Drug targeting

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Drug targeting or targeted drug delivery , sometimes also called smart drug delivery , is the targeted and selective accumulation or release of a drug at one or more desired sites of action. In this way, the effectiveness of the effect is to be increased and at the same time systemic side effects are to be reduced. Targeting a drug is possible with the help of chemical modifications of the active ingredient, with the help of biotechnology or with the help of pharmaceutical technology .

purpose

There are pharmaceutical , biopharmaceutical , pharmacodynamic , pharmacokinetic and pharmaco-economic reasons for a targeted supply of the tissue to be treated . Examples of this are a reduced number of undesirable drug effects, a modified and more targeted release of active ingredients, fewer doses required or increased patient compliance. In addition, a sufficient supply of the affected cells, the affected tissue or the affected organs using classic methods can be difficult in numerous diseases such as central nervous disorders, rheumatoid arthritis , tumor diseases and tuberculosis . Drug targeting can also be helpful in these cases.

Drug Targeting Strategies

In general, active and passive drug targeting can be distinguished.

Passive targeting

The principle of passive targeting is based on the accumulation of the active ingredient at the desired location or tissue. In the case of tumors, for example, the induction of angiogenesis, the increased activity of proliferative signaling or the deregulation of the cellular energy metabolism (see Warburg effect) of the tumor cells can be used.

Active targeting

With active targeting, ligand-receptor interactions are influenced. These can only occur at distances of less than approximately 0.5 mm, which is what the drug delivery systems cause.

Methods

Targeting based on the physicochemical properties of the drug

The simplest form of drug targeting consists in optimizing the physicochemical properties, in particular the solubility , the lipophilicity and the acidity or basicity of the drug. Such drug targeting is generally not dependent on a drug carrier. The selectivity for a specific target tissue, however, is usually limited.

Such a targeting effect based on the physicochemical properties of the substance is discussed for the acidic non-opioid analgesics . Acid non-opioid analgesics such as acetylsalicylic acid , ibuprofen , naproxen , diclofenac , indomethacin and other representatives are predominantly in their deprotonated anionic form at a physiological pH value . In the acidic, inflamed tissue, on the other hand, they can accumulate, since they are protonated and thus immobilized in relevant quantities here. This property of non-opioid acidic analgesics is cited as the rationale for their therapeutic superiority over non-acidic analgesics such as phenazone , metamizole and paracetamol in the treatment of inflammatory diseases.

Target-selective activation of prodrugs

Another option are inactive prodrugs , which are selectively converted into their active form (active metabolites ) within the target tissue . An example of this are the proton pump inhibitors , one of which is omeprazole . Proton pump inhibitors are prodrugs that are activated in a strongly acidic environment, especially on the surface of the gastric acid- producing parietal cells , and as a result inactivate proteins such as the H + / K + -ATPase ( proton pump ) through covalent bonding.

Activation of omeprazole: After oral administration of omeprazole in an enteric form, the drug is absorbed in the small intestine into the bloodstream and thus reaches the parietal cells of the gastric mucosa, among other things. Due to the high proton concentration on the surface of the parietal cells, omeprazole is activated at its destination and locally inhibits the H + / K + -ATPase (proton pump)

Another example of drug targeting with the aid of prodrugs that are selectively activated in the target tissue are antibiotics from the group of nitroimidazoles , such as metronidazole . Nitroimidazoles are particularly effective under anaerobic conditions and have a broad spectrum of activity against anaerobic germs. In the anaerobic environment, the prodrug metronidazole is enzymatically split by the bacteria with the participation of ferredoxin into its highly reactive intermediate product N- (2-hydroxyethyl) -oxamic acid. This intermediate product leads to DNA strand breaks within the bacterial DNA and is therefore responsible for the bactericidal effect of metronidazole.

Vectorization

One form of drug targeting is vectorization, the conjugation of the drug to be administered to a molecule that is known to bind to the target cells. For this purpose, drugs can be coupled to antibodies , transferrin or other biomolecules . Alternatively, synthetic polymers can also be used.

Antibody conjugates

Antibody conjugates are macromolecular drugs in which at least one molecule of the actual active ingredient is bound to an antibody via a covalent bond . The antibody is usually directed against a surface molecule that is specific for the target cells or the target tissue. After binding to the target cells, the conjugates can optionally be taken up into the target cells via a receptor-mediated endocytosis via vesicles. Drugs that are coupled to antibodies are used in particular in the chemotherapy of malignant tumors . Examples are gemtuzumab ozogamicin and ibritumomab tiuxetan .

In the case of gemtuzumab Ozogamicins was monoclonal , against the CD33 - antigen antibodies directed gemtuzumab to the cytostatic ozogamicin , a relative of calicheamicin coupled. In order to be effective, the antibody-cytostatic conjugate must be absorbed into the cell. The systemic toxicity of ozogamicin is reduced through conjugation and targeting.

Ibritumomab tiuxetan is in radioimmunotherapy of various malignant B-cell - lymphoma applied (lymphoma). It is a conjugate of a monoclonal antibody directed against the CD20 B-lymphocyte antigen is directed at the surface of, and the chelator tiuxetan (a DTPA - derivative ), for example, the radioactive isotope yttrium can complex -90. This targeting of radioactive isotopes also corresponds to targeted radiation therapy .

More recent developments include conjugates consisting of an active ingredient and antibody fragments, such as F (ab) 2 fragments , Fab fragments and single domain antibodies or antibody mimetics such as e.g. B. Anticalins . These conjugates are said to be characterized by lower immunogenicity and improved tissue permeability.

Peptide conjugates

The conjugation of a drug to a peptide or to low molecular weight substances can also contribute to an accumulation of the drug in the target tissue and optionally enable it to be introduced into the target cells. As vectors for active ingredients such as doxorubicin, the so - called cell - penetrating peptides are of particular interest for research and development. For their endocytic uptake, depending on the pharmacological and physicochemical properties of the peptide, both receptor-mediated and non-specific, adsorption-mediated mechanisms play a role. The latter can be observed in particular with basic peptides and, via electrostatic interactions between the cell surface negatively charged by glycoproteins and positively charged vector peptides, lead to unspecific binding to the cell surface, as a result of which vesicular uptake into the cytoplasm takes place.

Basic protegrin derivatives, such as Syn-B, and penetratin derived from the homeodomain of Antennapedia , a transcription factor from Drosophila , are used experimentally for CNS targeting . Another peptide vector is the HIV-TAT ( Trans-Activator of Transcription ) , which consists of eleven predominantly basic amino acids and is isolated from the transduction domain of the HI virus . A peptide with similar properties is Transportan , which is made up of 27 amino acids .

Polymer conjugates

Schematic structure of drug-polymer conjugates. 1 polymer, 2 drug, 3 cleavable linker (optional), 4 target-specific ligand (optional)

Another possibility is the conjugation of a drug with a soluble polymer such as cyclodextrin , polyglutamate, polyaspartate, hydroxypropyl methacrylamide (HPMA) or polyethylene glycol (PEG). Ideally, the drug is linked to the polymer via a hydrolyzable linker and, in its bound form, is pharmacologically inactive (prodrug). After it has been taken up in the target cells by endocytosis and under the action of lysosomal enzymes, the drug can be released from the conjugate in its active form. In this way, a delayed release of the active ingredient can also be achieved. However, the target selectivity of the polymer conjugates is usually limited, as it is shaped by the physicochemical properties of the polymer. Regardless of this, many polymer conjugates show a tendency to accumulate in tumor tissue due to the EPR effect . The tissue selectivity of drug-polymer conjugates can be increased by further conjugation with antibodies.

With the aim of drug targeting, numerous potential drugs that exploit the EPR effect have been developed. Polymer conjugates such as HPMA- doxorubicin , HPMA- camptothecin , HPMA- paclitaxel and pegamotecan (PEG-camptothecin) are currently in clinical trials. Drug approval is expected soon for paclitaxel-poliglumex , a conjugate of paclitaxel and polyglutamate.

Particulate carriers

Particulate carriers represent a possibility of pharmaceutical technology to transport a drug in a targeted manner. As in the case of polymer conjugates, the EPR effect can be used for drug targeting in order to transport a drug into the tumor tissue. In addition, particulate carriers can be conjugated with cell- or tissue-specific antibodies or cell-penetrating peptides in order to selectively transport the drug into the target tissue. The medicinal substance is usually physically bound in or on the carrier and can be released from its carrier after reaching its destination. Inside the carrier, the drug is also protected against metabolism . The carriers most commonly used for targeting include micelles , nanoparticles, and liposomes .

Liposomes

Liposome

Liposomes are particulate carriers with a size of 50 to 1000 nm, the aqueous inner phase of which is separated from the outer phase by a phospholipid bilayer. A water-soluble drug can be encapsulated inside a liposome. Alternatively, liposoluble drugs can accumulate in limited amounts in the phospholipid membrane. Artificial liposomes are largely stable in the organism and, like their naturally occurring counterparts, have low toxicity and allergenicity . Their degradation occurs preferentially after endocytotic uptake in the cells of the reticuloendothelial system . A modification of the liposome surface with polyethylene glycol, the so-called PEGylation , can mask liposomes and thus protect them from degradation (“ stealth liposomes ”). Optionally, a target-seeking ligand, for example an antibody, can be anchored in the liposome shell.

Some examples of liposomal drugs that have already been approved for therapy are listed in the table below. Further liposomal drugs, such as liposomally encapsulated cisplatin , lurtotecan , tretinoin and vincristine , are currently in clinical trials. Liposomes are also used in transfection , the smuggling of DNA into cells, and thus represent potential vehicles in gene therapy . For this application, which is also referred to as lipofection , liposomes in particular are used which are composed of cationic lipids.

drug Drug Target tissue indication
AmBisome Amphotericin B severe systemic or deep mycoses
DaunoXome Daunorubicin Tumor tissue Kaposi's sarcoma
Myocet, Doxil Doxorubicin Tumor tissue Breast cancer
Caelyx Doxorubicin Tumor tissue Kaposi's sarcoma, ovarian cancer, breast cancer, multiple myeloma

Micelles

Micelles are a way of producing particulate carriers using amphiphilic block copolymers (polymers with different types of monomers) in aqueous solution. The active ingredient or active ingredients can be located within the block copolymers (5-50 nm) and transported by them to places where they would normally not dissolve. The formation of a shell around the active ingredient also provides protection against hydrolysis or enzymatic degradation.

Nanoparticles

Nanoparticles are carriers made of natural or synthetic polymers with a size of approximately 10 to 1000 nm. The active ingredient can either be attached as a crystal in the nanoparticle (see mixed crystal), adsorbed on its surface or chemically bound.

A potential advantage of these drug delivery systems is that, under certain conditions, they can cross the blood-brain barrier . The hexapeptide dalargin (Tyr- D -Ala-Gly-Phe-Leu-Arg) was the first active ingredient that was able to cross the blood-brain barrier in vivo with the help of polybutyl cyanoacrylate nanoparticles coated with polysorbate 80 . It is a leu- enkephalin analog that has activity on opioid receptors and can consequently influence the sensation of pain. The mechanism by which the blood-brain barrier is crossed is not yet fully understood. However, it is assumed that there are connections with particle size and structure. For example, PEG-coated nanoparticles, which mimic the structure of LDL (low-density lipoprotein), are transported into the brain.

Individual evidence

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  22. ↑ Product information AmBisome ® 50 mg powder for solution for infusion. Gilead. As of April 2009.
  23. ↑ Technical information Myocet ® . Cephalon. As of November 2008.
  24. ↑ specialized information Caelyx ® 2 mg / ml. As of December 2007.
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