Sulfated Seaweed Polysaccharides As Multifunctional Materials in Drug Delivery Applications
Total Page：16
File Type：pdf, Size：1020Kb
marine drugs Review Sulfated Seaweed Polysaccharides as Multifunctional Materials in Drug Delivery Applications Ludmylla Cunha 1,2 and Ana Grenha 1,2,* 1 Centre for Marine Sciences, University of Algarve, 8005-139 Faro, Portugal; [email protected] 2 Drug Delivery Laboratory, Centre for Biomedical Research (CBMR), Faculty of Sciences and Technology, University of Algarve, Gambelas Campus, 8005-139 Faro, Portugal * Correspondence: [email protected]; Tel.: +351-289-244-441; Fax: +351-289-800-066 Academic Editor: Paola Laurienzo Received: 14 January 2016; Accepted: 15 February 2016; Published: 25 February 2016 Abstract: In the last decades, the discovery of metabolites from marine resources showing biological activity has increased significantly. Among marine resources, seaweed is a valuable source of structurally diverse bioactive compounds. The cell walls of marine algae are rich in sulfated polysaccharides, including carrageenan in red algae, ulvan in green algae and fucoidan in brown algae. Sulfated polysaccharides have been increasingly studied over the years in the pharmaceutical field, given their potential usefulness in applications such as the design of drug delivery systems. The purpose of this review is to discuss potential applications of these polymers in drug delivery systems, with a focus on carrageenan, ulvan and fucoidan. General information regarding structure, extraction process and physicochemical properties is presented, along with a brief reference to reported biological activities. For each material, specific applications under the scope of drug delivery are described, addressing in privileged manner particulate carriers, as well as hydrogels and beads. A final section approaches the application of sulfated polysaccharides in targeted drug delivery, focusing with particular interest the capacity for macrophage targeting. Keywords: carrageenan; drug delivery; fucoidan; macrophage targeting; ulvan; sulfated polysaccharides 1. Introduction Marine environment and the associated wide diversity of organisms offer a rich source of valuable materials. Among marine resources, algae, which are sometimes referred as seaweeds, are well known natural sources of polysaccharides. Sulfated polysaccharides are of the most common in the cell walls of seaweeds. The number and chemical structure of these polymers vary according to the specific algal species [1]. Marine algae can be classified into three main groups based on the exhibited photosynthetic pigments: red, brown and green. Botanists refer to these groups as Rhodophyceae, Phaeophyceae and Chlorophyceae, respectively. Brown seaweeds are usually large and range from the giant kelp that is often 20 m long, to thick, leather-like seaweeds of 2–4 m long, to smaller species 30–60 cm long. Red seaweeds are usually smaller, generally ranging from a few centimeters to about a meter in length. Curiously, red seaweeds are not always red, sometimes being purple, even brownish red, but still being classified by botanists as Rhodophyceae because of other characteristics. Green seaweeds are also small, with a size range similar to that of red seaweeds [2]. In the last decades, sulfated polysaccharides of algal origin have attracted much attention as functional additives in the pharmaceutical field, but also in food and cosmetic industries. The major Mar. Drugs 2016, 14, 42; doi:10.3390/md14030042 www.mdpi.com/journal/marinedrugs Mar. Drugs 2016, 14, 42 2 of 41 sulfated polysaccharides found in marine algae include carrageenan from red algae, ulvan isolated Mar. Drugs 2016, 14, x 2 of 40 from green algae and fucoidan from brown algae [3]. Carrageenan is the most used of the three, widewith wideapplication application as emulsifier, as emulsifier, stabilizer stabilizer or thickener. or thickener. Fucoidan, Fucoidan, in in turn, turn, is is available available commercially commercially from variousvarious cheap cheap sources sources and and has has been been investigated investigated in recent in yearsrecent to years develop to noveldevelop drugs, novel medicines drugs, medicinesand functional and foods. functional Ulvan foods. is the lessUlvan known is the of the less group. known It displays of the severalgroup. physicochemicalIt displays several and physicochemicalbiological features and of potential biological interest features for food,of potential pharmaceutical, interest for agricultural food, pharmaceutical, and chemical applications,agricultural andbut needschemical deeper applications, investigation. but Various needs deeper studies haveinvestigation. revealed thatVarious sulfated studies polysaccharides have revealed isolated that sulfatedfrom marine polysaccharides algae exhibit aisolated variety offrom biological marine activities algae exhibit [4–6], potentiatinga variety of theirbiological use in activities pharmaceutical [4–6], potentiatingapplications. their These use polymers in pharmaceutical have been increasinglyapplications. studied These polymers over the years have inbeen this increasingly context, given studied their overpotential the years usefulness in this in context, applications given thattheir mainly potential involve usefulness the design in applications of drug delivery that mainly systems. involve Figure the1 designdepicts of the drug number delivery of publications systems. Figure retrieved 1 depicts on ISI the Web number of Knowledge of publications with theretrieved keywords on ISI “name Web of Knowledgethe polymer” with and the “drug keywords delivery”, “name showing of the the polymer” increasing and interest “drug indelivery”, carrageenan showing and fucoidan the increasing in the interestrecent years, in carrageenan with the undoubted and fucoidan prevalence in the recent of the years, former. with Additionally, the undoubted it confirms prevalence that of ulvan the former. is the Additionally,less explored ofit confirms the three that polymers. ulvan is the less explored of the three polymers. Figure 1. NumberNumber of of scientific scientific publications published published on on the topic “name of polymer” and “drug delivery” as a function of publication years. Taken Taken from ISI Web of Knowledge. The colors allude to thethe colors of algae ( red: carrageenan, carrageenan, brown:: fucoidan, fucoidan, green:: ulvan). ulvan). The purpose of this review is to discuss potential applications of sulfated polysaccharides, with The purpose of this review is to discuss potential applications of sulfated polysaccharides, with a special emphasis on carrageenan, ulvan and fucoidan, in designing drug delivery systems and also a special emphasis on carrageenan, ulvan and fucoidan, in designing drug delivery systems and address their suitability for specific applications, such as cell targeting. A summary of basic also address their suitability for specific applications, such as cell targeting. A summary of basic characteristics of the three carbohydrates is displayed in Table 1. characteristics of the three carbohydrates is displayed in Table1. Mar. Drugs 2016, 14, 42 3 of 41 Table 1. Description of several characteristics of carrageenan, fucoidan and ulvan. Sulfated Marine Algae Molecular Weight Solubility in Viscosity pH in Aqueous Main Genera References Polysaccharide Group (kDa) Water (cps, in Water) Solution Chondrus Euchema Furcellaria * κ-, ι- and 5–800 Carrageenan Rhodophyceae Gigartina 100–1000 λ-carrageenan 7.0–10.0 [2,7–10] (1.5% w/v, 75 ˝C) Hypnea soluble at 80 ˝C Iridae Kappaphycus Analipus Chorda Dictyota Fucus 10 mg/mL Fucoidan Phaeophyceae 10–950 n.a. n.a. [11–19] Kjellmaniella (F. vesiculosus) Pelvetia Sargassum Undaria Enteromorpha 18–100 Ulvan Chlorophyceae 1.14 to > 2 ˆ 106 n.a. 7.5 (Ulva spp.) [20–22] Ulva (1.6% w/v, Ulva spp.) * Further solubility conditions in Reference [10]; n.a.: not available. Mar. Drugs 2016, 14, 42 4 of 41 2. Carrageenan: Sulfated Polysaccharide of Red Seaweeds Historically, red seaweeds (Rhodophyta) have been harvested and consumed as foods for at least 2800 years. Although red algae are consumed by humans, the carrageenan extracted from seaweed is not assimilated by the human body, merely providing bulk. However, these algae do provide functional properties that are exploited on a commercial scale [23]. As one of its main properties relies on the ability to form thermoreversible gels or highly viscous solutions, carrageenan is commonly used as gelifying, stabilizing and emulsifying agent in food, pharmaceutical and cosmetic industry [24]. A broad and recent review on the industrial applications of carrageenan, including in food and pharmaceutical related areas, is available on [25]. 2.1. Origin, Extraction and Processing The original source of carrageenan was the red seaweed Chondrus crispus (also known as Irish Moss). With the expansion of the carrageenan industry over time, the increasing demand for the raw material led to the introduction of the cultivation of species of Eucheuma, originally E. cottonii and E. spinosum, now referred to as Kappaphycus alvarezii and Eucheuma denticulatum, respectively [2,23]. The advantage thereof compared to the natural Chondrus crispus, is a predominant content of kappa- and iota-carrageenan, respectively, while Chondrus crispus contains a mixture of kappa and lambda carrageenan that cannot be separated during commercial extraction. Therefore, most of carrageenan is now extracted from K. alvarezii and E. denticulatum but several species of Gigartina, Iridae, Hypnea and Furcellaria genera have been exploited, providing different types of carrageenan extracts [2,26,27]. Carrageenan