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Graphene Reinforced Chitosan Nanocomposites for Drug Delivery 465
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Carbon Nanofiber-Based Materials for Drug Delivery
Namrata Khanna, Tanushri Chatterji, and Tanya Bhagat
Abstract Polymeric nanofibers with their large surface area per unit mass, biocom-
patibility, easy fabrication and surface modification find extensive use as filters and scaffolds in several biomedical applications like precision drug delivery, tissue engi­neering, formation of reinforced composite molecules and sensors. Though most of these applications are in nascent stages of development, some are being used commercially. Several strategies have been employed for development of nanofibers, but electrospinning technique has been used widely to modify several polymers into nanofibers and is probably the only strategy with potential for large-scale commercial production. It is a versatile process and has the ability to fabricate several nanofiber assemblies by enhancing the performance and introducing variations conducive for specific applications. Organic, inorganic or hybrid nanofibers exhibit refined mechan­ical features for enhanced sustained release or for regulated release of loaded drugs, which facilitates the application of nanofibers in precise delivery of drugs. This chapter provides a succinct account of the progress in preparation, performance and application of several nanofibers as drug delivery carriers for anti-inflammatory, antimicrobial, antitumor, cardiovascular, gastrointestinal and palliative therapies, emphasizing role of electrospinning process in the above applications.
·
Keywords Carbon nanofibers Electrospinning · Drug delivery
N. Khanna Department of Biochemistry, M. A. Rangoonwala College of Dental Sciences and Research Centre, 2390-B, K.B. Hidayatullah Road, Azam Campus, Camp, Pune, Maharashtra 411001, India
T. Cha tter ji ( Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), Adhyatmik Nagar, NH-09, Ghaziabad, Uttar Pradesh 201015, India e-mail: tanushri@gmail.com
T. Bhagat Department of Biochemistry, Manav Rachna International Institute of Research and Studies, Sector – 43, Aravalli Hills, Delhi – Surajkund Road, Faridabad, Haryana 121004, India
) · T. Bhagat
B
Surface modification·Polymers
·
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Abbreviations
AC Aceclofenac ACV Acyclovir AMB Amphotericin B AMOX Amocycilin APAP Acetaminophen; N-acetyl-para-aminophenol APIs Active pharmaceutical ingredients CAF Caffeine CAP Cellulose acetate phthalate CHS Chitosan CIPRO Ciprofloxacin DMAc Dimethylacetamide CNTs Carbon nanotubes CNFs Carbon nanofibers DOC Docetaxel DOX Doxorubicin DPH Diphenhydramine DSC Differential scanning calorimetry EC Ethyl cellulose GML Glycerol Monolaurate GRIS Griseofulvin HOPG Highly oriented pyrolytic graphite HPMC Hydroxypropylmethyl cellulose IBU Ibuprofen INDO Indomethacin ITR Itraconazole KETO Ketoprofen LOR Loratadine MEL Meloxicam MET-HCl Metoclopramide hydrochloride MWCNT Multi-walled carbon nanotube PAA Poly(acrylic acid) PAN Poly(acrylonitrile) PCL Poly(ε-caprolactone) PEO Poly(ethylene oxide) PLGA Poly(lactic-co-glycolic acid) PLLA Poly(L- lactic acid) PTX Paclitaxel PU Poly (urethane) PVAL Poly(vinyl alcohol) PVP Poly(vinylpyrrolidone) RFN Riboflavin SDS Sodium dodecylsulfate
Carbon Nanofiber-Based Materials for Drug Delivery 471
SPIRO Spirolactone SWCNT Single walled carbon nanotube SUM Sumatriptan TCH Tetracycline hydrochloride TCN Tetracycline TGA Thermo-gravimetric analysis TDF Tenofovir disoproxil fumarate

1 Introduction

Among nanomolecules, carbon nanotubes (CNTs) and nanofibers (CNFs) have drawn wide recognition owing to their structural, electrical, mechanical, thermal and optical characteristics. CNTs are well-arranged hollow structures made up of carbon atoms linked through strong sp ical strength, along with electrical and thermal conductivity to the CNTs [14]. CNTs can be visualized as cylindrical structures, which are formed by a graphene sheet (Fig. 1a and b). A single graphene sheet on rolling creates a single walled carbon nanotube (SWCNT), whereas multiple concentric graphene sheets form a multi-walled carbon nanotube (MWCNT). Alignment of atoms in carbon nanofibers (CNFs) is less refined. A CNF is formed when graphene sheets bend at a certain angle, α, resulting in stacks of conical nanostructures (Fig. 1c), while CNTs exhibit α = 0 (Fig. 1b). SWCNTs have diameters within a range of 0.5 to 1.5 nm and length in a range of 100 nm to many micrometers. MWCNTs possess bigger diameters (above 100 nm), owing to a multilayered structure. Diameter of CNFs can range from 3.5 nm to a few hundred nanometers and length can be up to many microm­eters. Transmission electron microscopy (TEM) images of MWCNT and CNFs are represented in Fig. 1(d–f).
Exceptional electrical, surface and mechanical features make CNFs perfect for several biomedical applications. Their high aspect ratio (length to diameter ratio), large surface area and several dangling bonds along the side walls provide CNFs with the flexibility to be modified by many bioactive molecules for clinical application. The current chapter reviews the use of CNFs in precision drug delivery, which is critical in treatment of several malignancies and other disorders. CNFs have the advantage of low production cost in comparison with CNTs, which facilitates their involvement in commercial production. CNFs are composed of graphene and exhibit different planes which are not concentric. Based on structure, they are classified as [5]“platelet,” “fishbone,” “ribbon,” or “stacked cup.”
2
bonds, which are critical in providing high mechan-
472 N. Khanna et al.
Fig. 1 Representation of a graphene sheet b CNT c and nanofiber structures (Reproduced with permission from AIP Publishing [4]), TEM pictures showing cross section of d MWCNT (Repro- duced with permission from Elsevier [1]) and e and f nanofiber (Reproduced with permission from ACS [2])

2 Functionalization of CNFs

Though there are differences in their structure, CNFs are related to CNTs as the CNFs have morphology similar to MWCNTs; nevertheless, they have distinct chemical and physical characteristics. CNTs exhibit ballistic transport of electrons [6] and an axial diamond-like tensile strength [7]. The strength of nanofibers is proved by their individual, independent configuration, which exhibits a high reactivity and electron transfer beyond the sidewalls of nanofibres, a significant aspect in facilitating their functionalization [810] and utilization of electrochemical technique [8, 10, 11], respectively. Initial studies on highly oriented pyrolytic graphite (HOPG) and glassy carbon show that in graphite, the edge planes have 105 times higher electron transport rates as compared to those exhibited by basal planes [11].
Carbon Nanofiber-Based Materials for Drug Delivery 473

2.1 The Need for Functionalization

Functionalization of nanofibres is similar to that of nanotubes and has been reviewed by Klein et al. [3]. Functionalization of CNFs involves reactions at the fibre surface, while for CNTs, the sidewalls along with tube caps are the sites of chemical reactions. Pristine carbon nanomaterials aggregate as bundles and are insoluble [12]; hence, they are difficult for biomedical application. Some non-functionalized nanoparticles exhibit cytotoxicity [1315], which is attributed to the presence of residual metallic catalysts and also to the insoluble character of pristine nanoparticles [16]. There­fore, to make them biocompatible, functionalization is significant, as it enhances the solubility and decreases their cytotoxicity. Furthermore, conjugation of bioac­tive materials with the nanoparticle through the process of functionalization aids in carrying drugs, antigens and gene towards target tissues.
2.2 Techniques Employed for Functionalization of Carbon
Nanomaterials
Various strategies for functionalization are employed and mainly involve two approaches, the first strategy involves additional reactions for attachment of organic moieties on the sidewalls and tips and the second approach includes oxidation along with carboxyl couplings. The first strategy involves blending of pristine carbon nanoparticles and aniline and the pressure applied during mixing facilitates liber­ation of the bundled outer nanoparticles, which react with the reagent to initiate the process of functionalization. This leads to covalent functionalization of the individual nanoparticle, which prevents it from bundling with other particles and increases surface area for attachment of molecules along with improving the solu­bility. This strategy is a simple procedure, which generates soluble nanoparticles and facilitates their industrial application [17]. However, this method has a major limi­tation of preventing many essential changes in the nanoparticle. The second method used for functionalization involves oxidation and couplings that are carboxyl group based. This procedure involves creation of cap openings and holes along the side walls through oxidation, which uses concentrated acids. Furthermore, carboxylic groups are also introduced, which increase the solubility of nanoparticles in aqueous medium [18]. Carboxylic group forms amide and ester linked covalent bonds with several biologically active molecules such as peptides [19, 20], nucleic acids [21, 22], proteins [23] and anti-tumor drugs [24, 25]. Appropriate bonding enhances solubility of nanoparticles in both aqueous [26] as well as organic solvents [27]. Carboxylic functional groups decrease interactions driven by Van der Waals forces between the nanoparticles, facilitating separation of bundles [28].
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3 Electrospinning of Nanofibers
Electrospinning is a process employing electrostatic forces to generate extremely fine fibers with size in the range of submicron to nanometer. Electrospinning can be used to produce nanofibers which can be natural [29], synthetic [30], biodegradable [31, 32], non-degradable [33] or combinations of the above types [31, 34]. Though, there are many traditional strategies for nanofiber fabrication like template synthesis [35, 36], phase separation [37], mechanical drawing [38] and self-assembly [36,
39, 40], electrospinning has attracted more attention and is widely accepted as it is
easy to perform, is cost effective, needs uncomplicated tools, and produces ultrafine nanofibers by employing a simple step-up production.
The process involves a high voltage electric field, which on application to the nanofiber fluid (in solution or molten) causes generation of a jet, which ejects from the eluting nozzle and proceeds towards the grounded collector that is oppositely charged. In absence of an electric field, surface tension holds the nanofiber droplet at the tip of capillary [41, 42]. On applying the electrostatic forces, the surface tension gets balanced and the droplet elongates to form a “Taylor Cone.” When the electrical field is strong enough to balance the surface tension, a fine jet ejects out through the tip of the cone [43, 44]. When liquid jet passes in air, the fluid evaporates and solidified nanofibers are collected in the form of a scaffold or mesh [45]. The electrospinning process is illustrated in Fig. 2.
Nanofibers spun by traditional methods are thinned and elongated by aerody­namic, rheological, tensile, gravitational, or inertial forces [46]. The charge induced by effect of electric field generates tensile forces towards the direction of axial jet flow, which causes spinning of the fiber [47]. Recent studies exhibit that the jet, after traversing a short distance, loses stability and whips owing to reciprocal action between the external electrostatic force of attraction and the internal forces of repul­sion generated by surface charges in the jet [48]. This causes elongation of length and reduction in diameter of the nanofiber manifold as compared to nanofibers generated
Fig. 2 The process of electrospinning employed for generating and improving the structure of nanofibers. Adapted with permission from RSC [45]