Micelles as potential drug delivery systems for colorectal cancer treatment

Table 1 Overview of micelles used for drug delivery in colorectal cancer treatment, their characteristics and cellular and molecular mechanisms of action

Block copolymer	CMC	Size in nm	Zeta potential in mV	Entrapment efficiency in %	Therapeutic agent	Cell line or animal model	Cellular and molecular mechanisms of action of micelles loaded with the therapeutic agents	Ref.
PEG-poly (glutamic acid)	N/A	20	N/A	N/A	SN-38	WiDR, SW480, Lovo and HT-29 human colon cancer cells; Female BALB/c nude mice subcutaneously injected with HT-29 cells		Koizumi et al[50]
mPEG5kDa-b-[(Dox-hydGlu)6-r-Leu10]	4.6 ± 0.2 μmol/L	29.2 ± 1.1	3.61 ± 0.28	N/A	Doxorubucin	CT26 murine colorectal cancer cells; BALB/c mice subcutaneously injected with CT26 cells	(1) Do not cause hemolysis; (2) Do not induce a significant increase of the levels of blood markers for organ toxicity AST, BUN and CPK; and (3) Induce a slight increase of ALT and LDH	Brunato et al[52]
PEG-poly (L-lactate-co-hexamethylene-co-adipate) (PEG-PLLHA) and FA-PEG-poly (hexamethylene adipate-co-hexamethylene 2-hydroxyl succinate)	3.65 µg/mL	215.6 ± 3.1	−2.4 ± 0.2	82.1 ± 0.6	Docetaxel	CT-26 cells; Female BALB/c mice subcutaneously injected with CT-26 cells	(1) Induce a more severe tumor necrosis compared to their non-targeted counterparts; (2) Do not cause hemolysis or erythrocyte agglutination; (3) Do not induce histological damage to the major organs of the treated mice; (4) Induce a slight increase of BUN levels; and (5) Do not affect the concentrations of ALT, AST, ALP, and CRE	Su et al[54]
PEG-poly (D,L lactate-co-hexamethylene-co-adipate) (PEG-PDLLHA) and FA-PEG-poly (hexamethylene adipate-co-hexamethylene 2-hydroxyl succinate)	3.50 µg/mL	245.5 ± 4.3	−2.8 ± 0.1	79.9 ± 1.0
D-α-tocopherol succinate (TOS)-conjugated-hyaluronic acid	N/A	95.5 ± 13.7	N/A	90	Paclitaxel	CT26 mouse colon carcinoma cells; NIH-3T3 mouse embryo fibroblasts; HT29 and Lovo human colorectal adenocarcinoma cells; BALB/c mouse subcutaneously injected with CT26 cells	(1) Induce early and late apoptosis in HT29 and Lovo cancer cells in vitro; and (2) Induce apoptosis and decrease tumor cell proliferation in vivo	Zhu et al[58]
mPEG-PCL and DOTAP	N/A	144.8	46.4	N/A	Bcl-xl siRNA and Mcl1 siRNA	C26 cells; BALB/c mice inoculated with C26 cells		Lu et al[59]
mPEG-PCL and DOTAP	N/A	46.4 ± 3.7	44.1 ± 1.5	N/A	Plasmid pVAX1-mIL22BP expressing murine IL-22BP	C26 Mus musculus colon carcinoma cells; 293t human embryonic kidney cells; BALB/c mice intraperitoneally injected with C26 cells	(1) Induce apoptosis in vitro; (2) Decrease the microvessel density characterized by CD31 positive staining; and (3) Induce lymphocyte infiltration in tumor microenvironment as indicated by the detection of CD8+ and CD4+ cells in the tumor tissues	Men et al[60]
mPEG-PCL and DOTAP	N/A	46 ± 5.6	41.8 ± 0.5	N/A	Plasmid pcDNA-Survivin-T34A expressing Survivin-T34A	C-26 murine colon adenocarcinoma cells; BALB/c mice intraperitoneally injected with C-26 cells		Duan et al[61]
PEI-deoxycholic acid	N/A	88.4 ± 16	N/A	N/A	XIAP siRNA and paclitaxel	HCT-116 human colorectal cancer cells; Male BALB/c nu/nu mice subcutaneously injected with HCT-116 cells		Jang et al[63]
PEI-poly (DL-lactic acid)	0.1167 mg/mL	235 ± 25	−22	100	Survivin shRNA and camptothecin	C26 and CHO cells; Female BALB/c mice subcutaneously inoculated with C26 cells	(1) Induce a more pronounced apoptosis in vitro compared with their non-targeted counterparts; and (2) Have a lower accumulation in vital organs in vivo compared with their non-targeted counterparts	Sanati et al[64]
PDMA-b-PCL and mPEG-PCL	N/A	222.1	21.1	N/A	SN-38, USPIO and VEGF siRNA	LS174T human colon adenocarcinoma cells; Female BALB/c athymic nu+/nu+ mice subcutaneously injected with LS174T cells		Lee et al[66]
PEI-poly (D,L lactide) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-mPEG	N/A	171.25 ± 4.70	15.12 ± 0.36	81.25 ± 3.12	miRNA-34a and irinotecan	CT-26 murine colon adenocarcinoma cells; Female BALB/c mice injected with CT-26 cells	(1) Upregulate miR-34a and reduce the expression of Bcl-2 and the phosphorylation level of mTOR; (2) Negligible hemolytic activity; and (3) Do not significantly alter the levels of ALP, ALT, ALB, AST, CK, LDH, BUN and CRE	Li et al[67]
PEG-lysyl-(α-fluorenylmethyloxycarbonyl-ε-Cbz-lysine)2	2.6 μmol/L	25.4 ± 0.8	0.519 ± 0.730	N/A	Doxorubicin and dasatinib	HCT-116 human colon cancer cells		Zhang et al[69]
Poly {(N-methyldietheneamine sebacate)-co-[(cholesteryl oxocarbonylamido ethyl) methyl bis (ethylene) ammonium bromide] sebacate}	N/A	230	70	N/A	Doxorubicin and TRAIL	SW480 human colorectal adenocarcinoma epithelial cells; WI38 human lung fibroblasts	Induce caspase-dependent apoptosis	Lee et al[70]
Cholesteryl-modified single strand DNA (Chl–ssDNA) and its complementary sequence	249 pmol/L	371.3 ± 3.1	-7.07 ± 2.3	84.9 ± 5.21	Doxorubicin and KLA peptide	C57/BL6 mice injected with C26 cells		Charbgoo et al[71]
FA-dextran-paclitaxel	3.1 µg/mL	76 ± 2	-11.2 ± 0.8	N/A	Adjudin and paclitaxel	HCT-8 and HCT-8/PTX cells; Mouse subcutaneously injected with HCT-8/PTX cells	(1) Reduce mitochondrial membrane potential and the levels of ATP; and (2) Do not cause hemolysis	Chen et al[72]
Poly-lactic-co-glycolic acid grafted branched PEI	1.32 ± 0.003 mg/mL	137.98 ± 2.13	12.3 ± 0.2	70.38 ± 2.34	5-fluorouracil and methotrexate	HCT 116 colon cancer cells		Ashwanikumar et al[73]
mPEG-PCL	56 mg/L	167.5	-0.11	68.8	Doxifluridine and doxorubicin	HT-29 human colorectal adenocarcinoma cells		Sawdon et al[74]
		267.5	1.01	86.3	Doxifluridine and SN-38
Chitosan-PCL	40 mg/mL	163.7	38.8	N/A	Doxifluridine and SN-38	HT-29 human colorectal adenocarcinoma cells		Wang et al[75]

CMC: Critical micelle concentration; mPEG: Methoxypolyethylene glycol; Dox: Doxorubicin; hydGlu: Acid-γ-hydrazide; Leu: Leucine; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; BUN: Blood urea nitrogen; CPK: Creatine phosphokinase; CK: Creatine kinase; LDH: Lactate dehydrogenase; FA: Folic acid; ALP: Alkaline phosphatase; CRE: Creatinine; DOTAP: N-[1-(2, 3-dioleoyloxy) propyl]-N, N, N-trimethylammonium methyl sulfate; PEI: Polyethyleneimine; PCL: Poly(ε-caprolactone); ALB: Albumin; siRNA: Small interfering RNA; XIAP: X-linked inhibitor of apoptosis; shRNA: Short hairpin RNA; VEGF: Vascular endothelial growth factor; USPIO: Ultra-small superparamagnetic iron oxide nanoparticles; miR-34a: microRNA-34a; TRAIL: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand; IL-22BP: Interleukin-22 binding protein; mTOR: Mammalian target of rapamycin; SN-38: 7-ethyl-10-hydroxy-camptothecin; N/A: Not available; PEG: Polyethylene glycol; TOS: D-α-tocopherol succinate; PTX: Paclitaxel.