Chapter 1
Application of Nanocellulose for Controlled Drug Delivery

Lalduhsanga Pachuau

Assam University, Department of Pharmaceutical Sciences, Silchar, Assam, 788011, India

1.1 Introduction

The therapeutic effectiveness of a pharmacological treatment depends upon the availability of the active drug at the site of action in a concentration that exceeds the minimum effective concentration. However, more often than not, this ideal condition for therapeutic activity is not met due to several inherent pharmaceutical and pharmacological properties of the drug. In fact, it has been generally recognized that for many disease states, there are substantially good numbers of therapeutically effective compounds available on offer [1]. The obvious cause of therapeutic failure with several of these otherwise promising compounds when used in a clinical setting is that they are unable to reach the site of action. The potential reasons for the poor bioavailability of the drugs at the required site include (i) poor water solubility, (ii) poor permeability across the biological membranes, and (iii) rapid metabolism and clearance from the body [2]. The aim of controlled drug delivery is, therefore, to overcome these limitations to effective drug therapy by localizing drug release at the site of action, reducing the dose required, and providing constant drug release. As a result, controlled drug delivery systems offer several advantages over conventional system in reducing the toxicity, enhancing the activity, and ultimately improving the patient convenience and compliance [3]. Several dosage forms, conventional and nonconventional, have been developed and continuously improved over the years to achieve better drug therapy. One of the newer approaches for improved drug delivery that received enormous interest in recent times is nanomedicine. The applications of nanotechnology for treatment, diagnosis, monitoring, and control of biological systems have recently been referred to as nanomedicine by the National Institutes of Health [4]. Drug delivery is the dominant area of nanomedicine research as it accounts for 76% and 59% of all recent scientific papers and patents on nanomedicine, respectively [5].

Polymers are the backbone of controlled drug delivery systems. Over the past few decades, there has been considerable interest in the development of effective drug delivery devices based on biodegradable nanoparticles [6]. Both natural and synthetic polymers with a wide range of safety and functionalities are extensively investigated in designing controlled delivery systems. The investigations into the novel synthetic and fabrication methods, and mathematical models to study the mechanisms of controlled drug release, have resulted in the ability to create tunable polymeric nanoparticulate drug delivery systems that are capable of taking care of the spatial and temporal aspects of controlled drug delivery [7]. Due to their cytocompatibility, biodegradability, and availability of reactive sites amenable for ligand conjugation, cross-linking, and other modifications, natural polymers have been successfully used in controlled drug delivery [8, 9]. Plant-derived nanostructures such as starch, cellulose, zeins, legume proteins, and others are particularly attractive sources as they are cost effective, sustainable, and renewable with excellent tunable properties [10].

Nanocellulose obtained from cellulose - the most abundant biopolymer on Earth - is an emerging renewable polymeric nanomaterial that holds promise in many different applications including food and pharmaceuticals [11, 12]. Due to its excellent biocompatibility, biodegradability, and low ecological toxicity risk and low cytotoxicity to a range of animal and human cell types [13], nanocellulose is currently a subject of interdisciplinary material of interest. Excellent discussions on the chemistry, preparation, and the general properties of nanocellulose are available from several literatures [12, 14-17]. Nanocellulose can be obtained from a wide variety of sources and their properties were also found to depend on the source from which they are prepared (Figure 1.1). Broadly, they are divided into three categories such as bacterial cellulose (BC), cellulose nanocrystals (CNCs) (also called as cellulose nanowhiskers or nanocrystalline cellulose), and cellulose nanofibrils (CNFs) depending on their source and methods of production [18]. Those obtained from acid or enzyme hydrolysis are commonly called as CNC, while those obtained through mechanical treatments are termed as cellulose nanofibrils (CNFs). Bacterial nanocellulose is another highly crystalline form of cellulose, which is obtained mainly from Gluconacetobacter xylinus [19]. The presence of free reactive hydroxyl group exposed at the surface and its nanometer size dimension rendered nanocellulose a good candidate for imparting different functionalities through chemical derivatization. Since cellulose is stable to a wide range of temperatures, it can also be subjected to heat sterilization methods, which is often required in biomedical applications [20]. All the different categories of nanocelluloses have been widely investigated in drug delivery systems. Also, since BC can be purified using sodium hydroxide to the US Food and Drug Administration (FDA) acceptable range of endotoxin values for implants, that is, <20 endotoxin units/device, they are also potentially safe for use in intravenous applications [21].

Figure 1.1 TEM images of (a) bacterial HCl, (b) bacterial sulfate, (c) tunicate sulfate, (d) wood enzymatic, (e) wood mechanically refined, (f) wood sulfate, and (g) wood TEMPO.

(Sacui et al. 2014 [17]. Reproduced with permission of American Chemical Society.)

Different cellulose derivatives including ethylcellulose, methylcellulose, carboxymethyl cellulose, and hydroxypropylmethyl cellulose are indispensable in drug delivery and pharmaceutical technology. They are listed as generally recognized as safe (GRAS) by the FDA and are widely used in the preparation of drug products [22]. Even though it was way back in 1949 that Ranby [23] successfully produced a micellar cellulose solution, it is only in the last few years that the potential of nanocellulose in drug delivery has been realized and research into this material has began to pick up. Current research into the application of nanocellulose in drug delivery includes formulation of nanoparticles, microparticles, tablets, aerogels, hydrogels, and transdermal drug delivery systems. This chapter will describe the current and recent research activities in the application of nanocellulose in the preparation of different dosage forms.

1.2 Biodegradability, Cytotoxicity, and Cellular Internalization of Nanocellulose

Choosing a suitable polymer that is biocompatible, able to encapsulate, control, and target the release of the drug and yet biodegradable is highly critical for the successful formulation of nanomedicine. The ability of nanomedicines to target specific sites depends upon the particle size, surface charge, surface modification, and hydrophobicity, which in turn determine their interaction with the cell membrane and their penetration across the physiological drug barriers [24]. Therefore, it is important that the biodegradability, cytotoxicity to a range of human cell types, and the mechanism of cellular uptake of nanocellulose-based delivery systems are investigated (Table 1.1). When investigated against nine different cell lines such as HBMEC, bEnd.3, RAW 264.7, MCF-10A, MDA-MB-231, MDA-MB-468, KB, PC-3, and C6 following the MTT and LDH assay methods, the filamentous CNCs showed no cytotoxic effects against any of these cell lines in the concentration range (0-50 µg ml-1) during the exposure time (48 h) [25, 26]. Low nonspecific cellular uptake was observed when cellular uptake was evaluated through fluorescein-5´-isothiocyanate labeling, which indicates that CNCs are good candidates for nano drug delivery applications. In another study, the cellular uptake of negatively charged fluorescein isothiocyanate (FITC)-labeled CNCs was evaluated and compared against the positively charged rhodamine B isothiocyanate-labeled CNCs (RBITC) in human embryonic kidney 293 (HEK 293) and Spodoptera frugiperda (Sf9) cells [27]. This study reports that the positively charged CNC-RBITC conjugate was uptaken by the cells without affecting the integrity of the cell membrane and there was no noticeable cytotoxic effect observed (Figure 1.2), whereas the negatively charged CNC-FITC conjugate resulted in no significant internalization at physiological pH but the effector cells were surrounded by CNC-FITC, leading to eventual cell rupture showing the importance of the surface charge of CNC for bioimaging and drug delivery.

Table 1.1 Cellular uptake mechanisms of different formulations.