activity. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  P. Hammond,et al.  MAD (multiagent delivery) nanolayer: delivering multiple therapeutics from hierarchically assembled surface coatings. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[18]  Local drug delivery using coated stents: new developments and future perspectives. , 2004, Current pharmaceutical design.

[19]  Si-Shen Feng,et al.  The drug encapsulation efficiency, in vitro drug release, cellular uptake and cytotoxicity of paclitaxel-loaded poly(lactide)-tocopheryl polyethylene glycol succinate nanoparticles. , 2006, Biomaterials.

[20]  Myron Spector,et al.  The effectiveness of the controlled release of gentamicin from polyelectrolyte multilayers in the treatment of Staphylococcus aureus infection in a rabbit bone model. , 2010, Biomaterials.

[21]  James M. Anderson,et al.  Foreign body reaction to biomaterials. , 2008, Seminars in immunology.

[22]  J. Jacobs,et al.  Hypersensitivity to metallic biomaterials: a review of leukocyte migration inhibition assays. , 2000, Biomaterials.

[23]  H. Schliephake,et al.  Chemical and biological functionalization of titanium for dental implants , 2008 .

[24]  N Nakabayashi,et al.  Why do phospholipid polymers reduce protein adsorption? , 1998, Journal of biomedical materials research.

[25]  Tomiharu Matsushita,et al.  Surface grafting of artificial joints with a biocompatible polymer for preventing periprosthetic osteolysis , 2004, Nature materials.

[26]  Zhiyong Tang,et al.  Biomedical Applications of Layer‐by‐Layer Assembly: From Biomimetics to Tissue Engineering , 2006 .

[27]  M. Jordan,et al.  Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[28]  K. Ishihara,et al.  Surface immobilization of biocompatible phospholipid polymer multilayered hydrogel on titanium alloy. , 2008, Colloids and surfaces. B, Biointerfaces.

[29]  H Hoshino,et al.  Glucose-sensing electrode coated with polymer complex gel containing phenylboronic Acid. , 1996, Analytical chemistry.

[30]  Rizhi Wang,et al.  Surface modifications of bone implants through wet chemistry , 2006 .

[31]  P. Hammond,et al.  Release of a model protein from biodegradable self assembled films for surface delivery applications. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[32]  Kazuhiko Ishihara,et al.  Preparation of Phospholipid Polylners and Their Properties as Polymer Hydrogel Membranes , 1990, Polymer Journal.

[33]  E K Rowinsky,et al.  Paclitaxel (taxol) , 1995, The New England journal of medicine.

[34]  K. Ishihara,et al.  Stress response of adherent cells on a polymer blend surface composed of a segmented polyurethane and MPC copolymers. , 2006, Journal of biomedical materials research. Part A.

[35]  C. Lieu,et al.  Cell cycle specific induction of apoptosis and necrosis by paclitaxel in the leukemic U937 cells. , 2005, Life sciences.

[36]  K. Ishihara,et al.  Polymeric Lipid Nanosphere Consisting of Water-Soluble Poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) , 1999 .

[37]  M. Rubner,et al.  Design of Antibacterial Surfaces and Interfaces: Polyelectrolyte Multilayers as a Multifunctional Platform , 2009 .

[38]  N Nakabayashi,et al.  Reduced thrombogenicity of polymers having phospholipid polar groups. , 1990, Journal of biomedical materials research.

[39]  Johannes Schmitt,et al.  Buildup of ultrathin multilayer films by a self-assembly process: III. Consecutively alternating adsorption of anionic and cationic polyelectrolytes on charged surfaces , 1992 .

[40]  Christine Jérôme,et al.  Polymers in modern ophthalmic implants—Historical background and recent advances , 2010 .

[41]  K. Ishihara,et al.  Temporal and spatially controllable cell encapsulation using a water-soluble phospholipid polymer with phenylboronic acid moiety. , 2007, Biomaterials.

[42]  D. M. Lynn,et al.  Multilayered polyelectrolyte assemblies as platforms for the delivery of DNA and other nucleic acid-based therapeutics. , 2008, Advanced drug delivery reviews.

[43]  R. Virmani,et al.  Stent‐based delivery of ABT‐578 via a phosphorylcholine surface coating reduces neointimal formation in the porcine coronary model , 2005, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.