Elsevier

Journal of Controlled Release

Volume 193, 10 November 2014, Pages 202-213
Journal of Controlled Release

Self-assembled glycol chitosan nanoparticles for disease-specific theranostics

https://doi.org/10.1016/j.jconrel.2014.05.009Get rights and content

Abstract

Hydrophobically modified glycol chitosan (hGC) conjugates spontaneously form self-assembled nanoparticles (NPs) in aqueous conditions, and glycol chitosan NPs (CNPs) have been extensively studied for the past few decades. For disease-specific theranostics, CNPs could be simply modified with imaging agents, and the hydrophobic domains of hGC are available for encapsulation of various drugs. Based on the excellent physiochemical and biological properties, CNPs have been investigated for multimodal imaging and target specific drug delivery. In particular, a recent application of CNPs has shown great potential as an efficient theranostic system because the CNPs could be utilized for a disease-specific theranostic delivery system of different imaging agents and therapeutics, simultaneously. Furthermore, various therapeutic agents including chemo-drugs, nucleotides, peptides, and photodynamic chemicals could be simply encapsulated into the CNPs through hydrophobic or charge–charge interactions. Under in vivo conditions, the encapsulated imaging agents and therapeutic drugs have been successfully delivered to targeted diseases. In this article, the overall research progress on CNPs is reviewed from early works. The current challenges of CNPs to overcome in theranostics are also discussed, and continuous studies would provide more opportunities for early diagnosis of diseases and personalized medicine.

Introduction

In the early 2000s, nanotechnology-based medical techniques emerged as a powerful tool for theranostics. The concept of theranostics, a combination of diagnostics and therapy as a single platform, emerged with progress in molecular imaging and nanomedicine. Advances in nanomedicine contributed to theranostics with targeted drug delivery strategies to reduce the systemic toxicity of drugs. A variety of nanoprobes also have been designed for molecular imaging to visualize cellular function or changes in biomarkers, which reflect the progression and therapeutic response of a disease [1]. These nanoprobes, in most cases, can chemically interact with biomarkers to alter the signals for imaging and provide biological information on pathological lesions [2]. The combination of these two advanced technologies for theranostics is expected to achieve early diagnosis and personalized medicine in the near future, and nanoparticles will play a significant role in the concept of theranostics.

In general, nano-sized particles accumulate more in pathological lesions than in normal tissues. In particular, tumor-accumulation of nanoparticles (NPs) has been extensively studied for cancer theranostics. Based on the size-dependent property, NPs can extravasate from angiogenic blood vessels which consist of coarsely connected vascular endothelial cells. The poor lymphatic systems cause retention of NPs in tumors, and the so-called enhanced permeability and retention (EPR) effect is the most well-known mechanism for tumor targeted delivery of NPs [3]. Besides tumors, NPs also can escape from ruptured or damaged blood vessels and travel to other pathological lesions including trauma, hemorrhagic stroke, and inflammation [4], [5], [6]. In inflammation, a variety of immunocytes release chemotactic factors and vasodilators including histamines and bradykinins. Under such conditions, increase in local blood flow and endothelial permeability can be observed, subsequently increasing the accumulation of NPs in the pathological lesions. In addition, NPs can be delivered within macrophages. A recent study showed that macrophage migration is dependent on the size of the treated NPs [7]. The NPs with 100 nm diameters were effectively taken up by the macrophages and showed enhanced vector migration rates compared to smaller NPs 30 and 50 nm in diameter. Indeed, nanoparticle-loaded exogenous macrophages migrated into brain lesions through the disrupted blood–brain barrier [8]. These results suggest that the NPs circulating in the blood also may be phagocytized by macrophages to be delivered to the site of blood vessel disruption and the foci of inflammation. These reports suggest that NPs can be applied in targeted delivery to non-tumoral lesions, such as chronic inflammation and autoimmune diseases.

A variety of theranostic NPs have been developed for biomedical applications. In particular, chitosan has been widely used for nanoparticle fabrication during recent decades. Chitosan, a deacetylated chitin, is a natural polymer that has many functional groups in its backbone structure. The abundant functional groups of chitosan allow easy chemical modification, and the inherent cationic charges are useful for developing chitosan as a gene carrier. Furthermore, chitosan and chitosan derivatives are attractive materials for their excellent biocompatibility, biodegradability, and low immunogenicity. In particular, hydrophobically modified glycol chitosan (hGC) spontaneously forms self-assemblies in aqueous conditions, and the glycol chitosan NPs (CNPs) have been extensively studied for the past few decades. The hydrophobic modifications provide glycol chitosan (GC) polymers with interesting properties to form NP structures enabling them to be delivered to pathological lesions in a targeted-manner.

The CNPs have demonstrated great potential as an innovative theranostic system. In particular, a recent application of multifunctional CNPs holds promise for efficient theranostics with low systemic toxicity. In this article, we will review all of the CNPs including the early works on the development of CNPs. Several factors affecting target specificity, physicochemical/biological properties, and practical applications of CNPs in theranostics will be described to understand the research progress of the CNPs-related studies. In addition, the current issues and challenges of CNPs to overcome in theranostics will also be discussed in the last part of this review.

Section snippets

Self-assembled glycol chitosan nanoparticles (CNPs)

Polymeric amphiphiles can form micelles or micelle-like aggregates, spontaneously. In aqueous environments, the hydrophobic moieties of the polymeric amphiphiles are facing toward the core, and the hydrophilic moieties are exposed to the surface. Although chitosan has a low solubility above its pKa (6.4) in water, GC is a hydrophilic polymer which exhibits complete solubility in water in broad pH conditions [9], [10]. Based on this property, several hydrophobic moieties have been introduced to

Application of CNPs for in vivo diagnostic imaging

To provide anatomical information on diseases, CNPs can be labeled using simple contrast agents for medical imaging. The EPR effects, enhanced vascular permeability, or vascular leakage induce the accumulation of CNPs in pathological lesions, and the diseased region generally has an intense image signal. Based on this property, various contrast agents and relevant imaging modules for CNPs have been studied. As shown in Section 2, NIRF dyes and whole body NIRF scanning devices are the most

Targeted drug delivery using theranostic CNPs

Nano-formulations of polymeric micelles and micelle-like aggregates have been traditionally considered as promising drug carrier systems [65], [66], [67]. Their hydrophobic domains in the core are available for encapsulation of hydrophobic drugs, and the hydrophilic outer shell can protect the drugs before they reach the target site. CNPs have not only been designed for carrying chemo-drugs, but also for the delivery of other therapeutic agents, including therapeutic genes, peptides, and

Perspectives

During recent decades, nanoparticle-based drug delivery systems have made tremendous progress in theranostics. Current biomedical research on theranostic NPs provides real-time non-invasive molecular imaging of pathological lesions with target specific drug delivery. The significant advances in theranostic NPs also have enabled the controlled release of drugs, leading to improvement in therapeutic effects with convenient protocols. Riding on this success, CNPs have been steadily studied in

Acknowledgments

This study was funded by the National Research Foundation of Korea (NRF-2013K1A1A2032346 and 2012K1A1A2A01056095) and Intramural Research Program (Global siRNA Carrier Initiative) of KIST.

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    These authors contributed equally to this paper.

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