Herbal and polymeric approaches for liver-targeting drug delivery: novel strategies and their significance

Figures & data

Table 1. List of receptors which are found on different liver cells.

Hepatic cells	Receptors on different cells	References
Hepatocytes	1. Asialoglycoprotein receptor (ASGP-R) 2. IgA-Receptors 3. Transferrin receptors 4. HDL receptors 5. LDL receptors 6. Insulin receptors 7. Scavenger receptors	Yang et al. (2014) Liu et al. (2014) McDonald et al. (2014) Martinez et al. (2003) Goldstein & Brown (2009) Jiang et al. (2014) Li et al. (2014)
Endothelial cells	1. Scavenger receptors 2. Mannose/N-acetyl glucosamine receptors 3. Fc Receptors immune complexes 4. Hyaluronan fibronectin, denatured collagen receptors	Li et al. (2014) Ramirez-Garcia et al. (2013) Storch et al. (2002) Rost & Sumanas (2014)
Hepatic stellate cells	1. Uroplasminogen receptors 2. Thrombin receptors 3. Ferritin receptors 4. α2-macroglobulin receptors 5. IGF II receptors	Friedman (2008) Kallis et al. (2014) Moss et al. (1992) Strickland et al. (2014) List et al. (2014)
Kupffer cells	1. LDL receptors 2. Mannose receptors 3. Galactose receptors 4. Scavenger receptors (Class AI, BI, BII, MARCO CD3 etc.) 5. Complement receptors (C3b, C1q) 6. Fc receptors (opsonized materials, immune complexes receptors)	Goldstein & Brown, 2009) Ramirez-Garcia et al. (2013) Coombs et al. (2006) Li et al. (2014) Woods & Greally (1979) Storch et al. (2002)

Table 2. Main patterns of liver injury during hepatotoxicity.

Liver injury	Characteristics of liver injury during hepatotoxicity
Zonal necrosis	• Substances like Paracetamol (Deng et al., 2009) and carbon tetrachloride (Kedderis, 1996; Bleibel et al., 2007) may  cause this type of injury. • Amatoxins cause necrosis of liver due to the inhibition of RNA synthesis (Chang & Schiano, 2007). • Herbal plants like Atractylis gummifera and Callilepsis laureola (Naruse et al., 2007), Larrea trdentata (Uetrecht, 2005)  and Teucrium polium (Olson et al., 2000) also cause necrosis. • Such injury is largely confined to a particular zone of the liver lobule. • It may manifest as a very high level of alanine amino transferase and severe disturbance of liver function leading to acute  liver failure.
Hepatitis	• Viral hepatitis may be caused by halothane (Murray et al., 2008), isoniazid, acetaminophen, bromofenac, nevirapine,  ritonavir, troglitazone (Kaplowitz, 2004) and phenytoin (Saukkonen et al., 2006). • Focal hepatitis where scattered foci of cell necrosis may accompany lymphocytic infiltration may be caused by aspirin. • Chronic hepatitis, may be caused by methyldopa, diclofenac, dantrolene, minocycline and nitrofurantoin  (Kaplowitz, 2004).
Cholestasis	• This type of liver injury leads to harm of bile flow, itching and jaundice. • Kaplowitz (2004) reported angiotensin-converting enzyme (ACE) inhibitors, amoxicillin, chlorpromazine,  erythromycins and sulindac to be associated with etiology of cholestasis.
Steatosis	• This type of liver injury may manifest as triglyceride accumulation (Angulo, 2002; Saukkonen et al., 2006). • Aspirin, ketoprofen, tetracycline, nucleoside reverse transcriptase inhibitors and valproic acid (Kaplowitz, 2004;  Chang & Schiano, 2007) may lead to micro vesicular steatosis while acetaminophen and methotrexate  (Langman et al., 2001) may lead to macro vesicular steatosis (Garg et al., 2011).
Granuloma	• Drugs like allopurinol, sulfonamides pyrazinamide, phenytoin, isoniazid, penicillin and quinidine have been found  to cause such injury (Saukkonen et al., 2006; Chang & Schiano, 2007).
Vascular lesions	• Such condition is caused by injury to the vascular endothelium and may be caused by chemotherapeutic agents  (King & Perry, 2001) bush tea [Crotalaria spp.] and anabolic steroids (Ishak & Zimmerman, 1995).
Neoplasm	• Some medications and toxins like vinyl chloride, anabolic steroids, arsenic and thorotrast may cause neoplasms  like hepatocellular carcinoma, angiosarcoma and liver adenomas (Brind, 2007).
Veno-occlusive	• The hepatic vein becomes clogged, blocking off the blood supply to the liver. • It is a non-thrombotic obliteration of small intra-hepatic veins by sub endothelial fibrin (Rollins, 1986) associated  with congestion and potentially fatal necrosis of centrilobular hepatocytes. • The pyrrolizidine alkaloids cause this hepatotoxicity (Kaplowitz, 2001). • Busulfan and cyclophosphamide also cause veno occlusive disease (King & Perry, 2001; Kaplowitz, 2004).

There are several factors which are responsible for liver injuries, include plants, drugs, industrial toxins, water, alcohol and many more.

Table 3. Plants having hepatotoxicity.

Plants	Toxic agents	Mechanism	Effects	Reference
Crotalaria Senecio Heliotropium Symphytum officinale (Comfrey)	Pyrrolizidine alkaloids	Endothelial cell glutathione depletion, central vein necrosis, thrombosis and fibrosis	Veno-occlusive disease	Arzt & Mount (1999)
Atractylis gummifera	Atractylate, gummiferin	Inhibition of oxidative phosphorylation, hepatic necrosis	Hepatitis	Stickel et al. (2001)
Callilepsis laureola	Atractylate	Hepatocyte necrosis	Hepatitis	Stickel et al. (2000)
Chelidonum majus (greater celandine)	Chelidonine, sanguinarine, berberine, coptisine	Lymphocyte infiltration	Hepatitis (cholestatic)	Teschke et al. (2012)
Larreatridentata (chaparral)	Guaiaretic acid derivatives	–	Hepatitis	Haller et al. (2002)
Teucrium chamaedrys(germander)	Furano-diterpenoids	Hepatocyte glutathione depletion and apoptosis	Hepatitis	Kouzi et al. (1994)
Chinese herbal mixtures (Artemisia, hare’s ear, chrysanthemum, plantago seed)	Largely undefined	–	Hepatitis	Jeong et al. (2013)
Lantana Camara	Lantadene A and B	Affect bile canalicular membrane	Jaundice	Sharma et al. (1988)
Aconitum carmichaeli (chuanwu) Aconitum kusnezoffi (caowu)	Pyrrolizidine alkaloids	Central vein necrosis	Aconitine poisoning	Chan et al. (1994)
Aflatoxin – contaminant of plant materials grown/stored in humid areas.	Lipopolysaccharide (LPS) augments AFB(1)	Occurs as a mycotoxin from growth of Aspergillus flavus mould on stored nuts and other foods.	Liver cancer-causing agent	Henry et al. (1999)
Atractylis gummifera (African remedy)	Atractyloside and carboxy atractyloside	Inhibiting mitochondrial oxidative phosphorylation	Diffuse hepatic necrosis	Daniele et al. (2005)
Azadirachta indica (margosa oil)	Chelidonium majus	–	Reye’s Syndrome and steatosis	Chitturi & Farrell (2002)
Bajiaolian	Podophyllo toxin	Podophyllum glycosides are directly toxic to cells	Abnormal liver function tests	Kao et al. (1992)
Heliotropium lasocarpium	Pyrrolizidine alkaloids	–	Hepatotoxicity, veno-occlusive disease	Larrey (1997)
Larreatridentata (Chaparral, creosote bush, grease wood)	Creosote bush	Cytochrome P450- dependent metabolism of NDGA	Hepatic necrosis and chronic hepatitis	Gordon et al. (1995)
Lycopodiumserratum	Pyrrolizidine alkaloids, tetrahydropalmatine	Non-nucleoside reverse transcriptase inhibitors	Acute/chronic hepatitis, fibrosis and steatosis	Om (2011)
Petasites hybridus (butterbur)	Pyrrolizidine alkaloids.	–	Hepatotoxic and carcinogenic	Kälin (2003)
Symphytum officinale, Symphytum uplandicum	Hepatotoxic pyrrolizidine alkaloids.	Reduction of N-oxides	Hepatic veno-occlusive disease	Yeong et al. (1990)

Table 4. Drugs having hepatotoxicity.

Class	Drug	Mechanism	Effect	References
Aniline analgesics	Acetaminophen	A toxic metabolite, NABQI, which is produced by cytochrome P-450 enzymes in the liver	Hydro alcoholic extract of Aervalanata has been reported to possess hepatoprotective activity against paracetamol-induced hepatotoxicity.	Wallace (2004), Manokaran et al. (2008)
Aniline antibiotics	Sulfonamides	By increasing the oxidation to toxic metabolites by the P 450 system	Wide range of adverse reaction and hepatotoxicity	Navarro & Senior (2006)
Anticoagulants	Warfarin, Ximelagatran, Enoxaparin, Acenocoumarin, Phenprocoumon and Heparin	Asymptomatic elevation of serum transaminases, Cytochrome P-450 enzymes, causing decline of adenosine triphosphate levels, loss of ionic gradients, cell swelling and rupture.	Anticoagulants, Showing hepatotoxicity	Arora & Goldhaber (2006), Schimanski et al. (2004)
Anesthesia	Halothane	Toxicity by forming a reactive trifluoroacetyl chloride reactive metabolite by cytochrome P450	Clinical investigations reveal elevated transaminases compatible with hepatitis	Chitturi & Farrell (2002)
Anti-hyperlipidemic drugs	Atorvastatin, Lovastatin, simvastatin, provastatin, Fenofibrate, Ezetimibe	Dose-related toxicity	Cholestatic hepatitis and acute autoimmune hepatitis, acute intrahepatic cholestasis	Bhardwaj & Chalasani (2007), Ricaurte et al. (2006)
Antimalarial drugs	Amodiaquine, iminoquinone	Oxidation to a reactive metabolite, can irreversibly bind to proteins which lead to direct toxicity by disrupting the cell function	Can induce immune response, cause hepatotoxicity	Shimizu et al. (2009)
Antiretroviral	Didanosine and Stavudine	Mitochondrial damage	Hepatotoxicity	Brind (2007)
	Nevirapine, Efavirenz and Abacavir	Hypersensitivity reactions	Hepatotoxicity	Moses (2005)
	Stavudine, Didanosine Zidovudine	Lactic acidosis and hepatic steatosis	Hepatotoxicity	Piroth (2005)
	Fosamprenavir, Ritonavir, Nelfinavir, Tipranavir	Protease inhibitors	Low-hepatotoxicity	Sulkowski et al. (2004)
Anti-tubercular drugs	Isoniazid, Rifampicin, Pyrazinamide, Ethambutol	Increased levels of transaminases	Liver cholestatic jaundice, hepatotoxicity	Khalili et al. (2009)
Arthritis medication	Methotrexate	Transaminase elevation	Hepatotoxicity	Kremer et al. (1989)
Cortico-steroids or glucocorticoids and anabolic androgenic steroids	Glucocorticoids	Promote glycogen storage in the liver	Serious hepatotoxicity, steatosis	Edmondson & Peters (1983), Iancu et al. (1986)
Non-steroidal anti-inflammatory drugs	Aspirin, Phenylbutazone, Ibuprofen, Sulindac, Piroxicam, Diclofenac, Indomethacin	ATP synthesis by mitochondria, and the production of active metabolites, particularly N,5-dihydroxydiclofenac	Jaundice, intrinsic hepatotoxicity, idiosyncratic reaction	O'connor et al. (2003)

Table 5. Industrial toxins causing hepatotoxicity.

Metals	Characteristics	Treatment	References
Mercury	Show Hazardous effect both in animals and humans Mercuric chloride is highly toxic to liver function	Zingiber officinalis	Ezeuko Vitalis et al. (2007)
Lead	Hepatotoxicity caused by lead causes generation of reactive oxygen species and decreased antioxidant defense system	Etlingera elatior	Haleagrahara et al. (2010)
Arsenic	Oxidative stress is causative factor in the development of arsenic-induced hepatotoxicity	Phenyl propanoid compound	Pari & Mohamed Jalaludeen (2011)
Carbon Tetra-chloride	Trichloromethyl is a type of free radical obtained from the oxidation of Carbon tetrachloride which causes degradation in adipose tissue leading to fatty infiltration of hepatocytes (Boll et al., 2001; Klaassen, 2001; Mochizuki et al., 2009)	Spirulina laxissima West, Phenolic extract of chnocarpus frutescense	Kuriakose & Kurup (2011)
Chloroform	Lead to cellular glutathione depletion and increased covalent binding to hepatocellular macromolecules	Rhododendron arboretum	Purushotham et al. (1988)
Vinyl chloride	It is more potent, faster acting than carbon tetrachloride or 1,2-dichloroethylene	Schisandra chinensis	Jenkins et al. (1972), Jaeger et al. (1973)

Table 6. List of some medicinal preparations, which are approved by the IMPCPS (Indian Medicinal Practitioner’s Co-operative pharmacy and Stores), used for the treatment of various chronic liver disorders.

Unani medicinal system	Siddha medicinal system	Ayurvedic medicinal system
Sherbeth-e-anarshreen	Loha mandooram	Guduchi satwam
Muffarah-e-Ahmedi	Ayakantha chendooram	Panchatiktakwatha churnam
Bhoi-Amla	Karisalai lehyam	Tapyadi loham
Jawarish-e-Amilasada	Kantha chendooram	Saptamiruda loham
Kurs-e-gul	Arumuga chendooram	Bhringarajasava
Rue-e-amila	Ayabringaraja karpam	Drakahadi rasayam
Jawarish-e-Amilaluluvi	Mandooradi kudineer	Chandraprabhavati
Sherbeth-e-deenar	Annabedhi chendooram no. 1 and 2	Jambeeradi panakam

Table 7. List of some medicinal important plants found in India which are having hepatoprotective properties.

Plant name	Common name	Family	Chemical constituents	Hepatoprotective constituent	Other uses	References
Acacia catechu	Catechu	Fabaceae	Catechins, Catechol’s and Catecholamine	Catechins	Anti-dyslipidemia, anti-inflammatory, anthelminthic, anti-diuretic, anti-pruritic, coolant, curing skin disorders	Shen et al. (2006)
Azadirachta indica	Neem	Meliaceae	Nimbin, Nimbinin, Nimbidin	Azadirachtin, Margolone	Anthelmintic, antifungal, antibacterial, antidiabetic, antibacterial, antiviral, contraceptive sedative	Raphael (2012)
Boerhaaviadiffusa	Punarnava	Nyctaginaceae	β-Sitosterol, α-2-sitosterol, Palmitic acid, ester of β-sitosterol	β-Sitosterol	Improve and protect eyesight, diuretic properties, anti-diabetes, antibacterial activity, antioxidant, hepatoprotective properties, anticancer, antiestrogenic, immunomodulatory, antiamoebic activity.	Mahesh et al. (2012)
Chelidonium majus	–	Papaveraceae	Coptisine, allocryptopine, stylopine, protopine, norchelidonine, berberine, chelidonine, sanguinarine	–	Antimicrobial, antiviral and antiparasitic effects, cardiovascular effects, anti-inflammatory and analgesic activity, choleretic effects	Colombo & Bosisio (1996)
Daucuscarota	Wild carrot	Apiaceae	Camphene, Sabinene, α-pinene, Limonene, Terpinolene	–	Phytophotodermatitis, lower heart attack risk, intestinal parasites, persistent diarrhea	Bishayee et al. (1995)
Withaniasomnifera	Ashwagandha	Solanaceae	Withanolides, withaferin A, withanolide D, Anaferine	Withanolides	Anti-carcinogenic, anti-oxidant, cardio protective activity, anti-aging activity, osteoarthritis	Singh et al. (2010)
Verbena officinalis	Mosquito plant	Verbenaceae	Apigenin, Luteolin, 3α,24-dihydroxy-urs-12-en-28-oic acid	–	Use during pregnancy, antiperiodic, diaphoretic, expectorant, anthelmintic	Verma & Siddiqui (2011)
Tephrosiapurpuria	Auhola	Fabaceae	Aromatic ester, prenylated flavonoid, sesquiterpene, Tephrosiapurpuria	Tephrosim, Quercetin	Hepatoprotective, anthelmintic, alexiteric, dyspepsia, diarrhea	Khatri et al. (2009)
Sidarhombifolia	Indian hemp	Malvaceae	Ephedrine, pseudoephedrine, palmitic, stearic and hexacosanoic acids, Vasicinol, Vasicinone, Hypaphorine	–	Antimicrobial agents, anticancerous agent, anti-bacterial activity	Joseph (2011)
Picrorhizakurroa	Katuka	Scrophulariaceae	Iridoid glycosides and cucurbitacins, apocynin, andorsin and cucurbitacin glycosides	Picroside I, Picroside II, Kutkosides	Asthma, liver damage, wound healing, vitiligo, digestive problems	Luper (1998), Gagandeep et al. (2014)
Ricinuscommunis	Castor oil plant	Euphorbiaceae	Alkaloid ricinin, toxalbumin ricin	–	Antimicrobial, antihistamine, anti-inflammatory, analgesic	Singh et al. (2013)
Ocimum sanctum	Tulasi	Lamiaceae	Ursolic acid, apigenin, luteolin	–	Antimicrobial, antimalarial, antiallergic, immunomodulator, antifertility, antidiabetic	Lahon & Das (2011)
Phyllanthusniruri/amarus	Stonebreaker	Phyllanthaceae	Phyllanthin, hypophyllanthin, flavonoids, glycosides, tannins, alkaloids, ellagitannins	Phyllanthin, Niranthin	Anti-spasmodic, laxative, diuretic, carminative, against constipation	Narendra et al. (2012)
Mikaniacordata	Mile-a-Minute Vine	Asteraceae	Linalool and α-pinene, terpineol, camphene, α-felandrene, geraniol	Felandrene	Antibacterial and anti-inflammatory	Perez-Amador et al. (2010)
Cichoriumintybus	Chicory	Asteraceae	Lactucin, lactucopicrin, loliolide, artesin, cichoriolide, malic acid	Lactucin, lactucopicrin	Antimicrobial activity, anthelmintic activity, antimalarial and hepatoprotective activity, antidiabetic activity, anti-inflammatory activity	Street et al. (2013)
Achilleamillfolium	Yarrow	Asteraceae	Α-Pinene, Camphene, Sabinene, β-Pinene, Myrcene, p-Cymene, Limonene, 1,8-Cineole, methanol, Cyclohexane	–	Antiphlogistic, gastrointestinal disorders, choleretic	Nadim et al. (2011)
Eclipta alba	Bhringraj	Asteraceae	Wedelolactone, Desmethylwedelolactone, Desmethyl-wedelolactone-7-glucoside, stigmasterol, Wedelolactone	Wedelolactone	Improve hair growth, uterine hemorrhage and monnorrage, remedy for jaundice, in liver cirrhosis	Shaikh et al. (2012)
Swertiachirata	Chirayata	Gentianaceae	Sawertiamarine, mangeferin and amarogenitine, balanophonin, oleanolic acid, maslinic acid, sumaresinolic acid	Sawertiamarine	Hepatoprotective, digestive, astringent, laxative, anti-inflammatory and anti-malarial	Tabassum et al. (2012)
Boerhaviadiffusa	Punarnava	Nyctaginaceae	Punarnavine, arachidic acid, Sitosterol, 2-sitosterol, palmitic acid, ester of sitosterol	Punarnavine	Antibacterial, antidiabetic, antistress, antitumor, anticonvulsant, analgesic, anti-inflammatory	Rawat et al. (1997)
Fumaria officinalis	–	Papaveraceae	Canadine, fumaricine, protopine, allocryptopine	Canadine, fumaricine	Treat skin diseases, conjunctivitis, treating gallbladder	Mortazavi et al. (2007)
Glycyrrhiza glabra	Liquorice	Leguminosae	Saponin, glycyrrhizin, glycyrrhetinic acid	Saponin, glycyrrhizin	Hepatoprotective, stomach ulcers, sore throat, bronchitis, cough and infections caused by bacteria or viruses	Lee et al. (2007)
Hydrastiscanadeni	Yellow puccoon	Berberidaceae	Hydrastine, berberine, hydrastine, berberine, berberastine, hydrastinine	Hydrastine, berberine	Hepatic, alterative, anticatarrhal, anti-inflammatory, antimicrobial, laxative	Yamaura et al. (2011)
Schisandra chinensis	Five flavor berry	Schisandraceae	Lignans, schizandrin, lignansschizandrin, deoxyschizandrin, gomisins and pregomisin	Lignans, schizandrin, deoxyschizandrin	In pregnancy, treat diarrhea, arrest excessive sweating, treating liver disease (hepatitis)	Cheng et al. (2013c)
Taraxacum officinale	Dandelion	Compositae	Taraerol, taraxol, laevulin, inulin	Taraerol, taraxol	Diuretic, in kidney and liver disorders, mild laxative	You et al. (2010)
Mallotusjaponicus	Akamegashiwa	Euphorbiaceae	Bergenin, mallotophenonemallotojaponin, isomallotochromeneandmalloto chroman	Bergenin	Gastric ulcer, duodenal ulcer, gastric hyperacidity, hepatoprotective	Kim et al. (2000)

Table 8. Clinical significance of nanotechnological approaches which are having hepatoprotective properties.

S. No.	Targeting ligand	Targeting cells	API used	Clinical significance	Result	References
Liposomal preparations for achieving liver targeting
1	Polyaspartic acid, poly-l-glutamic acid, chondroitin sulfate C modified with cholesterol	Hepatocytes	Small interfering (siRNA)	siRNA therapy	Cholesterol-modified polyaspartic acid, poly-l-glutamic acid, chondroitin sulfate coated liposomes showed high liver targeting with lesser kidney targeting after i.v. injection. No increase in GOT and GPT level was observed representing least toxicity.	Hattori et al. (2014), Garg & Goyal (2014b)
2	Cyclic peptide (pPB)	Human stellate cells	Interferon-γ	Anti-fibrotic agent	The tissue distribution study shows the prepared liposomal conjugate mostly accumulated in liver until 24 h and showed more significant remission of hepatic fibrosis.	Bansal et al. (2014)
3	Galactose	Hepatocytes	Small interfering (siRNA)	siRNA therapy	siRNA accumulated concentration was found to be 45 µg/ml, which was 30 times higher than the concentration required for silencing in vitro.	Sonoke et al. (2011)
4	Asialofetuin	Hepatocytes	–	Anti-cancer therapy	In vivo study in rat model confirmed the hepatocyte specific targeting and high internalization of prepared liposomes which could be competitively inhibited by co injection of unbounded asialofetuin.	Detampel et al. (2013)
5	β-Sitosterol	Parenchymal cells of liver	Silymarin	Hepatoprotective action	The formulation showed high liver targeting. Antihepatoprotective action of prepared preparation was checked on CCl4 induced liver toxicity and was found that PEGylated targeting silymarin-loaded liposome did not affect silymarin hepatoprotective action.	Samy et al. (2014)
6	β-sitosterol β-d-glucoside (Sito-G)	Hepatocytes	Silymarin	Hepatoprotective action	The cellular drug uptake of PEGylated formulation was found to be 18% achieved at 0.17 and 0.33 M ratio of added Sito-G. The formulation when stored in HEPES buffer (pH 7.4) showed stability for at least 2 months.	Elmowafy et al. (2013)
7	Glycyrrhetinic acid	Hepatocytes	Wogonin	Anti-tumor effect	Glycyrrhetinic acid modified liposomes showed rapid accumulation in liver with long retention time. Preparation showed modified accumulation in tumor, modified bio-distribution with high therapeutic efficacy.	Garg & Goyal (2012), Tian et al. (2013)
8	Infusion in bile duct	Hepatic stellate cells	Growth factor gene	Anti-fibrosis	Dimethyl nitrosamine-induced liver fibrosis was treated using prepared formulation targeted to hepatic stellate cells which showed increased transgene expression at the fibrotic foci leading to enhanced antifibrotic effects.	Narmada et al. (2013)
9	Galactose	Hepatocytes	Doxorubicin	Anti-cancer therapy	The results showed that the specific cell uptake by human hepatocellular carcinoma HepG2 cells was stronger of galactose containing liposomes as compared to the non-targeted liposomes.	Zhao et al. (2013)
10	Antibody domain specific to hepatocytes (DOM26h-196-61)	Hepatocytes	Interferon α (INFα)	Against hepatitis C infection	The prepared liposomes showed desirable biophysical properties and high activity in vitro. The preparation showed high liver targeting as compared to non-targeted system in vivo with improved safety and patient compliance.	Coulstock et al. (2013)
Nanoparticles for liver targeting
1	Galactose	Hepatocytes	Oridonin	Anti-tumor therapy	The prepared spherical nanoparticles showed size distribution below 200 nm having zeta potential of about −30 mv. DSC and X-ray diffraction confirmed the amorphous state of nanoparticles. In vitro showed biphasic pattern with initial burst effect and then sustained release.	Li et al. (2013)
2	Galactose	Hepatocytes	Doxorubicin	Anti-cancer therapy	Prepared spherical nanoparticles (mean size of 181.9 nm) showed sustained and pH-dependent drug release in vitro. In vivo study showed higher AUC value and residence time in blood circulation. Nanoparticles showed high uptake of drug in liver and spleen as compared to heart, lung and kidney.	Guo et al. (2014)
3	Glycyrrhizin	Hepatocytes	Lamivudine	Hepatitis B treatment	Drug release from nanoparticles showed first burst release and consequently sustained release. In-vivo biodistribution study showed high target ability and hematological study showed lesser tissue damage.	Mishra et al. (2014)
4	Lactic acid, glycyrrhetinic acid and chitosan	Hepatocytes	5-Fluoro uracil	Anti-cancer therapy	Prepared nanoparticles showed particle size of 239.9 nm, PDI of 0.040, zeta potential of +21.2 mV with drug loading of 3.90%. Nanoparticles showed drug release pattern of small burst release, gentle release, second burst release, steady release and slow release with high liver targeting.	Cheng et al. (2013a)
5	Lactobionic acid	Hepatocytes	5-Fluoro uracil	Anti-cancer therapy	The prepared nanoparticles showed proper particle morphology, particle size (below 150 nm), PDI ∼0.35, entrapment efficiency (∼60.23%). In vivo studies showed higher drug concentration (37.52 ± 0.68%) in liver as compared to other organs and plasma.	Dangi et al. (2014)
6	–	Reticulo-endothelial cells	Buparvaquone	Theleriosis	DSC and powder X-ray diffraction showed decreased crystallinity of nanoparticles and spherical morphology. High RES targeting (about 75%). Good stability at 4 and 25°C.	Soni et al. (2014)
7	Galactose	Hepatocytes	Acyclovir	Liver cancer	The spherical nanoparticles showed size (198.1 nm), electrical charge (−8.5 mV), entrapment efficiency (84.1%) and in vitro drug release (40% over 48 h). Nanoparticles were remarkably targeted to liver, the accumulation in the liver was found to be 36.71 ± 0.68% at 24 h.	Jain & Kumar (2013)
8	Glycyrrhetinic acid	Cancerous cells of liver	5-Fluoro uracil	Anti-cancer therapy	The preparation showed particle size (193.7 nm), drug loading 1.56% and PDI 0.003 and show sustained release of drug. The preparation showed high liver targeting with less effects on non-cancerous cells.	Cheng et al. (2013b)
9	Galactose	Hepatocytes	Gene delivery	Genetic disorders in liver	The preparation showed asialoglycoprotein mediated endocytosis of the polyplexes with minimum cytotoxicity to HepG2 cells making it potential non-viral gene delivery to liver.	Ong et al. (2013)
10	Galactose	Hepatocytes	Adenosine triphosphate	Hepatocellular carcinoma treatment	The prepared nanoparticles showed average diameter and zeta potential of about 51.03 ± 3.26 nm and 30.50 ± 1.25 mV, respectively. The preparation showed high liver targeting through asialoglycoprotein receptors with least cytotoxicity to normal cells.	Zhu et al. (2013)
Micelles for achieving liver targeting
1	Glycyrrhetinic acid	Cancerous cells of liver	Doxorubicin	Anti-cancer therapy	IC50 of prepared conjugate against HepG2 cells was 54.7 ng/mL, which was extremely lower than without GA loaded micelles. In addition, prepared micelles showed higher affinity for liver cancer cells (HepG2 cells) than normal cells.	Tian et al. (2012)
2	Lactose and glycyrrhetinic acid	Hepatocytes	Diammonium glycyrrhizinate	Hepatic disorders	Both glycyrrhetinic and lactose conjugated micelles showed encapsulation efficiency of 97.4 and 96.7%, respectively, having spherical micelles of size 21.6 and 26.4 nm. Through TEM, lactose conjugated system showed high liver targeting as compared to glycyrrhetinic acid conjugated system.	Tian et al. (2012)
3	Glycyrrhetinic acid	Hepatocytes	Doxorubicin	Anti-cancer therapy	In vitro drug release study of the prepared formulation showed the pH dependent release with Fickian diffusion kinetics. The prepared micelles showed high liver targeting of about 4.9-fold higher than that of free doxorubicin solution.	Huang et al. (2011)
4	N-acetyl galactosamine	Hepatocytes	siRNA	siRNA therapy	Successful down-regulation of liver-specific Apo lipoprotein B at both transcriptional and protein level was found in mouse liver after i.v. injection of prepared micelles. Systemic delivery of prepared preparation did not show any innate immune response or hepatotoxicity.	Wang et al. (2013)
5	Lactobionic acid	Hepatocytes	Silybin	Hepatoprotective action	The prepared formulation showed remarkable increase in the dissolubility of silybin in lactobionic acid conjugated system (627 µg/ml) as compared to water (4.6 µg/ml). Bio-distribution study showed high liver targeting as compared to the other organs.	Li et al. (2009)
6	Galactose	Hepatocytes	Prednisone	Anti-inflammatory action	TEM study showed spherical shape of the micelles. Size of micelles was found to be 120 nm. The study showed high liver targeting using HepG2 micelles. In vivo study showed high liver uptake as compared to other cells.	Wu et al. (2009)
7	Glycyrrhetinic acid	Hepatocytes	Paclitaxel	Anti-cancer therapy	The prepared nanosized micelles showed mean diameter of about 159.21 ± 2.2 nm. Prepared micelles showed low cytotoxicity and high ability of delivering drug to hepatic cells both in vivo and in vitro by the targeting moiety glycyrrhetinic acid.	Wu et al. (2013)
8	Lactose	Hepatocytes	Harmine	Anti-cancer therapy	Self-assembled micelles showed particle size (∼200 nm). In vivo study showed that the prepared micelles significantly inhibit tumor growth and lifetime of mice bearing H22 tumors was extended after i.v. administration. In vivo near-infrared fluorescence showed satisfactory liver tumor-targeting effect.	Bei et al. (2014)
9	Galactose	Hepatocytes	Sorafenib	Hepatocarcinoma treatment	Liver-targeted sorafenib-loaded micelles showed nanometer size and positive zeta potential. Biodistribution studies on mice showed that after oral administration, the drug sorafenib mainly accumulated into the liver as compared to other organs.	Craparo et al. (2014)
10	Galactose	Hepatic stellate cells and hepatocytes	siRNA	siRNA therapy	It was found that the prepared conjugate could silence luciferase gene expression (40%) without any transfection reagents, while with the help of cationic liposomes, the gene silencing effects reached more than 98% at the same dose. The prepared conjugate showed targeted delivery to hepatocytes and hepatic stellate cells of siRNAs for efficient gene silencing in vivo.	Zhu & Mahato (2010)
Nanosuspensions, polymeric conjugates and niosomes used for liver targeting
1	–	Hepatocytes	Silybin	Hepatoprotective activity	The prepared nanosuspension when given orally or i.v. produces hepatoprotective action by reducing enzymes like AST, ALT, TBIL, ALP and GGT. Prepared nanosuspension showed high targeting at liver and spleen.	Wang et al. (2012b)
2	Folate	Cancerous cells	Docetaxel	Anti-cancer activity	The particle size of prepared nanosuspension was found to be 220.6 ± 9.54 nm. The cytotoxicity of the prepared nanosuspension against B16 (FR+) cell line was higher. In vivo study showed that the nanosuspension showed higher antitumor efficacy by reducing the tumor volume (p < 0.01) as compared to PEG-modified preparation.	Wang et al. (2012a)
3	Coating with Serum albumin, polysaccharides	Viral infected cells	Nevirapine	Anti-viral therapy	The biodistribution study of the prepared nanosuspension showed high organ-specific targeting as compared to plain drug solution when given intravenously. The preparation showed high MRT, enhanced bioavailability and high residence of drug in targeted organs.	Shegokar & Singh (2011)
4	Galactose	Hepatocytes	Primaquine and chloroquine	Antimalarial activity	The conjugate was prepared using polymer polyamidoamine. Final preparation showed twice antimalarial action and low unspecific toxicity as compared to free drug combinations. The preparation showed high selective internalization into parasite infected RBC’s.	Vale et al. (2009)
5	Galactosamine	Hepatocytes	Doxorubicin	Anticancer activity	The prepared conjugate was prepared using polymer HPMA N-(2-hydroxy propyl) methacryl-amide which shows about 16.9 ± 3.9% drug targeting. Conjugate prepared without the galactosamine showed no liver targeting.	Jiwpanich (2011)
6	Glycyrrhetinic acid	Hepatocytes	Paclitaxel	Anticancer activity	Nanoparticles were prepared using glycyrrhetinic acid as targeting ligand and hyaluronic acid as polymer. Prepared nanoparticles showed high efficiency up to 31.16% and entrapment efficiency of 92.02%. The prepared conjugate showed high liver targeting as compared to other organs.	Huang et al. (2010)
7	–	Liver cells	Ribavirin	Chronic hepatitis C	The niosomes were prepared using thin film hydration method using span 60 and cholesterol (1:1). The results showed that the liver targeting of the drug was about 6-fold higher as compared to the normal ribavirin-free solution without any targeting.	Hashim et al. (2010)
8	Mannose	Non-parenchymal cells	Oral vaccination	Hepatitis B	The serum anti-HBsAg obtained after oral administration of niosomal formulations was less as compared to naked DNA, but the mice were seroprotective within 2 weeks. Intramuscular naked DNA did not elicit sIgA titer in mucosal secretions which were induced by oral administration of niosomes. Niosomes produced humoral and cellular immune response after oral administration.	Jain et al. (2005)
9	–	Liver cells	Hydroxycamptothecin	Anti-tumor effect	The prepared niosomes showed strongest cytotoxicity to KB, K562 and S180 carcinomatous cell lines and greatest intracellular uptake, especially in nuclei. The preparation showed most powerful anti-tumor activity by inhibiting the S180 tumor in mice of about 70%.	Hong et al. (2009)

Yang W, Zhang X, Liu Y. (2014). Asialoglycoprotein receptor-targeted radiopharmaceuticals for measurement of liver function. Curr Med Chem 21:4–23

 PubMed Web of Science ®Google Scholar

Liu G, Bi Y, Wang R, et al. (2014). Targeting S1P1 receptor protects against murine immunological hepatic injury through myeloid-derived suppressor cells. J Immunol 192:3068–79

 PubMed Web of Science ®Google Scholar

McDonald CJ, Wallace DF, Ostini L, Subramaniam VN. (2014). Parenteral vs. oral iron: influence on hepcidin signaling pathways through analysis of Hfe/Tfr2-null mice. Am J Physiol Gastrointest Liver Physiol 306:G132–9

 PubMed Web of Science ®Google Scholar

Martinez LO, Jacquet S, Esteve J-P, et al. (2003). Ectopic β-chain of ATP synthase is an apolipoprotein AI receptor in hepatic HDL endocytosis. Nature 421:75–9

 PubMed Web of Science ®Google Scholar

Goldstein JL, Brown MS. (2009). The LDL receptor. Arterioscl Thromb Vasc Biol 29:431–8

 PubMed Web of Science ®Google Scholar

Jiang S, Gavrikova TA, Messina JL. (2014). Regulation of hepatic insulin receptor activity following injury. Am J Physiol Gastrointest Liver Physiol 306:G886–92

 PubMed Web of Science ®Google Scholar

Li B, Yu M, Pan X, et al. (2014). Artesunate reduces serum lipopolysaccharide in cecal ligation/puncture mice via enhanced LPS internalization by macrophages through increased mRNA expression of scavenger receptors. Int J Mol Sci 15:1143–61

 PubMed Web of Science ®Google Scholar

Ramirez-Garcia A, Arteta B, Abad-Diaz-De-Cerio A, et al. (2013). Candida albicans increases tumor cell adhesion to endothelial cells in vitro: intraspecific differences and importance of the mannose receptor. PLoS One 8:e53584

 PubMed Web of Science ®Google Scholar

Storch K-F, Lipan O, Leykin I, et al. (2002). Extensive and divergent circadian gene expression in liver and heart. Nature 417:78–83

 PubMed Web of Science ®Google Scholar

Rost MS, Sumanas S. (2014). Hyaluronic acid receptor stabilin-2 regulates Erk phosphorylation and arterial-venous differentiation in zebrafish. PLoS One 9:e88614

 PubMed Web of Science ®Google Scholar

Friedman SL. (2008). Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–72

 PubMed Web of Science ®Google Scholar

Kallis YN, Scotton CJ, Mackinnon AC, et al. (2014). Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages. PLoS One 9:e86241

 PubMed Web of Science ®Google Scholar

Moss D, Powell LW, Halliday JW, et al. (1992). Functional roles of the ferritin receptors of human liver, hepatoma, lymphoid and erythroid cells. J Inorg Biochem 47:219–27

 PubMed Web of Science ®Google Scholar

Strickland DK, Au DT, Cunfer P, Muratoglu SC. (2014). Low-density lipoprotein receptor-related protein-1: role in the regulation of vascular integrity. Arterioscler Thromb Vasc Biol 34:487–98

 PubMed Web of Science ®Google Scholar

List EO, Berryman DE, Funk K, et al. (2014). Liver-specific GH receptor gene disrupted (LiGHRKO) mice have decreased endocrine IGF-I, increased local IGF-I, and altered body size, body composition, and adipokine profiles. Endocrinology 155:1793–805

 PubMed Web of Science ®Google Scholar

Coombs PJ, Taylor ME, Drickamer K. (2006). Two categories of mammalian galactose-binding receptors distinguished by glycan array profiling. Glycobiology 16:1C–7C

 PubMed Web of Science ®Google Scholar

Woods R, Greally J. (1979). Complement receptors on mouse foetal liver cells. Dev Comp Immunol 3:161–74

 PubMed Web of Science ®Google Scholar

Deng X, Luyendyk JP, Ganey PE, Roth RA. (2009). Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacol Rev 61:262–82

 PubMed Web of Science ®Google Scholar

Kedderis GL. (1996). Biochemical basis of hepatocellular injury. Toxicol Pathol 24:77–83

 PubMed Web of Science ®Google Scholar

Bleibel W, Kim S, D’Silva K, Lemmer ER. (2007). Drug-induced liver injury: review article. Dig Dis Sci 52:2463–71

 PubMed Web of Science ®Google Scholar

Chang C, Schiano T. (2007). Review article: drug hepatotoxicity. Aliment Pharmacol Ther 25:1135–51

 PubMed Web of Science ®Google Scholar

Naruse K, Tang W, Makuuchi M. (2007). Artificial and bioartificial liver support: a review of perfusion treatment for hepatic failure patients. World J Gastroenterol 13:1516–21

 PubMed Web of Science ®Google Scholar

Uetrecht J. (2005). Role of animal models in the study of drug-induced hypersensitivity reactions. AAPS J 7:E914–21

 Web of Science ®Google Scholar

Olson H, Betton G, Robinson D, et al. (2000). Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32:56–67

 PubMed Web of Science ®Google Scholar

Murray KF, Hadzic N, Wirth S, et al. (2008). Drug-related hepatotoxicity and acute liver failure. J Pediatr Gastroenterol Nutr 47:395–405

 PubMed Web of Science ®Google Scholar

Kaplowitz N. (2004). Drug-induced liver injury. Clin Infect Dis 38:S44–8

 PubMed Web of Science ®Google Scholar

Saukkonen JJ, Cohn DL, Jasmer RM, et al. (2006). An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 174:935–52

 PubMed Web of Science ®Google Scholar

Angulo P. (2002). Nonalcoholic fatty liver disease. N Engl J Med 346:1221–31

 PubMed Web of Science ®Google Scholar

Langman G, Hall PDLM, Todd G. (2001). Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. J Gastroenterol Hepatol 16:1395–401

 PubMed Web of Science ®Google Scholar

Garg T, Singh O, Arora S, Murthy R. (2011). Patented microencapsulation techniques and its application. J Pharm Res 4:2097–102

 Google Scholar

King PD, Perry MC. (2001). Hepatotoxicity of chemotherapy. Semin Oncol 6:162–76

 Google Scholar

Ishak KG, Zimmerman HJ. (1995). Morphologic spectrum of drug-induced hepatic disease. Gastroenterol Clin North Am 24:759–86

 PubMed Web of Science ®Google Scholar

Brind AM. (2007). Drugs that damage the liver. Medicine 35:26–30

 Google Scholar

Rollins BJ. (1986). Hepatic veno-occlusive disease. Am J Med 81:297–306

 PubMed Web of Science ®Google Scholar

Kaplowitz N. (2001). Drug-induced liver disorders. Drug Saf 24:483–90

 PubMed Web of Science ®Google Scholar

Arzt J, Mount M. (1999). Hepatotoxicity associated with pyrrolizidine alkaloid (Crotalaria spp) ingestion in a horse on Easter Island. Vet Hum Toxicol 41:96–9

 PubMedGoogle Scholar

Stickel F, Seitz H, Hahn E, Schuppan D. (2001). Liver toxicity of drugs of plant origin. Zeitsch Gastroenterol 39:225–32, 234–7

 PubMed Web of Science ®Google Scholar

Stickel F, Egerer G, Seitz HK. (2000). Hepatotoxicity of botanicals. Public Health Nutr 3:113–24

 PubMed Web of Science ®Google Scholar

Teschke R, Glass X, Schulze J, Eickhoff A. (2012). Suspected greater celandine hepatotoxicity: liver-specific causality evaluation of published case reports from Europe. Eur J Gastroenterol Hepatol 24:270–80

 PubMed Web of Science ®Google Scholar

Haller CA, Dyer JE, Ko R, Olson KR. (2002). Evidence-based case reviews: making a diagnosis of herbal-related toxic hepatitis. West J Med 176:39–44

 PubMedGoogle Scholar

Kouzi SA, McMurtry RJ, Nelson SD. (1994). Hepatotoxicity of germander (Teucrium chamaedrys L.) and one of its constituent neoclerodane diterpenes teucrin A in the mouse. Chem Res Toxicol 7:850–6

 PubMed Web of Science ®Google Scholar

Jeong SC, Kim SM, Jeong YT, Song CH. (2013). Hepatoprotective effect of water extract from Chrysanthemum indicum L. flower. Chin Med 8:7

 PubMed Web of Science ®Google Scholar

Sharma OP, Makkar HPS, Dawra RK. (1988). A review of the noxious plant Lantana camara. Toxicon 26:975–87

 PubMed Web of Science ®Google Scholar

Chan TY, Chan JC, Tomlinson B, Critchley JA. (1994). Poisoning by Chinese herbal medicines in Hong Kong: a hospital-based study. Vet Hum Toxicol 36:546–7

 PubMedGoogle Scholar

Henry SH, Bosch FX, Troxell TC, Bolger PM. (1999). Policy forum: public health. Reducing liver cancer – global control of aflatoxin. Science 286:2453–4

 PubMed Web of Science ®Google Scholar

Daniele C, Dahamna S, Firuzi O, et al. (2005). Atractylis gummifera L. poisoning: an ethnopharmacological review. J Ethnopharmacol 97:175–81

 PubMed Web of Science ®Google Scholar

Chitturi S, Farrell GC. (2002). Drug-induced liver disease. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's diseases of the liver, 11th ed. Philadelphia: Lippincott-Raven, 703–83

 Google Scholar

Kao W-F, Hung D-Z, Tsai W-J, et al. (1992). Podophyllotoxin intoxication: toxic effect of Bajiaolian in herbal therapeutics. Hum Exp Toxicol 11:480–7

 PubMed Web of Science ®Google Scholar

Larrey D. (1997). Hepatotoxicity of herbal remedies. J Hepatol 26:47–51

 PubMedGoogle Scholar

Gordon DW, Rosenthal G, Hart J, et al. (1995). Chaparral ingestionthe broadening spectrum of liver injury caused by herbal medications. JAMA 273:489–90

 PubMed Web of Science ®Google Scholar

Om P. (2011). Clinical biochemistry of hepatotoxicity. J Clin Toxicol S4:1–19

 Google Scholar

Kälin P. (2003). The common butterbur (Petasites hybridus)–portrait of a medicinal herb. Forsch Komplementarmed Klass Naturheilkd 10:41–4. [In German]

 PubMedGoogle Scholar

Yeong ML, Swinburn B, Kennedy M, Nicholson G. (1990). Hepatic veno-occlusive disease associated with comfrey ingestion. J Gastroenterol Hepatol 5:211–4

 PubMed Web of Science ®Google Scholar

Wallace JL. (2004). Acetaminophen hepatotoxicity: NO to the rescue. Br J Pharmacol 143:1–2

 PubMed Web of Science ®Google Scholar

Manokaran S, Jaswanth A, Sengottuvelu S, et al. (2008). Hepatoprotective activity of Aerva lanata Linn. against paracetamol induced hepatotoxicity in rats. Res J Pharm Technol 1:398–400

 Google Scholar

Navarro VJ, Senior JR. (2006). Drug-related hepatotoxicity. N Engl J Med 354:731–9

 PubMed Web of Science ®Google Scholar

Arora N, Goldhaber SZ. (2006). Anticoagulants and transaminase elevation. Circulation 113:e698–702

 PubMed Web of Science ®Google Scholar

Schimanski CC, Burg J, Möhler M, et al. (2004). Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure. J Hepatol 41:67–74

 PubMed Web of Science ®Google Scholar

Bhardwaj SS, Chalasani N. (2007). Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis 11:597–613

 PubMedGoogle Scholar

Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. (2006). Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother 40:753–7

 PubMed Web of Science ®Google Scholar

Shimizu S, Atsumi R, Itokawa K, et al. (2009). Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice. Arch Toxicol 83:701–7

 PubMed Web of Science ®Google Scholar

Moses G. (2005). Complementary and alternative medicine use in the elderly. J Pharm Pract Res 35:63–8

 Google Scholar

Piroth L. (2005). Liver steatosis in HIV-infected patients. AIDS Rev 7:197–209

 PubMed Web of Science ®Google Scholar

Sulkowski MS, Mehta SH, Chaisson RE, et al. (2004). Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. Aids 18:2277–84

 PubMed Web of Science ®Google Scholar

Khalili H, Dashti-Khavidaki S, Rasoolinejad M, et al. (2009). Anti-tuberculosis drugs related hepatotoxicity; incidence, risk factors, pattern of changes in liver enzymes and outcome. Daru 17:163–7

 Web of Science ®Google Scholar

Kremer JM, Lee RG, Tolman KG. (1989). Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples. Arthritis Rheum 32:121–7

 PubMed Web of Science ®Google Scholar

Edmondson HA, Peters RL. (1983). Tumors of the liver: pathologic features. Sem Roentgenol (Elsevier) 18:75–83

 PubMed Web of Science ®Google Scholar

Iancu TC, Shiloh H, Dembo L. (1986). Hepatomegaly following short-term high-dose steroid therapy. J Pediatr Gastroenterol Nutr 5:41–6

 PubMed Web of Science ®Google Scholar

O'Connor N, Dargan PI, Jones AL. (2003). Hepatocellular damage from non-steroidal anti-inflammatory drugs. QJM 96:787–91

 PubMed Web of Science ®Google Scholar

Ezeuko Vitalis C, Nwokocha Chukwuemeka R, Mounmbegna Philippe E, et al. (2007). Effects of Zingiber officinale on liver function of mercuric chloride-induced hepatotoxicity in adult wistar rats. Electron J Biomed 3:40–5

 Google Scholar

Haleagrahara N, Jackie T, Chakravarthi S, et al. (2010). Protective effect of Etlingera elatior (torch ginger) extract on lead acetate-induced hepatotoxicity in rats. J Toxicol Sci 35:663–71

 PubMed Web of Science ®Google Scholar

Pari L, Mohamed Jalaludeen A. (2011). Protective role of sinapic acid against arsenic-induced toxicity in rats. Chem Biol Interact 194:40–7

 PubMed Web of Science ®Google Scholar

Boll M, Weber LW, Becker E, Stampfl A. (2001). Mechanism of carbon tetrachloride-induced hepatotoxicity. Hepatocellular damage by reactive carbon tetrachloride metabolites. Z Naturforsch C 56:649–59

 PubMed Web of Science ®Google Scholar

Klaassen CD. (2001). Casarett and Doull's toxicology: the basic science of poisons. New York: McGraw-Hill

 Google Scholar

Mochizuki M, Shimizu S, Urasoko Y, et al. (2009). Carbon tetrachloride-induced hepatotoxicity in pregnant and lactating rats. J Toxicol Sci 34:175–81

 PubMed Web of Science ®Google Scholar

Kuriakose GC, Kurup MG. (2011). Antioxidant and antihepatotoxic effect of Spirulina laxissima against carbon tetrachloride induced hepatotoxicity in rats. Food Funct 2:190–6

 PubMed Web of Science ®Google Scholar

Purushotham KR, Lockard VG, Mehendale HM. (1988). Amplification of chloroform hepatotoxicity and lethality by dietary chlordecone (Kepone®) in mice. Toxicol Pathol 16:27–34

 PubMed Web of Science ®Google Scholar

Jenkins L Jr, Trabulus M, Murphy S. (1972). Biochemical effects of 1,1-dichloroethylene in rats: comparison with carbon tetrachloride and 1,2-dichloroethylene. Toxicol Appl Pharmacol 23:501–10

 PubMed Web of Science ®Google Scholar

Jaeger R, Trabulus M, Murphy S. (1973). Biochemical effects of 1, 1-dichloroethylene in rats: dissociation of its hepatotoxicity from a lipoperoxidative mechanism. Toxicol Appl Pharmacol 24:457–67

 PubMed Web of Science ®Google Scholar

Shen D, Wu Q, Wang M, et al. (2006). Determination of the predominant catechins in Acacia catechu by liquid chromatography/electrospray ionization-mass spectrometry. J Agric Food Chem 54:3219–24

 PubMed Web of Science ®Google Scholar

Raphael E. (2012). Phytochemical constituents of some leaves extract of Aloe vera and Azadirachta indica plant species. Global Adv Res J Environ Sci Toxicol 1:14–7

 Google Scholar

Mahesh A, Kumar H, Ranganath M, Devkar RA. (2012). Detail study on Boerhaavia diffusa plant for its medicinal importance – a review. Res J Pharm Sci 1:28–36

 Google Scholar

Colombo ML, Bosisio E. (1996). Pharmacological activities of Chelidonium majus L. (Papaveraceae). Pharmacol Res 33:127–34

 PubMed Web of Science ®Google Scholar

Bishayee A, Sarkar A, Chatterjee M. (1995). Hepatoprotective activity of carrot (Daucus carota L.) against carbon tetrachloride intoxication in mouse liver. J Ethnopharmacol 47:69–74

 PubMed Web of Science ®Google Scholar

Singh G, Sharma P, Dudhe R, Singh S. (2010). Biological activities of Withania somnifera. Ann Biol Res 1:56–63

 Google Scholar

Verma VK, Siddiqui N. (2011). Bioactive chemical constituents from the plant Verbena officinalis Linn. Int J Pharm Pharm Sci 3:108–9

 Google Scholar

Khatri A, Garg A, Agrawal SS. (2009). Evaluation of hepatoprotective activity of aerial parts of Tephrosia purpurea L. and stem bark of Tecomella undulata. J Ethnopharmacol 122:1–5

 PubMed Web of Science ®Google Scholar

Joseph B. (2011). Effect of bioactive compounds and its pharmaceutical activities of sida cordifolia (Linn.). Int J Biol Med Res 2:1038–42

 Google Scholar

Luper S. (1998). A review of plants used in the treatment of liver disease: part 1. Altern Med Rev J Clin Ther 3:410–21

 PubMedGoogle Scholar

Gagandeep Garg T, Malik B, Rath G, Goyal AK. (2014). Development and characterization of nano-fiber patch for the treatment of glaucoma. Eur J Pharm Sci 53:10–6

 PubMed Web of Science ®Google Scholar

Singh V, Sharma S, Dhar K, Kalia A. (2013). Activity guided isolation of anti-inflammatory compound/fraction from root of Ricinus communis Linn. Int J PharmTech Res 5:1142–9

 Google Scholar

Lahon K, Das S. (2011). Hepatoprotective activity of Ocimum sanctum alcoholic leaf extract against paracetamol-induced liver damage in Albino rats. Pharmacognosy Res 3:13–8

 PubMedGoogle Scholar

Narendra K, Swathi J, Sowjanya K, Satya AK. (2012). Phyllanthus niruri: a review on its ethno botanical, phytochemical and pharmacological profile. J Pharm Res 5:4681–91

 Google Scholar

Perez-Amador M, Munoz Ocotero V, Ibarra Balcazar R, Garcia Jimenez F. (2010). Phytochemical and pharmacological studies on Mikania micrantha HBK (Asteraceae). Phyton Rev Int Bot Exp 79:77–80

 Web of Science ®Google Scholar

Street RA, Sidana J, Prinsloo G. (2013). Cichorium intybus: traditional uses, phytochemistry, pharmacology, and toxicology. Evidence-Based Complement Altern Med 1–13

 Web of Science ®Google Scholar

Nadim M, Malik AA, Ahmad J, Bakshi S. (2011). The essential oil composition of Achillea millefolium L. cultivated under tropical condition in India. World J Agric Sci 7:561–5

 Google Scholar

Shaikh M, Sancheti J, Sathaye S. (2012). Phytochemical and pharmacological investigations of Eclipta alba (Linn.) hassak leaves for antiepileptic activity. Int J Pharm Pharm Sci 4:77–80

 Google Scholar

Tabassum S, Mahmood S, Hanif J, et al. (2012). An overview of medicinal importance of SWERTIA CHIRAYITA. Int J Appl Sci Technol 2:298–304

 Google Scholar

Rawat A, Mehrotra S, Tripathi S, Shome U. (1997). Hepatoprotective activity of Boerhaavia diffusa L. roots – a popular Indian ethnomedicine. J Ethnopharmacol 56:61–6

 PubMed Web of Science ®Google Scholar

Mortazavi SR, Nassiri-Asl M, Farahani-Nick Z, et al. (2007). Protective effects of Fumaria vaillantii extract on carbon tetrachloride induced hepatotoxicity in rats. Pharmacol Online 3:385–93

 Google Scholar

Lee C, Park S, Kim YS, et al. (2007). Protective mechanism of glycyrrhizin on acute liver injury induced by carbon tetrachloride in mice. Biol Pharm Bull 30:1898–904

 PubMed Web of Science ®Google Scholar

Yamaura K, Shimada M, Nakayama N, Ueno K. (2011). Protective effects of goldenseal (Hydrastis canadensis L.) on acetaminophen-induced hepatotoxicity through inhibition of CYP2E1 in rats. Pharmacognosy Res 3:250–5

 PubMedGoogle Scholar

Cheng N, Ren N, Gao H, et al. (2013c). Antioxidant and hepatoprotective effects of Schisandra chinensis pollen extract on CCl4-induced acute liver damage in mice. Food Chem Toxicol 55:234–40

 PubMed Web of Science ®Google Scholar

You Y, Yoo S, Yoon H-G, et al. (2010). In vitro and in vivo hepatoprotective effects of the aqueous extract from Taraxacum officinale (dandelion) root against alcohol-induced oxidative stress. Food Chem Toxicol 48:1632–7

 PubMed Web of Science ®Google Scholar

Kim H-S, Lim H-K, Chung M-W, Kim YC. (2000). Antihepatotoxic activity of bergenin, the major constituent of Mallotus japonicus, on carbon tetrachloride-intoxicated hepatocytes. J Ethnopharmacol 69:79–83

 PubMed Web of Science ®Google Scholar

Hattori Y, Nakamura A, Arai S, et al. (2014). In vivo siRNA delivery system for targeting to the liver by poly-l-glutamic acid-coated lipoplex. Results Pharma Sci 4:1–7

 PubMedGoogle Scholar

Garg T, Goyal AK. (2014b). Liposomes: targeted and controlled delivery system. Drug Deliv Lett 4:62–71

 Google Scholar

Bansal R, Prakash J, De Ruiter M, Poelstra K. (2014). Targeted recombinant fusion proteins of IFNγ and mimetic IFNγ with PDGFβR bicyclic peptide inhibits liver fibrogenesis in vivo. PLoS One 9:e89878

 PubMed Web of Science ®Google Scholar

Sonoke S, Ueda T, Fujiwara K, et al. (2011). Galactose-modified cationic liposomes as a liver-targeting delivery system for small interfering RNA. Biol Pharm Bull 34:1338–42

 PubMed Web of Science ®Google Scholar

Detampel P, Witzigmann D, Krähenbühl S, Huwyler J. (2013). Hepatocyte targeting using pegylated asialofetuin-conjugated liposomes. J Drug Target 22:1–10

 PubMed Web of Science ®Google Scholar

Samy A, Elmowafy M, Arafa M, et al. (2014). Complement activation assay and in vivo evaluation of silymarin loaded liver targeting liposome. J Life Med 2

 Google Scholar

Elmowafy M, Viitala T, Ibrahim HM, et al. (2013). Silymarin loaded liposomes for hepatic targeting: in vitro evaluation and HepG2 drug uptake. Eur J Pharm Sci 50:161–71

 PubMed Web of Science ®Google Scholar

Garg T, Goyal AK. (2012). Iontophoresis: drug delivery system by applying an electrical potential across the skin. Drug Deliv Lett 2:270–80

 Google Scholar

Tian J, Wang L, Wang L, Ke X. (2013). A wogonin-loaded glycyrrhetinic acid-modified liposome for hepatic targeting with anti-tumor effects. Drug Deliv 1–7

 Web of Science ®Google Scholar

Narmada BC, Kang Y, Venkatraman L, et al. (2013). Hepatic stellate cell-targeted delivery of hepatocyte growth factor transgene via bile duct infusion enhances its expression at fibrotic foci to regress dimethylnitrosamine-induced liver fibrosis. Hum Gene Ther 24:508–19

 PubMed Web of Science ®Google Scholar

Zhao C, Feng Q, Dou Z, et al. (2013). Local targeted therapy of liver metastasis from colon cancer by galactosylated liposome encapsulated with doxorubicin. PLoS One 8:e73860

 PubMed Web of Science ®Google Scholar

Coulstock E, Sosabowski J, Ovečka M, et al. (2013). Liver-targeting of interferon-alpha with tissue-specific domain antibodies. PLoS one 8:e57263

 PubMed Web of Science ®Google Scholar

Li C, Zhang D, Guo H, et al. (2013). Preparation and characterization of galactosylated bovine serum albumin nanoparticles for liver-targeted delivery of oridonin. Int J Pharm 448:79–86

 PubMed Web of Science ®Google Scholar

Guo H, Zhang D, Li T, et al. (2014). In vitro and in vivo study of gal-os self-assembled nanoparticles for liver-targeting delivery of doxorubicin. J Pharm Sci 103:987–93

 PubMed Web of Science ®Google Scholar

Mishra D, Jain N, Rajoriya V, Jain AK. (2014). Glycyrrhizin conjugated chitosan nanoparticles for hepatocyte-targeted delivery of lamivudine. J Pharm Pharmacol 66:1082–93

 PubMed Web of Science ®Google Scholar

Cheng M, Gao X, Wang Y, et al. (2013a). Synthesis of liver-targeting dual-ligand modified GCGA/5-FU nanoparticles and their characteristics in vitro and in vivo. Int J Nanomed 8:4265–76

 PubMed Web of Science ®Google Scholar

Dangi R, Hurkat P, Jain A, et al. (2014). Targeting liver cancer via ASGP receptor using 5-FU-loaded surface-modified PLGA nanoparticles. J Microencapsul 31:1–9

 PubMed Web of Science ®Google Scholar

Soni MP, Shelkar N, Gaikwad RV, et al. (2014). Buparvaquone loaded solid lipid nanoparticles for targeted delivery in theleriosis. J Pharm Bioallied Sci 6:22–30

 PubMedGoogle Scholar

Jain D, Kumar A. (2013). Galactosylated poly(d,l-Lactic-co-glycolic acid) nanoparticles for liver targeted delivery of acyclovir. J Biomed Pharm Res 2:7–14

 Google Scholar

Cheng M, Xu H, Wang Y, et al. (2013b). Glycyrrhetinic acid-modified chitosan nanoparticles enhanced the effect of 5-fluorouracil in murine liver cancer model via regulatory T-cells. Drug Des Dev Ther 7:1287–99

 PubMed Web of Science ®Google Scholar

Ong ZY, Yang C, Gao SJ, et al. (2013). Galactose-functionalized cationic polycarbonate diblock copolymer for targeted gene delivery to hepatocytes. Macromol Rapid Commun 34:1714–20

 PubMed Web of Science ®Google Scholar

Zhu XL, Du YZ, Yu RS, et al. (2013). Galactosylated chitosan oligosaccharide nanoparticles for hepatocellular carcinoma cell-targeted delivery of adenosine triphosphate. Int J Mol Sci 14:15755–66

 PubMed Web of Science ®Google Scholar

Tian Q, Wang X-H, Wang W, et al. (2012). Self-assembly and liver targeting of sulfated chitosan nanoparticles functionalized with glycyrrhetinic acid. Nanomedicine Nanotechnol Biol Med 8:870–9

 PubMed Web of Science ®Google Scholar

Huang W, Wang W, Wang P, et al. (2011). Glycyrrhetinic acid-functionalized degradable micelles as liver-targeted drug carrier. J Mater Sci Mater Med 22:853–63

 PubMed Web of Science ®Google Scholar

Wang H-X, Xiong M-H, Wang Y-C, et al. (2013). N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver. J Control Release 166:106–14

 PubMed Web of Science ®Google Scholar

Li X, Huang Y, Chen X, et al. (2009). Self-assembly and characterization of Pluronic P105 micelles for liver-targeted delivery of silybin. J Drug Target 17:739–50

 PubMed Web of Science ®Google Scholar

Wu D-Q, Lu B, Chang C, et al. (2009). Galactosylated fluorescent labeled micelles as a liver targeting drug carrier. Biomaterials 30:1363–71

 PubMed Web of Science ®Google Scholar

Wu F, Xu T, Liu C, et al. (2013). Glycyrrhetinic acid-poly (ethylene glycol)-glycyrrhetinic acid tri-block conjugates based self-assembled micelles for hepatic targeted delivery of poorly water soluble drug. Sci World J 2013:1–10

 Google Scholar

Bei Y-Y, Yuan Z-Q, Zhang L, et al. (2014). Novel self-assembled micelles based on palmitoyl-trimethyl-chitosan for efficient delivery of harmine to liver cancer. Exp Opin Drug Deliv 11:843–54

 PubMed Web of Science ®Google Scholar

Craparo EF, Sardo C, Serio R, et al. (2014). Galactosylated polymeric carriers for liver targeting of sorafenib. Int J Pharm 466:172–80

 PubMed Web of Science ®Google Scholar

Zhu L, Mahato RI. (2010). Targeted delivery of siRNA to hepatocytes and hepatic stellate cells by bioconjugation. Bioconjug Chem 21:2119–27

 PubMed Web of Science ®Google Scholar

Wang Y, Wang L, Liu Z, et al. (2012b). In vivo evaluation of silybin nanosuspensions targeting liver. J Biomed Nanotechnol 8:760–9

 PubMed Web of Science ®Google Scholar

Wang L, Li M, Zhang N. (2012a). Folate-targeted docetaxel-lipid-based-nanosuspensions for active-targeted cancer therapy. Int J Nanomedicine 7:3281–94

 PubMed Web of Science ®Google Scholar

Shegokar R, Singh KK. (2011). Surface modified nevirapine nanosuspensions for viral reservoir targeting: in vitro and in vivo evaluation. Int J Pharm 421:341–52

 PubMed Web of Science ®Google Scholar

Vale N, Moreira R, Gomes P. (2009). Primaquine revisited six decades after its discovery. Eur J Med Chem 44:937–53

 PubMed Web of Science ®Google Scholar

Jiwpanich S. (2011). Design and synthesis of a new class of self-cross-linked polymer nanogels. Dissertations, University of Massachusetts, Amherst

 Google Scholar

Huang W, Wang W, Wang P, et al. (2010). Glycyrrhetinic acid-modified poly (ethylene glycol)–b-poly (γ-benzyl l-glutamate) micelles for liver targeting therapy. Acta Biomater 6:3927–35

 PubMed Web of Science ®Google Scholar

Hashim F, El-Ridy M, Nasr M, Abdallah Y. (2010). Preparation and characterization of niosomes containing ribavirin for liver targeting. Drug Deliv 17:282–7

 PubMed Web of Science ®Google Scholar

Jain S, Singh P, Mishra V, Vyas S. (2005). Mannosylated niosomes as adjuvant–carrier system for oral genetic immunization against Hepatitis B. Immunol Lett 101:41–9

 PubMed Web of Science ®Google Scholar

Hong M, Zhu S, Jiang Y, et al. (2009). Efficient tumor targeting of hydroxycamptothecin loaded PEGylated niosomes modified with transferrin. J Control Release 133:96–102

 PubMed Web of Science ®Google Scholar