Enhanced permeability and retention effect

Last updated

The enhanced permeability and retention (EPR) effect is a controversial concept [1] [2] by which molecules of certain sizes (typically liposomes, nanoparticles, and macromolecular drugs) tend to accumulate in tumor tissue much more than they do in normal tissues. [3] [4] [5] The general explanation that is given for this phenomenon is that, in order for tumor cells to grow quickly, they must stimulate the production of blood vessels. VEGF and other growth factors are involved in cancer angiogenesis. Tumor cell aggregates as small as 150–200 μm, start to become dependent on blood supply carried out by neovasculature for their nutritional and oxygen supply. These newly formed tumor vessels are usually abnormal in form and architecture. They are poorly aligned defective endothelial cells with wide fenestrations, lacking a smooth muscle layer, or innervation with a wider lumen, and impaired functional receptors for angiotensin II. Furthermore, tumor tissues usually lack effective lymphatic drainage. All of these factors lead to abnormal molecular and fluid transport dynamics, especially for macromolecular drugs. This phenomenon is referred to as the "enhanced permeability and retention (EPR) effect" of macromolecules and lipids in solid tumors. The EPR effect is further enhanced by many pathophysiological factors involved in enhancement of the extravasation of macromolecules in solid tumor tissues. For instance, bradykinin, nitric oxide / peroxynitrite, prostaglandins, vascular permeability factor (also known as vascular endothelial growth factor VEGF), tumor necrosis factor and others. One factor that leads to the increased retention is the lack of lymphatics around the tumor region which would filter out such particles under normal conditions.

The EPR effect is usually employed to describe nanoparticle and liposome delivery to cancer tissue. [6] One of many examples is the work regarding thermal ablation with gold nanoparticles. Halas, West and coworkers have shown a possible complement to radiation and chemotherapy in cancer therapy, wherein once nanoparticles are at the cancer site they can be heated up in response to a skin penetrating near IR laser (Photothermal effect). This therapy has shown to work best in conjunction with chemotherapeutics or other cancer therapies. [7] Although the EPR effect has been postulated to carry the nanoparticles and spread inside the cancer tissue, only a small percentage (0.7% median) of the total administered nanoparticle dose is usually able to reach a solid tumor. [8]

See also

Related Research Articles

Angiogenesis

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Tumor hypoxia

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

Anthracycline

Anthracyclines is a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin, which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.

Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. This means of delivery is largely founded on nanomedicine, which plans to employ nanoparticle-mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue. The conventional drug delivery system is the absorption of the drug across a biological membrane, whereas the targeted release system releases the drug in a dosage form. The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side-effects, and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost, which makes productivity more difficult and the reduced ability to adjust the dosages.

Photothermal therapy (PTT) refers to efforts to use electromagnetic radiation for the treatment of various medical conditions, including cancer. This approach is an extension of photodynamic therapy, in which a photosensitizer is excited with specific band light. This activation brings the sensitizer to an excited state where it then releases vibrational energy (heat), which is what kills the targeted cells.

Vascular endothelial growth factor C

Vascular endothelial growth factor C (VEGF-C) is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the VEGFC gene, which is located on chromosome 4q34.

C-fos-induced growth factor

C-fos-induced growth factor (FIGF) is a vascular endothelial growth factor that in humans is encoded by the FIGF gene.

Epithelioid sarcoma Medical condition

Epithelioid sarcoma is a rare soft tissue sarcoma arising from mesenchymal tissue and characterized by epithelioid-like features. It accounts for less than 1% of all soft tissue sarcomas. It was first clearly characterized by F.M. Enzinger in 1970. It commonly presents itself in the distal limbs of young adults as a small, soft mass or a series of bumps. A proximal version has also been described, frequently occurring in the upper extremities. Rare cases have been reported in the pelvis, vulva, penis, and spine.

Vascular endothelial growth factor A

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

Follicular dendritic cell sarcoma Dendritic cell sarcoma cancer that effects the follicular dendritic cells

Follicular dendritic cell sarcoma (FDCS) is an extremely rare neoplasm. While the existence of FDC tumors was predicted by Lennert in 1978, the tumor wasn't fully recognized as its own cancer until 1986 after characterization by Monda et al. It accounts for only 0.4% of soft tissue sarcomas, but has significant recurrent and metastatic potential and is considered an intermediate grade malignancy. The major hurdle in treating FDCS has been misdiagnosis. It is a newly characterized cancer, and because of its similarities in presentation and markers to lymphoma, both Hodgkin and Non-Hodgkin subtypes, diagnosis of FDCS can be difficult. With recent advancements in cancer biology better diagnostic assays and chemotherapeutic agents have been made to more accurately diagnose and treat FDCS.

Arginylglycylaspartic acid Chemical compound

Arginylglycylaspartic acid (RGD) is the most common peptide motif responsible for cell adhesion to the extracellular matrix (ECM), found in species ranging from Drosophila to humans. Cell adhesion proteins called integrins recognize and bind to this sequence, which is found within many matrix proteins, including fibronectin, fibrinogen, vitronectin, osteopontin, and several other adhesive extracellular matrix proteins. The discovery of RGD and elucidation of how RGD binds to integrins has led to the development of a number of drugs and diagnostics, while the peptide itself is used ubiquitously in bioengineering. Depending on the application and the integrin targeted, RGD can be chemically modified or replaced by a similar peptide which promotes cell adhesion.

Microbubbles (MBs) are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, life science, and medicine. The composition of the bubble shell and filling material determine important design features such as buoyancy, crush strength, thermal conductivity, and acoustic properties.

<i>N</i>-(2-Hydroxypropyl) methacrylamide Chemical compound

N-(2-Hydroxypropyl)methacrylamide or HPMA is the monomer used to make the polymer poly(N- methacrylamide).

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

Tumor microenvironment

The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

Gold nanoparticles in chemotherapy

Gold nanoparticles in chemotherapy and radiotherapy is the use of colloidal gold in therapeutic treatments, often for cancer or arthritis. Gold nanoparticle technology shows promise in the advancement of cancer treatments. Some of the properties that gold nanoparticles possess, such as small size, non-toxicity and non-immunogenicity make these molecules useful candidates for targeted drug delivery systems. With tumor-targeting delivery vectors becoming smaller, the ability to by-pass the natural barriers and obstacles of the body becomes more probable. To increase specificity and likelihood of drug delivery, tumor specific ligands may be grafted onto the particles along with the chemotherapeutic drug molecules, to allow these molecules to circulate throughout the tumor without being redistributed into the body.

Tumor-associated endothelial cell

Tumor-associated endothelial cells or tumor endothelial cells (TECs) refers to cells lining the tumor-associated blood vessels that control the passage of nutrients into surrounding tumor tissue. Across different cancer types, tumor-associated blood vessels have been discovered to differ significantly from normal blood vessels in morphology, gene expression, and functionality in ways that promote cancer progression. There has been notable interest in developing cancer therapeutics that capitalize on these abnormalities of the tumor-associated endothelium to destroy tumors.

Nanoparticle drug delivery systems are engineered technologies that use nanoparticles for the targeted delivery and controlled release of therapeutic agents. The modern form of a drug delivery system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery.

References

  1. ↑ Nichols, Joseph W.; Bae, You Han (September 2014). "EPR: Evidence and fallacy". Journal of Controlled Release. 190: 451–464. doi:10.1016/j.jconrel.2014.03.057. PMID   24794900.
  2. ↑ Danhier, F. (December 2016). "To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?". Journal of Controlled Release. 244 (Pt A): 108–121. doi:10.1016/j.jconrel.2016.11.015. PMID   27871992.
  3. ↑ Matsumura Y, Maeda H (December 1986). "A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs". Cancer Research. 46 (12 Pt 1): 6387–92. PMID   2946403.
  4. ↑ Duncan, R.; Sat Y.-N. (1998). "Tumour targeting by enhanced permeability and retention (EPR) effect". Ann. Oncol. 9 (Suppl.2): 39.[ verification needed ]
  5. ↑ Vasey PA, Kaye SB, Morrison R, et al. (January 1999). "Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee". Clinical Cancer Research. 5 (1): 83–94. PMID   9918206.
  6. ↑ Maeda H (2012). "Macromolecular therapeutics in cancer treatment: the EPR effect and beyond". J Control Release. 164 (2): 138–44. doi:10.1016/j.jconrel.2012.04.038. PMID   22595146.
  7. ↑ Poon RT, Borys N (February 2009). "Lyso-thermosensitive liposomal doxorubicin: a novel approach to enhance efficacy of thermal ablation of liver cancer". Expert Opinion on Pharmacotherapy. 10 (2): 333–43. doi:10.1517/14656560802677874. PMID   19236203. S2CID   73112213.
  8. ↑ Wilhelm S, Taveres AJ, Dai Q, Ohta S, Audet J, Dvorak HF, Chan WC (April 2016). "Analysis of nanoparticle delivery to tumours". Nature Reviews Materials. 1 (5): 16014. Bibcode:2016NatRM...116014W. doi:10.1038/natrevmats.2016.14.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.