Insight to drug delivery aspects for colorectal cancer

Table 1 Formulation and materials investigated for colorectal cancer

Polymer/material	Bioactives	Formulation	Remark	Ref.
Chitin	Paclitaxel	Nanoparticles	The nanoparticles were hemocompatible and in vitro drug release studies showed a sustained release of PTX. Anticancer activity studies proved the toxicity of PTX-AC NPs toward colon cancer cells	[35]
Chitosan derivatives	5-aminolevulinic acid (5-ALA)	Nanoparticles of methoxy poly(ethyleneglycol)-chitosan copolymer	PEG-Chito-5-ALA nanoparticles showed superior delivery capacity of 5-ALA and phototoxicity against tumor cells. These can be photodynamic therapy of colon cancer cells	[36]
Dextran	rlL-2	Dextran/PLGA-PLA core/shell microspheres	In the subcutaneous colon carcinoma BALB/c mice models, intratumorally administrated microspheres showed better local efficacy at tumor site mediated by rIL-2 from a single dose of microspheres than that of multiple rIL-2 solution injections	[37]
Pectin	5-fluorouracil (5-FU)	Zinc pectinate pellets	In situ intracapsular wetting of pectin coat by dissolution medium resulted in the formation of ethylcellulose plug interconnecting with pellets through the binding action of pectin. Less than 25% of drug was released at the upper gastrointestinal tract. The majority of drug was released upon prolonged dissolution and in response to colonic enzyme pectinase, which digested core pellets	[38]
Guar gum	Piroxicam	Tabletted guar gum microspheres	Crosslinked guar gum microspheres of piroxicam were directly compressed into matrix tablet and coated with Eudragit S100. The optimized tablet that displayed 0% release in simulated gastric fluid, 15% in simulated intestinal fluid and 97.1% in simulated colonic fluid underwent roentgenographic study in rabbits to check its safe transit to the colon. This could be used as targeted adjuvant therapy for colonic adenocarcinomas	[39]
Chondroitin sulphate	Indomethacin	Tablets	Tablets were prepared by cross-linking very low water soluble and relatively high water soluble polymers	[40]
Alginate	Iron-saturated bovine lactoferrin (Fe-bLf) protein	Alginate-enclosed chitosan-calcium phosphate-loaded iron-saturated bovine lactoferrin nanocarriers (Fe-bLf-loaded NCs)	After oral delivery, the pharmacokinetic and bioavailability studies indicated that nanoformulated Fe-bLf was predominantly present on tumor cells (Caco-2) compared to non-nanoformulated Fe-bLf. Fe-bLf-loaded NCs were found to help in absorption of iron	[41]
Hyaluronic acid	A near-infrared fluorescence imaging dye (Cy 5.5) and irinotecan	Poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (P-HA-NPs)	Cy5.5-P-HA-NPs and IRT-P-HA-NPs showed theranostic and therapeutic monitoring potential for colon cancer	[42]
Heparin	Plasmid-expressing mouse survivin-T34A (ms-T34A)	Heparin-polyethyleneimine (HPEI) nanoparticles	Intratumoral injection of HPEI nanoparticle-mediated ms-T34A significantly inhibited growth of subcutaneous C-26 carcinoma in vivo by induction of apoptosis and inhibition of angiogenesis	[43]
Pullulan	Paclitaxel	Nanoparticles of hydrophobized Pullulan (PA)	Pullulan was hydrophobically modified using acetic anhydride. The nanoparticles showed lower antitumor activity in vitro against HCT116 human colon carcinoma cells than that of paclitaxel itself, indicating the sustained release properties of nanoparticles. An in vivo study using HCT116 human colon carcinoma-bearing mice showed that paclitaxel-incorporated PA nanoparticles reduced tumor growth more than that of paclitaxel itself	[44]
Copolymer of 2-hydroxyethyl methacrylate with 4-methacryloyloxy	5-fluorouracil	Hydrogel	Drug release was faster and greater in human fecal media compared to simulated gastric and intestinal fluids. Faster release due to the cleavage of the azo crosslinks in the hydrogel by the azoreductase	[45]
pectin	Methotrexate	Microparticles (Ionotropic gelation with calcium ions)	In vitro drug release study showed good release of drug in presence of 3% rat caecal contents, which was further increased to more than 90% when enzyme induction was carried out for 7 d	[46]
Hydrogenated soybean phosphatidylcholine and poly ethylene glycol-2000	Doxorubicin	Liposomal coated with PEG	Investigated the effect of PEG in a male mouse tumour model and exhibited that the cytotoxic effect of DOX on vascular endothelial cells in tumor tissues would be involved in the in vivo anti-tumor effect of PEG liposomal DOX in P-gp over-expressing tumor-bearing mice	[33]
Triglyceride esters	5-FU	Solid lipid nanoparticles by evaporation technique	SLNs system has a high potential to improve the uptake of anticancer drugs inside colon tumors. The release profile of the drug in simulated colonic medium showed a prolonged pattern that may allow spreading of the drug inside the colon to cover most of the colonic area wherever the tumors may exist	[47]
Tablets	Meloxicam	Polyethylene oxide were dually coated with ethyl cellulose containing hydrophilic material, polyethylene glycol as an inner coating layer and Eudragit® FS 30D as outer coating	Meloxicam-loaded colon targeted system exhibited promising targeting efficacy and may be used for prophylaxis of colorectal cancer	[48]

Table 2 Receptor based drug targeting for the treatment of colorectal cancer

Ligand	Receptor	Formulations	Bioactives	Remarks	Ref.
Cetuximab (Ctx)	Epidermal growth factor receptor (EGFR)	Magneto-fluorescent silica nanoparticles (MFSN)	-	MFSN-Ctx produced significant MRI signal changes in a human colon cancer xenograft mouse model. The local concentration of MFSN-Ctx in a tumor was amplified by the use of an external magnetic field. MFSN-Ctx can be used for the detection of EGFR-expressing colon cancer using in vivo imaging approaches	[59]
Folic acid (FA)	Folate	Folic acid conjugated guar gum nanoparticles (MTX-FA-GGNP)	Methotrexate (MTX)	MTX-FA-GGNP showed better growth inhibition of Caco 2 cells due to folate receptor mediated uptake. The MTX-GGNP not only protected the release of MTX in upper gastrointestinal tract but also showed maximum release of MTX in simulated colonic fluids (pH 6.8). The in vivo uptake studies revealed preferential uptake of nanoparticles formulation in the colon	[60]
Wheat germ agglutinin (WGA)	WGA receptor	Wheat germ agglutinin (WGA)-functionalised chitosan-Ca-alginate (CTS-Ca-ALG) microparticles (MPs)	5-FU	MPs significantly delivered 5-FU to Caco-2 cells and increased [methyl-³H]thymidine uptake. Gastrointestinal distribution was in favour of increased localization and concentration of the particles in colon region	[1]
Anti-vascular endothelial growth factor (VEGF)-antibody	VEGF receptor	Anti-VEGF antibody-conjugated dextran-coated iron oxide nanoparticles (anti-VEGF-NPs)	-	anti-VEGF-NPs demonstrated in vivo tumor targeting and efficient accumulation in tumor tissues after systemic delivery in a colon cancer model	[61]
Hyaluronic acid (HA)	HA receptor, CD44	HA modified mesoporous silica nanoparticles (HA-MSNs)	Doxorubicin hydrochloride (Dox)	Dox loaded HA-MSNs showed greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs.	[62]