Transporters as Targets for Drugs: 4 (Topics in Medicinal Chemistry)

His main research topics are neuromedicinal chemistry with focus on glutamate, GABA 4 γ-Aminobutyric Acid and Glycine Neurotransmitter Transporters
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TryTransDB: A web-based resource for transport proteins in Trypanosomatidae

Once accumulated at the target site, hydrophobic biodegradable polymeric nanoparticles can act as a local drug depot, depending upon the make-up of the carrier, thus providing a reservoir for continuous supply of encapsulated therapeutic compound at the disease site, such as, a solid tumor.

Thus, the advantages of using nanoparticles for drug delivery result from two main basic properties: Many studies have demonstrated that nanoparticles of sub-micron size have a number of advantages over conventional dosage forms as drug delivery carriers [ 17 ].

A further advantage over conventional drug delivery systems is their better suitability for intravenous i. Additionally, some types of cells permit the uptake of only sub-micron particles and not their larger counterparts. Generally nanoparticles have relatively higher intracellular uptake compared to microparticles and are available to a much wider range of biological targets due to their small size and relative mobility. Secondly, the use of biodegradable materials for nanoparticle preparation allows sustained drug release within the target site over a period of days or even weeks.

With regards to the material of formulation, biodegradable nanoparticles formulated from polymers and lipids have been developed for intracellular sustained drug delivery, especially for drugs with an intracellular target [ 13 , 16 ]. Rapid escape of these nanoparticles from the endo-lysosomal compartment to the cytoplasmic compartment has been demonstrated [ 13 , 17 ]. Additionally, they were demonstrated to effectively sustain the intracellular drug levels, thus allowing a more efficient interaction with the cytoplasmic receptors.


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Thus, nanoparticles could serve as effective delivery vehicles for drugs with cytoplasmic targets. To summarize, nanoparticles have proven advantages over the conventional dosage forms. They offer a reliable alternative to the pharmaceutical industry to improve the therapeutic effects of existing drugs, elicit better effect from new chemical entities and to deliver sensitive molecules like proteins, peptides, DNA and RNA.

Among these, TAT is the most frequently used. Several studies have shown the potential of TAT-modified nanodrug carrier transport into the brain for diagnosis and treatment of CNS disorders. Higher brain concentrations of doxorubicin were achieved resulting in higher survival rates of glioma-bearing rats.


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    • Vectors that have been used include cationized albumin, liposomes, nanoparticles, and antibodies to receptors such as transferrin. Transferrin receptor is constitutively expressed at the BBB at higher levels than other capillary beds, and is involved in the transport of iron into the brain.

    The use of transferrin receptor has been investigated for the transport of various peptides across the BBB. For example, a murine monoclonal antibody to the rat transferring receptor OX26 has been successfully used to increase brain uptake of proteins and peptides in a receptor-mediated manner.

    Receptor-mediated transport has also been investigated in the delivery of angiopep-2 peptide, whose sequence is derived from ligands that bind to low-density lipoprotein receptor-related protein-1 LRP LRP-1 is highly expressed in the brain endothelial cells, neurons, and astrocytes as well as in brain tumor cells and can be used to deliver drugs to the brain.

    In vivo injection of ANG, a conjugate of containing Angiopep-2 and the antineoplastic drug paclitaxel, inhibited growth of orthotopic human glioblastoma brain tumors in mice more potently than paclitaxel alone and significantly increased animal survival rate. Although receptor-mediated transport represents a potent strategy, it has some disadvantages.

    First, the vector used for receptor-mediated transport could lead to potential steric inhibition of the peptide or drug at the target receptor. Second, not many peptides can be delivered via this mechanism. Third, when targeting by a vector such as the transferrin receptor, it is important to consider how it impacts the transport of the native substrate. In receptor-mediated transport, drugs act either as a ligand for surface-attached receptors or as a receptor for surface-attached ligands [43]. This process involves cell invagination, which leads to formation of a vesicle.

    This process, in general, is known as endocytosis and comprises phagocytosis, pinocytosis, receptor-mediated endocytosis clathrin mediated , and potocytosis nonclathrin mediated [44]. Small peptides such as di- and tri-peptides, as well as monosaccharides and amino acids, are thought to be transported by carrier-mediated systems [8,45,46].

    After a drug is absorbed in the GI tract, it gains access to the systemic circulation via two separate and functionally distinct absorption pathways: The physicochemical and metabolic features of the drug and the characteristics of the formulation largely control the relative proportion of drug absorbed via these two pathways. Portal blood represents the major pathway for the majority of orally administered drugs as it has higher capacity to transport both water-soluble and poorly water-soluble compounds.

    During this process, hydrophilic molecules are carried to the liver via the hepatic portal vein, and then by the hepatic artery gain access to the systemic circulation, for subsequent delivery to their sites of action. The first stage of drug transport from a formulation to the skin is the drug release. As shown in equation 3. In this equation, M is the amount of drug release into the skin, C 0 the drug concentration in the matrix, D the diffusion coefficient, and t the time.

    The time to reach the M vs. The methodology of an in vitro release test and its applications have been discussed and summarized in an AAPS—FDA sponsored workshop report Flynn et al. The testing conditions were evaluated and established by Shah et al. It was demonstrated that: This is an interesting and extensive study, which provided a quantitative insight into the optimization of semisolid formulations, particularly emulsions, for salicylic acid.

    It is known that most of these effects, if not all, are compound dependent, and that a release test is often not a reliable indicator of drug delivery because the use of an aqueous solution as the receptor phase in release tests differs significantly from use of a formulation—skin interface.

    Taft, in Pharmacology , A second important family of drug transport proteins are the solute carrier transporters SLC. SLC proteins play important physiological roles in the transport of nutrients and drugs. SLCs function by one of several mechanisms including facilitated, ion-coupled, and ion-exchange transport. These families are discussed individually later.

    The OAT family plays a key role in drug excretion by the kidney, although these proteins are expressed in other tissues including the liver and the brain. In terms of drug disposition, OAT1 is the most important member of this transport family. Expressed mainly in the kidney tubule cell, OAT1 is a dicarboxylate exchange protein that is responsible for basolateral uptake of organic anions such as para-aminohippurate PAH. OAT1 mediates the excretion of a diverse array of substrates, including environmental toxins.

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    Substrates for this transporter include antibiotics, antiviral nucleoside analogs, and nonsteroidal anti-inflammatory medications. In fact, more than medications and toxic compounds have been found to interact with OAT1. OAT2 is expressed in the liver and kidney. OAT3 has a broader tissue distribution including the brain, liver, and kidney.

    OATP is a family of membrane transporters that mediate uptake of endogenous substrates and drugs. Although certain OATP isoforms are selectively involved in hepatic uptake of hydrophobic anions, most OATPs are widely expressed in various physiological barriers in the body, including the intestine, kidney, brain brain capillary endothelial cells and choroid plexus , lungs, and placenta Table 9.

    Consequently, the nomenclature of OATP transporters is quite complicated. The importance of OATPs to drug disposition is still evolving and remains to be clarified, although a role in renal and hepatic transport as well as uptake across the blood—brain barrier has been demonstrated.

    Drug Transport

    Despite the designation, OATP substrates are not limited to organic anions, but also include cations as well as neutral and zwitterionic compounds. The transport of cationic compounds across cells of the kidney, liver, and brain is mediated by a combination of two distinct transport families: Accordingly, these transporters play important roles in drug excretion.

    Six OCT proteins have been identified.

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