Natural Polymers in Drug Delivery Systems: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Ahmad Khusairi Azemi.

Natural polymers have received a great deal of interest for their potential use in the encapsulation and transportation of pharmaceuticals and other bioactive compounds for disease treatment. In this perspective, the drug delivery systems (DDS) constructed by representative natural polymers from animals (gelatin and hyaluronic acid), plants (pectin and starch), and microbes (Xanthan gum and Dextran) are provided. In order to enhance the efficiency of polymers in DDS by delivering the medicine to the right location, reducing the medication’s adverse effects on neighboring organs or tissues, and controlling the medication’s release to stop the cycle of over- and under-dosing, the incorporation of Fe3O4 magnetic nanoparticles with the polymers has engaged the most consideration due to their rare characteristics, such as easy separation, superparamagnetism, and high surface area. 

  • natural polymer
  • magnetic nanoparticles
  • drug delivery

1. Introduction

Initially, natural polymers were created for use in a variety of biomaterials applications. The main focus is to review the development of natural polymers, specifically gelatin, hyaluronic acid, pectin, starch, xanthan gum, and dextran polymers for drug delivery applications. Generally, blood flow and the extravasation effect (named passive targeting) are the main mechanisms used by most polymer carriers for cell targeting, which depends on blood circulation [17][1]. On the other hand, active targeting by polymeric systems is accomplished by coupling ligands that are recognized by certain receptors overexpressed on the cell [18][2]. Besides that, the polymeric systems may target the cell via the use of stimuli-responsive carriers, intracellular drug targeting, intratumoral drug targeting, and cell vasculature drug targeting [19][3].

2. Gelatin

Gelatin is hydrophilic in nature and derived from the controlled denaturation of protein or collagen hydrolysis obtained from animal tissues (e.g., cartilage, skin, and bone) of animals such as porcine, bovine, or fish [20][4]. The different types and ages of animals, as well as the collagen type such as type I or type II, will affect the physical and chemical characteristics of the extracted collagen [21][5]. A number of functional side groups in gelatin allow an appropriate mechanical property via chemical crosslinking [22][6]. Cell–biomaterial interactions of gelatin have shown effectiveness through the exposure of various ligands, such as peptide motifs of Arg-Gly-Asp peptides (RGD) that promote the binding of cells and carriers [21,23][5][7].
Curcumin, an anticancer drug, is known as an unstable and less soluble drug [24][8]. A few attempts have been made to enhance its stability and solubility using gelatin polymer in various forms. A hydrogel-based MN fabricated from gelatin methacryloyl and β-cyclodextrin (GelMA-β-CD) loaded with curcumin is introduced to overcome the limitations [25][9]. MN arrays on 3D B16F10 melanoma spheroids were assessed for in vitro anticancer efficacy, and higher therapeutic efficacy compared to non-transdermal patches. In vivo analysis was conducted to verify the degradability and compatibility of the MN arrays patch of GelMA-β-CD. Another application was presented by formulating curcumin into the gelatin hydrophilic network and hydroxyapatite nanoparticles [26][10]. This formulation showed a sustained release of curcumin, demonstrating higher internalization into the cell and toxicity towards A549 cells (lung cells) than free curcumin. Both studies on curcumin showed the same results through improvement in the stability and solubility of the curcumin and gelatin polymer, a good biomaterial to be included in the formulation. Another application of natural polymer gelatin is as a drug delivery carrier of carvedilol (CAR) (i.e., a drug used to treat respiratory disorders that possess limitations in terms of solubility and bioavailability) [27][11]. To overcome these weaknesses, CAR was packed into halloysite nanotubes (HNTs) and was capsulated in a gelatin-based microsphere that was responsive to internal stimuli pHs (HNTs/CAR@GM) [27][11]. The results showed HNTs/CAR@GM having fast drug release under acidic conditions (pH = 1.2) and non-toxicity against Caco-2 cells.
Transdermal drug delivery can be achieved by incorporating drugs of interest into a hydrogel (i.e., crosslinked polymeric networks that are capable to sustain high water amounts). The above studies represent good approaches to gelatin usage in making hydrogel benefiting from its high solubility and amphoteric behavior. MN hydrogels serve as a novel method for transdermal drug delivery with less pain than percutaneous administration, and gelatin serves as a promising natural polymeric material for this system.

3. Hyaluronic Acid (HA)

HA is an anionic polymer of naturally occurring mucopolysaccharide, non-sulfated glycosaminoglycan commonly found in various body parts (e.g., vitreous humor, joints, connective tissue, umbilical cord, and skin) [28,29][12][13]. HA comprises N-acetyl-D-glucosamine and D-glucuronic acid that are linked together by glycosidic bonds of β-(1,4) and β-(1,3) [30][14]. CD44 is a protein surrounded by a membrane that is often highly expressed in various cancer cells [31][15] and a major receptor for HA. Therefore, HA can target CD44 targeted signaling [32][16] and is a promising candidate for polymer in delivering anti-cancer drugs to target specific tumor sites.
Extensive research was conducted on HA in targeting CD44 in various cancer cells. Conjugation of HA-tetraphenyl ethylene (HA-SS-TPE) with glutathione-responsiveness, a novel DDS was designed. This system was developed by self-assembling HA-SS-TPE and loaded with doxorubicin (DOX) to create DOX-loaded polymeric micelles [33][17]. Interestingly, this novel DDS showed great efficacy in unloading DOX through fast glutathione-triggered dissociation. CD44-positive cells (ES2 and Hela) exhibited a greater intercellular release ratio of DOX compared to CD44-negative cells. The above results showed the great system capability to be incorporated in overexpressed CD44 cancer cells. In addition, an avant-garde halloysite nanotube-based DDS was designed with an HA-modified halloysite (HNTs-NH-HA) compound loaded with DOX [34][18]. HNTs-NH-HA/DOX increased the DOX therapeutic efficacy and showed high antitumor efficiency in CD44-positive Hela cells compared to HNTs/DOX or free DOX. This concluded that added HA in the system effectively improved DOX targeting, and this serves as a new possibility in cancer treatment.
DOX-loaded micelle-like nanoparticles for targeted DDS were created by self-assembling conjugate HA–human serum albumin (HAssHSA) attained by covalent attachment of HSA to a cystamine-modified HA [35][19]. The efficacy of this system is demonstrated by higher cytotoxicity of MDA-MB231 cells conducted by the system compared to free DOX. CD44-mediated internalization of nanoparticles was also confirmed; thus, this system serves as a safety strategy for DOX delivery. HA has been constructed by MN loaded with the drug minoxidil (MXD) for alopecia therapy [36][20]. In vivo trial was conducted on alopecia mice, and the results showed enhancement of hair dermal papilla (HDP) cells facilitated by a cluster of distinction CD44 and serine-threonine kinase (Akt) phosphorylation. Thus, reduced hair loss in alopecia indicated the effectiveness of delivering MXD using MXD-HA-MNs with minimized side effects of MXD. This was the first to report the explicit anti-alopecia effects of using MXD-HA-MNs. Next, the HA hydrogel interpenetrating network (IPN) of HA/Poloxamer 407-co-poly (methacrylic acid) was designed to target 5-fluorouracil (5-FU) in colorectal cancer [37][21]. pH-dependent swelling and release (hydrogen swelled at pH 7.4 and released more drug at pH 1.2) were maintained in a controlled manner for a more extended period of 5-FU. The toxicity assessment on rabbits also showed the compatibility of this hydrogel with biological systems. Thus, this hydrogel formulation is promising to be used in drug delivery to the colon.
In addition, multi-stimuli responsive HA-hydrogels were effectively formulated with cross-linker diselenide bonds for precise release of DOX [38][22]. DOX-loaded hydrogel resulted in an antitumor impact in breast cancer cells (BT-29). Incorporating indocyanine green (ICG) into the DOX-loaded hydrogel further improved the antitumor efficacy of DOX. Drug contents in DOX/ICG-loaded hydrogel were higher compared to DOX-loaded hydrogel, 94% and 4.54%, respectively.

4. Pectin

Pectin, a naturally occurring negatively charged polysaccharide is commonly found in plant cell walls of peaches, apples, and citruses. This anionic polysaccharide resembles HA and alginate, but it holds unique characteristics owing to its stiffening and solidifying abilities. These capabilities are vital in creating an excellent DDS for the gastrointestinal (GI) system. Notably, the excellent mucoadhesion and superior stability in the GI are due to its high resistance towards enzyme degradation (e.g., proteases and amylases) [39,40][23][24]. Pectin’s benefits to its gelling property make it a superior choice for oral insulin delivery compared to other anionic polysaccharides. However, pectin faces two major problems in the GI environment: the limited capacity of enterocytes to target the polymer and untimely drug release [39][23].
This system was prepared by a dual-crosslinking process using calcium ions and adipic dihydrazide (ADH) as crosslinkers to overcome the limitations [39][23]. Initially, pectin was isolated from head residues of sunflower to produce low-methoxyl pectin (AHP). Findings from in vitro experiments showed the insulin dispersion behaviors of INS/DFAN influenced by the COOH/ADH molar ratio in the dual-crosslinking procedure. INS/DFAN can efficiently prevent the untimely release of insulin compared to ionic-crosslinked nanoparticles (INS/FAN). INS/DFAN also exhibited high encapsulation efficiency, excellent stability, and enhanced insulin delivery, whereas in vivo experiments on type 1 diabetic rats demonstrated improved hypoglycaemic effects and improved insulin bioavailability over INS/FAN. Overall, the combination of dual crosslinking and FA modification on pectin nano-vehicles was found to serve as a good strategy to enhance oral insulin delivery.
Next, a study by Bostanudin et al. proposed nanoformulations of amphipathically modified pectin-containing fusidic acid [41][25]. The amphipathic properties of a nanocarrier are important to surmount cell membrane impenetrability to boost drug permeation through the skin and to allow the delivery of both hydrophilic and hydrophobic particles or macromolecules into cells [41,42][25][26]. Amphipathically modified pectin (GBE-PEC) fabrication material is then converted into spherical nanostructures (NSs) [41][25]. Encapsulated fusidic acid was released in a more controlled manner (loading degree 14.9%), and in vitro interaction with HaCaT cells showed a non-cytotoxicity profile and demonstrated a greater (two-fold) penetration rate through the Strat-M® membrane compared to the native pectin NSs. The improvement in the amphipathic properties drove the efficiency of poorly penetrating actives such as fusidic acid through percutaneous delivery.
Pectin has been shown as a good polymer to carry drugs through the oral delivery system, influenced by its ability in gelling to produce high stability and high resistance towards the harsh environment in the GI. Integrating pectin polymer for oral drugs such as diabetic drugs represents a therapeutic window for diabetes treatments.

5. Starch

Starch is the amplest biopolymer obtained from plant sources; it is disposed of two macromolecules and linear- and branched-chain polymers. Its sensitivity to physical and chemical alterations and its capability to form thermoplastics are among its unique properties [43][27]. Starch is a major excipient in the pharmaceutical industry, especially in oral drug delivery. However, there are several major drawbacks of starch; 1. weak mechanical properties, 2. fast degradation in the body, 3. extreme viscosity after heating, 4. not soluble in cold water, and 5. capable of decomposing again [44][28]. Therefore, to overcome the limitations of this high-potential biomaterial, much current research was conducted with a new formulation strategy.
Nanoparticles can serve as co-distributers of anti-inflammatory medicines and reactive oxygen species (ROS) scavengers for inflammatory bowel disease (IBD) therapy. Curcumin can be conjugated with hydroxyethyl starch (HES) and loaded with dexamethasone (DEX) to create DEX-loaded HES-CUR nanoparticles (DHC NPs) [45][29]. α-amylase is present in inflamed colon-degraded HES and allows the drugs to be released in an α-amylase-responsive way. DHC NPs also showed effective internalization and cytocompatibility with macrophages. DHC NPs are significantly greater in efficacy compared to free DEX in treated ulcerative colitis in the in vivo study. Thus, the results stated that DHC NPs are having a therapeutic window for the emergence of novel oral formulations for IBD rehabilitation. Carvacrol is a phenolic compound that is prone to degrade in harsh conditions, especially in the GI. This drug requires a good carrier to protect them and ensure the optimal release of the drug in a controlled pattern. Thus, incorporating carvacrol in starch nanofiber by electrospinning a starch solution serves a great deal [46][30]. Carvacrol was delivered successfully by resisting in vitro digestion and produced a 50% decline in tumoral cells in glioma cells of C6 rats. Carvacrol-loaded starch nanofibers are safe and non-toxic to the cell. This suggests a good formulation for cancer treatment.
Targeting colon cancer therapy concurrently uses co-loaded DOX and 5-Fu on as-created layered double hydroxides LDH(Mg-Al) (LDH(MgAl)@DOX,5-Fu) [44][28]. The system was then encapsulated into carboxymethyl starch, forming CMS@LDH(MgAl)@DOX,5-Fu microspheres. It presented a reassuring constant drug release pattern and precise release profile of DOX and 5-Fu of ~22% and ~29%, respectively. The findings suggested the potential of the proposed microsphere for oral co-drug delivery.

6. Xanthan Gum (XG)

XG is a natural polymer originating from the fermentation process of the microorganism Xanthomonas campestris [47][31]. Its high molecular weight is owed to its unique chemical properties; i.e., it is composed mainly of a β-1,4-D-glucopyranose glucan backbone with a pendant trisaccharide side chain, disposed of mannose (β-1,4) and glucuronic acid (β-1,2), as well as terminal mannose residues. This chemical structure makes XG polysaccharides with polyanionic characters. A more detailed chemical structure of XG was discussed [48][32]. XG stimulated the thickening behavior or assisted suspension in aqueous solutions by influencing the temperature and pH that affect the viscosity of XG. XG confers weak gel-like properties as an outcome of its 3D association with XG chains [49][33]; thus, hydrogel serves as a better medium for XG through crosslinked 3D networks of hydrophilic polymers through physical–chemical methods. Although XG hydrogel’s biocompatibility is well established [50][34], some disadvantages such as poor mechanical strength, harsh gelation conditions, and lack of cell attachment moieties are still something appealing to be explored for further improvement. Thus, subsequent studies discuss recent research on XG modification.
XG has been widely used in incorporating diabetes medication, and the following studies are discussed. The repaglinide drug to treat type 2 diabetes was loaded into hydrogel particles of XG derivatives, carboxyethyl XG and carboxymethyl XG, in a ratio of 1:2 (i.e., maximum drug entrapment efficiency of 92%) [51][35]. The system released 97% of the drug in 4 h stimulated by GI pH and prolonged drug release for 8 h. The repaglinide’s amorphous dispersion was observed after the entrapment. The clinical benefit shown by this system was a reduction in blood glucose levels (maximum 52.8%), indicating that this system is beneficial in future diabetes treatment. Another diabetes drug is glibenclamide (i.e., an oral agent) loaded into mouth-dissolving films (MDFs), named GMDFs [52][36]. XG was added into the composition of GMDF as a film matrix through the solvent casting method, and the GMDF3 formulation composed of 200 mg presented the highest drug entrapment (96.1 ± 5.89). This GMDF also showed an instant release of the drug, rapid dissolution, and optimum mechanical strength. The GMDF1-3 showed a 96–98% discharge of the drug, and a 94% and 90% discharge of the drug in GMDF4 and GMDF5, respectively. These results suggested an XG film matrix can produce a stable DDS for glibenclamide in diabetes treatment using MDF.
Another MDFs was created using XG by loading amlodipine (i.e., hypertensive drug) aiming to rapidly release the drug for the faster relief of hypertension [53][37]. This formulation shows exceptionally rapid results (i.e., complete drug release within 10 min) and drug release dispersion with optimum mechanical strength. Accelerated drug release in this formulation represented a therapeutic window in hypertension treatment. Hesperidin (HSP) (i.e., drug against P. vulgaris) was characterized as having low solubility. Therefore, Alam and colleagues produced HSP-enabled gold nanoparticles (AuNPs) stabilized with xanthan gum (XA), indicated as HSP@XA@AuNPs. HSP@XA@AuNPs gel was also prepared by integrating the formulation into a Carbopol gel base [54][38]. The results showed greater effectiveness in drug release by HSP@XA@AuNPs gel compared to HSP@XA@AuNPs, 86.26% and 73.08%, respectively. In addition, the gel demonstrated antimicrobial activity as opposed to P. vulgaris (i.e., minimum inhibitory concentration of 1.78 µg/mL). In conclusion, the HSP@XA@AuNPs gel may represent a new strategy to inhibit P. vulgaris infection.
In summary, XG’s limitation on its mechanical strength has been successfully defeated by XG derivative modification on its backbone through carboxymethylation and acetylation as shown by Patel et al. [51][35]. The steady hydrogel networks developed the subsequent formation of polymeric ionic bridges or synchronized ties among carboxylate ions of XG derivatives and aluminum ions. In addition, adding XG in formulations improved the DDSs of MDFs to a higher par [52,53][36][37]. Moreover, XG has been utilized in the oral and transdermal DDSs of various drugs. 

7. Dextran

Dextran is a naturally biodegradable polymer obtained from microbe sources. It is feasibly isolated from numerous Gram-positive, facultatively anaerobe cocci (e.g., leuconostoc and streptococcus strains) [55][39]. Dextran is highly soluble in water, DMSO glycerol, and ethylene glycol because of its neutral complex amylopectin-chain glucan composed of α-1, six glycosidic linkages in the middle of glucose monomers [56][40]. Dextran-based nanocarriers have great aqueous solubility, which can accelerate drug suspension. Dextran is also a non-toxic biopolymer as it does not accumulate toxicity in the GI compared to synthetic polymers due to its ability to metabolize with digestive enzymes, making dextran a favorable polymer in oral drug delivery [55][39]. However, natural dextran still retains shortcomings regarding its physiochemical properties such as surface-immobilized dextran limiting cell adhesion and spreading [57][41], which limits its utility for tissue engineering [58][42]. Thus, it requires the modification of its backbone through conjugation with drugs, amidation, carboxymethylation, acetylation, cross-linking, and grafting with other natural, synthetic, or semisynthetic polymers [59][43]. Dextran is supported by modification as shown in the following studies.
Dextran is an example of an ultrasound-responsive polymeric material (i.e., combination of imaging techniques plus therapeutic) in DDSs that represents cost effectiveness and is non-invasive and more targeted compared to other internal or external stimuli-responsive (e.g., UV-, thermal, and pH-responsive) materials [60,61][44][45]. Dextran has been integrated into the novel nanotechnology of nanodroplets for ultrasound-induced cancer treatment [62][46]. Dextran stabilized perfluorohexane nanodroplets comprising the DOX drug. The outcomes are reported as follows: its particle size and encapsulation effectiveness were significantly amplified by elevating polymer concentrations, and in vitro analysis showed a biphasic drug release system of 82.95% of the DOX from the optimal formulation (0.1% w/v dextran, 24,000 rpm homogenization speed and 500 µg DOX content) after 10 min of exposure to ultrasound. Thus, this formulation showed a therapeutic window in ultrasound-induced cancer treatment.
NIR light has intelligently worked with DDSs by having robust trigger levels, deeper dissemination through concerned sites, and a small number of side effects compared to UV light [63][47]. Topical photothermal hydrogel for NIR-controlled DDSs was prepared by the polymerization of vinyl-functionalized dextran (DexIEM), vinyl-modified graphene oxide (GM), and Laponite; the hydrogel was then inserted with ciprofloxacin (i.e., an antibacterial drug) [64][48]. Ciprofloxacin in the DexIEM-GM-Laponite hydrogel dispersion remained in a NIR-controlled manner in an ex vivo trial. Interestingly, this hydrogel system exhibited excellent performance in terms of antibacterial effects and good compatibility with blood. This suggested a novel system for a NIR-responsive DDS. Celastrol (Cel), rheumatoid arthritis (RA) drug, was loaded into nanoparticles made up of modified dextran (dextran-sulfate-PVGLIG), named DPC [65][49]. It resulted in a high entrapment of DPC@Cel micelles (around 44.04%) and a zeta potential of −11.91 mV. The nanoparticles effectively delivered the drug to the inflammatory joint and metalloproteinase-2 (MMP-2) at the accelerated Cel released through in vitro observation. An in vivo trial confirmed that DPC@Cel improved anti-RA effects and decreased systemic toxicity in comparison to free Cel. This indicated an effective system of Cel delivery to the target site.
Lastly, a pH-sensitive dextran-based micelle scheme was fabricated using an ester click reaction of copper-free azide-propiolate, self-constructed from amphiphilic dextran-graft-poly(2-(diisopropylamino) ethyl methacrylate-co-2-(2′,3′,5′-triiodobenzoyl) ethyl methacrylate), or dextran-g-P(DPA-co-TIBMA) [66][50]. DOX-loaded dextran-g-P(DPA-co-TIBMA) micelles showed a reduced speed release of DOX at pH 7.4 but were significantly sped up under an acidic state (pH 6 and 5). Micelles of dextran-g-P(DPA-co-TIBMA) optimally released DOX into MCF-7 cells. DOX-loaded dextran-g-P(DPA-co-TIBMA) was found to have excellent anticancer efficacy and effectively reduced the growth of tumors with little body weight reduction in in vitro and in vivo studies, respectively. Both in vitro and in vivo studies demonstrated a promising strategy using this system in tumor suppression.
To conclude, the recent applications of dextran polymeric materials have been directed towards multi-stimuli responsive DDSs such as pH, NIR light, and ultrasound. Stimuli-responsive materials are of vast importance because of their capacity to undergo adjustment of their properties in response to their environment. For example, the pH-responsive polymer is characterized by its features of moieties that can donate or accept cations upon an environmental change in pH [67][51]. However, light-reactive polymers use light as a versatile stimulus through their subsequent light-responsive moieties which can be related to photoinduced isomerization and/or photochromism [68][52]. This smart polymer produces more refined applications, due to the variability that is introduced to the responsiveness. 

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