Drug Targeting Organ-Specific Strategies
.pdf370 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
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Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)
14Drug Targeting Strategy: Scrutinize the Concepts Before Screening the Constructs
Dirk K. F. Meijer
14.1 Introduction
The current problems in controlling cancer, severe infections and chronic degenerative diseases, as well as the lack of effective and safe pharmacotherapeutic measures for such disorders, have renewed interest in the options of targeting drugs, peptides, genes and anti-sense material to sites of disease.
Structure–activity relationship studies and rational drug design procedures have led to the synthesis of many novel drugs that are highly potent. Yet, at the same time, they can exhibit severe toxicity since they are also accessible to non-target cells. In fact, the physicochemical features of drugs that dictate their pharmacologic activity also determine their distribution patterns in the body. To overcome the undesirable side-effects and to ‘uncouple’ the pharmacokinetic behaviour of the drug from its ‘pharmacodynamic profile’, the drug can be directed to its site of action and/or be diverted from sites where it will be potentially toxic by coupling to macromolecular carriers. The chosen carrier is then supposed to determine the fate of the coupled drug in the body.
The design and development of potential carriers for cell-specific delivery of therapeutics should be based on a detailed knowledge of recognition sites on the surface of target cells as well as on insight into the internalization and further cellular disposition of such macromolecules.
In the drug targeting approach, two different strategies can be distinguished: passive targeting and active targeting. In the case of passive targeting, the carrier-associated drug is, for instance, delivered to macrophages, resulting in gradual degradation of the carrier and slow release of the liberated drug from the cells. Through size-restricted extravasation of the carrier, the carrier–drug complex tends to stay in the systemic circulation and is, at least partly, prevented from distribution to sites where it may have a toxic effect. Active targeting, on the other hand, should lead to higher therapeutic concentrations at the site of action through cell-specific delivery via the macromolecular carrier. In principle, in active targeting, the dose of the drug can be reduced and the side-effects will thus be decreased.
Drug delivery research in practice requires professional planning and careful avoidance of intrinsic pitfalls. Some essential guidelines, derived from our own experience, are listed in Table 14.1. They should not only be taken into account before embarking on a drug delivery project, but should also be integrated during the developmental phases of the drug innovation process.
372 14 Drug Targeting Strategy: Scrutinize the Concepts Before Screening the Constructs
Table 14.1. General guidelines in drug targeting research.
•It is preferable to test the effects of drug-targeting preparations on the whole body as early as possible
•It is advisable to test drug targeting preparations with regard to possible immunogenicity at an early stage of development
•Cell-specific distribution of the drug-targeting preparations as well as the rate of drug release from the carrier should be studied both in the healthy and pathological situation
•Drug loading of the carrier should be carefully balanced: sufficient drug molecules should be internalized to obtain therapeutic levels. However, excessive loading may corrupt the cell specificity of the carrier
•The chosen carrier should be non-toxic, as should its degradation products
•The chosen carrier should be capable of traversing anatomical barriers in the body en route to the particular target tissues in the diseased state
•Since parenteral administration is required, drug targeting formulations should provide distinct advantages in efficacy and safety compared with the non-targeted drug
•Special attention should be paid to the patenting of targeting constructs: the unique combination of drug, linker and carrier may provide options for product protection
•The large gap between pre-clinical and clinical research can be (at least partly) bridged by screening of the disposition properties as well as the efficacy of drug delivery preparations in (diseased) human tissues in vitro
•Aspect of therapy costs of drug targeting preparations should be carefully weighed in relation to the present state of the art in the therapy and cost containment aspects of health care
14.2 Receptor-based drug targeting
The success of drug targeting with macromolecular carriers is intimately dependent on the selectivity of the cellular targets in the body. Other crucial factors are the anatomical and/or pathological barriers that have to be passed en route to these recognition sites and the events following receptor recognition and internalization of the drug conjugate: intracellular routing encompassing carrier degradation and drug release.
Table 14.2 lists a number of receptors for macromolecules that have been identified so far and that are more or less specific for the organ/tissue or even the cell type indicated. Some of these receptors are lectins which recognize oligosaccharide chains in a specific geometric arrangement with a specific type of terminal sugar or otherwise clustered sugars and/or randomly exposed sugars with sufficient density. Others are receptors for cytokines, growth factors and adhesion molecules which bind specific peptides that can be used as a homing devices. Such receptors can select their substrates on the basis of the specific conformation presented by the functional groups and the charge density of such macromolecules. Selectivity in binding can also be based on multivalency in sugar or peptide recognition.
Although such receptors often provide mechanisms for internalization followed by intracellular transport to compartments where degradation takes place, the rates of these processes can be markedly different in various cell types. In some cases only external binding occurs and consequently, the microclimate of the cell membrane at which local release of the drug from the carrier takes place, should provide sufficient driving force to ensure uptake of the drug into the target cell.
14.2 Receptor-based Drug Targeting |
373 |
Table 14.2. Organ and tissue selective distribution of potential drug carriers based on receptor recognizing principles: a few examples.
Organ/Tissue |
|
Carriers |
Species |
Diseases aimed at |
|
|
|
|
|
Liver |
Hepatocytes |
Lactosaminated (H)SA |
Rat, man |
Hepatitis B and C |
|
|
Arabinogalactan |
Man |
Liver cancer |
|
|
Asialoglycoproteins |
Rat, man |
|
|
Kupffer cells |
Mannosylated (H)SA |
Rat |
Inflammation, sepsis |
|
Endothelial cells |
Negatively charged (H)SA Rat, man |
Organ rejection, I/R |
|
|
|
|
|
damage |
|
Stellate cells |
Man - 6 P (H)SA |
Rat, man |
Liver fibrosis |
|
|
RGD oligopeptides - |
Rat |
Liver fibrosis |
|
|
(H)SA |
|
|
|
Cholangiocytes |
pol.IgA, alkaline |
Man, rat |
Peribiliary cirrhosis |
|
|
phosphatase |
|
|
Kidney |
Tubular cells |
Low MW proteins |
Rat, man |
Nephrotic syndrome |
|
|
(Lysozyme) |
|
Renal cancer |
|
Mesangial cells |
IgA (asialo) |
Rat |
Renal fibrosis |
|
|
Anti- Thy1-Ab |
Rat, man |
|
Brain |
BBB endothelia |
Transferrin |
Rat, man |
CNS infections |
|
|
Anti-Transferrin-R Ab |
Rat |
Parkinson’s disease |
|
|
Anti-Insulin-R Ab |
Rat |
Alzheimer disease |
|
|
|
|
Brain tumours |
Lung |
Alveolar macrophages |
Glucosylated proteins |
Rat |
Lung cancer |
|
|
|
|
Lung infections |
|
Endothelial cells |
Anti-CD31 Ab |
Rat |
Lung inflammation/ |
|
|
|
|
cancer |
Blood cells |
Monocytes/Macrophages ß-Glucans, |
Rat |
HIV infections |
|
|
|
Mannosylated proteins |
Rat |
Ovarian cancer |
|
T-lymphocytes |
HIV-gp120, IGF-I, sCD4 |
Rat, man |
HIV infections |
|
|
Anti-CD3 Ab |
|
Rejection transpl. |
|
|
|
|
organs |
|
B-lymphocytes |
Anti-CD20 Ab |
man |
B-cell cancer |
Blood vessels |
Endothelia |
Lactoferrin, OxLDL |
Rat |
Atherosclerosis |
|
Tumour vasculature |
Anti-VEGF-R Ab, VEGF |
|
Solid tumours |
Intestines |
Enterocytes |
Dimeric IgG1 |
Rat |
Colitis, Crohn’s |
|
|
Lactoferrin (enteral) |
Rat, man |
disease |
|
|
|
||
|
|
|
|
|
Ab, Antibody; BBB, Blood Brain Barrier; CNS, Central Nervous System; HIV, Human Immunodeficiency Virus; HSA, Human Serum Albumin; IGF, Insulin Growth Factor; I/R, Ischaemia/Reperfusion; MW, Molecular Weight; OxLDL, Oxidized Low Density Lipoprotein; -R, -receptor; sCD4, soluble CD4; VEGF, Vascular Endothelial Growth Factor.
With regard to the specificity of sugar–lectin interactions, it should be noted that interactions of sugar-based compounds with lectins on different cell types seem to be determined by the recognition of either a randomly presented sugar with sufficient density on the protein or a particular sugar arranged in an antennary structure.Alternatively, high affinity binding may involve recognition of a combination of different sugars. The use of one sugar type in inhibition experiments may therefore give an false picture of the true recognition sites.
374 14 Drug Targeting Strategy: Scrutinize the Concepts Before Screening the Constructs
A general warning should be given with regard to the design of drug targeting preparations for anti-infective drugs. If endocytosis is required for cellular delivery, infected cells may be less active in this respect, e.g. due to depletion of energy-rich metabolites or decreased expression of cell surface receptors. The efficiency of the delivery process may thus be decreased during infection, in particular after extensive transformation of cells leading to gross changes in the surface molecules and/or the ability of the cell to degrade the drug–car- rier complex.
Both receptor density and affinity for a given substrate as well as the presence of competing endogenous ligands, determine the extent of carrier–receptor occupation and thus the extraction of the carrier–drug complex by the target tissue. Endogenous ligands can include tumour antigens and soluble receptor molecules that are shed during the disease and its treatment, and may partly inactivate or neutralize the chosen drug carrier delivery system.
Finally, continuous exposure of certain receptors to their macromolecular ligands can lead to rapid downregulation of cell surface receptors, especially if receptor recycling within the cells is incomplete. Fortunately, expression of many receptors, for example for certain cytokines, growth hormones and adhesion factors, can be extensively upregulated in the disease process and this can result in disease-induced drug-targeting.
Downand upregulation of receptors should therefore be taken into account in predicting the pharmacokinetics of macromolecular carriers upon chronic administration. For instance, when the particular receptors to be targeted are present on more than one cell type in the body, and upor downregulation in these cells occurs at different rates, tissue specificity for drug–carrier complexes in the body may change with time during chronic dosing. Also the therapeutic effects attained may influence selective distribution through changes in receptor expression and/or carrier degradation.
Some of the drug carriers which are currently being developed, provide intrinsic therapeutic activity that may add to the effect of the coupled drug, a principle called dual targeting. Such multi-active drug targeting preparations may offer the advantages of synergistic effects and for instance, counteraction of drug resistance, in addition to improving the specificity of distribution within the body.
The rate-limiting steps in the distribution of drug targeting preparations throughout the body, can be elegantly simulated using appropriate (patho)physiology-based predictive models. Computer-assisted modelling can give further insight and a more accurate prediction of drug levels at the target and non-target sites. Such simulations should certainly include multiple dose regimens for obvious practical reasons. In general: drug delivery scientists should be less attracted by superficial (in vitro) concepts but rather should look for a realistic prediction of the particular value of the chosen targeting procedures in the in vivo setting.
14.3 Concluding remarks
Although, so far, some promising results have been achieved in vitro in the ‘targeting’ of various categories of drugs, it often remains unclear which fraction of the chosen carrier really enters the target cells in vivo. This was extensively studied for lactosaminated HSA in liver (hepatocyte) targeting, and for some monoclonal antibodies. However, much work remains
14.3 Concluding Remarks |
375 |
to be done with regard to carriers of the particle type, antibody preparations and (neo-)gly- coproteins as well as derivatized polyaminoacids and polymers. Rapid screening and structure optimization for such potential carriers should be performed in various species, both in the healthy and diseased state.
Coupling of drugs to macromolecular carrier systems a priori implies that parenteral formulations have to be used.Although parenteral dosing is quite acceptable for short-term and even long-term clinical use (e.g. insulin and other peptide drugs), it is clear that drug targeting preparations should have obvious advantages compared with the parent drug in order to justify their development. These advantages could include much higher potency, shorter treatment periods, therapy of intracellular infections in the case of poorly penetrating drugs, and/or a major reduction in the dosing frequency and toxicity.
It should be emphasized that site-specific drug delivery does not prevent the build up of steady-state plasma concentrations of the parent drug: even if the release rate for the drug in the target cells is slow, some of the targeted drug will tend to enter the general circulation. However, the plasma levels will be generally lower and the local concentration in the target tissue higher. It should also be taken into account that delivery procedures can lead to a shift in toxicity patterns. For example, inclusion of daunomycin in pegylated liposomes may reduce cardiac toxicity but, at the same time, may induce macrophage toxicity, since after multiple dosing liposomes (even surface modified) will finally end up in the monocyte-phagocyte system.
There is a current tendency to develop carriers on the basis of polypeptides and other polymeric carriers with rather simple structures. For instance, polylysines, polyhydrox- ymethyl-acrylamide and polylactic acid material with variations in charge and molecular weight can be tailor-made and equipped with clustered recognition sites. The biocompatibility of such carrier systems with chronic dosing should, however, be more clearly established.
In conclusion, it can be stated that the opportunities for targeting drugs seem to be abundant. Nevertheless, the manipulation of drug distribution in the diseased state in humans will require a multidisciplinary effort on the part of cell biologists, biochemists, molecular biologists, pharmacologists, pharmaceutical technologists and clinicians, before the many innovative technologies can be put into practice. In this respect, it is crucial that drug delivery technology is more structurally integrated in the overall activity of industrial drug innovation.
It is unlikely that novel compounds with promising pharmacodynamic profiles will at the same time possess completely adequate pharmacokinetic properties. Of note, attractive and potent drugs which exhibit unfavourable kinetic properties or show severe side-effects and toxicity, may be prematurely eliminated from the test bench, in spite of all the R & D money spent.
In general one should, in an early developmental phase, combine the available pharmacological and drug delivery know-how to aim for novel therapeutic modalities that display high efficacy and selectively. In other words, drug targeting options should be considered more as a high-tech extension of the process of drug design and development and less as an art of trouble-shooting in retrospect.