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Nanoparticles (NPs) have an outstanding position in pharmaceutical, biological, and medical disciplines. Polymeric NPs based on chitosan (CS) can act as excellent drug carriers because of some intrinsic beneficial properties including biocompatibility, biodegradability, non-toxicity, bioactivity, easy preparation, and targeting specificity. Drug transport and release from CS-based particulate systems depend on the extent of cross-linking, morphology, size, and density of the particulate system, as well as physicochemical properties of the drug. All these aspects have to be considered when developing new CS-based NPs as potential drug delivery systems. This review is summarizing and discussing recent advances in CS-based NPs being developed and examined for drug delivery including the following sections: (i) CS and its derivatives, basic characteristics of CS NPs, (ii) preparation procedures used for CS NPs, (iii) CS-based-nanocomposites with organic polymers and inorganic material, and (iv) implementations of CS NPs and nanocomposites in drug delivery.
Chitosan Derivative Groups/Derivatives |
Formula |
---|---|
Hydrophobic derivatives | |
Alkylated chitosan | ![]() |
Acylated chitosan | ![]() (A) N-acylated chitosan |
![]() (B) O-acylated chitosan |
|
N-phtaloylated chitosan | ![]() |
Benzoylated chitosan | ![]() |
Methacrylated chitosan | ![]() |
Amphiphilic derivatives | |
Cholic and deoxycholic acid-modified chitosan | ![]() (A) Deoxycholic acid ![]() (B) Cholic acid |
Ionic derivatives | |
Quarternary ammonium chitosan derivatives | ![]() |
Sulfated chitosan derivatives | ![]() |
Succinylated chitosan | ![]() |
Sulfonated chitosan | ![]() |
Phosphorylated chitosan | ![]() |
Carboxyalkylated chitosan (carboxymethylchitosan) | ![]() (A) N-CMC, (B) N,N-CMC, (C) O-CMC, and (D) N,O-CMC (showing the modification at the D-glucosamine unit) |
Chitosan copolymers | |
PEGylated chitosan | ![]() |
PEG-methacrylated chitosan | ![]() |
Derivatives with specific substituents | |
Sugar bound chitosan derivatives | ![]() Galactosylated chitosan |
![]() Sialo dendrimer hybrid chitosan |
|
Chitosan derivatives with cyclic structure |
![]() Crown ether-linked chitosan |
![]() Cyclodextrin-linked chitosan |
|
Chitosan derivatives with thiol groups | ![]() (A) Thiolated chitosan with –SH group |
![]() (B) Thiolated chitosan with cysteine: chitosan-N-acetyl-cysteine |
|
Glycol chitosan | ![]() |
Thiosemicarbazone linked chitosan derivatives | ![]() |
Crosslinked chitosan derivatives | |
Chitosan-glutaraldehyde crosslinked polymer | ![]() |
Chitosan-TPP crosslinked polymer | ![]() |
Chitosan-EDTA crosslinked polymer | ![]() |
Type of CS NP | Method of CS NP Preparation |
Formulated Drug | In Vitro and In Vivo Tests for Biological Activity and Drug Release | Citation |
---|---|---|---|---|
Oral drug delivery of antidiabetic drugs | ||||
TC NPs | Schiff-base linking with PETMP [pentaerythritol tetrakis (3-mercaptopropionate)] | Insulin | In vitro sustained drug release, in vitro cell viability, in vivo biodistribution, and pharmacokinetics | [139] |
Snail mucin/CS NPs | Self-assembly | Insulin | In vitro drug release, in vivo hypoglycemic activity in diabetic rats, and toxicity | [140] |
FD/TMC NPs | PEC method | Insulin | In vitro pH-dependent drug release, cytotoxicity, α-glucosidase inhibition assay | [141] |
CS/Dz13Scr NPs | Complex coacervation | Insulin | In vitro drug release, insulin kinetics, cytotoxicity, mucus permeation, endocytic absorption study | [142] |
CS NPs | Ionic gelation | Polydatin | In vitro drug release, cytotoxicity, in vivo antidiabetic activity in type 2 diabetic rats | [143] |
Oral delivery of anticancer drugs | ||||
FD/CS NPs | PEC method | Methotrexate (MTX) for lung cancer therapy | In vitro mucoadhesive study, in vitro antiproliferative assay and cellular uptake, apoptosis assay | [144] |
M CS/P NPs | Ionic gelation | Curcumin (CUR) | Cytotoxicity, cellular uptake | [93] |
chitosan-copaiba oil-poly (isobutyl cyanoacrylate) core-shell nanocapsules | Interfacial polymerization | For colon cancer therapy | In vitro mucoadhesion effect | [145] |
Cys/PLA/CS NPs | Self-assembly | Paclitaxel (PTX) | In vitro drug release, cytotoxicity, and cellular uptake, in vivo pharmacokinetic study, biodistribution study, antitumor efficacy | [146] |
TPGS/HPMC/CS NPs | Solvent evaporation method | Paclitaxel (PXT) | In vitro dissolution and swelling, Cytotoxicity, cellular uptake, transport study |
[147] |
Oral delivery of antihypertensive drugs | ||||
CS NPs | Ionic gelation (TPP) | Carvedilol | In vitro drug release, in vivo pharmacokinetics on rats | [148] |
Oral delivery of antioxidants | ||||
CS/Zein NPs | Liquid-liquid dispersion | Resveratrol (RVT) | In vitro drug release, antioxidant activity, in vitro mucoadhesion study | [149] |
Oral delivery of anti-inflammatory drugs | ||||
CS/WP-NPs | Self-assembly | polysaccharides from Ophiopogon japonicus (OJPs) IBD treatment |
In vitro drug release, Biocompatibility, cytotoxicity, antioxidant activity, gene expression, ex vivo mucoadhesion study | [150] |
CS NPs | Spray-drying method | Dexketoprofen trometamol (DT) | In vitro prolonged drug release, release kinetics, in vivo anti-inflammatory activity, HET-CAM assay | [71] |
AvrA NPs-ALG/CS MPs | Flow focusing microfluidic method | Salmonella effector enzyme (AvrA) | In vitro drug release, in vivo reduction of inflammation in murine dextran sulfate sodium (DSS) colitis model | [151] |
Oral vaccines | ||||
β-CD/CS NPs | Precipitation/coacervation method | Ovalbumin (OVA) | In vitro drug release, in vivo immune response in Balb/c mice | [152] |
CS chloride NPs | Ionic gelation (TPP) | Ovalbumin (OVA) | In vitro cell toxicity, permeability study, transepithelial electrical resistance studies, in vivo studies | [153] |
ALG/CS NPs anchored with lipopolysaccharide (LPS) as an adjuvant | Ionic gelation (TPP) | HBsAg antigen | In vitro drug release and mucoadhesion study, stability, cytotoxicity, in vivo immunization studies | [154] |
ALG/CS coating LDHs | Co-precipitation-hydrothermal method | BSA | In vitro drug release, cellular uptake, stability in biological fluids | [155] |
Oral delivery of other drugs | ||||
Cs PLNs | Self-assembly | Enoxaparin | Mucoadhesive properties, stability, in vivo anticoagulant activity in rats | [156] |
CS NPS | Double emulsification solvent evaporation method | Salmon calcitonin (sCT) and puerarin (PR) | In vitro drug release, stability, cellular uptake, in vivo pharmacokinetic study | [56] |
SA/CS and NaCAS/CS NPs | Ionic gelation (oxidized dextran) | Astaxanthin (ASTX) (hepatic fibrosis treatment) | ABTS radical scavenging assay, cytotoxicity, anti-fibrogenic activity | [92] |
Soy lecithin/CS hybrid NPs | Self-assembly | Raloxifene hydrochloride (RLX) | In vitro drug dissolution and release, MTT assay, intestinal drug uptake, in vivo pharmacokinetic studies, biodistribution, ex-vivo mucoadhesion studies | [157] |
Ocular drug delivery | ||||
GCS NPs | Self-assembly | Dexamethasone (DEX) | In vitro drug release, mucoadhesive, cytotoxicity, and anti-inflammatory efficacy, in vivo study: eye irritation test and distribution test | [158] |
CMC/GSH/GlySar/LDHs | Coprecipitation–hydrothermal method | Dexamethasone disodium phosphate (DEXP) DD to the posterior segment of the eye |
In vitro toxicity study on human conjunctival epithelial cells, cellular uptake, the in vivo precorneal retention study, the tissue distribution evaluation of rabbit’s eyes | [128] |
CS/LIP | Thin-film hydration method | Triamcinolone acetonide (TA) Treatment of posterior eye segment diseases |
In vitro drug release, in vivo drug release | [159] |
TCM/LNPs | Emulsion solvent evaporation method | Baicalein (BAI) | In vitro sustained drug release, in vivo ocular irritation study, pre-corneal retention evaluation, pharmacokinetic study | [160] |
CS NPs | Ionic gelation (TPP) | Levofloxacin (LFX) Therapy of ocular infections |
The antimicrobial study, in vitro ocular tolerance, in vivo pharmacoscintigraphic study | [161] |
CS/poly(ethylene glycol) methacrylate MNPs | Double crosslinking (ionic and covalent) in reverse emulsion | Bevacizumab Treatment of posterior segment of the eye |
In vitro drug release kinetics, hemocompatibility, in vivo study of antiangiogenic effect (eye) | [44] |
CS/PCL NPs | Single-step emulsification method | Dorzolamide (DRZ) Glaucoma treatment |
In vitro drug release, in vivo corneal flux experiment, corneal hydration study, ex vivo bioadhesion study, ocular tolerance study, Hen egg test-chorioallantoic membrane (HET-CAM) test | [59] |
CS/gelatin gel with CUR-NPs | - | Latanoprost (LP) and curcumin (CUR) Glaucoma treatment |
In vitro drug release, in vitro biocompatibility, in vivo incompatibility in rabbits | [162] |
Nasal drug delivery (topical) | ||||
CS NPs | Ionic gelation | Cromolyn Therapy of allergic rhinitis |
In vitro drug release, permeation, and penetration, mucoadhesion assay | [163] |
DCHBC NPs | Dialysis method | Cetirizine (CTZ) Therapy of allergic rhinitis |
In vitro stimuli-responsive drug release, cytotoxicity, hemolysis test, protein adsorption | [164] |
CS or CS maleimide NPs | Ionic gelation (TPP) | Japanese encephalitis-chimeric virus vaccineNasal vaccine | Mucoadhesive properties, antigen uptake study, in vivo study of immunization of mice | [165] |
Nose to brain delivery | ||||
CS/HSA NPs | Desolvation method | Tacrine and R-flurbiprofen | mucoadhesion properties, in vitro drug release, permeation, uptake, ex vivo diffusion experiments on rabbit nasal mucosa | [166] |
PLGA NPs and PLGA/CS NPs | Nanoprecipitation | Ropinirole hydrochloride Antiparkinson therapy |
In vitro drug release, mucoadhesion, hemolysis assay, stability study, studies on peripheral blood mononuclear cells and RAW 264.7 macrophage cell line—cytotoxicity, cellular uptake ex vivo permeability studies | [167] |
N,O-CMC NPs | Emulsion solvent evaporation method | Dopamine (DOPA) orTyrosine (Tyr) | In vitro drug release, mucoadhesive properties, cytotoxicity, cellular uptake | [168] |
CS NPs | - | Therapy of Huntington disease | Gene silencing studies | [169] |
CS NPs | Ionic gelation (TPP) | Zolmitriptan (ZOL) Therapy of migraine |
In vivo stability, in vivo pharmacokinetic study on Wistar rats | [170] |
CS NPs | Ionic gelation (TPP) | Rotigotine (R) Treatment of Parkinson’s disease |
In vitro cellular uptake, cytotoxicity assay, neuroprotective activity, antioxidant activity, in vivo pharmacodynamic and pharmacokinetic study | [171] |
Pulmonary (inhalation) drug delivery | ||||
CS NPs | Emulsion method | Nicotine hydrogen tartrate (NHT) Treatment of nicotine addiction |
In vitro evaluation of nose-only inhalation device, assessment of bioactivity of NHT-CS NPs via locomotor test by injection, histopathological analysis of lung tissues | [172] |
CS/PLGA NPs followed by coating with chitosan | Solvent evaporation (double-emulsion) method | Catechin hydrate (CTH) | In vitro drug release, ex-vivo permeation study on the nasal mucosa, cytotoxicity, in vivo comparative pulmokinetic study | [173] |
CS/SLNs | Hot ultrasonication | Rifampicin (RIF) Tuberculosis treatment |
In vitro drug release, mucoadhesive properties, in vitro cell viability and permeability studies, stability studies | [174] |
Mn-TMC NPs | Ionic gelation (TPP) | Etofylline (ETO) Asthma treatment |
Sustained drug release, biodegradation studies, stability, safety, and aerodynamic behavior | [175] |
HA/CS NPs | Self-assembly | Ferulic acid (FA) Asthma treatment |
In vivo inhalation toxicity assessment | [176] |
Buccal delivery | ||||
CS NPs | Ionic gelation (TPP) | Oxiplatin Anticancer therapy |
ex vivo its penetration in porcine mucosa under both passive and iontophoretic topical treatments | [80] |
Cat/CS/HA NPs | Ionic gelation | Doxorubicin (DOX) Oral cancer treatment | Ex vivo mucoadhesive study, in vitro drug release, cytotoxicity, cellular uptake, cancer cells death | [81] |
TTEC NPs | PEC method | Insulin | In vitro drug release, ex vivo permeation study on rabbit mucosa, MTT assay | [177] |
CS/PEO NFs | Electrospinning | Sublingval delivery | Ex vivo adhesion on porcine mucosa, swelling, compatibility | [178] |
Periodontal delivery | ||||
CS NPs | Ionic gelation | Minocycline, tetracycline Periodontal disease | Human gingival fibroblasts behavior, Cell viability and culture metabolic activity, cellular uptake, inflammatory gene expression | [179] |
Core-sheath NFs: shell layer: CS core: PVA containing drug |
Coaxial electrospinning and ionic gelation (genipin) |
Tetracycline hydrochloride (TH) Periodontitis treatment | In vitro sustained drug release, in vitro antimicrobial activity, cytotoxicity | [180] |
CS/IO NPs | - | Chlorhexidine (CHX) Antimicrobial and antibiofilm effect against oral disease | Determination of MIC, cytotoxicity by MTT assay | [102] |
Dermal drug delivery | ||||
CS NPs | Ionic gelation (TPP) | Nicotinamide | Clinical test, skin bioadhesion, deposition of drug in different skin layers | [181] |
Poly-(ε-caprolactone)-lipid core NCs nad CS/poly-(ε-caprolactone)-lipid-core NCs | Interfacial deposition technique | Dutasteride Hair follicle targeting after massage procedure | In vitro drug release, stability, in vitro skin permeation | [182] |
Transdermal drug delivery | ||||
CS Hydroxypropyltrimonium chloride/PLGA NPs | Antisolvent diffusion method | Hen egg-white lysozyme (HEL) allergen immunotherapy to hair follicles using iontophoresis | In vitro cellular uptake, ex vivo skin accumulation study, in vivo transcutaneous immunization experiment | [183] |
CS NFs | Electrospinning | Colchicine Anti-skin cancer therapy |
Ex vivo skin permeation, deposition analysis, release kinetic and anti-melanoma efficiency against A-375 cell line | [184] |
CS NPs | Nanospray-drying technique | 5-fluorouracil (FU) | Synergistic microwave delivery of anti-cancer | [185] |
Wound healing | ||||
CS/PEO NFs | Electrospinning | Teicoplanin Local antibiotic wound healing |
In vitro drug release, antibacterial test, cytotoxicity, in vivo study on rat full-thickness wound model | [43] |
PCL/CS NFs | Electrospinning | Curcumin (CUR) Wound dressing |
antibacterial, antioxidant properties, cell viability, and in vivo wound healing efficiency and histological assay | [186] |
hydrogel membranes based on HA/PU/PVA loaded with cefepime-CS NPs | Ionic gelation (TPP) | Cefepime | In vitro drug release, bacterial inhibition | [187] |
CS NPs loaded hydrogel | Ionic gelation (TPP) | Pterocarpus marsupium heartwood extract (PM) Therapy of diabetic wounds | In vitro drug release efficiency, in-vitro anti-microbial activity, in vivo wound healing action in streptozotocin administered diabetic rat models | [188] |
Vaginal drug delivery | ||||
CS NPs | Ionic gelation (TPP) | Miconazole nitrate Therapy of vulvovaginal candidiasis |
In vivo evaluation on vulvovaginal murine model | [189] |
CS NPs encapsulated in hydrophilic freeze-dried cylinders | Ionic gelation (TPP) | Insulin Peptide-based vaccines or delivery of microbicides |
In vitro drug release, ex vivo insulin penetration across porcine vaginal mucosa | [190] |
CS and spicules NPs | Ionic gelation (TPP) | Calophycin A (Cal A)—seaweed-derived metabolite Therapy of vaginal candidiasis |
In vitro anti-candidal activity, in vivo on mice | [191] |
Vaccine delivery | ||||
CS and ALG coated CS NPs | Precipitation/coacervation method | Hepatitis A vaccine (HAV) | Assay of HAV-specific antibodies and their isotypes, lymphoproliferation assay, the effect of HAV formulation on the splenocytes proliferation in vaccinated mice | [192] |
CS NPs | Ionic gelation (TPP) | Aah II toxin isolated from Androctonus australis hector (scorpion) venom | In vitro toxin-release study, in vivo immunization trial | [193] |
Gene delivery | ||||
MPC derived from carbonized CTS echitosan capsulated ZIF-8 | Carbonization | Luciferase-expressing plasmid (pGL3), and splice correction oligonucleotides (SCO) | Cell biocompatibility, transfection efficiency, mechanism of uptake | [194] |
LMW mannosylated CS NPs | Ionic gelation | CpG oligodeoxynucleotides | Cytotoxicity, cellular uptake, immunostimulatory effect-cytokine release in RAW264.7 cells, efficient vector for intracellular CpG ODN delivery | [195] |
TMC Cys, MABCMC, and CysMABC NPs | Ionic gelation | Plasmid DNA pEGFP-N1 | In vitro DNA transfection efficiency, cytotoxicity | [196] |
CS, PEI, and CMD NPs | Self-assembly | Anti-HIV siRNA HIV therapy |
In vitro cytotoxicity assay and siRNA delivery in two mammalian cell lines, macrophage RAW264.7, and HEK293 | [197] |
TMC/DS or ALG NPs | PEC method | hSET1 antisense—silencing oligonucleotide Cancer therapy |
In vitro cell viability, cellular uptake, in vivo study on mice | [198] |
CMC NPs labelled with FITC NPs (FITCCS/CMC) | Self-assembly | Anti-β-catenin siRNA Ultrasound-triggered targeted therapy of colon cancer |
In vitro drug release, cytotoxic assay, cellular uptake, therapeutic evaluation | [199] |
Guanidinylated O-CMC NPs (GOCMCS) | Self-assembly | SiRNA delivery | In vitro cell transfection studies with A549 cells, cellular uptake | [200] |
SPION NPs encapsulated with TAT peptide/TC and TMC | Electrostatic interaction | siRNA Targeted anti-cancer therapy |
Cytotoxicity, cellular internalization, in vivo pharmacokinetic and biodistribution, colony formation assay, wound healing assay, Chick chorioallantoic membrane (CAM) assay | [201] |
HA/PCL NPs | Ionic gelation (TPP) | IL6-specific siRNA and BV6 treatment of breast and colon cancer | In vitro drug release, cellular uptake, MTT assay, apoptosis assay, Chick chorioallantoic membrane assay, wound healing assay, a clonogenic assay of tumor cells in vitro, transwell migration assay, in vivo antitumor efficacy on mice | [202] |
CMD/TMC NPs | Nanoprecipitation | Codelivery of NIK/STAT3-specific siRNA and BV6 Cancer therapy |
Stability of NPs, in vitro drug release, cellular uptake, transfection of cells, MTT assay, Chick chorioallantoic membrane (CAM) assay, wound healing assay, colony formation assay | [203] |
HA/TMC NPs | PEC method | IL-6- and STAT3-specific siRNAs Cancer therapy |
In vitro drug release, stability in serum, MTT cytotoxicity assay, cellular uptake, transfection efficiency, Colony formation assay Wound healing assay | [204] |
CS NPs | - | Doxorubicin (DOX) and Bcl-2 siRNA co-delivery of therapeutics and si-RNA Cancer therapy |
In vitro drug release, in vivo tumor suppression test | [205] |
Polyethyleneglycol-poly lactic acid CS (PP CS NPs) | - | Nerve growth factor (NGF), acteoside (ACT), and plasmid DNA (pDNA) Treatment of Parkinson’s disease |
Plasmid DNA (pDNA), nerve growth factor (NGF), acteoside (Act) | [206] |
Vaginal delivery is very attractive for both local and systemic administration of drugs. For the latest purpose, it shows several advantages concerning conventional oral or parenteral ways, such as the avoidance of the stomach acidic pH, the hepatic first-pass effect, or the needle-based formulations uncomfortable for the patients. The vaginal mucosa is characterized by high robustness, ease of accessibility, and rich blood supply. The effectiveness of typical vaginal formulations (creams, foams, gels, tablets, films, rings, and suppositories) can be limited by their low active residence time due to the washing-effect of the vaginal physiological fluids, small absorption area, barrier properties of the mucosa, and inadequate spreading of the formulation on vaginal surfaces. Pharmaceutical nanocarriers provide several advantages such as a high surface area and great carrier capacity, improved stability of the therapeutic agents against chemical/enzymatic degradation, enhanced bioavailability, longer drug effect in the target tissue, and drug targeting upon inclusion of specific ligands. The development of NP-based vaginal drug delivery formulations has largely been focused on biological vaccine or microbicide delivery for prevention or treatment of sexually transmitted diseases such as human immunodeficiency virus (HIV), herpes simplex virus (HSV), or human papillomavirus (HPV). The vaginal route allows a localized delivery of peptide-based vaccines/microbicides close to both the site of infection and infectible cells. An opportune vaginal drug delivery system should provide mucosal interactions that facilitate bioadhesion with mucosa increasing drug residence time at the mucosal surface, and penetration enhancement properties to allow penetration into vaginal tissue cells. In the last years, many authors have studied the mucoadhesive and penetration enhancement properties of CS in this area [11][27].
3.4.11. Gene Delivery
The recent review and research papers indicate CS NPs play a vital role in biomedical applications such as drug/vaccine/gene delivery, bioimaging, wound healing, tissue engineering, etc. They highlighted an outstanding position of CS as a polysaccharide able to form NPs favorable for various drug delivery purposes because of its many beneficial properties, such as mucoadhesion, controlled drug release, transfection, permeation enhancement, in situ gelation, efflux pump inhibitory properties, and stimuli-responsive properties. Many works demonstrated, via in vitro and in vivo experiments, CS NPs designed for controlled drug delivery may improve the stability of the drug and increase the efficacy of therapeutic agents. The other advantages of CS NPs DDS, presented in recent works, involved reduced therapeutical doses leading to reduced possible side effects, better bioavailability, and finally better patient compliance.
Nevertheless, the current research is still oriented towards an additional improvement of the chitosan properties. There are efforts to enhance its low solubility in physiological pH, stimuli-responsive properties, and specificity towards complex biological systems by chemical modifications of pure CS or by blending CS with other polymers or inorganic materials. In this way, new modified CS-based nanoparticles and nanocomposites possessing more or less enhanced properties were developed. Such innovative CS particulate systems provided, to a more/less extent, non-toxic, biocompatible, stable, target-specific, and biodegradable delivery devices. In addition, the systems with a proper label (e.g., metal-based nanocomposites) enabled target-specific diagnostics (due to easy dual introduction of an imaging agent together with a therapeutic agent) along with a target-specific therapy (due to a stimulus-responsive matrix). Recent newly developed native CS NPs, modified CS NPs, or CS nanocomposites were applied as potential drug carriers for many drugs and various routes of administrations. They were mainly studied for anticancer agents, proteins, vaccines, and genetic material. For example, in oral DD, new CS NPs enhanced the absorption of the drugs through the opening of tight junctions of the mucosal membrane. In ocular DD, in situ gelling properties and mucoadhesive character of CS enabled prolonging drug release. In nasal delivery, CS NPs increased the permeability of the drugs. In vaccine delivery, CS NPs enabled to formulate oral vaccines providing enhanced absorption of these hydrophilic biomolecules.
Despite apparent current progress, safety and targeting specificity are remaining among the main challenges in the future development of CS-based nanoparticulate DDSs. Therefore, systematic studies on biodistribution, in vitro and in vivo toxicity, and selectivity will further continue with newly developed CS derivatives and their NPs and nanocomposites for various administration routes.