Principle And History Of Epr Effect

Cancer is one of the main leading causes of deaths worldwide, accounting for 8.2 million deaths in 2012. The reason for this is due to the poor results of the conventional chemotherapy. The primary cause of this is owing to the lack of selectivity of these drugs. Low molecular weight can enter all types of cells by random diffusion, hence they not only attack tumor cells but they also attack healthy cells with the same potency resulting in severe toxicity. Hence, scientists need to develop strategies to selectively target drugs to tumor cells, to prevent the toxic side effects. One of the most effective strategies to overcome this problem is to exploit the anatomical and pathophysiological abnormalities of tumor tissues such as the enhanced permeation and retention (EPR) effect (passive targeting). EPR effect is basically the gradual accumulation and retention of certain size molecules (such as nanoparticles, liposomes and macromolecular drugs) in tumor tissues.
Principle and History of EPR Effect
When tumor cells proliferate and reach 2mm3 size, the cells go into a state of hypoxia as the current vasculature fails to provide sufficient oxygen supply. As a result of this, cells start to die and secrete various growth factors that cause the formation of new blood vessels from the existing ones. This process is known as angiogenesis. As a result of angiogenesis, new blood vessels are formed which are irregular in shape and are defective. They have discontinuous epithelium, wide lumen, impaired functional receptors for angiotensin II (AT II) and either lack or have abnormal basement membrane and smooth muscle layer. Due to this the blood flow direction in tumor vessels is irregular and inconsistent. In addition to this, they have large fenestrations ranging from 200-2000 nm depending on the tumor type. As a result of this, tumor vasculature appears leaky leading to increased extravasation of blood plasma components such as macromolecules, nanoparticles and lipidic particles into the tumor tissue. Hence, enhanced vascular permeability is seen.
Another feature of tumors which are different from normal cells is that in normal cells the extracellular fluid is constantly being drained to the lymphatic vessels. Thus, there is a continuous draining and renewal of fluid. But in tumors, their lymphatic vessels are either absent or not functional, meaning no drainage from tumor tissue. Thus, whatever enters does not come out and you get retention of particle drugs. However, particles less than 4 nm can diffuse back to the blood circulation so it is important to control the size of the particle to ensure accumulation.EPR effect is simply accumulation of nanomaterial in tumor sites due to increased vascular permeability and lack of lymphatic drain.

EPR effect was first reported by Maeda and Matsumura in 1986 while they were working on poly(Styrene-co-Maleic Acid)-NeoCarzinostatin (SMANCS), a polymer conjugate of neocarzinostatin (NCS). NCS is an antitumor protein antibiotic. It was observed that SMANCS accumulated more in tumors and had an increased plasma half-life (20 fold higher) compared to NCS. This was due to SMANCS being able to bind non-covalently to albumin in circulation, thus increasing from 16 kDa to 80 kDa. Further studies were conducted with different plasma proteins which were different in molecular size and it was reported that proteins larger than 40 kDa accumulated in the tumor tissues to more extend than normal tissue and also stayed there for longer duration. This is due to 40 kDa being larger than renal clearance threshold.
Another experiment was conducted using dye Evan blue, which has the ability to bind to albumin and act as a macromolecule. After 24 hours of IV injection of this dye, it was revealed that there was no staining in healthy tissues and organs. Whereas, in certain tumor sites blue staining was seen indicating that there was accumulation of the complex.
Factors affecting EPR effect

Various vascular mediators are known to enhance the EPR effect. Such as bradykinin (kinin), nitric oxide (NO), peroxynitrite (ONOO-) and matrix metalloproteinases (MMPs), prostaglandins (PGs) and vascular endothelial growth factor (VEGF).
Bradykinin (kinin)
It is a major mediator of inflammation which is involved in extravasation and accumulation of body fluid in inflammation tissues. In tumors it acts as a vasodilator and also increases vascular permeability of blood vessels, enhancing the EPR effect. Further, in patients with late stage cancers, level of kinin is increased in blood plasma. The reason being, that tumor cells activate hageman factor (factor XII) which initiates a cascade leading to increased kinin levels: hageman factor ' prekallikrein ' kallikrein ' kinin. In addition to this kinin is also known to activate NO synthase (NOS) which is responsible for production of NO, another important mediator of tumor permeability.
Nitric oxide
NO is an important cellular signaling molecule generated by NOS by using L-arginine and O2 as substrates. NO is a powerful vasodilator and also plays a key role in angiogenesis, cell proliferation and extravasation. This can be seen by the experiment conducted by Maeda, in which they used specific NO scavenger 2-phenyl-4,4,5,5-tetramethyl-midazoline-1-oxyl-3-oxide (PTIO) and NOS inhibitor L-N??-nitro-L-arginine methyl ester (L-NAME) on solid mouse tumors to check their effect on vascular permeability. Results showed that PTIO suppressed extravasation of Evan blue by 47% in small tumors and 59% in larger tumors. L-NAME showed similar results. Hence, NO increases vascular permeability and enhances the EPR effect. In addition to this, it was found that expression on NOS is enhanced in tumors compared to normal cells.
Peroxynitrite (ONOO-) and matrix metalloproteinases (MMPs)

ONOO- is a strong oxidizing and nitrating agent and is formed by the reaction between NO and superoxide radical (O2??-). Tumors produce high amount of ONOO-, which then activates promatrix-metalloproteinases (proMMPs) to MMPs, which then increases vascular permeability by degradation of matrix protein. It can also enhance the EPR effect by activating the kinin cascade as seen in figure.
Prostaglandins (PGs)

PG is a lipid molecule that is synthesized by the enzyme cyclooxygenase (COX)-1 and -2. PGs also play an important role in vascular permeability and tumor growth. Among the various forms of PGs, PGE1 and PGI2 enhance extravasation by preventing platelet aggregation, leukocyte adhesion and thrombosis formation. Further, an experiment was conducted in which beraprost Na?? (analogue of PGI2) was administered to rats with tumors to see its effects on vascular permeability. Results showed that there was 2-3 times more extravasation of the Evan blue-albumin complex in tumor tissues. In addition to this, results also revealed that tumor blood flow was decreased to 70% compared to normal tissues. Hence, not only did it enhance the EPR effect but also inhibited tumor growth by stopping blood supply.
Vascular endothelial growth factor (VEGF)
VEGF plays an important role in angiogenesis and solid tumor growth. It is highly upregulated in tumor tissues. It increases vascular permeability, leading to enhanced EPR effect. Further studies also showed that VEGF interaction with its receptor can produce NO.
All these various factors play an important role in increasing vascular permeability and enhancing the EPR effect. These factors are interconnected; meaning inhibition of one may affect the other, making it a complex process. (summarized in figure)
Problems related to EPR effect

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