EPR effect (pharmacology)

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Schematic representation of the EPR effect

The phenomenon of passive accumulation of macromolecules , liposomes or nanoparticles in tumor tissues is referred to as EPR effect ( engl. Enhanced permeability and retention = "enhanced permeability and retention"), respectively. The EPR effect is a variant of passive drug targeting , that is, passive targeted pharmacotherapy .

Cause of the phenomenon

The tissue of most malignant tumors is physiologically and biochemically different from normal body tissue . Several causes are responsible for this differentiation:

  • The extensive formation of new blood vessels ( angiogenesis ), which is associated with hypervascularization. Tumors begin to neovascularization (formation of new blood vessels) from a size of 150 to 200 µm in order to ensure a sufficient supply of nutrients and oxygen, which is necessary for further tumor growth.
  • The newly formed blood vessels of the tumors have a number of peculiarities or defects in the vascular structure. This applies to both the shape and the structure. The endothelial cells of the capillary vessels of tumors are fenestrated, which means that they have significantly larger openings (fenestrations) compared to many other capillaries.
  • The lymphatic system of the tumors also shows considerable deficiencies compared to healthy tissue. Effective lymph drainage in the tumor is therefore not guaranteed.
  • The tumor cells increase the production of compounds that cause increased tissue permeability.

All of these factors mean that macromolecules, liposomes or nanoparticles can easily diffuse into the tumor tissue ( permeation ), which is normally much more difficult in healthy tissue. The removal of the diffused materials is more difficult due to the defective lymphatic system ( retention ). The increased permeability and the increased retention capacity for diffused macromolecules of the tumor tissue can be used for tumor-directed therapy of cancer diseases ( drug carrying ).

Therapeutic use

Conventional active ingredients made from “small molecules” usually only have a short plasma half-life in the bloodstream . Due to their small molecule size, these active ingredients are below the kidney threshold, i.e. they are separated from the blood in the kidney corpuscles and excreted in the urine ( renal clearance ). During the short period of time in the body, the active ingredient molecules also diffuse into the healthy tissue and are distributed almost evenly throughout the body. Only relatively small amounts of active ingredient reach the actual place of determination, the focus of the disease . In healthy tissue, the active ingredient can lead to undesirable side effects, which ultimately limit the active ingredient dose and thus often make effective treatment more difficult.

In contrast to the low molecular weight compounds, macromolecules can not overcome the capillary walls of the endothelial cells in healthy tissue by diffusion . Ideally, the healthy tissue is largely spared from side effects. In contrast, the EPR effect in tumors enables large molecules or groups of molecules to diffuse into the tumor tissue. Due to the defective lymphatic system, the substances diffused in this way can accumulate in the tumor. Compared to the application of active ingredients in the form of individual small molecules, the therapeutic range is improved . The active ingredient is present in higher concentrations at the specific site of action than, for example, in healthy tissue. This difference is of great advantage especially in the case of highly potent active ingredients, such as cytostatics , for example , which often have significant side effects .

The size of the macromolecule is of crucial importance for the EPR effect. The EPR effect is possible from a molar mass of around 20  kDalton . A large number of studies have been carried out with polymer-drug conjugates in recent years. The molar masses were in the range from about 20 to 200 kDa. In healthy people, the so-called kidney threshold is around 30 to 50 kDa (which corresponds to around 5 to 7 nm), which means that molecules in this size range are not excreted in the urine.

Biocompatible polymers such as polylactides or poly-N- (2-hydroxypropyl) methacrylamide (PHPMA) are used as macromolecular carriers , but dendrimers and nanoparticles are also clinically tested. A frequently used carrier molecule is albumin . The active substance molecules are conjugated to these carrier materials. These are mostly cytotoxic drugs such as doxorubicin . The active ingredient molecules can also be bound to the carrier molecule via cleavable linkers. The cleavable linker should enable the release of the active ingredient, that is, the separation from the carrier molecule. Several concepts are discussed and tested. For example, linkers that are cleaved in tumors due to the significantly lower pH value . These include the acid-labile hydrazones . Another concept are linkers that can easily be cleaved enzymatically, such as ester linkages that are cleaved by esterases . Short peptide sequences such as the tetrapeptide Gly - Phe - Leu -Gly, which can be cleaved by the enzyme cathepsin B present in the lysosome of many body cells , are also used.

The degree of permeation of the polymer into the tumor depends on several factors. In addition to the size, more precisely the molar mass of the polymer, its charge or the charge distribution in the polymer, the conformation of the polymer, its hydrophilicity and its immunogenicity are important parameters.

The rule of thumb is a molar mass above about 40 kDa, which prevents rapid excretion via the kidneys and a neutral charge of the polymer. Both measures can ensure the longest possible circulation in the bloodstream. The use of polyethylene glycol groups ( PEGylation ) is often advantageous . A long plasma half-life is of crucial importance for the accumulation of the polymer in the tumor.

In addition, the tumor size can also have an influence on the polymer uptake. Smaller tumors take up larger amounts of polymer than larger tumors.

Active ingredient examples

Caelyx is a special formulation of doxorubicin that is encapsulated in PEGylated liposomes. This significantly reduces the cardiotoxicity of doxorubicin. In Abraxane , the active ingredient paclitaxel is bound to albumin. In zinostatin is the active ingredient neocarzinostatin to a styrene - maleic acid - copolymer attached, which binds to albumin and plasma achieved a total mass of about 80 kDa.

In addition to these already approved drugs , a number of different active ingredients based on the EPR effect are in clinical trials.

Discovery story

Example of a polymeric drug delivery system according to Ringsdorf (here with doxorubicin as active ingredient)

In 1986 the two Japanese Yasuhiro Matsumura and Hiroshi Maeda first described the EPR effect. In several series of experiments , they marked various proteins of different molar masses, from 12 to 160 kDa, with 51 Cr . In terms of proteins, they used ovomucin (M = 29,000 g mol −1 ), bovine albumin (M = 69,000 g mol −1 ) and murine immunoglobulin G (M = 160,000 g mol −1 ), as well as the semi-synthetic SMANCS ( M = 16,000 g mol −1 ). They were able to determine significant accumulations of these peptides in the tumor tissue of mice with tumors. In these first experiments, the concentration in the tumor was up to five times higher than the concentration in the blood. SMANCS, a styrene-maleic acid copolymer to which the active ingredient neocarcinostatin chromophore (NCS) is conjugated, was first synthesized by Maeda a few years earlier as a cytostatic agent . For this conjugate, Matsumura and Maeda found 19 hours after application a concentration in the tumors that was 3.2 times higher (based on the blood concentration), while for the non-conjugated active substance NCS they found a molar mass of 659.6 g mol - 1 could not even reach a factor of 1 in previous experiments. With the intra-arterial application of SMANCS via an artery supplying the tumor, Maeda's working group was able to increase the concentration ratio of SMANCS tumor / blood to a factor of 1200. They postulated the a) hypervascularization of the tumors as the cause of the accumulation of proteins in the tumor, b) the increased vascular permeability in tumors previously determined by several other working groups, c) the weak transport of the macromolecules via the capillaries and d) the poorly developed one Lymphatic system in tumors, which also severely restricts the removal of these molecules. The poor development of a lymphatic system in tumors was demonstrated by Maeda's research group in 1984. In healthy tissue, on the other hand, macromolecules and lipids are transported out of the interstitium relatively quickly via the lymphatic system.

The first concepts for drug delivery systems based on synthetic polymers come from the German chemist Helmut Ringsdorf in 1975 .

Individual evidence

  1. ^ H. Maeda et al: Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. In: J Control Release . 65, 2000, pp. 271-284. PMID 10699287 (Review)
  2. ↑ a b c d e f R. Haag, F. Kratz: Polymers Therapeutics: Concepts and Applications. In: Angew Chem. 118, 2006, pp. 1218-1237. doi: 10.1002 / anie.200502113
  3. ↑ P. Caliceti, FM Veronese: Pharmacokinetic and biodistribution properties of poly (ethylene glycol) -protein conjugates. In: Adv Drug Deliv Rev . 55, 2003, 1261-1277. (Review) PMID 14499706
  4. ^ F. Vögtle et al.: Dendritic molecules. Vieweg + Teubner Verlag, 2007, ISBN 978-3-8351-0116-6 , p. 331.
  5. ↑ D. Kaufmann: Post-translational chemical modifications of an elastin-mimetic protein for medical applications. Dissertation. Technical University of Munich, 2006.
  6. ↑ H. Maeda et al .: Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. In: J Control Release. 74, 2001, pp. 47-61. PMID 11489482 (Review)
  7. ↑ K. Greish et al .: Macromolecular therapeutics: advantages and prospects with special emphasis on solid tumor targeting. In: Clin Pharmacokinet . 42, 2003, pp. 1089-1105. PMID 14531722 (Review)
  8. ↑ R. Satchi-Fainaro: tumor vasculature targeting: reality or a dream? In: J Drug Targeting. 10, 2002, pp. 529-533. PMID 12683719
  9. ↑ ema.europa.eu
  10. ^ T. Toyoshima: Biomaterial Research in Japan. (PDF; 443 kB) February 22, 2001, p. 35.
  11. ↑ H. Maeda et al .: Tailormaking of protein drugs by polymer conjugation for tumor targeting: a brief review on smancs. In: J Protein Chem. 3, 1983, pp. 181-193.
  12. ^ Y. Matsumura, H. Maeda: A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. In: Cancer Res . 12, 1986, pp. 6387-6392. PMID 2946403
  13. ↑ K. Iwai, H. Maeda, T. Konno: Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X-ray image. In: Cancer Res. 44, 1984, pp. 2115-2121. PMID 6324996
  14. ↑ DR Senger et al.: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. In: Science . 219, 1983, pp. 983-985. PMID 6823562
  15. ↑ HF Dvorak et al .: Regulation of extravascular coagulation by microvascular permeability. In: Science . 227, 1985, pp. 1059-1061. PMID 3975602
  16. ↑ IL Peterson et al.: Capillary permeability of two transplantable rat tumors as compared with various normal organs of the rat. In: Bibl Anat. 12, 1973, pp. 511-518. PMID 4790386
  17. ^ FC Courtice: The origin of lipoprotein in lymph. In: HS Mayersen (Ed.): Lymph and the Lymphatic System. C. C Thomas Springfield, IL, 1963, pp. 89-126.
  18. ^ H. Ringsdorf: Structure and properties of pharmacologically active polymers. In: J Polym Sci Polym Symp. 51, 1975, pp. 135-153.

literature

Reference books

  • H. Maeda et al: Polymer Drugs in the Clinical Stage. Verlag Springer, 2003, ISBN 0-306-47471-9 .
  • H. Maeda: Enhanced Permeability and Retention (EPR) Effect: Basis for Drug Targeting to Tumor. In: V. Muzykantov and VP Torchilin (eds.): Biomedical aspects of drug targeting. Verlag Springer, 2003, ISBN 1-4020-7232-5 , pp. 211f.

Review article

  • R. Duncan: The dawning era of polymer therapeutics. In: Nat Rev Drug Discov . 2, 2003, pp. 347-360. PMID 12750738
  • J. Fang et al: Factors and mechanism of “EPR” effect and the enhanced antitumor effects of macromolecular drugs including SMANCS. In: Adv Exp Med Biol. 519, 2003, pp. 29-49. PMID 12675206
  • K. Greish: Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. In: J Drug Target. 15, 2007, pp. 457-464. PMID 17671892
  • H. Maeda et al .: Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. In: Int Immunopharmacol . 3, 2003, pp. 319-328. PMID 12639809
  • Y- Luo, DG Prestwich: Cancer-targeted polymeric drugs. In: Curr Cancer Drug Targets . 2, 2002, pp. 209-226. PMID 12188908

Technical article