Research paper Polypropylene grafted with smart polymers (PNIPAAm/PAAc) for loading and controlled release of vancomycin Juan-Carlos Ruiz a,1 , Carmen Alvarez-Lorenzo b , Pablo Taboada c , Guillermina Burillo a , Emilio Bucio a , Kristof De Prijck d , Hans J. Nelis d , Tom Coenye d , Angel Concheiro b, * a Departamento de Química de Radiaciones y Radioquímica, Universidad Nacional Autónoma de México, México DF, Mexico b Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Santiago de Compostela, Santiago de Compostela, Spain c Departamento de Física de la Materia Condensada, Universidad de Santiago de Compostela, Santiago de Compostela, Spain d Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium article info Article history: Received 25 February 2008 Accepted in revised form 23 May 2008 Available online 6 June 2008 Keywords: IPN Surface-modified polypropylene Oxidative pre-irradiation Gamma irradiation Isothermal titration microcalorimetry Dually responsive Vancomycin local delivery Biofilm formation Biomedical devices abstract New smart surface-modified polypropylene (PP) was prepared for improving the loading and the sus- tained delivery of vancomycin and, thus, reducing the risk of biofilm formation when used as component of biomedical devices. Isothermal titration calorimetry (ITC) served for screening the most suitable monomers for grafting; the drug preferentially bonding to ionized acrylic acid (AAc). A net-PP-g-PNI- PAAm-inter-net-PAAc was synthesized by first grafting and cross-linking of N-isopropylacrylamide onto PP films and then interpenetrating a second network by redox polymerization and cross-linking of AAc. PP-g-PAAc slabs were prepared by grafting AAc and, optionally, cross-linking. The amount and composi- tion of grafted polymer (FTIR-ATR), morphology (SEM), temperature- and pH-responsiveness (swelling measurements), thermal behavior (DSC), friction coefficient (rheometry), drug loading and release rate, and effect against methicillin-resistant Staphylococcus aureus (MRSA) biofilms (modified robbins device) were evaluated. Grafting of AAc notably decreased the friction coefficient from 0.28 ± 0.03 to 0.05 ± 0.02 and enhanced the vancomycin loading (up to 2.5 mg/cm 2 ). Drug-loaded films showed a pH-dependent release rate, sustaining the release in pH 7.4 aqueous media at 37 °C for several hours. All drug-loaded films reduced biofilm formation by MRSA; the anti-biofilm effect being statistically significant (91.7% reduction, a < 0.05) for PP-g-PAAc with the thinnest grafting layer. Ó 2008 Elsevier B.V. All rights reserved. 1. Introduction The use of implants and medical devices has become a leading cause of health-care-related bloodstream infections, which are associated with considerable morbidity and mortality [1–4]. Vas- cular-catheter related septicemias have enormous economic and sanitary repercussions, the mortality rates being as high as 25% in critically ill patients [1–4]. The main source of infection is con- tamination from the skin at the moment of the insertion, mainly with opportunistic bacteria such as Staphylococcus spp. If the inoc- ula exceed threshold levels or if the host defenses are impaired, the bacteria can attach to the surface of the medical device and subsequently form a biofilm [5]. Cells in a biofilm (sessile cells) are phenotypically and physiologically different from non-ad- hered (planktonic) cells. One of the typical properties of sessile cells is their increased resistance to antimicrobial agents [5–7] which is reflected by the much higher minimal inhibitory concen- trations (MIC) for sessile cells compared to planktonic cells. The incorporation of antimicrobial agents in the device may be an effective way of preventing the development of these biofilm-re- lated infections, avoiding the systemic collateral effects of high doses of antibiotics, and overcoming concerns on bacterial resis- tance [4,8,9]. Antiseptics and antibiotics can be incorporated into the mate- rial of the device or covalently bound or adsorbed onto its surface to achieve sustained delivery of sufficient amounts of drug in the microenvironment of the medical device [10,11]. Despite the pro- gress in this field, the development of materials suitable for the production of catheters and implants, able to sorb a sufficient amount of drug and to provide a local delivery at the appropriate rate is still a challenging task [12]. The aim of this work was to explore the benefits of modifying polypropylene (PP) surfaces with stimuli-responsive polymers to improve the loading and con- trolled release of vancomycin without compromising the frictional properties. Vancomycin is one of the most frequently chosen anti- biotics for the treatment of methicillin-resistant Staphylococcus 0939-6411/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2008.05.020 * Corresponding author. Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain. Tel.: +34 981563100; fax: +34 981547148. E-mail addresses: ffancon@usc.es, angel.concheiro@usc.es (A. Concheiro). 1 Present address: École Polytechnique de Montréal, Canada. European Journal of Pharmaceutics and Biopharmaceutics 70 (2008) 467–477 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb