Open Access Article
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Recent developments in natural biopolymer based drug delivery systems

Tanzeela Fazal*a, Bibi Nazia Murtazab, Mazloom Shahc, Shahid Iqbal*d, Mujaddad-ur Rehmane, Fadi Jaberfg, Ayed A. Derah, Nasser S. Awwadi and Hala A. Ibrahiumj
aDepartment of Chemistry, Abbottabad University of Science and Technology, Pakistan. E-mail: tanzeelafazal@yahoo.com
bDepartment of Zoology, Abbottabad University of Science and Technology, Pakistan
cDepartment of Chemistry, Faculty of Science, Grand Asian University Sialkot, Pakistan
dDepartment of Chemistry, School of Natural Sciences (SNS), National University of Science and Technology (NUST), H-12, Islamabad 46000, Pakistan. E-mail: shahidgcs10@yahoo.com
eDepartment of Microbiology, Abbottabad University of Science & Technology, Pakistan
fDepartment of Biomedical Engineering, Ajman University, Ajman, UAE
gCenter of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, UAE
hDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
iChemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
jBiology Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia

Received 20th May 2023 , Accepted 24th July 2023

First published on 31st July 2023


Abstract

Targeted delivery of drug molecules to diseased sites is a great challenge in pharmaceutical and biomedical sciences. Fabrication of drug delivery systems (DDS) to target and/or diagnose sick cells is an effective means to achieve good therapeutic results along with a minimal toxicological impact on healthy cells. Biopolymers are becoming an important class of materials owing to their biodegradability, good compatibility, non-toxicity, non-immunogenicity, and long blood circulation time and high drug loading ratio for both macros as well as micro-sized drug molecules. This review summarizes the recent trends in biopolymer-based DDS, forecasting their broad future clinical applications. Cellulose chitosan, starch, silk fibroins, collagen, albumin, gelatin, alginate, agar, proteins and peptides have shown potential applications in DDS. A range of synthetic techniques have been reported to design the DDS and are discussed in the current study which is being successfully employed in ocular, dental, transdermal and intranasal delivery systems. Different formulations of DDS are also overviewed in this review article along with synthesis techniques employed for designing the DDS. The possibility of these biopolymer applications points to a new route for creating unique DDS with enhanced therapeutic qualities for scaling up creative formulations up to the clinical level.


1 Introduction

Biopolymers are diverse and remarkably versatile class compounds derived from biological systems or synthesized from biological sources. Like other polymers, biopolymers are composed of similar repeating units (monomers) which are linked together.1 Owing to the peculiar properties of biopolymers e.g. biodegradability, availability, and possibility of engineering the physicochemical characteristics, they are being engaged in innovative formulations. Particularly, while moving towards a green sustainable life, biopolymers offer a platform that fits into the paradigm of achieving an eco-friendly environment. Recently biopolymers have received special attention for designing and fabricating DDS (DDS).2 DDS is a tool to incorporate therapeutic agents to ensure the availability of a highly specific drug to target the diseased site with minimum side effects in the body.3 An ideal DDS can target as well as control release of the loaded drug. Drug delivery carriers act as a vehicle to protect the drugs from decomposition during transportation in the body before targeting the diseased site. DDS is intended to reduce side effects by virtue of being biocompatible and biodegradable. In order to provide the intended pharmacological response, it also modifies drug release at the target site. Both natural as well as synthetic polymers are recognized as potential candidate materials suitable for exploitation in designing the DDS.

Although natural polymers have shown remarkable contributions in developing the DDS but blending and functionalization of polymers through different physical and chemical means transfers into a state-of-the-art class of materials Natural polymers having though good biocompatibility and biodegradability but their low mechanical and thermal properties as well as low solubilities restrict their applications.4 Blending as well as functionalization of polymer to fabricate innovative materials with resultant properties reflecting the parent compounds, that are not exhibited by individual ones. Functionalization of biopolymers through blends/composites by forming hybrid structures is an approach, widely used in DDS to launch the combined roles in the resultant hybrid system.3,4 By reducing the negative effects, the beneficial properties of each biopolymer are enhanced, which improves the effectiveness of the created DDS.5

Polymer–polymer or filler–polymer combinations may be used to create polymeric nano-biocomposites. Metal nanoparticles (NPs), hydroxyapatite, organic or inorganic clays, and other materials may be used as fillers. The highest amount of drugs can be loaded into a nano-composite system while using the smallest possible amounts of carrier. Drug loading is typically done via an impregnation or inclusion approach. While the integration approach includes drug trapping by nano-composites at the time of manufacture, the impregnation involves drug entrapment by typically incubating the nano-composites from a solution.6

In DDS, polymer–drug complexes are formed usually via hydrophobic interactions, van der Waals forces, hydrogen bonding and electrostatic attractions between opposite charges of the biopolymers. To get mechanical strength, aggregates are sometimes cross-linked with suitable linker(s) to enhance stability and integrity. A cavity-bearing supra-molecular aggregation is often necessary for the inclusion complexation procedure in order to serve as a host for an entering guest molecule (s). Nanoprecipitation, another worthwhile method is generally adopted for hydrophobic polymers. In the supercritical fluid method, another precipitation technique, involves the liquid or gas, and polymer(s)/drug(s) are solubilized together above their supercritical points. The selection of the preparative method is determined by a number of factors, such as the thermal and chemical stability of the bioactive components, the toxicity of the leftover chemicals after processing, particle sizes, release kinetic profiles, and finally the kind of delivery system. Two separate drying techniques are often used: freeze-drying and spray-drying. For freeze-drying, heat-sensitive materials have been selected, while for spray-drying, the nanoparticle solution is introduced into a stream of hot air, causing the solvent to quickly evaporate and the dried particles to aggregate.7

This review is also aimed to summarize the contribution of different natural biopolymers, particularly sugar-based polymers, amino-sugars and polynucleotide-based polymers. Fig. 1 gives the classification of different natural polymers which have been employed to design the DDS. Although almost all polymers have a prestigious role in DDS still their derivatives, functionalized composites are also in clinical trials in different formulations for designing the DDS. These encouraging biopolymer applications provide us a new route for creating unique DDS with enhanced therapeutic qualities for scaling up creative formulations to the clinical level.


image file: d3ra03369d-f1.tif
Fig. 1 Classification of different polysaccharide, protein and nucleotide-based biopolymers.

2 Types of DDS

To improve the solubility of the pharmaceuticals for stable complex formation and their safety during delivery at the target location, many formulations of individual biopolymers and their composites have been described, including powder, tablets, beads, films, fibres, meshes, membranes, and hydrogels.4,8

2.1 Microspheres based DDS

The microsphere-based delivery method is often selected because of its long lifespan, control over drug release, and ability to distribute just certain types of medications. The interaction with counter ions, solvent evaporation, crosslinking, spray drying, ionic gelation, precipitation/coacervation, emulsion polymerization, and other processes may all be used to create microspheres17–20 Glutaraldehyde cross-linked microspheres by using mitoxantrone are also reported.9,10

2.2 Tablets/capsules based DDS

DDS based on tablets or capsules is often created using the wet granulation method or just direct compression. Diltiazem's release behaviour from oral mucosal adhesive tablets manufactured with the direct compression method and a matrix of chitosan and alginate was evaluated, and it showed a noteworthy response. The chitosan–sodium alginate matrix system exhibited comparable characteristics.11 Another study examined how different combinations of anionic polymers affected the release rate of chitosan.12

2.3 NPs based DDS

NPs are very effective in transferring macromolecules across the nasal, oral, tracheal, and ocular epithelium and improving pharmaceutical absorption via the nasal mucosa.13 For the production of biopolymer-based NPs, a number of techniques, including emulsion, nanoprecipitation coacervation, ionic gelation, reverse micellar approach, and sieving method, have been described.14,15 As the tumor-targeted carriers for the dextran–doxorubicin combination, chitosan nanoparticles (NPs).16 Similarly, it has been shown that chitosan nanoparticles can encapsulate DOX and N-trifluoroacetyl DOX.17 Significant anticancer activity of a photosensitizer meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylated and encapsulated in antibody-targeted chitosan–alginate nanoparticles.17 Chitosan NPs are also reported as suitable stable delivery devices for siRNA and protein.18 Entrapment of DOX in chitosan NPs is also reported.19 Chitosan NPs loaded with paclitaxel illustrated superb tumor-homing.20 The antiviral behavior of interferon-alpha via orally administered chitosan NPs is also evaluated.21

2.4 Nanofibers based DDS

To improve the properties like hydrophobicity, solubility, biological activity, biocompatibility etc. for widening their applications, chemical modification of biopolymers is an effectual tool. Another technique to increase the potential of biopolymer nanofibers for drug delivery applications is surface functionalization.22 For the announcement of controlled drugs, nanofibrous chitosan-polyethylene oxide was developed.23 Electrospun membranes with ibuprofen-loaded poly(lactide-co-glycolide)/poly(ethylene glycol)-g-chitosan have been used in controlled drug delivery applications.24 Quaternary electrospun polymers containing DOX showed enhanced cytotoxicity against the graffiti tumor cells.25 Chitosan and phospholipids hybrid nanofiber has been employed for transdermal drug delivery.26

2.5 Beads-based DDS

Crosslinked beads are an important form of biopolymers exploited broadly in delivery systems.27 The controlled release of diclofenac sodium from glutaraldehyde crosslinked polymeric beads were also evaluated.28 Multi-layered alginate and chitosan beads directed controlled gastrointestinal passage of ampicillin, which is a low molecular weight compound.29

2.6 Films-based DDS

Biopolymeric thin films find numerous applications in DDS. Mostly, casting methods are preferred to deposit thin films. In comparison to their parent material, hybrid materials have notably better characteristics. Drug delivery systems using biopolymeric crosslinked films have been researched in a number of applications, such as oral mucosal delivery,30 buccal delivery,31 transdermal delivery,32 sublingual delivery,33 and periodontal delivery.34 For oral mucosal administration, super critical solution impregnation technique films filled with ibuprofen have been studied.30

2.7 Hydrogels-based DDS

Three-dimensional crosslinked polymeric networks called hydrogels may absorb a lot of water without dissolving.35 Through implantation, the biocompatibility of crosslinked biopolymeric hydrogels is assessed.36 Swell behaviour and delivery in a pH-dependent manner The development of sensitive alginate–chitosan hydrogel beads loaded with nifedipine is also being studied.37 For the purpose of promoting wound healing, photosensitive cationic NPs based hydrogels of hyaluronic acid and chitosan, with chlorin e6 and quaternary ammonium salt, were described.38 Gallic acid conjugated with chitosan hydrogel beads are reported to be employed for the loading of rhodamine B.39 The mechanical characteristics of the treated cotton gauze were evaluated on drug-loaded silica during an ex vivo drug penetration research via isolated rat skin, and bio polysaccharides-based hydrogels were studied using the culture count technique.40 The injectable administration of the anticancer medication doxycycline hydrochloride has been reported to use Schiff base alginate–chitosan hydrogels with nanosilver incorporated in them.41 Epigallocatechin gallate has been found to be transported using lanthanum-modified chitosan hydrogel.42 5-Fluorouracil is delivered using chitosan/agarose/graphene oxide nanohydrogel in the treatment of breast cancer.43 Melaninin incorporated polysaccharide hydrogels of chitosan and oxidized β-glucanis has been reported for treating the bacterially infected diabetic wounds.44 Carboxymethyl cellulose based hydrogels have been reported for colon-specific delivery of gentamicin. For the administration of ciprofloxacin, composite hydrogels with ZnO embedded in polyethylene glycol diacrylate and cross-linked carboxymethyl tamarind kernel gum have been reported.45 Gelatin/lignin hydrogels have been utilized drug carriers for ribavirin.46 Three dimensional chitosan and carboxymethyl cellulose-based hydrogels, loaded with nano-curcumin for synergistic diabetic wounds have been very well reported.47 Polyacrylic acid-carboxymethyl cellulose hydrogel incorporating halloysite nanotubes have been reported for curcumin delivery release.48 Natural gums and their derivatives based hydrogels have also drug delivery potential.49

2.8 Conjugates-based DDS

It has been claimed that the development of nano-conjugates allows for both passive and active delivery of medicinal substances to the desired region. Using DOX hydrochloride, foliate-chitosan conjugated NPs improved tumour target selectivity without causing any harm.50 Polymers by functionalization with graphene oxide were employed as nanocarriers for camptothecin.51 Multi-walled carbon nano tubes have also been employed for the functionalization of biopolymers and showed good biocompatibility against HeLa cells and protein immobilization.52 Biopolymeric–biopolymeric functionalization i.e. alginate with chitosan is a combination reported with enhanced behavior.8

3 Formulations of biopolymers and their composites

Currently, natural polymers are revealing remarkable contributions in developing the DDS through physical and chemical means by blending and functionalization of polymers in different forms. In this review article, designs of different DDS made from natural biopolymer building blocks at nano and micro scale levels are tried explored and discussed individually. Fig. 1 classifies the natural biopolymers into different classes.

3.1 Polysaccharides based DDS

Polysaccharides are monosaccharides units attached by glycosidic linkages. They have properties i.e. bioactivity, biodegradability and processability, which make them promising biomaterials for developing the DDS under complex biological environments. Especially recent developments by using polysaccharides-derived functional biomaterials.53 The role of different cationic, anionic and neutral polysaccharides, their composites and derivatives for DDS is discussed.
3.1.1 Cellulose. The most common non-ionic polysaccharide that is found naturally is cellulose. It has also been used to release repaglinide orally using cellulose and chitosan nanoparticles (NPs).54 Specifically developed to target colon diseased sites, calcium alginate beads with carboxymethylcellulose loaded with 5-fluoroalkyl.55 These four cellulose derivatives—methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and cationic hydroxyethyl cellulose—have been used as DDS in the nasal mucosa.56 The impact of hydroxy propyl methylcellulose-based nanocomposites with cellulose nanofibrils for drug release in the form of thin films was explored.57 As magnetic-responsive drug carriers for in vitro anti-colon cancer treatment, Fe3O4 loaded at cellulose containing curcumin has been used.58 For use in in vitro ciprofloxacin drug release, cellulose–polyacrylamide hydrogel nanocomposite with gold nanoparticles has been developed.59 Table 1 lists some other instances of the use of cellulose and its mixtures for medication delivery.
Table 1 Cellulose and its composites in drug delivery
Polymer Bioactive agent References
Carboxymethyl cellulose DOX 60
Cellulose Betulinic acid 61
Microcrystalline cellulose Luteolin and luteoloside 62
Carboxymethyl cellulose 5-Fluorouracil 63
Carboxymethyl cellulose DOX 64
Passion fruit peel cellulose Tetracycline 65
Hydroxy ethyl cellulose DOX 66
Cellulose Felodipine 67
Ethylcellulose Multilayer layer coatings that allow for instant or customised release 68
Hydroxypropyl methylcellulose acetate succinate For creating capsules and coating layers for instantaneous or regulated release 68
Hydroxypropyl methylcellulose The release of nitrofurantoin might be impacted by the HPMC fraction of 0–40% 69
Hydroxypropyl methylcellulose For printing capsules and coating layers for immediate or modified release, barrier material 68
Hydroxypropylcellulose Design of the capsule and pulsatile drug release 70
Hydroxypropylcellulose Serving as a polymer carrier for theophylline release 71
As a carrier polymer for intragastric domperidone release 72
Poly(1-O-methacryloyl-β-dfructopyranose)-block-poly(methyl methacylate) Paclitexal 73
Graphene oxide in bacterial cellulose Nanocarrier of ibuprofen 74


3.1.2 Chitosan. The most prevalent naturally occurring cationic amino polysaccharide after cellulose is chitosan. Chitosan was discovered and discussed by Rouget in 1859 for the first time and entered the pharmaceuticals field in 1990 owing to the versatility of its active amino groups.8 Chitosan, a cationic polysaccharide derivative of chitin has been employed in different routes of administration including nasal, ocular, intravenous, oral, mucosal, etc. The nasal absorption of peptide medicines as an enhancer is one of its many biological uses that merits highlighting. Peptide pharmaceuticals are often employed as an adjuvant in immunotherapy, a carrier for siRNA/DNA and gene therapy, as anticancer drugs, and as a scaffold in the healing of wounds. Functionalization is a viable method to accomplish unattainable therapeutic objectives in order to fully realise the promise of nanomedicines.75 Chitosan along with amaranth red and microencapsulation with alginate released the intestinal and gastric fluids for the protection of molecules, after oral administration for intestinal release.76,77 It has also been claimed that chitosan–alginate nanocomposites improve the delivery of daptomycin to the ocular epithelium for antibacterial activities.78 Chitosan that has been functionalized to release catechol has been tried as a buccal medication delivery method for lidocaine.79

Chitosan nanoparticles have been discovered to significantly increase medication absorption through nasal mucosa and to transfer macromolecules across the nasal, ocular epithelium oral and tracheal.13 Chitosan NPs that were paclitaxel-loaded demonstrated excellent tumor-homing.20 Interferon-alpha administered by chitosan nanoparticles' antiviral efficacy is also evaluated.21 In the quest to search the thermosensitive and mucoadhesive biopolymers, moxifloxacin-loaded sustained release periodontal showed that poloxamer-and chitosan-based formulations sustained the drug release for 8 h with low initial burst release.80 Chitosan microspheres embedded with selenium NPs are reported to express gastroprotective potential.81 Amoxicillin is degraded by the acidic pH of the stomach, and was encapsulated in a biopolymer functionalized with lipids.82 Fe3O4/chitosan nanocomposite has been employed for the intravenous supply of gemcitabine (an anticancer nucleoside analog).83 Chitosan-encapsulated mesoporous Fe3O4/SiO2 nanocomposite is tested and shown to be adequate for the controlled release of DOX.84

A composite made of polyethylene glycol, chitosan, and iron oxide that also contains cyanin dye, a near-infrared fluorescent, and has paramagnetic, targeting, fluorescent, and anticancer properties is described for self-targeted curative drug delivery.85 It is also claimed that chitosan plus zinc oxide make an excellent medication delivery system.86 Iron oxide and cadmium telluride functionalized on zinc sulfide quantum dots with carboxymethyl chitosan have been employed for cell labeling and drug release.64,87,88 5-Fluorouracil encapsulated carboxymethyl chitosan for colon cancer therapy.89 Chitosan, cyclodextrin, and carboxymethyl chitosan were combined to create pH-sensitive magnetic hydrogels for the controlled release of the medication.90 The effect of the incorporation of Fe3O4 NPs was also explored on carboxymethyl chitosan, cyclodextrin, and chitosan hydrogel to deliver methotrexate.91 pH-sensitive chitosan and carboxymethyl chitosan biopolymers have also been used for colon-targeting medication delivery.92 Using carboxymethyl chitosan, cyclodextrin, and chitosan, Fe2O3 hydrogels sensitive to pH were created, and they have been employed for the controlled release of medications.90 The effect of the incorporation of iron oxide NPs was also explored on carboxymethyl chitosan, cyclodextrin, and chitosan hydrogel to deliver methotrexate.91 pH-sensitive chitosan and carboxymethyl chitosan biopolymers for colon-targeting drug delivery have also been reported.92

Chitosan–chondroitin sulfate is being used for transporting the lornoxicam as a gastroretentive delivery system.123 Hollow and bio-adhesive microspheres composed of ethyl cellulose and glyceryl monooleate have been fabricated and had proved to extend the drug retention time in the stomach.125 For an 8 hour continuous release of loratadine, oil-entrapped floating microbeads were developed as a gastro retentive controlled release device. Chitosan derivative with polyaniline side chain for effective suppression of tumor growth is also reported.93 An injectable succinate chitosan and oxidized alginate for in vitro release of DOX for inhibition of tumor growth breast cancer have been formulated.94 In order to transport the antibiotic ceftazidime to the eye, the effectiveness of hydroxypropyl methylcellulose containing chitosan, sodium tripolyphosphate, and hyaluronic acid NPs is assessed.95 For the oral delivery of medications, chitosan, alginate, and pectin NPs have shown promise.96 It is widely known that carboxymethyl chitosan may release intra-nasal carbamazepine by evading the blood–brain barrier membrane.97 Through γ-ray irradiation polymerization, poly(butyl acrylate) modified chitosan-organophilic nanocomposite has been devised for DDS.98 Through folate, conjugation of doped carboxymethyl chitosan-ferro-ferric oxide with cadmium telluride quantum dots a DDS has been synthesized.99 Hybrid polysaccharides composites with crosslinked chitosan with carboxymethyl-β-cyclodextrin grafted on Fe3O4 have been reported for the transportation of 5-fluorouracil.100 Using the drug's controlled release in N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride was similarly successful.101 Alginate nanocomposites with quaternized carboxymethyl chitosan clay are tested for their drug release characteristics.102 When combined with cloisite 30B, chitosan-polyvinyl alcohol effectively administers curcumin release.103 DOX release was observed using electrospun nanofibrous scaffolds made of polyethylene, chitosan, and graphene oxide.104

Chitosan and dextran were tested as carriers for the anticancer medication DOX after being modified with graphene oxide.105 Chitosan–alginate nanoblends with cloisite 30B have been evaluated for the controlled release of curcumin.106 Graphene/gold nanocomposite films for glucose biosensing are also reported. Commercially accessible, water-soluble derivatives of glycol chitosan have been utilised to deliver drugs like paclitaxel and DOX.107 Protonated chitosan with ionized alginate shows prolonged retention of the structures in the intestinal mucosa.108,109 In vitro, study revealed the ability to deliver DNA by folic acid–chitosan conjugates.110 Hyaluronan–cisplatin fabricated the nanoconjugates to target colon cancer.111 A chitosan-based hydrogel containing latanoprost eye drops was discovered in the aqueous humour seven days after the system had been applied topically only once112 and A polymer made of poly (N-isopropylacrylamide) and chitosan was used to administer timolol topically over a 12 hour period.113 Additionally, sustained drug release patterns were shown using carboxymethyl chitosan and a poloxamer made of polyethylene oxide, polypropylene oxide, and polyethylene oxide.114

Several conjugates with mitomycin C, exhibited good in vitro antitumor activities against sarcoma, melanoma, murine leukemias, hepatic cell carcinoma, and metastatic liver cancer.115 DOX–chitosan conjugates showed suppress tumor growth against breast cancer,116 melanoma,117 and mesothelioma cells.118 Paclitaxel-chitosan nanoconjugates, showed appreciable inhibition of murine melanoma when applied for oral administration,.119 For the purpose of developing the DDS, docetaxel–chitosan conjugates also shown desirable features, such as bioavailability, decreased acute toxicity, and in vivo effective anticancer activity.120 Targeted anticancer drug delivery and photothermal treatment have both been achieved using chitosan/sodium alginate functionalized magnetised graphene oxide nanocomposites.121 Silver NPs were physically crosslinked in chitosan to form hydrogel beads for application as DDSs.122 Chitosan supported ciprofloxacin Tween-80/tripolyphosphate along with bovine serum albumin are reported to target the site.123 Hydrogel nanocomposite of Fe3O4 NPs with acrylic acid/N-isopropyl acrylamide and chitosan for controlled release of DOX.124 Chitosan composite with mesoporous aluminosilicate thin films was employed for the delivery of metformin.125 Chitosan NP with Fe2O3 modification was created to regulate the distribution of DOX and cell imaging,88 for simultaneous cancer imaging and therapy using methotrexate and gemcitabine administration.83,126 Chitosan–alginate constructs have also been employed for delivering anticancer,127,128 ocular,129 pulmonary and asthma,130 and anti-inflammatory drugs.131 Chitosan-hyaluronic acid systems were also employed for ocular applications132,133 and for treating asthma and osteoarthritis.134,135 For sustained drug release in the intestine chitosan and xanthan gum-based tablets showed excellent results.136,137

The optimum encapsulation characteristics of benzalkonium chloride inside mesoporous silica/polysaccharide hybrid materials increase the amount of the drug release by improving the dispersion of the MSN and permitting enhanced drug diffusion.138 The prolonged administration of medications to the eye is improved by chitosan and gelatin hydrogels.139 Crosslinked chitosan with embedded Fe3O4 NPs showed good rational drug administration.140 Chitosan microspheres loaded with 5-fluorouracil to DDS were developed in order to understand in vitro cytotoxicity and in vivo efficacy for the treatment of colon cancer.141

Fe3O4 NPs functionalized with 3-amino propyl, triethoxy silane were covered in tragacanth gum and chitosan to create capsules for the medicine curcumin.142 Zinc oxide composites with chitosan have also been used as drug delivery platforms.143 Effective drug carriers for cancer treatment with improved absorption are pH-sensitive fluorinated carboxymethyl chitosan nanoparticles.144 In colorectal cancer treatment efficiency of 5-fluorouracil was seen to be enhanced via nanoencapsulation.145 Table 1 provides some other instances of the use of chitosan and its mixtures in medication administration.

3.1.3 Cellulose. Cellulose is a non-ionic polysaccharide. Cellulose and chitosan NPs are also employed for the oral release of repaglinide is also practiced.54 Targeting colon diseased cites, calcium alginate beads with carboxymethylcellulose loaded with 5-fluoroalkyl.55 These four cellulose derivatives—methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and cationic hydroxyethyl cellulose—have been used as DDS in the nasal mucosa.56 The impact of hydroxy propyl methylcellulose-based nanocomposites with cellulose nanofibrils for drug release in the form of thin films was explored.57 For in vitro anti-colon cancer treatment, magnetic-responsive drug carriers loaded at cellulose containing curcumin were utilised instead of Fe3O4.58 In vitro drug release of ciprofloxacin with a 96.6 percent success rate over a 5 hour period using gold nanoparticles with cellulose grafted polyacrylamide hydrogel.59 Colon cancer treatment with 5-fluorouracil-encapsulated carboxymethyl chitosan is widely documented.89 Chitosan, cyclodextrin, and carboxymethyl chitosan were combined to create pH-sensitive magnetic hydrogels for the controlled release of the medication.90 In order to distribute methotrexate, the impact of including Fe3O4 NPs on carboxymethyl chitosan, cyclodextrin, and chitosan hydrogel was also investigated.91 pH-sensitive chitosan and carboxymethyl chitosan biopolymers have also been used for colon-targeting medication delivery.92 Table 2 lists some other instances of the use of cellulose and its mixtures for medication delivery.
Table 2 Chitosan and its composites in drug deliver
Polymer Bioactive agent References
Polyurethane–alginate/chitosan A model antigen 146
Chitosan–alginate Silver 147
Crocin 148
Naringenin 149
Quercetin 150
Insulin 151
DOX 152
N-Octyl-N arginine chitosan Insulin 153
Alginate–chitosan Diclofenac sodium 154
Alginate–chitosan Verapamil 155
Alginate–chitosan microparticles Prednisolone 156
Chitosan-coated composite-sodium alginate microbeads Amoxicillin 157
Blend of chitosan–sodium alginate and cloisite 30b Curcumin 129
Chitosan 5-Fluorouracil, indomethacin 158
Chitosan/N-trimethyl azone Testosterone 159
Chitosan eucalyptol, transcutol® P Ondansetron hydrochloride 160
Chitosan, rhodamine, polydimethylsiloxane Bovine serum albumin 161
Chitosan, SL (SoftCAT™), sodium deoxycholate Lidocaine hydrochloride 162
Chitosan, hyaluronic acid, glyceryl monostearate, cetyltrimethylammonium bromide Lidocaine 163
Chitosan, hyaluronic acid, glycidyl methacrylate Lidocaine 164
Chitosan, b-CD, cineole, menthol, limonene, streptozotocin Glimepiride 165
Hydrochloride chitosan, PLGA Donepezil 166
Chitosan, oleic acid Propranolol hydrochloride 167
Chitosan, N-vinyl caprolactam, azobisisobutyronitrile Etoricoxib, paracetamol 168
Chitosan, cholesterol, deoxycorticosterone acetate Carvedilol 169
Chitosan, triphenylphosphine Aciclovir 170
Chitosan, lipoid S45, lipoid S100 Melatonin 171
Chitosan, hydroxypropyl methylcellulose, polyvinyl alcohol, polyamidoamine dendrimer, dibutyl phthalate Meloxicam 172
L-a-Phosphatidylcholine, chitosan, cholestrol, triton X 100, dihexadecyl phosphate Resveratrol 173
Chitosan oligosaccharide, cellulose nanocrystal, sodium tetraphenylborate Procaine hydrochloride 174
Chitosan, azolectin Curcumin, diclofenac and vitamin B12 chitosan 175
Chitosan, hydroxypropyl methylcellulose, dibutyl phthalate Metformin hydrochloride 176
Chitosan, lactic acid Lisinopril 177
Chitosan Bovine serum albumin 178
Chitosan, bovine serum albumin, poly(sodium-4-styrene sulfonate) Tetanus toxoid 179
Chitosan, mannitol, hydroxypropyl methylcellulose Ketoprofen, chondroitin sulfate 180
Chondroitin sulfate Methotrexate 181
Chorine6 182
Glycyl-prednisolone 183
Quercetin 184
Histamine 185
Diacerein 186
Chitosan, p-nitrophenyl chloroformate and amino1-propanol, Pluronic F127 Curcumin 187
Chitosan, DMPC, lipiodol, D-glucose (dextrose) Indocyanine green 188
Xanthan-graft-C16 alkyl chain Glibenclamide 189
Chitin-graft-hexadecyl DOX 190
Fucoidan-graft-octenyl succinic anhydride Cur 191


3.1.4 Hyaluronic acid. Different forms of cancer, such as breast cancer, lung cancer, and colon cancer, have been treated using a variety of hyaluronic acid (anionic polysaccharide) and its derivatives combined with paclitaxel.109 They are proved prospective carriers for butyric acid to treat Lewis lung, melanoma, and leukaemia and have undergone significant research for the transport of analgesics, siRNA, proteins, antibiotics and anticancer medicines.192 In human ovarian carcinoma xenografts, hyaluronic acid (HA) alone and in conjugation with DOX demonstrated targeted toxicity in vitro and potent anticancer action in vivo193 and bladder carcinoma respectively.194 HA functionalized by adipic dihydrazide or methacrylic anhydride showed an appreciable DD profile.195 Hyaluronic acid coupled with g-poly (N isoorpylacrylamide) has high drug-loading capabilities. Another system for loading cyclosporine A showed results comparable to commercially available DDS.196 Zhong et al. did extensive study on reversible crosslinked hyaluronic acid nanoparticles to address medicine resistance (NPs).197 Crosslinked hyaluronic acid composite hydrogels and nano-carriers have been used to deliver drugs to the eyes.195 The modified hyaluronic macromers were crosslinked with matrix metalloprotease peptides to allow for a sustained release of the growth hormones.198

The creation and subsequent loading of an injectable hydrogel based on the chemical bonds between hyaluronic acid and adipic acid dihydrazide and hyaluronic acid aldehyde.Paclitexal comes in micelle and microparticulate forms.199 Results revealed a significant tumor reduction. Cho et al. developed platinum-incorporated HA NPs to inhibit tumor growth.200 Ueda et al. developed an injectable interferon-alpha containing hyaluronic acid-tyramine that was subsequently combined with sorafenib in a kidney cancer xenograft mice model (a tyrosine kinase inhibitor).201 Ferrocenium tetradecyl coated with HA was used for the delivery of the DOX drug.94,202 An enhanced therapeutic effect was shown by a nanocomposite comprised of fluorochrome indocyanine green, carboxyl terminated dendrimer, HA and DOX.203 Iron oxide NPs with dopamine-modified Hyaluronic acid have been reported.204 For lung cancer treatment, an injectable alginate-calcium hydrogel containing dendrimer-encapsulated platinum NPs was used.205 Table 3 lists some further instances of hyaluronic acid and its compounds being used for medication delivery.

Table 3 Drug delivery using hyaluronic acid and its composites
Polymer Bioactive agent References
Adipic dihydrazole hyaluronic acid Quercetin 206
Hyaluronic acid Curcumin 207
Hyaluronic acid Curcumin 208
Dithiodipropionic acid hyaluronic acid Quercetin curcumin 209
Hyaluronic acid Paclitaxel 210
Butyric acid 211
Cisplatin 212
Cisplatin 213
Paclitaxel 214
Paclitaxel 215
Hyaluronic acid ceramide DOX 216
Hyaluronic acid-functionalized SLN Paclitaxel 217
Hyaluronic acid-nanographene oxide HA-conjugate NPs 218
Functionalized hyaluronic acid Noisome 219
Hyaluronic acid-functionalized transferases DOX 220
Hyaluronic acid-chitosan functionalized PCL nanofiber scaffold 221
Hyaluronic acid polymeric micelle Coenzyme Q10 222
Hyaluronic acid conjugate Human growth hormone 223


3.1.5 Xylan. Another prevalent cationic polysaccharide biopolymer, xylan is mostly found in plants and grains and is hemicellulose. Due of colonic microflora's ability to generate enzymes that may lead to biodegradation, it is a crucial factor in the development of colonic DDS. Thus, xylan was approved as a biopolymer that is only used in the colon.224 A sort of illness connected to the colon area is colorectal cancer. The activation of the carboxylic acid was employed by Sauraj and his collaborators to create xylan-5-fluorouracil-1-acetic acid conjugates, which they found to be more effective than the medicine when administered alone.225 Additionally, xylan–curcumin conjugates for the therapy of cancer have been described.226 These systems are described for the delivery of peptides and proteins, as well as for the treatment of Chron's disease and ulcerative colitis, in addition to having shown promise for colon medication delivery.227
3.1.6 Alginate/alginic acid. Alginate composites, conjugates, and derivatives with a variety of therapeutically active components have been described and are offered in the market commercially.228 Active compounds, ranging from microscopic drug molecules to macromolecular proteins, may be released from alginate gels in a controlled manner depending on the kind and cross-linking procedure. Their applications in the pharmaceutical sector are expanded by the fact that they may also be administered orally or through injection.228 HT-29 cells were used as the test subject for the in vitro cytotoxicity of capecitabine-loaded interpenetrating polymeric network created by the ionotropic gelation process employing the polymers locust bean gum and sodium alginate. Results showed that cell proliferation has been significantly reduced.229 For the treatment of depression, alginate NPs have been used to release venlafaxine through intranasal delivery.230 Moxifloxacin hydrochloride is effectively delivered over time using sodium alginate.231 Anti-inflammatory medications have also been administered to the eye using sodium alginate hydrogels. Another such very effective formulation is created.232 Román et al. developed alginate microcapsules containing epidermal growth factor linked to its exterior section to precisely target the non-small cell lung cancer cells.233 Additionally put in the NPs was cisplatin. To increase the penetration of daptomycin into the ocular epithelium in an effort to have an antibacterial impact, chitosan-coated alginate NPs were used.78

To create drug delivery systems, alginate nanoaggregates of 250 to 850 nm may be coupled with chitosan and glycol chitosan.234 Alginate nano aggregates have been used to deliver DNA, antisense oligonucleotides, insulin, cisplatin, and DOX.107 Using galactosylated chitosan graft dextran, DNA complexes have been delivered to the liver.235 Chitosan/hyaluronic acid microparticles were used to load the DOX hydrochloride drug.236 To deliver 5-fluorouracil for colon cancer therapy and blood drug concentration, a mesoporous silica-alginate/folic acid-conjugated O-carboxymethyl chitosan-gelatin nanocomposite was developed.237 By avoiding the burst release, sodium alginate-ZnO hydrogel beads improved the release of curcumin.237 Films made of calcium alginate loaded with diclofenac sodium and other hydrophilic polymers performed well.238 Ca-alginate composite films are used in clinical therapeutic applications.239 Table 4 lists some other instances of the use of alginate and its mixtures for medication administration.

Table 4 Drug delivery using alginate and its composites
Polymer Bioactive agent References
Alginate Zidovudine 240
Alginate DOX loaded liposomes 241
Sodium-alginate Indomethacin 242
Retinoic acid 243
DOX 244
5-Fluorouracil 245
Alginate Ibuprofen 246
Sodium-alginate Ketoprofen 247
Alginic acid DOX 248
Alginate–calcium phosphate NPs Glucocerebrosidase 249
Alginate–montmorillonite NPs Vitamin B1 and B6 250
Alginate–magnesium stearate NPs entrapped in oil Ibuprofen 251
Alginate gel entrapped in oil- Risperidone 252
Alginate tamarind gum magnesium stearate buoyant NPs Metronidazole 253
Alginate-calcium silicate effervescent beads Alfuzocin HCl 254
Alginate-calcium silicate muco adhesive NPs 5-Fluorouracil 255
Glass-alginate-samarium composite DOX and paclitaxel 256
Alginate-calcium carbonate hybrid NPs DOX 257
Alginate-strontium-substituted hydroxyapatite nanocomposites Vancomycin 258
Montmorillonitealginate composites Diclofenac sodium 259
Composite of calcium alginate and methyl cellulose Gliclazide 260
Microbeads made of polyvinylpyrrolidone and calcium alginate Diclofenac sodium 261
Alginate-polysaccharide beads made of linseed Diclofenac sodium 262
Okra gum with zinc alginate beads Diclofenac sodium 263
Mucilage-alginate mucoadhesive beads made from paghula husk Gliclazide 264
NPs made of ispaghula husk and alginate Glibenclamide 265
Microspheres made of tamarind seed polysaccharide that are mucoadhesive Gliclazide 266
Polysaccharide-alginate mucoadhesive beads made with tamarind seeds Metformin HCl 267
Microspheres of esterified gellan gum and alginate Aceclofenac 268
Lipid/alginate Dexamethasone 269
Calcium/alginate Hector (Aah), attenuated androctonus australis venom 270
Graphene conjugated sodium alginate Carrier of DOX hydrochlorid 271
Carboxymethyl cellulose and sodium alginate protected silver NPs Nanomedicine 272
Polyurethane–alginate Insulin 229
Poly vinyl alcohol–alginate Metformin 273
Lipid/alginate Dexamethasone 269
Calcium/alginate Attenuated Androctonus australis hector (Aah) venom 270
Alginate Curcumin 274 and 275
Galactosylated alginate Curcumin 276
Sterculia gum–alginate floating beads with oil entrapment Aceclofeanc 277
Mucilage-alginate mucoadhesive beads made from fenugreek seeds Metformin HCl 278
Tamarind seed polysaccharide–alginate floating beads that have been emulsion-gelled Diclofenac sodium 279
Microbeads of zinc alginate-carboxymethyl cashew gum Isoxsuprine HCl 280
Sodium alginate Theophylline 247
Diltiazem HCl 281
Metronidazole 282
Gliclazide 283
Sulindac 284
Ampicillin 285
Diclofenac sodium 286
Furosemide 287
Alginate–locust bean gum Diclofenac sodium 288
Alginate–pectinate Aceclofenac 289
Alginate–gellan gum Glipizide 290
Alginate–gellan gum Aceclofenac 268
Alginate–xanthan gum Diclofenac sodium 291
Alginate, guar gum, locust bean gum, and xanthan gum Diclofenac sodium 292
Alginate–gum Arabic Glibenclamide 293
Sterculia gum–alginate Pantoprazole 294
Gum Arabic–alginate Glibenclamide 293
Tamarind gum–alginate Gliclazide 266
Tamarind gum–alginate Metformin HCl 267
Tamarind gum–pectinate Metformin HCl 295
Tamarind gum–alginate Diclofenac sodium 296
Tamarind gum–gellan gum Metformin HCl 297
Gum–alginate of okra Diclofenac sodium 263
Alginate from okra Glibenclamide 263
Linseed polysaccharide–alginate Diclofenac sodium 262
Seed mucilage-alginate of fenugreek Metformin HCl 265
Mucilage-alginate from the ispaghula husk Glibenclamide 298
Gliclazide 298
Isoniazid 299
Metformin HCl 300
Fruit gum–alginate from dellinia Timolol maleate 301
Kondagogu-alginate gum Glipizide 302
Mucilage-alginate from fenugreek seeds Metformin HCl 265
Alginate Zidovudine 240
Alginate DOX loaded liposomes 241
Sodium-alginate Indomethacin 242
Retinoic acid 243
DOX 244
5-Fluorouracil 245
Alginate Ibuprofen 246
Sodium-alginate Ketoprofen 247
Alginic acid DOX 248
Chitosan, sodium alginate Rabeprazole sodium 303
Alginate–locust bean gum Diclofenac sodium 288
Alginate–pectinate Aceclofenac 289
Alginate–gellan gum Glipizide 290
Alginate–gellan gum Aceclofenac 268
Alginate–xanthan gum Diclofenac sodium 291
Alginate, guar gum, locust bean gum, and xanthan gum Diclofenac sodium 292
Alginate–gum Arabic Glibenclamide 293
Sterculia gum–alginate Pantoprazole 294
Gum Arabic–alginate Glibenclamide 293
Tamarind gum–alginate Gliclazide 266
Tamarind gum–alginate Metformin HCl 267
Tamarind gum–pectinate Metformin HCl 295
Tamarind gum–alginate Diclofenac sodium 296
Gellan gum with tamarind gum Metformin HCl 297
Gum-alginate of okra Diclofenac sodium 263
Gum-alginate of okra Glibenclamide 263
Linseed polysaccharide–alginate Diclofenac sodium 262
Seed mucilage-alginate of fenugreek Metformin HCl 265
Mucilage-alginate from the ispaghula husk Glibenclamide 298
Mucilage-alginate made from spigola husk Gliclazide 298
Mucilage-pectinate from the ispaghula husk Aceclofenac 304
Spaghula husk mucilage-pectinate Metformin HCl 305
Mucilage-gellan gum made from spaghetti husk Metformin HCl 306


3.1.7 Dextran. The microbially produced dextran is a complex branching poly-d-glucoside with variable-length glycosidic linkages. On a group of human tumour xenografts and colon cancer, a dextran–camptothecin combination demonstrated strong anticancer efficacy in vivo.192 A combination of dextran and exatecan demonstrated substantial therapeutic effectiveness against a panel of murine solid tumours and human xenografts.307 Compared to the free medication, methotrexate to dextran combination demonstrated enhanced activity against human tumour xenograft models.308 Multiple colon cancer cell lines exposed to paclitexal–carboxymethyl–dextran ester conjugates shown strong anticancer activity in vivo.309 In a Lewis lung cancer rat model, an imine conjugation of DOX to Ox-dextran shown greater therapeutic effectiveness.192 Additionally, a clinical investigation for a CM-dextran combination with delimotecan has begun.310 Dextran nanogels that have been PEGylated have been used for gene therapy using short interfering RNA,311 which, in human hepatoma and glioblastoma, have effectively accomplished gene knockdown. Drug-resistant cancer cell lines may be treated using Dextran nanogels that carry siRNA to silence the genes that cause multidrug resistance.192 Fast-dissolving oral medication administration was achieved by electrospinning metronidazole/hydroxypropyl-β-cyclodextrin inclusion complex nanofibrous webs.312

For complexation, cyclodextrins are most often used. Examples include budesonide (for pulmonary drug delivery), acetazolamide (for ocular drug administration), and buserelin (nasal drug delivery).313 To overcome drug resistance, a gold-paclitaxel nanoconjugate was developed using -cyclodextrin.314 Additionally, diisocyanate-modified Fe3O4 and cyclodextrin were used to create magnetic nanoconjugates of dacarbazine.315 Methotrexate was conjugated with dextran to lower the dosage and lessen unwanted effects.316 Dextran and 5-aminosalicylic acid conjugates have been utilised to carry drugs to the small intestine and stomach. The prodrug of the azo-coupled dextran-salicylic acid combination regulated the drug's release into the colon.317 Since nalidixic acid alone is pH sensitive, dextran-nalidixic acid ester conjugate is used as a colon-specific prodrug.318 When used to treat human ovarian cancer cells, dextran nanocomposites with paclitaxel and DOX shown encouraging results for more tumour mass penetration and less side effects than the pure medication.210 Curcumin- and curcumin-γ-hydroxypropyl cyclodextrin-loaded nanoconjugates were shown to be more efficient than the pure medication for delivering genetic material in cancer cells.319 Table 5 lists some further instances of dextran and its compounds being used for medication delivery.

Table 5 Drug delivery using dextran and its compounds
Polymer Bioactive agent References
Dextran Curcumin 320
Indomethacin 321
Indomethacin 322
Fructose Curcumin 323
Cyclodextrin Paclitaxel 324
Cyclodextrin Dacarbazine 314
Dextran 5 Aminosalicylic acid 315
Nalidixic acid 317
Methotrexate 325
Ibuprofen 316
DOX and paclitaxel 326
Cyclodextrin Camptothecin 327
β-cyclodextrin Camptothecin 328
Carboxymethyl dextran Delimotecan 329
Carboxymethyl dextran Exatecan 330
Dextran DOX 331


3.1.8 Heparin. A member of the glycosaminoglycan family, heparin is a sulfated polysaccharide containing a linear anionic unit composition that is mostly composed of 2-O-sulfo-iduonic acid and 2-deoxy-2-sulfamino-6-O-sulfo-d-glucose, with trace quantities of 2-acetamido-2-deoxy-d-glucose. DDS also came into contact with heparin anionic polysaccharides. All-trans-retinoic acid and DOX were combined to form a system that Zhang and colleagues created. It was coupled to low molecular weight heparin, and DOX was physically loaded.109 A heparin/DOX complex-containing composite system was described. To create self-assembled NPs encapsulating docetaxel, a polymer in the coupling of stearyl amine with low molecular weight heparin was employed. The research examined the NPs' effects on human breast cancer cell lines.332 Table 6 lists some further instances of the use of heparin and its mixtures in medication administration.
Table 6 Drug delivery using heparin and its blends
Polymer Bioactive agent References
Heparin DOX 333
DOX and all trans retinoic acid 334
A peptide-modified DOX 335
Retinoic acid 336
Heparin-graft-α-tocopherol Docetaxel 337
Heparin-graft-deocycholate DOX 338
Pegylated heparin a Pyropheophorbide-a 339
Heparin Paclitaxel 340


3.1.9 Xanthan gum. A polysaccharide, xanthan gum is often used as a food ingredient in industry. It has been reported that the drug release mechanism from binary composition tablets made of quetiapine fumarate, xanthan, and tragacanth gum (anionic polysaccharide) obtained a drug control release similar to that of the commercial product.341,342 A successful report of ibuprofen-loaded xanthan gum microsphere.343 When combined with xanthan gum, Terminalia chebula, Glycyrrhiza glabra, Emblica Officinalis, Terminalia belerica, and Turbinella rapa herbal extracts shown increased efficacy.344 Lamivudine microsphere made from xanthan and guar gum revealed a slower release rate and continuous release for up to 24 hours.345 Metformin hydrochloride mucoadhesive microspheres produced with various XG and guar gum concentrations have been reported.346 A carbamazepine mucoadhesive nanoemulgel for targeting the brain via the olfactory mucosa is also disclosed.347 For effective transport of curcumin to the brain through the nose, xanthan gum-coated mucoadhesive liposomes were studied. The ability to effectively carry medication into the brain through the nasal route using xanthan gum-coated liposomes or other nanocarriers has been shown.348 Drug release from formulations including xanthan gum and carbopol 934 was maintained for 8 hours.349
3.1.10 Pectin. The major goal of the work was to alter specific pectin characteristics by adding thiol moieties to the polymer via the construction of pectin (anionic polysaccharide)–cysteine conjugates.109 Pectin-cysteine beads with zinc added showed increased stability in simulated gastrointestinal settings, but their insulin release profile was identical to that of unaltered zinc pectinate beads.109 To administer paclitaxel, a pectin-conjugated magnetic graphene oxide composite was created.109 Methotrexate-conjugated pectin nanoparticles (NPs) were developed for the delivery of a cytotoxic drug to hepatic cancer cells.350 Pectin–adriamycin conjugates' potential for lymphatic targeting was investigated.351 Using pectin matrices coated with eudragit 100, the release of 5-fluorouracil in the colon was examined. Pectin formulation reduced cytotoxicity concentration in cells by 50% in human colon cancer cells.352 Some other examples of pectin in drug delivery are reported in Table 7.
Table 7 Role of Pectin in drug delivery
Polymer Bioactive agent References
Pectin Indomethacin 353
Rutin 354 and 355
Theophylline 356
Ketoprofen 357
Cisplatin 358
Insulin 359
Paclitaxel 360
Methotrexate 350
Adriamycin 351
5-Flourouracil 352


3.1.11 Polyarginine. This sugar containing molecules also made its space for designing DDS. Because of its capacity to permeate membranes, polyarginine is often employed in DDS as a cell-penetrating peptide.361 For the delivery of quantum dots, arginine-rich peptides have been widely used.362 Role of arginine peptides in drug delivery is reported in Table 8.
Table 8 Role of Polyarginine in drug delivery
Polymer Bioactive agent References
Polyarginine Cyclosporin A 363
NLC encapsulated spantide II and ketoprofen 364
Liposomes encapsulated curcumin 365
Liposomes encapsulated polygonium 366


3.1.12 Pullulan. A polysaccharide made of maltotriose trimers is pullulan. A neutral polysaccharide called pullulan has been researched for non-viral gene delivery techniques.107 In order to explore their potential for usage in gene delivery applications, Rekha and colleagues produced polyethyleneimine-conjugated pullulans.367 Utilizing pullulan-deoxycholic acid conjugated for medication administration in cancer patients, Na and colleagues created a self-organized nano gel of DOX. The effective transfer of plasmid DNA to the liver was made possible by serine pullulan samples.368 DNA could be quantitatively loaded into pullulan microspheres using 1,2-chloro-2,3-epoxypropane without DNA degradation.369 Pullulan nanoparticles disulfide-cross-linked with folic acid for antitumoral hepatic drug delivery.370 In order to functionalize nanocarriers for targeted medication delivery in the treatment of cancer, heparin has been widely researched for its anticancer action.109 Table 9 lists some further instances of pullulan and its mixtures being used for medication delivery.
Table 9 Drug delivery using pullulan and its composites
Polymer Bioactive agent References
Pullulan-graft-polycaprolactone Ciprofloxacin 371
Pullulan-graft-α-tocopherol ε-Caprolactone 372
Pullulan–graft-SA DOX 373
Pullulan-graft, biotin, and retinoic acid DOX 374
Desaxycholic acid from pullulan grafts -graft-polyethyleneimine DOX DNA 375
Pulullan-graft-retinoic acid DOX 376
Dibutyl amino propyl carbamate-pululan-graft DNA 377
Pullulan-graft-cholesterol Methotrexate 378
Cysteine from heparin-graft-β-sitosterol DOX 90
Pullulan Polyethyleneimine, DOX, adriamycin 367 and 379
Schizophyllan-graft-styrene acrylonitrile Paclitexal 380


3.1.13 Starch. Starch is a non-ionic carbohydrate. Occurring in situ during the formation of CuO NPs, oxidised starch-CuO nanocomposite hydrogels allowed for the measurement of extended drug release for the CuO NPs containing oxidised starch that was elevated by increasing the CuO amount. In a separate study, two controlled-release drug carriers for the medicine methylprednisolone were developed as silver-starch nanocomposite beads.121 Table 10 lists some other instances of the use of starch and its composites for medication delivery.
Table 10 Starch and its Composites in drug delivery
Polymer Bioactive agent References
Hydroxyethyl starch Curcumin 381
Starch coated onto the Fe3O4 Magnetic carrier 272
Pectinate–high amylase starch Diclofenac sodium 382
Tapioca starch–alginate Metoprolol tartrate 383
Potato starch–alginate Tolbutamide 384
Potato starch–alginate Ibuprofen 385
Assam bora rice starch–alginate Metformin HCl 386
Jackfruit seed starch–alginate Pioglitazone 279
Jackfruit seed starch–pectinate Metformin HCl 387
Jackfruit seed starch–alginate Metformin HCl 388
Jackfruit seed starch–gellan gum Metformin HCl 389
Starch DOX, hydroxycamptothecin, chlorpheniramine maleate 390
Aminated starch Curcumin 391
Starch Tungstophosphoric acid 392
Carboxymethyl starch Mesalamine 393
PEGylated starch DOX 394
Starch acetate Cisplatin 395
Commercial glycerin latex, glutinous starch, rice, and potatoes Lidocaine 396
Alginate-starch beads Aceclofenac 397
Alginate beads made from jackfruit seed Pioglitazone 398
Alginate-starch beads made of jackfruit seeds Metformin HCl 292
Particles made of soluble starch composites with Ca21–Zn21-alginate Aceclofenac 399
Rice-starch-alginate beads from Assam Metformin HCl 386
Particles made of soluble starch composites with Ca21–Zn21-alginate Aceclofenac 399


3.1.14 Guar gum. To assess their potential for drug delivery, neutral and cationic guar gum nanocomposites containing montmorillonite-loaded ibuprofen have been studied.400 Guar gum-graft-acrylic acid was synthesized by an L-alanine crosslinker for hydrophilic drug delivery.401 Guar-gum-polyacrylamide incorporated with diltiazem hydrochloride has been reported.402 Acrylamide-grafted-guar-gum blended with chitosan as DDS has been evaluated.403 For the transdermal distribution of the medication diclofenac sodium, carboxymethyl guar gum containing nano silica was created.404 Guar-gum nanocomposite hydrogels and multiwalled carbon nanotubes have been utilised to administer the drug diclofenac sodium.405

Target-specific crosslinked hydrogels based biopolymers for the controlled release of cephradine.406 For the in vitro release of cephradine, chitosan/guar gum hydrogels were created by mixing with PEG. Results indicated that 85 percent of the cephradine was released in 130 minutes. Gelatin is a linear polypeptide made up of 18 distinct kinds of amino acids and a hydrophilic biopolymer. To treat resected primary/metastatic bone locations, zoledronic acid-containing nanocomposites of gelatin and beta-tricalcium phosphate were created.150 The biocompatible gelatin was filled with methotrexate.151 Zinc oxide was synthesised in situ to create antibacterial chitosan/zinc oxide nanocomposite hydrogels that were used as naproxen drug delivery systems.152 Table 11 lists further instances of gelatin being used for medication delivery.

Table 11 Examples of Gealtin in drug delivery
Polymer Bioactive agent References
Gelatin Tizanidine hydrochloride 407
408
Gatifloxacin 409
Fluconazole 410


The local administration of anticancer medications using injectable chitosan-based gels has shown significant potential. For instance, liposomal DOX was loaded into a thermosensitive injectable hydrogel with chitosan and -glycerophosphate that released DOX in vitro in a pH-dependent manner.217 Some other examples of gum and its composites in drug delivery are reported in Table 12.

Table 12 Some examples of Gum and its composites in drug delivery
Polymer Bioactive agent References
Guar gum galactomannan-graft-acetic anhydride Cur 411
Bletilla striata-graft-SA DOX 412
Phthalated cashew gum Benznidazole 413
Gellan gum Amoxicillin, amoxicillin trihydrate, cephalexin 414 and 415
Fenugreek seed mucilage–pectinate Metformin HCl 416
Fenugreek seed mucilage–gellan gum Metformin HCl 417


3.2 Protein-based DDS

Natural poly(amino acids), a kind of biodegradable ionic polymers, has only one type of amino acid. The biomaterials that are examined the most often are poly(γ-glutamic acid) and poly(L-lysine). The glutamic acid polymer Because of the polymer's reactive side carboxylate centres, other functional groups and medications may be attached covalently.4 Antibiotics, vaccines, DNA, and proteins have all been explored to be transported using poly(γ-glutamic acid)-based particles. A poly(glutamic acid)-based carrier that contains paclitaxel is a well-known cancer product. In biomedical applications, it has been employed as a carrier to increase the effectiveness of several interferon inducers, antiviral medications, and anticancer medications. Biomedical uses for polynucleotides like DNA and RNA exist.418 The role of individual proteinaceous polymers is discussed below:
3.2.1 Collagen. Collagen, the primary element of connective tissues, is the most abundant protein in the human body. Due to their diverse qualities, which include mechanical strength and biocompatibility-degradability, 29 distinct kinds of collagen have been identified and are being intensively explored for use in the fabrication of the DDS.79 Low-molecular-weight pharmaceuticals may be transported well by collagen; gentamicin-loaded collagen-based delivery systems are one example of this. Numerous different collagen and synthetic polymer composite systems are being described as DDS.79,419 Polylactic-co-glycolic acid and alginate microparticles containing collagen have been produced for continuous administration of recombinant human bone morphogenetic protein 2, making them an effective controlled delivery vehicle of the pro osteogenic factor.420 Additionally, collagen/polyvinyl alcohol is being tested for the continuous administration of salicylic acid.421 To combat bacterial infections, collagen scaffolds crosslinked with hexamethylene diisocyanate and containing cefaclor have been created.422 Collagen bandage contact lenses to lubricate the eye along with active ingredients are reported.423 It has been reported to use collagen-alginate microspheres to deliver medications to the eyes.424 In order to lubricate the eye, collagen bandage contact lenses containing active substances and a coating of collagen have been used.423 Alginate hydrogels with composite collagen content have been described for medication administration to the eye.425 Table 13 discusses the few applications of collagen and its composite.
Table 13 Collagen and its composites in drug delivery
Polymer Bioactive agent References
Collagen DOX 426
Hydrolyzed collagen Hydrocortisone 8
Collagen DOX 427
Chloramphenicol 428
Ibuprofen 429
Fludarabine/epirubicin 430
Cardamom extract 431
5-Fluorouracil 432
Econazole nitrate 433
Ciprofloxacin 434
Hydroxyapatite-collagen alginate composites Bone morphogenetic protein 435


3.2.2 Natural rubber. Natural rubber is a very elastic polymer with a strongly crosslinked structure that is an intriguing biomaterial for DDS for proteins, antitumoral drugs, and antimicrobial chitosan.4 Pilocarpine was released from gelatin hydrogels created by Natu et al. during an 8 hour period at a rate ranging from 29 to 99 percent.436 Human elastin-like polypeptides were included into the creation of bioactive molecules, which showed how therapeutic compounds may be delivered in response to proteolytic stimuli.437 In order to combine the best qualities of two materials that may be employed for therapeutic molecule administration, a composite matrix made of human elastin-like polypeptide hydrogel and electrospun poly-L-lactic acid was created.438,439 Some examples of starch and its composites in drug delivery are reported in Table 14.
Table 14 Natural rubber and its composites in drug delivery
Polymer Bioactive agent References
Polyethylene glycol, natural rubber, carbazole, ammonium persulfate, 2-methyl-4-(methylthio)-2-morpholino propiophenone Indomethacin 440
Hevea brasiliensis' isolated natural rubber latex Diclofenac potassium 441
Natural rubber latex Ketoprofen natural 442
3-Mercaptopropionate, 2-methyl-4-(methylthio)-2-morpholinopropiophenone, and natural rubber Ibuprofen 443


3.2.3 Keratin. In clinical medicine, the administration of anticancer drugs may be possible using keratin, which is a highly practical and affordable protein for biomedical purposes.418,444 Han et al. used keratin for drug release of rhBMP-2, rhIGF-1, and ciprofloxacin, as well as simple alkylation on keratin for regulated release of gel G, which demonstrated no toxicity.445 As a model drug, rhodamine B dye release from films made of keratin and polyvinyl alcohol that were crosslinked with starch was studied.446 DOX-loaded keratin NPs are also well reported.447
3.2.4 Albumin. Proteins are water-soluble, three-dimensional folded structures, made up of amino acids joined together by amide bonds.35 Different drug binding sites are found in albumin, allowing a range of medicines to be loaded.448 The most potent drug ever developed, albumin paclitaxel nanoparticle, is the first DDS approved by the FDA for the treatment of metastatic breast cancer. Levemir, created by Novo Nordisk, is another medication with albumin that is authorised for use in the treatment of type 1 and type 2 diabetes. A human insulin derivative that binds to albumin is present. Additionally, Herceptin and Avastin, which are NPs for the antibodies trastuzumab and bevacizumab, respectively, have been studied to learn more about their potential.449 An N-lysinal-N′-succinyl chitosan and poly (N-isopropylacrylamide) hydrogel was enclosed within a crosslinked bovine serum albumin shell in order to function as an effective carrier of chemotherapeutic drugs.450 Calcium corbonate hybrid particles with bovine serum albumin along with polydopamine showed good DDS applications.451 Table 15 lists some further instances of albumin and its mixtures being used for medication delivery.
Table 15 Albumin and its composites in drug delivery
Polymer Bioactive agent References
Albumin Paclitaxel, warfarin, silibinin, diazepam 452
Bovine serum albumin Curcumin 453
Albumin Vancomycin 454
HAS 5-Aminosalicylic acid 455
Bovine serum albumin Dimethylcurcumin 456
Bovine serum albumin Curcumin 457
Albumin Ibuprofen 458
Irinotecan 459
Panobinostat 460
Cabazitaxel, noscapine, mitoxantrone 407
461
462
Bovine serum albumin is a polymer made of oligo (ethylene glycol) methyl ether methacrylate Sprouty 1 (C-12) (Spry1) protein 463
Human serum albumin Adriamycin 464


3.2.5 Fibrin. The protein substance known as fibrin is often rigid and organised into long fibrous threads. Numerous fibrin matrices come in different forms that enable the controlled release and/or targeted administration of chemotherapeutics, growth factors, and cells.438 The organic protein biopolymer called silk sericin is derived from silkworms. Because of its abilities to promote cell growth, distribute drugs, heal wounds, and have certain therapeutic benefits, it is referred to as a biomaterial.418 Additionally, the kinetics of physically crosslinked silk films carrying the medicines crizotinib and DOX are evaluated.465 Core-shell silk fibroin hydrogels incorporated with albumin for drug delivery are also designed.466 Silk NPs that are DOX-loaded exhibit better NP cell uptake and promote cytotoxicity against cancer cells.467 Insulin was employed as a growth factor in silk NPs by Wenk et al., who demonstrated that the release was constant for 7 weeks.468 Some other examples of silk fibroin and its composites in drug delivery are reported in Table 16.
Table 16 Silk fibroin and its composites in drug delivery
Polymer Bioactive agent References
Silk fibroin 5-Fluorouracil 469
Methacrylated silk fibroin Mouse articular chondrocytes 470
Silk fibroin or gelatin Ibuprofen 471
Ibuprofen 472
Curcumin 473
DOX 474
Ciprofloxacin 475
DOX 476
DOX 477
Silk NPs FITC 478
Silk microcapsules FITC labeled dextrans 479
Silk NPs FITC 480
Silk DOX 481
5-Fluorouracil 469
DOX, indocyanine green 482
3-Mercapto propionic acid coated CdTe quantum dots 483
Rhodamine B 484
Methylene blue 485
Recombinant human insulin 486
FITC dextran 487
Insulin 488
Tetracycline 489
Ibuprofen 490
Antibiotics 491


3.2.6 Soy protein and pea legumin. Soy and pea proteins are very protein-dense with around 90% protein content while soy protein is widely-known for its abundance of essential amino acids, pea protein is gaining ground for its vegan-friendly profile. Combinations of proteins (soy protein and pea legumin) substances with other biopolymers are also reported to be engaged in DDS to deliver active ingredients like nutraceuticals.418 Legumin was employed to deliver methylene blue as a model drug.492 Soy proteins was used to deliver the timolol maleate.493 Soy protein-based films by glycerol and gelatin are also reported.494 Various formulations e.g. micro and nano hydrogel, tablet and electrospun fibers were reported.419 Soy protein is a well-characterized resource for the production of nanogel-based drug delivery and nutraceutical delivery applications.495 The enzymes pepsin and pancreatin are capable of degrading soy protein compositions. Additional reports of soy protein hydrogel and tablets containing riboflavin are available.496
3.2.7 Zein. Zein, a hydrophobic protein abundant in prolamine and present in the endosperm of the maize kernel, is often employed in films and coatings. Zein is typically extracted by aqueous alcohol at 60 °C from corn gluten meal. Zein NPs coated with sodium deoxycholate are stable, biocompatible colloidal carriers that may be utilised as effective DDS.3,438 The bioavailability of carvedilol was improved by up to 7 times by NPs made from casein-silk fibroin.497 In vivo tests on rats using NPs created by crosslinking silk fibroin and casein revealed enhanced bioavailability.498 Rutin was enclosed by pectin–casein NPs in simulated gastric and intestinal settings, extending the period of release and sustaining release.499 Casein NPs with alfuzosin hydrochloride loaded on them showed persistent alfuzosin hydrochloride release for 24 hours.500 Whey proteins, synthetic and biopolymers, and electrospun fibres and microspheres were used to create a number of different compositions.419 Due to matrix degradation, riboflavin-loaded whey proteins and alginate NPs showed pH-sensitive drug release.501 Some other examples of protein and its composites in drug delivery are reported in Table 17.
Table 17 Protein and its composites in drug delivery
Polymer Bioactive agent References
Milk protein casein DOX indocyanine green 502
Lactoferrin and glycomacropeptide Nanocarrier for curcumin 503
Gliadin Carbazole 504 and 505
Whey protein Ndomethacin 506
Investigational new drug 507
Carvedilol 508
Folic acid 509
Fenofibric acid 510
Curcumin 511
Saffron 512
Vitamin E 513
Resveratrol and naringenin 514
Curcumin 515
Theophylline 516
Riboflavin 517
Insulin 518
Curcumin 519
Proguanil hydrochloride, chloroquine diphosphate 520
Daidzein 521
Lycopene 522
Zinc citrate 523
Zinc 524
Theophylline 525
Puerarin 5 526
Indomethacin, carvedilol, and furosemide 527
Whey protein isolate Curcumin 528
Curcumin with amylase Encapsulated curcumin 272
ABD035 peptide Paclitaxel 529


Conjugates with insulin released the payload for several hours in the intestine hence, controls the blood glucose levels effectively by increasing its bioavailability.530 DOX-loaded nanospheres functionalized showed great promise against breast and ovarian cancers with targeting antibodies.313 Deoxycholic acid NPs that have been crosslinked with chitosan and are filled with plasmid DNA successfully transfect COS-1 cells. Chitosan NPs delivered tumor-suppressing interleukin receptor B, siRNA and DOX to inhibit the migration of breast cancer cells. Gal-1 expression in tumor-bearing mice was significantly reduced by chitosan NPs, which were created to carry siRNA against a brain tumour.192 It was shown that chitosan conjugates with CdS might function as adaptable nanoplatforms for the creation of in vivo and in vitro cancer treatments.531 Using chitosan-DOX nanoconjugates for targeted administration, ovarian and breast cancer outcomes were favourable.313

A variety of therapeutic molecules e.g. proteins and vaccines are delivered by zein microsphere, particularly for drugs with low solubility in water in oral delivery.192 Zein films showed proven biocompatibility by successfully culturing in the mice fibroblasts and liver cells of human.202 According to reports, it is also used as a covering material for tablets because of its exceptional resistance to abrasion, heat, and humidity. Ivermectin, coumarin, and 5-fluorouracil will be delivered via Zein.407,532 Zein (core) and pectin (shell) are also reported to deliver encapsulated curcumin.533 Electrospun woven fibres made of zein and hydroxyapatite showed improved calcium phosphate mineralization in simulated bodily fluid and were shown to be biocompatible with adipose-derived stem cells.196 Hyaluronic acid has been combined with mesoporous based-silica nanoconjugates for cell-specific regulated and targeted drug release for the enzymes at target location.534

3.2.8 Gellan gum. Gellan gum is an anionic, water-soluble polymer that is produced by the bacterium Sphingomonas elodea. Gellan gum-based nano-hydrogel systems have been widely documented for use in ophthalmic, gastric, and nasal drug administration applications. These systems take the shape of micro/macrobeads, films, hydrogels, fibres, granules, particles, pellets, spheres, and spheroids. It has been reported that paclitaxel and prednisolone are put onto gellan gum.535 To explore gold nanoparticles stabilised by gellan gum, human glioma cell lines and mouse embryonic fibroblast cells were employed.536 Gellan gum were also loaded with DOX hydrochloride.537 Along with gold, silver NPs swere also tabilized with the help of gellan gum for testing the cytotoxic activity and for intercellular drug delivery and imaging in mouse embryonic fibroblast cells,538. Hydrocolloid bead based gellan gum was also evaluated for slow drug release applications.539 For applications in mucoadhesive and gastroretentive drug administration, ofloxacin-loaded gellan gum and polyvinyl alcohol nanofibers.540 Resveratrol loaded chitosan/gellan gum nanofibers have also been reported for gastrointestinal delivery system.541 Sericin (natural protein)-chitosan doped maleate gellan gum composites have also benn reported to cure Mycobacterium tuberculosis.542 It has been reported that gellan gum in the form of hydrogels combined with LAPONITE® clay makes an effective medication delivery mechanism.543 Gellan gum composites with sericin and rice bran albumin has also been employed as a drug carrier DOX.542 For the buccal delivery of aceclofenac, composites of gellan gum-amino methacrylate has been employed.544 There have also been reports of gellan gum derivatives for the controlled release of ciprofloxacin.545 Metformin HCl was delivered intragastrially under regulated conditions using gellan gum hydrogel composites with olive oil-incorporated pectin that had been modified by diethanolamine.546
3.2.9 Gum acacia/gum Arabic. Gum acacia is an environmentally benevolent and biodegradable natural polymer. Gum arabic has reportedly been used to construct multiple-unit DDS, such as beads, microparticles, NPs, etc. for sustained drug release for a variety of medicines.547 It has been utilized for the release of bisphosphonate drugs.548 Gum acacia–hydroxyapatite nanocomposite was utilized to deliver the naringenin drug.549 Additionally, it has been used as a controlled release method for antiprotozoal medications including curcumin and derivatives of the 4-aminoquinoline ring.550 When prednisone was delivered using polyvinyl alcohol/gum acacia/titania nanocomposites, it was revealed that the release of the medication was pH-responsive.136 Acacia-carbopol-polyvinyl imidazole hydrogel loaded with gentamicin and lidocaine has also been reported.551

4 Conclusions and future perspectives

Natural biopolymers and their derivatives play a remarkable role in improving the biosafety of medication cargo and targeted delivery while reducing adverse effects. The above-discussed promising uses for biopolymers point the way to a new technique for creating unique DDS with enhanced therapeutic benefits for scaling up novel formulations to the clinical level. Above discussion also revealed that since properties and hence applications of the resultant biopolymer composites are dictated by the composition of the constituents, reaction parameters and synthetic techniques, therefore it is very crucial to optimize the biopolymeric formulations for any specific application. Another important consideration is the polymeric carrier's bioacceptability, which is influenced by the shape, size and physicochemical characteristics of both the polymer and the medication. The above discussion reviewed here motivates to devise the of engineered biopolymer-based materials with optimized properties by composites and functionalization fabrication. But there are still some things to think about before using these nanocarrier systems for therapeutic purposes. One of these entails improving biosafety even further, as well as the effects of repeated doses at the intended spot. Important issues that need additional research are chemical and structural stability during application and storage, as well as the interpretation of drug delivery design from an experimental to a commercial development perspective.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Author contributions

The manuscript was written with the contributions of all authors. All authors have approved the final version of the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for supporting this work through research groups program under grant number RGP.2/273/44.

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