Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma

Table 1 Summary of studied targeted nanoparticles used in vitro/in vivo for drug delivery in hepatocellular carcinoma using different targeting moieties

Type of nanocarrier	NPs composition	Targeted for receptor	Active moiety	Specific Remarks	Ref.
Synthetic or natural polymeric NPs	Polyethylenglycol (PEG), dithiodipropionate, hyaluronic acid	Asialogycoprotein receptor (ASGPR) , no receptor (EPR effect)	Doxorubicin (DOX)	The NPs were sensitive to acidic environment of endosomes and high intracellular Glutathion concentrations	[62]
Synthetic or natural polymeric NPs	poly(caprolactone), PEG	no receptor (EPR effect)	Docetaxel	The NPs had a long circulating characteristic and longer retention time in tumor cells	[63]
Synthetic or natural polymeric NPs	Galactose (GA), chitosan,	ASGPR	5-FU	-	[66,74,75]
Synthetic or natural polymeric NPs	O-carboxymethyl chitosan, GA	ASGPR	Paclitaxel (PTX)	-	[68]
Synthetic or natural polymeric NPs	Hyaluronic acid (HA), GA	ASGPR	PTX	The dual targeting allows for the NPs to get internalized by tumor cells more specifically	[69]
Synthetic or natural polymeric NPs	Hematoporphyrin, Bovine serum albumin (BSA)	LDL	DOX	The photosensitizing properties of hematoporphyrin allowed for an accurate monitoring of NP uptake by imaging	[88]
Synthetic or natural polymeric NPs	Heat-liable enterotoxin subunite B (LTB), BSA	Ganglioside GM1 receptor	5-FU	-	[92]
Synthetic or natural polymeric NPs	Galactosylated chitosan, polycaprolactone	ASGPR	Curcumin	-	[72]
Synthetic or natural polymeric NPs	Galactosylated chitosan, mPEG-SH	ASGPR	Norcantharidin (NCTD)	The drug was actually loaded using ionic cross linkage between NCTD and chitosan	[76]
Synthetic or natural polymeric NPs	SM5-1, PLA	Membrane antigens	5-FU	-	[96]
Synthetic or natural polymeric NPs	Apotransferin, BSA	transferrin receptor	DOX	-	[138]
Synthetic or natural polymeric NPsSynthetic or natural polymeric NPs	Apotransferrin, LactoferrinChitosan, retinoic acid (RA), Albumin	Transferrin receptorRA receptor	DOXDOX	--	[139][105]
Mixed NPs	GA, DOX, Alginate	ASGPR	DOX	-	[70]
Mesoporous high surface area silica core fused to a liposome (protocell)	Silica, PEG, Zwitterionic lipids, phosphatidylethanolamine	SP94 receptor, no receptor (EPR effect)	DOX	The fusogenic peptide used allows for more efficient internalization. The nanoporous silica core also gives the NPs, a significantly higher surface area	[64]
Nano micelle	PEG, polycaprolactone, SPION, folate	Folate receptor	Sorafenib	The SPION loaded NPs could be efficiently monitored using MR imaging	[128]
Nano micelle	RGD, PEG, stearic acid, chitosan	Integrins	DOX	-	[112]
Nano liposome	egg phosphatidylcholine, cholesterol, monomethoxy PEG-distearoyl phosphatidylethanolamine, and Lactose - dioleyl phosphatidylethanolamine (DOPE)	ASGPR	DOX	-	[73]
Nano liposome	Anti CD44 antibody, cholesterol, DOPE, DSPC, DSPE-(PEO)4-cRGDfK, DSPE-mPEG	CD44	DOX	-	[97]
Lipid nanocarriers	Lactobionic acid, Stearyl amine, lecithin, glyceryl monostearate, oleic acid	AGPR	5-FU	-	[71]
Magnetic NPs	FeCl2, FeCl3, CMC, EpCAM aptamer	Epithelial cell adhesion molecule	DOX	These magnetic nanoparticles were suggested as a candidate for MR imagine of HCC	[113]
Magnetic NPs	Fe3O4/Fe, silica	no receptor (EPR effect)	ABT-888, Temozolamide	The co-delivery of the two drugs both inhibits transcription of survival genes and has cytotoxic effect	[65]
BSA NPs	Glycyrrhizic acid (GA), BSA, 10-hydroxycamptothecin (HCPT)	ASGPR	FITC	-	[67]
Gold NP	Gold, cetuximab	EGFR	gemcitabine	When coupled with RF-hyperthermia, these NPs were significantly effective at tumor growth inhibition	[94]
Nanosuspension	DSPE, PEG, FA, soy lecithin	Folate receptor	Docetaxel	-	[136]
Dendrimer	poly(methacryloyl sulfadimethoxine) (PSD), PEG, Lactose	ASGPR	DOX	-	[77]
Virus-like NP	MS2 capsid, Ricin toxin A chain, SP94, H5WYG fusogenic peptide, PEG	SP94 receptor	DOX, cisplatin, 5-FU	-	[142]
Core-shell NP	Poly(vinyl alcohol), albumin	Transferrin receptor	DOX, sorafenib	The synergistic effect of DOX and sorafenib here increased tumor inhibition more significantly	[141]
Miscellaneous	PLGA, PVA, chitosan, Asialofetuin	ASGPR	EPI	Co-delivery of EPI with tocotrienols as anti-oxidative agents, resulted in significantly lower cardiotoxicity and higher apoptosis level	[85]
Miscellaneous	Benzyl malolactonate, PEG, Fluorescein amine, Biotin, cyclic Biotin-RGD peptide, streptavidin	Biotin Receptor, integrins	DOX	The use of streptavidin for grafting a peptide suggests that a number of peptides could be grafted in NPs without needing any additional chemistry	[115]

NP: Nanoparticle; LDL: Low-density lipoprotein; EPR: Enhanced permeation and retention; FITC: Fluorescein isothiocyanate.

Table 2 Summary of studied targeted nanoparticles used in vitro/in vivo for small interfering RNA delivery in hepatocellular carcinoma using different targeting moieties

Type of nanocarrier	Active moiety	Targeted receptor	Suggested Mechanism	Ref.
Lipid nanoparticle	TetR siRNA	-	-	[31]
Novel nonocarrier consisting of a silica core fused to liposomes (called protocell)	Model siRNA	SP94 protein and EPR	-	[64]
Galactose mediated trimethylchitosan cysteine NPs	VEGF-siRNA and Survivin shRNA-expression pDNA (iSUR-pDNA)	ASGPR	Silencing of tumor growth genes	[86]
A phospholipid-cholesterol nanocomplex	Pokemon siRNA	LDL receptor	Cell growth inhibition	[89]
A SPION called SilenceMag	Human VEGF siRNA	EGFR	Tumor growth inhibition	[95]
PEGylated Polyethyleneamine SPION	Survivin siRNA	Integrin	Induction of apoptosis	[114]
Virus-like nanoparticle of bacteriophage MS2	Anti-cyclin siRNA	Folic acid receptor, SP94, transferrin receptor	Induction of apoptosis	[142]
Lipid nanoparticle	Integrin b1 siRNA	integrin	Inhibition of proliferation and tumor cell death	[116]

SPION: Superparamagnetic iron oxide nanoparticle; siRNA: Small interfering RNA; LDL: Low-density lipoprotein; EPR: Enhanced permeation and retention; EGFR: Epidermal growth factor receptor; ASGPR: Asialoglycoprotein receptor.