Current Advances in Chitosan Nanoparticles Based Oral Drug Delivery for Colorectal Cancer Treatment

Figures & data

Figure 1 Examples of nanoparticles used in the therapeutic management of colorectal cancer.

Figure 2 Deacetylation of chitin into chitosan.

Table 1 Characteristics of Different Parts of the GIT

Segment	Luminal pH	Length (cm)	Mean Diameter (cm)	Transit Time (Hour)	Mucus Average Thickness (µm)	Mucus Turnover (Hour)
Stomach	0.8–5	20	NA	0–6	245 ± 200	24–48
				(0–2 fast)
				(2–6 fed)
Duodenum	~7	17–56	4	2–6	15.5
Jejunum	7.4	280–1000	2–2.5			24–48
Ileum			3
Colon	7–8	80–313	4–4.8	6–70	135 ± 25	−48

Figure 3 Schematic illustration of the interaction between chitosan loaded nanoparticles with the mucus layer.

Figure 4 Synthesis of N,N,N-trimethyl chitosan.

Table 2 Advantages and Potential Limitations of Nanotechnology in Drug Delivery

Advantages	Limitations
Encapsulating of hydrophilic or hydrophobic drugs	Poor drug loading
Drug release control	Burst or rapid release before reaching site of action
Protecting the loaded-drugs from degradation	Probability of clearance through kidney filtration due to its nanosize
Enhancing drug absorption and permeation	Formulation designing difficulty

Table 3 Main Differences Between Passive and Active Targeting

Passive Targeting	Active Targeting
Targeting is possible because of the unique changes in the cancer environment of incomplete vasculature	Targeting depend on the overexpressed species in the tumour, and the ligand conjugated on nanocarrier.
Less selective	Highly selective
Restricted in use	Very versatile
More likely to cause side effects	Less likely to cause side effects

Table 4 Chitosan-Based Nanoparticles Studies of Colon Targeted Drug Delivery System

Formulation	Active Compound	Nanoparticles Characteristics	Active Targeting Molecule	Targeted Receptor	Cell Line	Outcome	Ref
Chitosan modified citrus pectinate nanoparticles	Curcumin	PS= 178 ± 0.896 nm, ZP= +35.7 ± 1.41 mV	Galactose moiety of pectin	Galectin 3 (Gal-3) protein	-	Displayed pH-responsive release, presented mucoadhesive property at pH representing the colon region	[199]
Cetuximab-conjugated chitosan modified citrus pectinate composite nanoparticles	Curcumin	PS= 249.33 ± 5.15 nm, ZP= +39.1 ± 0.87 mV	Cetuximab, a monolocal antibody	Epidermal growth factor receptor	Caco-2, HCT116	Enhanced internalization and cellular uptake, enhanced apoptosis by increasing cycle arrest in the G2/M phase	[200]
Imatinib-conjugated CSNPs (IMT-NPs)	Imatinib	PS= 208 ± 0.01 nm, ZP= −32.56 ± 0.03 mV	Imatinib	-	CT-26	Wide spread of IMT-NPs within epithelial tissues of colon after 1 h, high accumulation of chitosan in tumour cells improving EPR, enhanced anti-cancer effect by increasing the demotion effect of p-glycoprotein leading to S phase arrest in cancer cells.	[201]
Mesoporous silica nanoparticle based galactosylated chitosans (5-FU@MSN-NH2/GC)	5-fluorouracil	PS= 511.57 ± 9.69 nm, PDI < 0.2, ZP= 29.9 ± 0.8 mV	Galactose-moieties of galactosylated chitosans	Galactin receptor	SW-620	Enhanced anti-cancer activity of (5-FU@MSN-NH2/GC) through cell apoptosis and higher cytotoxic activity against SW620 cell line. Specifically recognize and bind to galectin-receptor on cancer cells	[202]
Photothermal (IR780) and photodynamic 5-Aminolevulinic acid loaded CSNPs	5-Aminolevulinic acid (5-ALA), IR780	PS= 180 nm	-	-	CT-26	Improved nanoparticles local accumulation in colon tumour cells (CT-26),Elevated oxidative stress, including the increasing the production of ROS, superoxide and 1O2 by the photothermally enhanced photodynamic effects against CT-26.	[203]
CSNPs	Gallic acid-quercetin	Size= 218.33 nm ZP= +11.50 mV	-	-	HCT-116	A higher change in aberrant crypt foci in CSNPs than polyherbal extract that were observed, with a significant decrease in the colonic catalase, glutathione and superoxide dismutase levels.	[36]
Chitosan mesoporous	Zinc nitrate hexahydrate	PS= 20–40 nm	-	-	DLD-1	The NPs stimulated the apoptotic process, moreover, they induced in vitro DNA fragmentation in DLD-1 cell line with significantly different affinity by 20% versus 52% reduction by Cisplatin. The NPs (IC50) showed anti-invasive activity and dramatically inhibited the migration of DLD-1 cell line.	[204]
Chitosan-coated solid lipid nanoparticles	5-Fluorouracil cinnamon oregano	Size= 254.77 nm PDI= 0.28 ZP= +15.26 mV EE (cinnamon)= 77.3% EE (Oregano)= 69.1%	-	-	HCT116	Both cinnamon and oregano inhibited HCT 116 cells. Combining both extracts with 5-Flourouracil showed highest cell inhibition (62.8% and 71.1%), high apoptotic cells (28.9% and 39.7%), high caspase-3 activation (2.94 and 4.46) and high suppression of mitochondrial membrane potential (58.1 and 21.76) for encapsulated and unencapsulated formulation, respectively.	[205]
Chitosan-gum arabic nanoparticles	Curcumin	Size= 136 nm ZP= +48 mV EE= 95%	-	-	HCT116 HT-29	An in vitro release study showed that nanoparticles could reach the colon without degrading by the gastric of the stomach. In addition, the formulation led to better anticolorectal cancer activities against HCT-116 and HT 29 cell lines due to it provided easier cellular uptake as well as more readily induced cell apoptosis.	[206]
Chitosan-cellulose nanoparticles	5-Fluorouracil	PS= 48.73 ± 1.52 nm EE= 86 ± 2.75%	-	-	HCT-116	The formulation triggered release 42.37 ± 0.43% of encapsulant in SGF pH 1.2 and 76.82 ± 1.29% in the colorectal fluid with pH 7.4. In in vitro cytotoxicity assays, at 250 µg/mL concentration of nanoparticles eliminated only 8.16 ± 2.11% of CCD112 normal cells and 56.42 ± 0.41% of HCT-116 cancer cells.	[207]
Chitosan collides nanoparticles	Curcumin 7-ethyl-10-hydroxycamptothecin	Curcumin nanoparticles PS= 81.2 ± 8.0 nm	-	-	DLD1 HCT116	The synergy of curcumin and 7-ethyl-10-hydroxycamptothecin was shown to provide a suitable strategy for the simultaneous treatment of inflammatory bowel diseases and related colorectal cancer. The combinatorial therapy also resulted in a remarkable tumor shrinkage (~6%) of the total tumors exceeding 4 mm.	[208]
Chitosan coated polylactic-co-glycolic acid/ polycaprolactone nanoparticles	5-Fluorouracil	PLGA as coated material PS= 302.2 ± 9.1 nm PDI= 0.226 ± 0.019 ZP= +15.21 ± 1.72 mV EE= 44.05 ± 3.98%	-	-	HT-29	Nanoparticles exhibited a sustained release behaviour as well as the cytotoxicity study showed a greater cytotoxic effect against HT-29 cells compared with 5-Fluorouracil solution and unloaded nanoparticles.	[38]
		Polycaprolactone as coated material PS= 271.3 ± 2.8 nm PDI= 0.296 ± 0.032 ZP= +12.08 ± 1.87 mV EE= 51.16 ± 2.77%

Abbreviations: PS, particle size; ZP, zeta potential; PDI, polydispersity index; EE, encapsulation efficiency.

Figure 5 Synthesis of N,O-carboxymethyl chitosan.

Figure 6 Chemical structure of N-succinyl-chitosan.

Figure 7 Possible chemical structure of hyaluronic acid (HA)-conjugated chitosan (CS).

Notes: Adapted from: Sionkowska A, Gadomska M, Musiał K, Piatek J. Hyaluronic Acid as a Component of Natural Polymer Blends for Biomedical Applications: A Review. Mol. 2020;25: 4035. doi.org/10.3390/molecules25184035.¹⁸⁵ © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Figure 8 Chemical structure of PEG-conjugated chitosan.

Figure 9 Chemical structure of folic acid-conjugated chitosan.

Table 5 Summary of Recent Studies of Chitosan and Chitosan Derivatives as Anticolorectal Cancer Drug Nanocarrier

Formulation	Active Compound	Targeted Receptor	Nanoparticles Characteristics	Cell Line	Outcome	Ref
Folic acid conjugated CSNPs	Protoporphyrin IX	Folate receptor	PS= 100 nm ZP= 20 mV LE= 35–40%	HT-29 Caco-2	Nanoparticles were taken up by HT-29 and Caco-2 cell lines after short-term of uptake period and the drug accumulated in cancer cells as a result of the folate receptor as well as the folic acid modification.	[209]
Hyaluronic acid-coupled CSNPs	Oxaliplatin	-	PS= 152 ± 5.2 nm, PDI= 0.155 ZP= +10.0 ± 0.5 mV	HT-29 in C57BL mice	Improved colon and tumour-targeting of the hyaluronic acid-coupled formulation compared to the uncoupled one	[210]
Folate-targeted chitosan/chondroitin nanoparticles (Bor/CS/Chs-FA)	Bortezomib	DSPE-PEG conjugated to folic acid	PS= 196.5 ± 1.2 nm, PDI= 0.21 ± 0.5	HCT116, HT-29	Overexpression of folate receptor leading to enhanced anti-tumour effect, improved sustained release and loading capacity	[211]
Mesoporous silica nanoparticles coated with folic acid chitosan-glycin complex (MSNsPCOL/CG-FA)	Colchicine (COL)	Folate receptor	PS= 330 ± 22.2 nm ZP >+ 40 mV	HCT116	MSNsPCOL/CG-FA showed low toxicity (4%) against normal cells compared to COL alone (60%).Enhanced anti-tumour effect mainly by primarily intrinsic apoptosis.	[145]
N,O-carboxymethyl CSNPs	Oxaliplatin/ resveratrol	-	Oxaliplatin as encapsulant PS= 190 nm EE= 60%	SW480 cells and CT26	Both nanoparticle formulations exhibited higher anticancer activity than the free drugs by enhancing the permeability and retention effect in solid tumors and improving the solubility and stability of drugs by the used drug delivery system. the cytotoxicity was confirmed against SW480 cells and CT26 cells was confirmed. In vivo study, resveratrol regulated the microenvironment of cancer cells.	[43]
			Resveratrol as encapsulant PS= 164.2 nm EE= 65%
Hyaluronic acid–coupled CSNPs encapsulated in Eudragit S100–coated pellets	Oxaliplatin	CD44 and RHAMM	PS= 152 ± 5.2 nm ZP= +10.0 ± 0.5 mV EE= 40 ± 3.9%	HT-29	The distribution of coated pellets after oral administration was significantly different from that of uncoated. The oxaliplatin was protected by coated pellets from the whole upper GIT and delivered also to the colon and in the vicinity of tumors. Hyaluronic acid coupling on the surface of nanoparticles made the drug delivery more specific to tumors of the colon.	[210]
N-succinyl CSNPs	Paclitaxel and gemcitabine	-	PS= ~200 nm PDI= 0.2 ZP= −10 mV	HT-29	The prepared nanoparticles showed a swelling behaviour at colonic pH that resulted in a sequential release profile for both the drugs. The drug combination also exhibited a cytotoxic effect against HT-29 cell line, besides of a remarkable G2/M phase arrest.	[212]
Thiolated chitosan-alginate nanoparticles coated Eudragit L100	α-Mangostin	-	PS= 767.4 ± 73.4 nm PDI= 0.680 ± 0.148 ZP= +50.8 ± 2.5 mV EE= 57.7 ± 6.5%	HT-29	Eudragit coating reduced the release of a-mangostin at gastric environment while it increased its release at the colon site. Moreover, the coated nanoparticles provided higher mucoadhesion that resulted in the drug remaining at the colon site via forming disulfide between thiolated chitosan and mucosa.	[44]
Folic acid-conjugated chitosan/ chondroitin sulfate self-assembled nanoparticles	Bortezomib	Folate receptors	Size= ∼196.5 ± 1.2 nm PDI= ∼0.21 ± 0.5 ZP= ∼+18 mV EE= 21.4%	HCT116 HT-29 A549	Nanoparticles facilitated the drug release under an acidic tumor microenvironment. In vitro study showed higher cellular uptake and apoptosis in colorectal cancer cells (HCT-116 and HT-29), via binding the folate receptor, compared to that in lung cancer cells (A549).	[211]
N-trimethyl chitosan	Camptothecin	-	-	CT26	The final formulation remarkably showed cytotoxic activities and apoptotic effects against CT26 cell line. Tumor growth and prolonged the survival time were efficiently suppressed by N-trimethyl chitosan nanocolloids compared with free camptothecin in the CT26 colon carcinoma subcutaneous model.	[213]
N,N,N-trimethyl chitosan chloride/poly (acrylic acid)/silver (TMC/PAA/Ag) nanocomposites	-	-	PS= 30–65 nm	HCT116	TMC/PAA/Ag (3%) had the highest cytotoxicity effect (the less cell viability %) on colon cancer line compared with TMC/PAA/Ag (2%) and TMC/PAA nanocomposites.	[214]
PLGA nanoparticles coated with folic acid-chitosan (αT-PCF-NPs)	Alpha terpineol	Folate receptor	PS= 263.95 nm PDI= 25% ZP= +38.20 mV EE= 88.1%	HT-29	αT-PCF-NPs had an inhibitory effect on HT-29 cells compared to HFF cells through pro-apoptotic effect and anti-apoptotic genes. In vivo study reported a decrease in the size of murine tumors in exposure of αT-PCF-NPs.	[215]
Folic acid conjugated hesperetin encapsulated chitosan nanoparticles (CFH)	Doublecortin like kinase 1 (DCLK1)	Folate receptor	PS= 182 nm ZP= +17 mV EE= 88.2%	HCT116	CFH-DCLK1 nanoparticles enhance apoptosis and inhibited the migration and invasion of HCT116 cells. Real time PCR and Western blot results have demonstrated that the treatment with CFH-DCLK1 nanoparticles The CSC markers STAT1, NOTCH1 and DCLK1 were reduced the expression significantly after treating the HCT116 cells by CFH-DCLK1 nanoparticles compared to the CFH alone. Furthermore, the colonosphere growth in the 3D spheroid model was also inhibited significantly.	[216]
Chitosan folate nanoparticle	Hesperetin	Folate receptor	PS= 457 nm PDI= 60% ZP= +18 EE= 98.3%	HCT-15	Chitosan folate hesperetin nanoparticle caused a proliferation inhibition with a IC50 value of 28 μM. Additionally, they induced apoptosis and inhibited colony formation via regulating the expression of proapoptotic genes expression.	[217]
Folic-acid-modified chitosan nanoparticles	5-Fluorouracil	Folate receptor	PS= 235 ± 12 PDI= 25% ZP= +20 ± 2 mV EE= 59 ± 2%	caco-2	The caco-2 cell death was enhanced in the presence of folic acid due to the overexpression of folate receptors on the caco-2 cancer cells.	[218]
Aminated mesoporous silica nanoparticles-alginate/folic acid conjugated O-Carboxymethyl chitosan-gelatin (AMSN-Alg/FA-CMCT-gel)	5-Fluorouracil (5-FU) Bisdemethoxycurcumin (BDC)	Folate receptor	PS= 203 nm ZP= +42.42 mV EE= 85.8% (BDC), 89.4% (5-FU)	HCT116	The combinatorial of 5-FU and BDC in HCT116 cells showed an anticancer effect as well as the intracellular uptake of the combination into nanocarriers was also confirmed by Confocal Microscopy.	[219]
solid lipid nanoparticles of irinotecan coupled with chitosan surface modification	5-fluorouracil and curcumin	Folate receptor	PS= 1201.50 ± 386.34 nm PDI= 50 ± 0.09% ZP= +48.70 ± 1.55 mV EE= 62.24 ± 2.90%	HCT116	The sulforhodamine B assay results showed the superior cytotoxicity of SLNs on HCT-116 cells over the standard drug. Biodistribution studies conducted on Wistar rats reported that higher concentration of prepared SLNs in the colon after surface modification.	[220]
Thiolated chitosan-based nanoparticles coated by Eudragit^® S100	Alpha-mangostin resveratrol	-	(Without coating) PS= 540 nm ZP= +39 mV	-	The dual loaded of Alpha-mangostin and resveratrol into the NPs decreased the half-maximal inhibitory concentration levels of NPs dramatically, which indicated a synergistic efficiency of the system against colon cancer cells.	[221]

Abbreviations: PS, particle size; ZP, zeta potential; PDI, polydisper sity index; EE, encapsulation efficiency; LE, loading efficiency.

Table 6 Summary of Recent Studies of Chitosan and Chitosan Derivatives Nanoparticles for siRNA Delivery in Colorectal Cancer Therapy

Formulation	Active Compound	Nanoparticles Characteristics	Cell Line	Outcome	Ref
Carboxymethyl dextran-CSNPs	Snail siRNA doxorubicin	PS= 172 ± 6 nm PDI= 0.33 ZP= +11.8 mv ± 0.5 EC (siRNA)= 79% EC (doxorubicin)= 77%	HCT116	Delivering snail siRNA and doxorubicin via CSNPs led to significant changes of Epithelial mesenchymal transition genes as (Down regulation the expression of Vimentin and MMP-9 and upregulation of E-cadherin) well as inhibited growth, migration and induced apoptosis cell death of HCT-116 cells.	[197]
Carboxymethyl dextran–CSNPs	HMGA2 siRNAdoxorubicin	PS= 174 ± 6 nm PDI= 0.3 ZP= +11.8 ± 0.5 EC (siRNA)= 78% EC (doxorubicin)= 75%	HT-29	HMGA2 siRNA and doxorubicin nanoparticles had an effective to induce tumour cell death and also decreased the expressions of HMGA2, MMP-9 as well as vimentin and enhance E-cadherin expression.	[222]
Carboxymethyl chitosan and labeled fluorescein isothiocyanate-chitosan hydrochloride	Anti-β-catenin siRNA	PS= 374 ± 7.2 nm ZP= +21.8 mV EE= 76.7 ± 3.7%	HT-29	siRNA was protected against acidic degradation with controlled release through responding to external stimulus under pH 5.5. The β-catenin protein that promotes colon cancer proliferation was reduced to around 40.10%.	[223]
Carboxymethyl dextran trimethyl CSNPs	NIK/STAT3-specific siRNA BV6	PS= ~105 nm PDI= < 0.2 ZP= +17 mV	CT26	The combination therapy reduced proliferation, improved proapoptotic effects, colony formation, cell migration, and angiogenesis, besides the expression of factors including HIF and IL-10 in tumor cells.	[224]

Abbreviations: PS, particle size; ZP, zeta potential; PDI, polydispersity index; EE, encapsulation efficiency; EC, encapsulation capacity.

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