DOI: 10.1002/ijch.201300068 Sweet Fairytale: Carbohydrates as Backbones for Glyconanomedicine Shoshy Mizrahy, [a] Dalit Landesman-Milo, [a] and Dan Peer* [a] 1. Introduction Nanoparticle (NP)-based therapeutics have been used for the treatment of cancer, neurodegenerative diseases, in- fections, allergies, diabetes, and inflammation, both in pre-clinical models and in clinical investigations. In fact, several “nanodrugs” have already been approved by the regulatory agencies. [1–3] The growing interest in NPs for medical applications is attributed to the exceptional ad- vantages they offer, which include protection of the drug from premature degradation, lower therapeutic toxicity, the ability to deliver poorly water soluble drugs, con- trolled drug release mechanisms, and improved intracellu- lar penetration. [4] Structural and physicochemical properties, including particle shape, zeta potential, size distribution, and rough- ness, control the biodistribution of the NPs in vivo. [5] Their small size enables NPs to pass through the smallest capillaries and, thereby, promotes passive tumor target- ing, due to the enhanced permeability and retention (EPR) effect of the tumor vasculature. [3,6] The passive tar- geting is achieved by extravasation of NPs through the fenestrations in the tumor vasculature and ineffective lymphatic drainage. [7] Active cellular targeting is achieved by decorating the surface of NPs with natural or mimetic ligands, such as monoclonal antibodies (mAb) or their fragments. [3,6] As the requirements for clinically applicable NPs are becoming clearer, so are the requirements for the materials used for their preparation. These materials should be biocompatible and, preferably, biodegradable, well characterized, and easily functionalized. [4] Carbohy- drates accomplish all of these requirements and are there- fore widely used for the preparation of nanoparticles for drug delivery. 2. Carbohydrates Carbohydrates are highly abundant molecules that are derived from various origins, including algal origin (e.g., alginate and carrageenan), plant origin (e.g., cellulose, pectin, and guar gum), microbial origin (e.g., dextran and xanthan gum), and animal origin (e.g., chitosan [CS], hya- luronan [HA], chondroitin, and heparin). [8] Naturally oc- curring carbohydrates are diverse in their physiochemical properties, including a great variety of chemical structures (Figure 1), molecular weights (Mw), and ionic nature. This versatility also contributes to a wide range of biolog- ical activities. From a pharmaceutical standpoint, carbo- hydrates possess many favorable characteristics, such as low toxicity, biocompatibility, stability, low cost, hydro- philic nature, and availability of reactive sites for chemi- cal modification. [8,9] Chemical functionalization, using Abstract : The use of nanoparticles (NPs) in medical applica- tions is rapidly growing, with more than 30 NP-based drugs approved for clinical use. Different building blocks are used to generate NPs for drug and imaging delivery tasks. Among them, carbohydrates represent an exciting option that is currently being exploited in vivo and in clinical trials. Carbohydrates have excellent biocompatibility, biodegrada- bility, low toxicity, and low cost. In addition, the ease of chemical modification enables the preparation of a wide col- lection of NPs for a variety of tasks. Here, we will describe the properties of common carbohydrates and the main mechanisms for carbohydrates-based NP preparation and discuss several key concepts from the physicochemical and structural features of NP-based carbohydrates for pre-clini- cal and clinical applications. Keywords: drug delivery · glycobiology · glyconanotechnology · hyaluronan · nanomedicine [a] S. Mizrahy, D. Landesman-Milo, D. Peer Laboratory of Nanomedicine, Dept. of Cell Research and Immu- nology George S. Wise Faculty of Life Science and The Center for Nanoscience and Nanotechnology Tel Aviv University Tel Aviv, 69978 (Israel) phone: (+ 972) 3-6407925 fax: (+ 972) 3-6405926 e-mail: peer@tauex.tau.ac.il 616  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Isr. J. Chem. 2013, 53, 616 – 629 Review D. Peer et al.