Pectin in drug delivery applications

C H A P T E R 10

Pectin in drug delivery applications ´n-Chu, Gabriel H. Gomez-Rodriguez, Elizabeth Carvajal-Millan, Agustin Rasco Alma C. Campa-Mada Research Center for Food and Development, CIAD, A.C., Hermosillo, Sonora, Mexico

Chapter Outline List of abbreviations 249 1. Introduction 249 2. Prebiotic effect 250 3. Hypoglycemic effect 251 4. Hypocholesterolemia effect 252 5. Effect on the mechanism of metastasis and apoptosis in cancer cells 6. Controlled and directed release matrix 255 7. Perspectives 258 8. Conclusion 259 References 259

253

List of abbreviations CMC DM FDA Gal-3 HDL HG LDL MCP PHH RG-I RG-II

Carboxymethylcellulose Diabetes mellitus Food and Drug Administration Galectin-3 High-density lipoprotein Homogalacturonan Low-density lipoprotein Modified citric pectin Pectinehoney hydrogel Rhamnogalacturonan I Rhamnogalacturonan II

1. Introduction Pectins are a group of complex heteropolysaccharides abundant in dicotyledonous plant cell walls, used at first as texturizer, and diverse new applications are emerging and extensively reviewed in the past two decades. Besides the plant physiology functionality, Natural Polysaccharides in Drug Delivery and Biomedical Applications. https://doi.org/10.1016/B978-0-12-817055-7.00010-8 Copyright © 2019 Elsevier Inc. All rights reserved.

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250 Chapter 10 pectins are an ingredient of high value in food industry as a texturizing agent and the recent impact on health has attracted research interest [1e3]. The properties of pectins as texturizers have been known for more than 200 years, but in the past three decades, many advances have been achieved in understanding their complex structure and effects on human health because of their consumption. Historically, the scientific reports on pectic substances started with Louis Nicolas Vauquelin in 1790 [4] followed a 100 years later by Henri Braconnot who described them for the first time and coined the name “pectins” derived from the Greek word “pekticos” which means to freeze or solidify [5]. Currently, pectins are described as linear polysaccharides consisting mainly of D-galacturonic acid units linked in chains by a(1e4)-glycosidic linkages called homogalacturonan (HG) [6]. This galacturonic acid residues may be methylated, acetylated, or amidated to different degree [7] although “hairy” regions are presently known as rhamnogalacturonan I (RG-I) and rhamnogalacturonan II (RG-II) [8]. Commercially, pectin is extracted from different vegetable sources such as citrus peel (85%), apple pomace (14%), sugar beet pulp, and others (1%) [9]. Pectin-based biomaterials have a wide variety of applications in tissue engineering, wound dressing, controlled release systems for cancer drugs, emulsifier or thickener for cosmetics such as creams and lotions, and texturizer in the food industry in the manufacturing of foods such as jams, jellies, and fruit juices, among others [2]. Pectins also have prebiotic activity, as well as reduction of glucose intolerance in diabetics, even lowering the blood cholesterol level [10]. Because all the properties mentioned above, there has been interest in the development of new technological applications. This chapter reviews the different beneficial aspects that these macromolecules have and are currently being exploited to further develop human well-being. In the following sections, the text reports on prebiotic effect, hypoglycemic effect, hypocholesterolemic effect, the alleged effect on metastasis and apoptosis in cancer cells, and matrices for controlled and target directed release of therapeutic compounds applications. Finally, perspectives for the near future are considered before a conclusion is presented.

2. Prebiotic effect Our ancestors living on trees found at hand a varied supply of fruits rich in fibers and vitamins to feed on. In this perspective, the adaptation to pectin from fruits on their digestive tract physiology and microbiota within was an evident, and coevolution of our digestive tract and now complex interaction with microbiota were somewhat of unavoidable consequences when we emerged as species after enormous periods of time. In modern days, the relationship with microbial populations through our digestive system is being rediscovered and getting much attention as our increased understanding impacts human health directly.

Pectin in drug delivery applications 251 In the past three decades, the interest of consumers on food products with health benefits besides just known nutrition “classical” facts has increased constantly, looking for a higher quality of life. Consequently, additional efforts have been made in research to develop new food technologies to exploit the market opportunity [9]. Among the former are the prebiotics, for their direct benefits and those derived from the secondary products from their use by the colon microbiota, mainly. Within a variety of plant-derived dietary fibers, pectins and their low-molecular-weight derivatives (oligosaccharides) constitute an emerging prebiotic group with features enhanced by their ability to modulate microbiota [11]. Some examples include the growth of Faecalibacterium prausnitzii [12] and Roseburia intestinalis, among many other species within the gastrointestinal tract and further the beneficial effects in the distal colon where risk of colon cancer and ulcerative colitis happen [13]. Pectins constitute a group of polysaccharides of complex structure. Accordingly, some lines of research have focused on the possibility to derive several components from partial degradation processes by colon microbiota, which could show different prebiotic effects [11]. Among many products, acetate and butyrate are short chain fatty acids derived from the intestinal fermentation of pectins (but not limited to) that exert a beneficial effect on the digestibility and fermentation of pectin [14]. Probiotics may feed on pectins and thrive producing secondary metabolites and compete with nonprobiotic microorganisms. For instance, the fermentation of pectin and its oligosaccharides extracted from sugar beet and lemon peel increased the populations of bifidobacteria and lactobacilli from 19 up to 29% and 32 up to 34%, respectively. Interestingly, low-molecular-weight derivatives have shown greater prebiotic capacity than the original pectins [13]. Nevertheless, we may hypothesize that low-molecular-weight derivatives may be produced by the action of colon microbiota on long-chain pectins and possibly protect mostly toward distal colon. The latter raises the interest to design molecules for biomedicine; in fact, this property is an added benefit to the design of controlled delivery matrices targeted to colon based on pectin w/o other biopolymers.

3. Hypoglycemic effect Sugar in our blood is essential to get energy fast and efficiently. Nevertheless, the unbalanced diet in our current society is causing deep alterations and, eventually, chronic diseases. A major concern of our time is diabetes mellitus. Diabetes mellitus (DM) is characterized mainly by a marked hyperglycemia caused by a dysfunction in the activity and/or secretion of insulin. Worldwide, DM affects approximately 371 million people aged 20e79 years; the increase in people suffering from this disease in recent years has the interest on the science of prevention and control, which has led to a substantial increase in the lines of research related to this metabolic disease. In this context, plant-derived dietary

252 Chapter 10 fibers are part of the strategy to provide health benefits; these products include dietary fibers such as pectin in the form of capsules or in food concentrates. In fact, the intake of dietary fibers (pectins included) may moderate hyperglycemia; this effect is attributed to the capacity with which the dietary fibers decrease the speed of the gastrointestinal transit because of higher food viscosity [15]. Consequently, the glycemic response is less drastic; for lower rate of intestinal absorption of glucose, this reflects in a decrease in the production of insulin. The mechanism involved is still poorly understood, but some authors propose that high viscosity of the fibers in diets can promote the formation of small micelles and generally causes a low absorption; concomitantly, the fermentation of these fibers by colonic bacteria could play a role in the effect on glycemic response. In addition, the selective fermentation of pectins produces propionate, which can also reduce the production of cholesterol in the liver and eventually reduce the risk of suffering fatty liver disease [16]. Given the effects of pectin on decreasing blood glucose levels, pectin-derived composites have been used to design particles for the controlled administration of insulin by oral via. Maciel et al. [17] reported the encapsulation of insulin hormone with an encapsulation efficiency of 62%, using nano- and microparticles based on chitosanepectin composite obtaining small particles among 240 and 1900 nm and tested them under simulated gastric conditions. In addition, Rasco´n-Chu et al. [18] reported the fabrication of microbeads based on pectinearabinoxylans for the transport of insulin. The structure of the polymers allowed the production of small particle sizes with limited size dispersion. A small size dispersion will eventually allow controlled delivery of insulin in a reliable dose manner.

4. Hypocholesterolemia effect In the past 50 years, a great interest has been on the raise for the effects of dietary fibers on the reduction of cholesterol, where the Food and Drug Administration (FDA) of the United States has accepted the benefits that these fibers represent in the reduction of cholesterol levels; and has promoted its use as a measure to reduce the risk of cardiovascular disease. Gunness and Gidley [19] proposed a series of three possible mechanisms to explain the reduction in total cholesterol and LDL given the consumption of pectin as one of various dietary fibers. The first mechanism proposes the inhibition of the absorption of bile salts. Second, pectin and other fibers reduce the glycemic response and the activity of HMG-CoA, an intermediate in the route of mevalonate for the synthesis of cholesterol. Finally, the microbiota in the colon produces short-chain fatty acids as secondary metabolites when consuming pectins and other fibers, which has been shown to reduce the synthesis of cholesterol. In this regard, some animal studies confirm to some extent that the physicochemical characteristics of pectin as dietary fiber affect the metabolism of cholesterol. Interestingly,

Pectin in drug delivery applications 253 pectins’ chemical structure has proven essential for reduction of cholesterol levels in plasma and liver when high methoxyl pectins are consumed, better than low methoxyl pectins. In addition, pectins with relatively high viscosity have been shown to modify the secretion of bile acidsdwhich are derived from cholesteroldin the enterohepatic circulation, which leads to a greater indirect “excretion of cholesterol” outside the organism [10]. In addition, Espinal-Ruiz et al. [20] evaluated the impact of citrus and banana pectins on lipid digestion and showed that the structure of pectins affected the lipid digestion profile in simulated gastrointestinal conditions when higher-molecular-weight and degree of methoxylation pectins decreased lipid digestion. In theory, pectins increase hydrophobicity and lower the overall load of the system, as they change the rheological properties of gastrointestinal fluids. These authors suggest that in the future design of food products, the inclusion of specific polysaccharides could better control the digestibility of lipids within the gastrointestinal tract to promote beneficial effects for health. In counterpart, the proper design of a daily diet could also benefit from this knowledge. At the end, it only concerns to each person to decide between education and market.

5. Effect on the mechanism of metastasis and apoptosis in cancer cells Despite the enormous progress on the oncological therapies in the past decadesdespecially in alternative drugs for chemotherapydcancer continues to be one of the leading causes of death in the world, and the development of new therapeutic strategies remains a high priority. In this regard, the role of dietary fibers on the diet components in the prevention and progression of cancer has been under study. Interestingly, the World Health Organization (WHO) infers that between 30% and 50% of cancer cases could be impeded by healthy lifestyle, avoiding exposure to carcinogens in food and environment [21]. In this regard, pectin is an important cell wall polysaccharide from plant and plant-derived food and reportedly has potential anticancer activity [22]. Recently, scientific literature shows a significant amount of research providing evidence where molecular structure of pectins shows antiproliferative effects on various cancer cell lines [23,24]. For instance, colon and prostate cancer [22,25], breast cancer [26], pancreatic cancer [27], and metastasis processes of various cell lines [23,28] are commonly reported. Several cancer types and mechanisms have been extensively reviewed elsewhere. In particular, Maxwell et al. [29] reviewed molecular fragments of pectins and their ability to reduce cell proliferation, as well as migration and adhesion besides inducing apoptosis in a wide variety of cancer cell lines. The mechanism is being elucidated and apparently involves galectin-3 (Gal-3). Leclere et al. [30] reported a significant increase of galectin-3 on liver metastasis and also its inhibition by modified citrus pectin (MCP). Galectin-3 is a lectin from the betaegalactoside-binding family, related to cell growth, and found highly related to cancer cells [31] (see Fig. 10.1). On the

254 Chapter 10 Plasma Membrane Cell-cell adhesion

Cell-ECM Interactions GAL3 GAL3

MP VEGF

GAL3

Extracellular

GAL3

GAL3

MP β3

RTK

αν

MAPK GAL3 KRAS SHC/GRB/SOS Pathway RAF

GDP

GTR

P13k

Integrin Wnt Pathway

P13K/Akt Pathway

GAL3

GAL3 MEK1/2

ERK1/2

Intracellular

AKT

β-catenin/TCF4

GSK3β

Cyclin D1/c-MYC

BID

BCL-2

BAX

TRAIL

Formation of Blood Vessels Cell Migration Cell attachment

Cell Proliferation

GAL3 Cell Proliferation

Apoptosis

Figure 10.1 Roles that perform galectin-3 at extracellular and intracellular level. At an extracellular level, Gal-3 participates in cell adhesion. At the intracellular level, Gal-3 activates different signaling pathways such as MAPK, PI3K/Akt, and Wnt and induces cell proliferation and apoptosis or binds to different integrin receptors that activate VEGF to induce angiogenesis (Maxwell et al. [29] based on Yang et al. [31]).

other hand, galactose is a monosaccharide commonly found in the structure of RG I pectin region and capable to interact and compete for Gal-3. Briefly, cellecell competes with endogenous ligands of galactoside-binding proteins, particularly Gal-3, purportedly in a dose-dependent manner [32]. Most antineoplastic drugs currently used induce the apoptosis of tumor cells through the intrinsic or mitochondrial pathway; however, Gal-3 directly regulates the sensitivity of cancer cells to various chemotherapeutic agents [33]. In addition, other reports have shown that Gal-3 affects the expression of cyclin D1 and its inhibition induces the arrest of G1 by decreasing cyclin E2, cyclin D2, and CDK6 inhibiting the cell cycle [34,35]; however, other compounds besides pectins can inhibit cdk for apoptosis [36,37]. However, Hossein et al. [38] reported the Gal-3 increase in SKOV-3 ovarian cancer cell line proliferation, adhesion to collagen, and antiapoptotic effect, but 0.1% modified citrus pectin showed

Pectin in drug delivery applications 255 synergistic cytotoxic effect with an otherwise ineffective dose of paclitaxel 100 nM. In fact, the combined compounds reduced cell viability by 75% and subsequent 3.9-fold increase in caspase-3 activity. Hopes are high for this type of compounds and their Gal-3 interaction. Although cell line models are way far from actual cancer patients’ treatment, subsequent reports are generating evidence to support this line of research and approach, to more conclusive assays. The relationship between the modified pectin structure and its inhibitory activity on Gal-3 has been reported in several studies [39,40]. In a model of liver metastasis of colon cancer induced in mice, the level of Gal-3 expression was higher compared with that of normal mice; MCP showed an effective inhibition on expression of Gal-3, in addition to the size of the tumor volume of colon cancer in a model [28]. Maxwell et al. [32] investigated the expression of genes involved in cell adhesion, where the rhamnogalacturonan I (RG-I) region of pectin decreased the proliferation of cancer cells by reducing expression of the ICAM1 gene in colon cancer cells. The evidence strongly suggests that the segments of RG-I, with its neutral sugars, are essential to the effect on colon cancer cells. Similarly, Maxwell et al. [41] evaluated the antiproliferative activity of a sugar beet pectin alkali extracted with increased RG-I content. Interestingly, the fractions triggered apoptosis processes in a cancer cell line. Sugar beet pectin RG I fragments feature residues of galactose, arabinose, mannose and phenolics (mainly ferulic acid) [8] and are the main possible key residues to explain the reported observations. Aze´mar et al. [42] evaluated the modified citrus pectin on patients with advanced tumors in a pilot clinical trial. The results showed a significant improvement in the quality of life and stabilization of patients with cancer, with the advantage that no patient developed any serious secondary adverse effect related to the therapy. In fact, a patient who had advanced prostate cancer resistant to hormones showed a 50% decrease in the level of prostatic antigen in serum, with a significant lesser pain after 16 weeks of treatment; likewise, most patients had improvements in their quality of life for little secondary effects of chemotherapy where stressed out. Although promising reports are emerging, attention to proper positive and negative controls on experiment is necessary to fully determine the role of pectin-derived compounds in cancer prevention and treatment. Cancer patients deserve respect and rigorously tested treatments before rush conclusions and recommendations. Further research is still needed on mechanisms, molecular interaction, and secondary effects.

6. Controlled and directed release matrix The controlled delivery administration of drugs is still the subject of research in the area of biomedicine, and its purpose is to improve the efficiency of certain drugs, reducing

256 Chapter 10

Figure 10.2 Diagram to produce pectin/arabinoxylan beads using coaxial electrospray system [18].

adverse side effects, dose, or target a specific site. For this reason, researchers have emphasized the manufacture of matrices that function as a controlled release and/or target delivery [43]. In the formulation of pectin hydrogels for controlled release for oral administration, high methoxyl pectins can be used, but pH changes limit their effectiveness; so wound dressings might benefit more. In terms of a desirable pectin structure, the use of low methoxyl pectins is preferable because they have low molecular weights and the amidation of low methoxyl pectins influences the binding zones. Fast gelling time of low methoxyl pectins permitted to fabricate microbeads with low size dispersion by electrospray method and trap a matrix of AX and insulin for a composite vehicle intended for oral administration of colon-targeted insulin [18,44] (Fig. 10.2). Jantrawut et al. [45] fabricated microbeads by extrusion on CaCl2 assisted with electrospray (similar to Fig. 10.2) and evaluated the antiproliferative activity of rutin encapsulated in beads of low methoxyl pectin, on HT-29, HepG2, and KB cancer cell lines. In these studies, the rutin encapsulated in low methoxyl pectin showed a major anticancer activity than the nonencapsulated rutin for HT-29 and KB, but no significant effect on HepG2. In general, pectins can be used as a vehicle for oral application, with the extra benefits associated with their own effects on health. Several investigations have been published during the past decade on the use of pectin as a matrix for the controlled release of drugs and/or to treat colon cancer [46,47]. Fahrurroji

Pectin in drug delivery applications 257 et al. [48] formulated a hesperidin hydrogel using a combined chitosanepectin matrix, where the highest entrapment efficiency (96.65%) was achieved with pectin 5%, likewise greater mucoadhesivity. Awasthi et al. [49] evaluated the controlled release of repaglinide, an oral antidiabetic agent with a very short half-life, successfully entrapped in a matrix of algae beads and cross-linked pectin. The study showed that there was no interaction between the drug and the excipients. The developed beads had ideal physical properties with an incorporation efficiency of 82.29% and release profiles of up to 60.96% after 12 h with the aim of controlled release drug delivery system to maintain the release of drugs over a period. In this sense, the research carried out by Jung et al. [50] evaluated in vitro the encapsulation of indomethacin in pearls of modified citrus pectin hydrogels, obtaining a high loading efficiency. In addition, the hydrogel beads were able to protect the drug from the adverse conditions generated in the simulated gastric environment, being a suitable candidate for a drug delivery system directed to the colon. However, in vitro assays do not always behave the same when tested in vivo, and pectin has not being effective for all drug formulations capable of reaching the distal colon without undergoing alterations. To overcome this disadvantage, some authors have reported formulations on pectin matrices covered with different polymers that complement the lacking properties for its journey through the upper digestive tract. This is because pectin alone is susceptible to pH values changes in the upper gastrointestinal tract; and premature release of drugs may be caused by its swelling and solubility in the aqueous medium. Composite matrices have been proposed extensively. For instance, the mixture of pectin-gelatin matrices has been proposed by Pramanik and Ganguly [51] for the release of metronidazole successfully in colon and for eventual treatment of amebiasis, giardiasis, trichomonas, or anaerobic bacterial infections. In the immediate future, we may expect that controlled release of different drugs would minimize possible side effects and lower the dose administration by preventing their release in the upper part of the gastrointestinal tract. The potential for pectins is not limited to oral administration. There are studies on the use of pectins for topical application for ophthalmological problems, because it is the most effective route of administration for treatment of eye disorders where the bioavailability of ophthalmic drugs is evidently and logically limited by natural physiological eye protection mechanisms such as blinking and lacrimation [52e54]. In this order, the use of natural polymers capable of forming hydrogels under physiological conditions has been evaluated to extend the contact and penetration time of the drug. Among different polysaccharides, a pectin system for the formation of gel in situ has been under testing. Pectin is applied as a liquid causing the formation of gels in the eye, where the gelation could be triggered mainly by electrolytes in tears [55] (US Patent No. 6,777,000). Likewise, Bobokalonov et al. [56] evaluated the use of pectin microspheres as an ocular administration system for piroxicam through preliminary studies. The system seems to assure high bioavailability and reduce some disadvantages of

258 Chapter 10 other ophthalmic administration systems; mainly blurred vision, need for insertion and extraction, and stability problems. Furthermore, topical skin applications are increasingly attracting interest in the research community. In general, wound healing is a complex process that involves many factors that significantly influence the restoration of the skin barrier. Currently, several compounds are used to facilitate the healing process of wounds with polysaccharides such as pectin alone or combined. Giusto et al. [57] evaluated different combinations including pectin, liquid honey, and a combined pectinehoney hydrogel (PHH); the results clearly showed a synergistic effect from each of the components included in the mixed gels. Interestingly, PHH was very effective accelerating wound healing, followed by pectin alone. These new mixed gels have potential in wound healing applications in the short time. Lim et al. [58] developed materials based on pectin and carboxymethylcellulose (CMC) in different proportions. They evaluated wound healing rates, the degree of epithelialization, and the collagen deposition in three different wound models (surgical, third-degree burn model, and infection wound model). From the data obtained in the above study, it can be asserted that a pectin/CMC ratio of 16/19 (pH 4.67) is the most interesting for all three wound models. In addition, the transdermal drug delivery systems are one of the novel means for the administration of therapeutic substances such as insulin and other sensitive drugs. In this regard, Hadebe et al. [59] developed dermal patches based on amidated pectins for slow release control to blood stream and alleviate a variety of diabetic symptoms in a SpragueeDawley rat model, increasing the plasma insulin concentration, demonstrating that pectin insulin patch can deliver pharmacologically active insulin. Accordingly, Sibiya and Mabandla [60] developed a pectineinsulin-based patch in a similar manner; the treatments used induced hyperglycemia, and in addition, the diabetic models showed a significant improvement in learning and spatial memory in comparison with diabetic controls when pectineinsulin patches were applied. Besides pharmacological applications, Suksaeree et al. [61] developed a nicotine patch based on pectin, which showed no incompatibility with the patch components or any degradation of the drug with a retention percentage of up to 90% and an apparent stability at ambient temperature. This suggests that the patches, nicotine-based pectins, may be an option to alleviate abstinence symptoms for tobacco smokers trying to quit.

7. Perspectives Pectins have applications not only in the food industry but also increasingly in the pharmaceutical and biomedical areas and are of great interest to research on how to potentiate and fully exploit their properties for human health and well-being. There are

Pectin in drug delivery applications 259 numerous studies that demonstrate its potential in the treatment of various diseases and conditions, opening the door to further study the positive impact on health and the mechanisms through which they act. The validity of the reports is more than ever under revision, for miraculous solutions to human health problems will always rise people’s attention and scientific rigor must be observed. The different structural properties that pectins possess are those derived from the neutral sugars content, having a wide range of applications. Recent reports of pectin as dietary fiber remarked its prebiotic effect and controlled release and directed drug matrix capabilities and many outstanding functions for the threats that cardiovascular, obesity, diabetes, and cancer represent to modern man. In some cases, pectins may undergo modification processes, to tailor shorter chain, less complex, more effective molecules, which can be better absorbed by the body and generate greater stability in front of changes of pH that may affect bioavailability. Further research studies are still undergoing and novel discoveries and innovations are yet to come.

8. Conclusion Pectins in addition to their already known properties in the food industry have great benefits and advantages that justify their importance as a polysaccharide of interest for biomedical innovations. The rediscovery of our relationship with colon microbiota and its dependence on plant-derived dietary fibers have triggered the innovation on many aspects of human nutrition and diet design, as well as biopolymers-based new drug delivery matrices, with concomitant benefits from their friendly nature. Pectins have by far the most versatile and diverse molecular structure that allows to relate to equally diverse drug molecules with therapeutic effects. Molecular tailoring of pectins gives place to new ways for human well-being in many different fronts. Obesity, diabetes, and heart disease are just a little fraction of all the possibilities that pectins may be applied to innovate in modern health care. Novel hydrogel formulations may soon help to overcome the threats to human health that our modern environment and lifestyle brought upon us.

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