Chitosan-based systems for molecular imaging

Abstract

Molecular imaging enables the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development. Molecular imaging allows a repetitive and non-invasive study of the same living subject using identical or alternative biological imaging assays at different time points, thus harnessing the statistical power of longitudinal studies, and reducing the number of animals required and cost. Chitosan is a hydrophilic and non-antigenic biopolymer and has a low toxicity toward mammalian cells. Hence, it has great potential as a biomaterial because of its excellent biocompatibility. Conjugated to additional materials, chitosan composites result in a new class of biomaterials that possess mechanical, physicochemical and functional properties, which have potential for use in advanced biomedical imaging applications. The present review will discuss the strengths, limitations and challenges of molecular imaging as well as applications of chitosan nanoparticles in the field of molecular imaging.

Introduction

Chitosan [poly(1,4-β-d-glucopyranosamine)], an abundant natural biopolymer, is produced by the deacetylation of chitin obtained from the shells of crustaceans. It is a polycationic polymer that has one amino group and two hydroxyl groups in the repeating hexosaminide residue (Fig. 1). Chitosan has great potential as a biomaterial because of its bio-compatible properties. It is hydrophilic, non-antigenic and has a low toxicity toward mammalian cells [1], [2], [3]. In addition, chitosan is known to facilitate drug delivery across cellular barriers and transiently open the tight junctions between epithelial cells [4], [5]. Chitin and chitosan are aminoglucopyrans composed of N-acetylglucosamine (GlcNAc) and glucosamine (GlcN) residues. These polysaccharides are renewable resources which are currently also being explored intensively for their applications in pharmaceutical, cosmetics, biomedical, biotechnological, agricultural and food industries [1], [6].

These polymers have emerged as a new class of physiological materials of highly sophisticated functions and to exploit the properties of these versatile polysaccharides, attempts are being made to derivatize them [7]. Chemical modifications have done an excellent job for the preparation of chitosan derivatives with higher solubility in water, such as O-,N-carboxymethyl-chitosan, [8]N-carboxymethyl-chitosan, [9]O-carboxymethyl-chitosan, [10], [11]N-sulfate-chitosan, [12]O-sulfate chitosan, [13]O-succinyl-chitosan, [14]N-methylene phosphonic chitosan, [15] hydroxypropyl chitosan, [16]N-trimethyl chitosan, [17] and others. The emergence of synthesis strategies for the fabrication of nanosized particles leads to advancements in the nanotechnology, which benefits molecular imaging for understanding of biological processes at the molecular level. In addition, with the added multifunctional features such particles may become an integral part of the development of next generation therapeutic, diagnostic and imaging technologies.

Molecular imaging holds the promise of the non-invasive assessment of biological and biochemical processes in living subjects. Since the inception of X-ray technology for medical imaging, many non-invasive methodologies have been invented and successfully used for applications ranging from clinical diagnosis to research in cellular biology and drug discovery. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development. The advantage of molecular imaging techniques over more conventional readouts (e.g. immunohistochemistry) is that they can be performed in the intact organism with sufficient spatial and temporal resolution for studying biological processes in vivo. Furthermore, molecular imaging allows a repetitive and non-invasive study of the same living subject using identical or alternative biological imaging assays at different time points, thus harnessing the statistical power of longitudinal studies, and reducing the number of animals required and cost. Molecular imaging usually exploits specific molecular probes as well as intrinsic tissue characteristics as the source of image contrast, and provides the potential for understanding of integrative biology, earlier detection and characterization of disease, and evaluation of treatment [18]. Molecular imaging could also aid decisions to select promising drug candidates that seem most likely to be successful or to halt the development of drugs that seem likely to ultimately fail [18].

Different imaging techniques are, in general, complementary rather than competitive and the choice of imaging modality depends primarily on the specific question that has to be addressed (Fig. 2). Imaging of biological specimens both in vitro and in vivo has long relied on light microscopy (fluorescence and luminescence imaging). The presently leading non-invasive imaging techniques are computed tomography (CT), magnetic resonance (MR), positron emission tomography (PET), single photon emission CT (SPECT), ultrasound (US) and optical imaging (OI), including their variations and subcategories [19], [20], [21], [22], [23], [24], [25]. Biomedical imaging research has prospered in recent years because of the significant advances in electronics, information technology and, more recently, nanotechnology.

The above imaging modalities can be broadly divided into two groups, i.e., morphological/anatomical and molecular (i.e. functional) imaging techniques. The morphological/anatomical imaging technologies, such as computed tomography (CT), MRI and ultrasound (US), are characterized by high spatial resolution (Fig. 2). However, they also share the limitation of not being able to detect diseases until structural changes in the tissue (for example, growth of a tumor, or extent of inflammation) are large enough to be morphologically detected. On the other hand molecular imaging modalities, such as optical imaging, PET and SPECT, offer the potential to detect molecular and cellular changes caused by disease (for example, before the tumor is large enough to cause structural changes). However, these molecular modalities suffer from a poor spatial resolution with currently available technology and do not provide anatomic information (Fig. 2).

The present review will discuss the strengths, limitations and challenges of molecular imaging as well as applications of chitosan nanoparticles in the field of molecular imaging. We will first explain the properties of chitosan, then will discuss different strategies of molecular imaging, including their advantages and disadvantages. In the last part of this review, agents for imaging will be reviewed as well as the potential role and application of chitosan as a constituent of molecular imaging contrast agents.