Liver-targeted drug delivery

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Chapter: Pharmaceutical Drugs and Dosage: Organ-specific drug delivery

Liver is the major organ responsible for the metabolism, detoxification, and storage of macromolecules; as well as the production and secretion of bile for digestion.

Liver-targeted drug delivery

Liver is the major organ responsible for the metabolism, detoxification, and storage of macromolecules; as well as the production and secretion of bile for digestion. It plays an important role in the clearance of pathogens and antigens entering the body via the GI tract. The need and modalities of liver-targeted drug therapy is best understood in the context of cellular components of the liver, the nature of liver diseases, and the cellular recep-tors on various liver cells that can be utilized for targeted drug therapy.

Cellular components of the liver

Liver is designed for the recognition, metabolism, and elimination of for-eign material, including bacteria, viruses, and noncellular particulates. This role is served through the anatomical design whereby venous blood is circulated through the liver, including the parts of the GI tract, via the hepatic portal vein, through a sinusoidal system.

The liver consists of four cell types—(1) hepatocyte, (2) endothelial, (3) Kupffer, and (4) stellate cells. The main parenchymal tissue of the liver is composed of hepatocytes, which make up 70%–85% of the liver mass and are involved in various liver activities including the formation and secretion of bile. Hepatocytes have metabolic, endocrine, and secretory functions. Liver endothelial cells form the discontinuous lining of the sinusoids and have fenestrations that are ~100 nm in diameter. This relatively large pore size plays an important role in determining the sizes of particles filtering between the blood and the liver parenchymal cells. A space of Disse sepa-rates hepatocytes from the sinusoids.

The hepatic sinusoids are lined with the Kupffer cells, which are the largest group of tissue macrophages in the liver. Their main function is to phagocytose and destroy foreign material, such as bacteria or colloids.

Hepatic stellate cells (HSCs) localize within the space of Disse in close proximity of both hepatocytes and endothelial cells (Figure 15.4a). HSCs are present in the perisinusoidal space, constituting about 5%–10% of the total number of liver cells. These are the mesenchymal cells that are involved in the liver’s response to injury. 

Figure 15.4 Physiology of the (a) normal and (b) diseased liver showing subsinusoidal events during liver injury. In response to liver injury, stellate cells secrete excessive extracellular matrix (ECM), which deposits in the subsinusoidal space of Disse as scar matrix and loss of fenestrae. Liver injury also causes Kupffer cell activation, which contribute to paracrine activation of stellate cells. (Reproduced from Friedman, S.L., J. Biol. Chem., 275(4), 2247–2250, 2000. With permission.)

Stellate cell activation transforms them into myofibroblasts, cells that are phenotypically between a fibroblast and a smooth muscle cell. The myofibroblasts produce fibrinogen, a glyco-protein involved in blood coagulation. Deposition of fibrinogen in the liver can lead to liver fibrosis.

Common diseases of the liver

The normal physiology of the liver is affected in the disease state. For example, in response to liver injury, stellate cells secrete excessive extracel-lular matrix (ECM), which deposits in the subsinusoidal space of Disse as scar matrix and loss of fenestrae. Liver injury also causes Kupffer cell activation, which contribute to paracrine activation of stellate cells (Figure 15.4b). The excessive ECM secretion contributes to the loss of hepatocyte microvilli and sinusoidal epithelial fenestrae, which leads to loss of liver function.

Drug delivery to the liver is indicated in several diseases. For example,

1.        Hepatocellular carcinoma: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated deaths worldwide. HCC has been associated with hepatitis B and C infections, metabolic liver dis-eases, and nonalcoholic fatty liver diseases.

2.        Cirrhosis: Activation of HSCs can lead to the deposition of fibrotic tissue. Continuation of the fibrotic process can lead to end-stage liver disease known as cirrhosis. Liver cirrhosis is associated with anatomical alteration of the sinusoidal architecture, reduced liver perfusion, compromised liver function, and increased risk of HCC. Liver cirrhosis is mainly caused by hepatitis B and C infections, alco-hol abuse, biliary problems, and fatty liver (steatohepatitis).

3.        Hepatitis: Hepatitis is a state of inflammation of the liver that is com-monly caused by viruses, which are of five main types A, B, C, D, and E. Hepatitis virus types B and C are the most prevalent, lead to chronic diseases, and are the most common cause of liver cirrhosis and cancer. Hepatitis virus types A and E are spread by contaminated food and water. Hepatitis virus types B, C, and D are spread by parenteral contact with infected body fluids by mechanisms such as injec-tion, infusion, sexual contact, and mother-to-baby transmission at the time of birth.

Natural mechanisms of hepatic drug uptake

The natural role of the liver in protecting the body from xenobiotics pro-vides mechanisms that allow passive drug targeting to the liver. These include the following:

1. Hepatic first-pass effect: Orally absorbed drugs are carried through the hepatic portal vein into the liver before they reach the systemic circulation. The liver metabolizes several drugs (e.g., diazepam and morphine) to a significant extent, leading to reduced oral bioavail-ability. This phenomenon can also be utilized for liver targeting through

a. High hepatic exposure of orally administered compound. For example, antiviral drugs targeted for the treatment of hepatitis C, such as ribavirin and telaprevir are administered orally.

b. Prolonging the circulation time of compounds targeted for the liver provides passive targeting to the hepatocytes through prolonging the duration of time a therapeutic is available for hepatocyte uptake. For example, PEGylated interferons α-2a (PEGASYS®) and α-2b (PegIntron®) have been used effectively in the treatment of hepatitis B and C in combination with ribavirin.

2. Enhanced permeation and retention effect: Liver tissue in diseases such as hepatocellular carcinoma (HCC) displays the enhanced per-meation and retention (EPR) effect. The EPR effect is attributed to the imperfect endothelium of neovasculature (newly formed blood vessels) of growing tumors that result in larger particulate drug carriers being able to concentrate in the tumor tissue more than the normal tissue with mature vasculature. This mechanism can be utilized for drug delivery to the liver by the utilization of particulate drug carriers such as liposomes and nanoparticles.

Cellular targets for disease therapy

Natural xenobiotic scavenging role of the liver cells through endocytotic and specific target/antigen-binding receptors on various cell types affords opportunities for actively targeted drug therapy for various liver cell types. The receptors that can be utilized for drug targeting to specific liver cells include the following:

1. Hepatocytes: They are involved in liver diseases such as hepatitis A, B, or C; alcohol-induced or nonalcohol-induced steatohepatitis (NASH); and genetic diseases such as Wilson’s disease and hemochromatosis. Hepatocytes can be targeted through the asialoglycoprotein receptors on their cell surface, which bind galactose and lactose.

a. Asialoglycoprotein receptors on hepatocytes are attractive as a target receptor for drug delivery because of limited distribution of these receptors elsewhere in the body, high binding affinity with the target ligand (e.g., galactose), and rapid ligand internalization. Galactosylated drug carriers (i.e., DDSs that display galactose res-idues on their surface) are readily delivered to hepatocytes due to the relatively wide sinusoidal gap (~100 nm diameter). Drug deliv-ery carriers that are modified with galactose or lactose have been utilized for drug delivery in HCC.

b. HCC cells also express several growth factor receptors, such as the epidermal growth factor receptor (EGFR). Antibodies against such growth factor receptors, such as the anti-EGFR antibody cetuximab have shown some activity against HCC.

c. Coxsackie- and adenoviral-receptor and integrin receptors on their cell surface that help internalize adenoviruses. Adenoviral vectors can be utilized to deliver genes. Hepatocyte selectivity of viral gene delivery can also be achieved from viral vectors that are derived from the human immunodeficiency virus (HIV) and the Sendai virus.

d. Apolipoprotein E is rapidly cleared from the systemic circulation by hepatocytes. The apolipoprotein E or the high-density lipid (HDL) particles has been utilized for the delivery of short-interfering RNAs (siRNAs) and microRNAs (miRNAs).

2. Kupffer cells are highly phagocytic cells that are a part of the reticu-loendothelial system (RES), also called the mononuclear phagocyte system (MPS) or the macrophage system. Kupffer cells can be targeted through a variety of ways. For example,

a. Sugar (mannose and fucose) receptors that serve to recognize natural foreign particles, such as bacteria and yeast, can be uti-lized to target proteins and drugs to the RES phagocytic cells. For example, mannose-modified human serum albumin (HSA) selec-tively accumulates in Kupffer cells.

b. Kupffer cells phagocytose noncellular particles of 100 nm or higher diameter. Passive targeting to these endocytotic cells can, therefore, be achieved using particulate drug delivery carriers.

c. Kupffer cells and endothelial cells express scavenger receptors, which predominantly bind negatively charged molecules. Proteins and liposomes with a net negative charge have been utilized for targeting the scavenger receptors. For example, coupling of the electroneutral dexamethasone to HSA through lysine residues increases the net negative charge on HSA, increasing its poten-tial uptake by the scavenger receptors. In addition, incorporation of succinyl-HSA (HSA conjugated with the polyanionic succinic acid) into liposomes has been targeted for drug delivery to the sinusoidal liver endothelial cells.

HSCs are involved in the fibrotic processes that can lead to liver cirrhosis. In the presence of chronic liver injury, HSCs get activated and transform into proliferative myofibroblasts, which are the major source of excessive ECM. The receptors that are highly upregulated on HSCs include the following:

1. Mannose-6-phosphate (M6P)/insulin-like growth factor II receptor

2. Collagen type VI receptor

3. Platelet derived growth factor-β (PDGF-β) receptor.

Conjugation of HSA to M6P or peptides that recognize the collagen type VI or the PDGF-β receptor has been utilized to target HSCs. These carri-ers have been utilized for the delivery of antifibrotic small-molecule drugs, proteins, siRNAs, and triplex-forming oligonucleotides (TFOs) through direct conjugation with the carrier molecules, complexation/conjugation with carrier molecule-modified HSA, or incorporation in liposomes that have been modified with the carrier molecule.

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