Regulating drug release from pH- and temperature-responsive electrospun CTS-g-PNIPAAm/poly(ethylene oxide) hydrogel nanofibers

Temperature- and pH-responsive polymers have been widely investigated as smart drug release systems. However, dual-sensitive polymers in the form of nanofibers, which is advantageous in achieving rapid transfer of stimulus to the smart polymeric structures for regulating drug release behavior, have rarely been explored. In this study, chitosan-graft-poly(N-isopropylacrylamide) (CTS-g-PNIPAAm) copolymer was synthesized by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxy succinimide (NHS) as grafting agents to graft carboxyl-terminated PNIPAAm (PNIPAAm-COOH) chains onto the CTS biomacromolecules, and then CTS-g-PNIPAAm with or without bovine serum albumin (BSA) was fabricated into nanofibers through electrospinning using poly(ethylene oxide) (PEO, 10 wt%) as a fiber-forming facilitating additive. The BSA laden CTS-g-PNIPAAm/PEO hydrogel nanofibers were tested to determine their drug release profiles by varying pH and temperature. Finally, cytotoxicity of the CTS-g-PNIPAAm/PEO hydrogel nanofibers was evaluated by assaying the L929 cell proliferation using the MTT method. It was found that the synthesized CTS-g-PNIPAAm possessed a temperature-induced phase transition and lower critical solution temperature (LCST) at 32° C in aqueous solutions. The rate of BSA release could be well modulated by altering the environmental pH and temperature of the hydrogel nanofibers. The CTS-g-PNIPAAm/PEO hydrogel nanofibers supported L929 cell growth, indicative of appropriate cytocompatibility. Our current work could pave the way towards developing multi-stimuli responsive nanofibrous smart materials for potential applications in the fields of drug delivery and tissue engineering.

[1]  R. Zhuo,et al.  Poly(N‐isopropylacrylamide) Nanoparticle‐Incorporated PNIPAAm Hydrogels with Fast Shrinking Kinetics , 2005 .

[2]  Myung-Seob Khil,et al.  Electrospun nanofibrous polyurethane membrane as wound dressing. , 2003, Journal of biomedical materials research. Part B, Applied biomaterials.

[3]  Xiu-li Wang,et al.  Poly (N-isopropylacrylamide)/poly (ethylene oxide) blend nanofibrous scaffolds: thermo-responsive carrier for controlled drug release. , 2011, Colloids and surfaces. B, Biointerfaces.

[4]  R K Jain,et al.  Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. , 1994, Cancer research.

[5]  Byong-Taek Lee,et al.  Preparation and characterization of electrospun PCL/PLGA membranes and chitosan/gelatin hydrogels for skin bioengineering applications , 2011, Journal of materials science. Materials in medicine.

[6]  K. Braeckmans,et al.  Stimuli-responsive electrospun fibers and their applications. , 2011, Chemical Society reviews.

[7]  Trong-Ming Don,et al.  Synthesis of Chitosan-Based Thermo- and pH-Responsive Porous Nanoparticles by Temperature-Dependent Self-Assembly Method and Their Application in Drug Release , 2009 .

[8]  A. Singer,et al.  Ultrafast and fast bioerodible electrospun fiber mats for topical delivery of a hydrophilic peptide. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[9]  L. Yu,et al.  Poly(N-isopropylacrylamide)-chitosan as thermosensitive in situ gel-forming system for ocular drug delivery. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[10]  Jia-cong Shen,et al.  The gene transfection efficiency of thermoresponsive N,N,N-trimethyl chitosan chloride-g-poly(N-isopropylacrylamide) copolymer. , 2007, Biomaterials.

[11]  S. Murdan.  Electro-responsive drug delivery from hydrogels. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[12]  Nicholas A. Peppas,et al.  Synthesis and Characterization of Thermo- and Chemomechanically Responsive Poly(N-isopropylacrylamide-co-methacrylic acid) Hydrogels , 1995 .

[13]  Eyal Zussman,et al.  Experimental investigation of the governing parameters in the electrospinning of polymer solutions , 2004 .

[14]  G. Wnek,et al.  Electrospinning of Collagen Type II: A Feasibility Study , 2003 .

[15]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[16]  K. Chennazhi,et al.  Curcumin-loaded biocompatible thermoresponsive polymeric nanoparticles for cancer drug delivery. , 2011, Journal of colloid and interface science.

[17]  M. Mozetič,et al.  Titanium nanostructures for biomedical applications , 2015, Nanotechnology.

[18]  Hitoshi Sashiwa,et al.  Chemically modified chitin and chitosan as biomaterials , 2004 .

[19]  Cato T Laurencin,et al.  Electrospun nanofibrous structure: a novel scaffold for tissue engineering. , 2002, Journal of biomedical materials research.

[20]  L. V. Doronina-Amitonova,et al.  Neurophotonics: optical methods to study and control the brain , 2015 .

[21]  Yanzhong Zhang,et al.  Stable jet electrospinning for easy fabrication of aligned ultrafine fibers , 2012 .

[22]  Horst A von Recum,et al.  Electrospinning: applications in drug delivery and tissue engineering. , 2008, Biomaterials.

[23]  Ian Soutar,et al.  Synthesis and conformational behaviour of luminescently labelled poly[styrene‐graft‐(N‐isopropyl acrylamide)] copolymers , 2006 .

[24]  J. Nie,et al.  Photopolymerization of methacrylated chitosan/PNIPAAm hybrid dual-sensitive hydrogels as carrier for drug delivery. , 2009, International journal of biological macromolecules.

[25]  M. Kotaki,et al.  Electrospun P(LLA-CL) nanofiber: a biomimetic extracellular matrix for smooth muscle cell and endothelial cell proliferation. , 2004, Biomaterials.

[26]  T. Okano,et al.  Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[27]  C. Perera,et al.  Evaluation of gallic acid loaded zein sub-micron electrospun fibre mats as novel active packaging materials. , 2013, Food chemistry.

[28]  Jyh-Ping Chen,et al.  Thermo-responsive chitosan-graft-poly(N-isopropylacrylamide) injectable hydrogel for cultivation of chondrocytes and meniscus cells. , 2006, Macromolecular bioscience.

[29]  Trong-Ming Don,et al.  Synthesis and characterization of AB-crosslinked graft copolymers based on maleilated chitosan and N-isopropylacrylamide , 2005 .

[30]  F. Winnik.  Phase transition of aqueous poly-(N-isopropylacrylamide) solutions: a study by non-radiative energy transfer , 1990 .

[31]  Yanzhong Zhang,et al.  Ultrasound-modulated shape memory and payload release effects in a biodegradable cylindrical rod made of chitosan-functionalized PLGA microspheres. , 2013, Biomacromolecules.

[32]  Seon Jeong Kim,et al.  pH/temperature‐responsive semi‐IPN hydrogels composed of alginate and poly(N‐isopropylacrylamide) , 2002 .

[33]  J. Mano,et al.  Stimuli-responsive hydrogels based on polysaccharides incorporated with thermo-responsive polymers as novel biomaterials. , 2006, Macromolecular bioscience.

[34]  Dean-Mo Liu,et al.  Magnetic-sensitive silica nanospheres for controlled drug release. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[35]  Toshiyuki Kanamori,et al.  Photoresponsive properties of poly(N-isopropylacrylamide) hydrogel partly modified with spirobenzopyran. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[36]  A. Domb,et al.  Chitosan chemistry and pharmaceutical perspectives. , 2004, Chemical reviews.

[37]  Adrian Bowyer,et al.  A novel pH- and ionic-strength-sensitive carboxy methyl dextran hydrogel. , 2005, Biomaterials.

[38]  S. Ramakrishna,et al.  Chitosan nanofibers from an easily electrospinnable UHMWPEO-doped chitosan solution system. , 2008, Biomacromolecules.

[39]  Y. H. Kim,et al.  Synthesis and thermo-responsive properties of chitosan-g-poly (N-isopropylacrylamide) and HTCC-g-poly(N-isopropylacrylamide) copolymers , 2010 .

[40]  Changren Zhou,et al.  Controlled dual release of hydrophobic and hydrophilic drugs from electrospun poly (l-lactic acid) fiber mats loaded with chitosan microspheres , 2011 .

[41]  M. Torres-Lugo,et al.  Molecular design and in vitro studies of novel pH-sensitive hydrogels for the oral delivery of calcitonin , 1999 .

[42]  Yanzhong Zhang,et al.  Implication of stable jet length in electrospinning for collecting well-aligned ultrafine PLLA fibers , 2013 .

[43]  Tejraj M Aminabhavi,et al.  Recent advances on chitosan-based micro- and nanoparticles in drug delivery. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[44]  Chia-Lung Lin,et al.  Morphology and temperature responsiveness-swelling relationship of poly(N-isopropylamide-chitosan) copolymers and their application to drug release , 2004 .

[45]  João F Mano,et al.  Hydroxypropyl chitosan bearing beta-cyclodextrin cavities: synthesis and slow release of its inclusion complex with a model hydrophobic drug. , 2005, Macromolecular bioscience.

[46]  B. Hsiao,et al.  Development of a nanostructured DNA delivery scaffold via electrospinning of PLGA and PLA-PEG block copolymers. , 2003, Journal of controlled release : official journal of the Controlled Release Society.