The EPR Effect

Although Bohm formalism provides the most forceful demonstration of the non-local character of quantum theory, the evidence has been around for many decades. The so-called EPR effect was first recognized by Einstein and his co-workers, Podolsky and Rosen in 1935 [3]. The purpose of their work was to demonstrate that the apparent non-local nature of quantum mechanics could only mean that a vital element was missing from the theory. The missing element had to be such as to counteract the non-local feature. 

The EPR effect was demonstrated in terms of a Gedanken experiment to show that quantum systems which became correlated at any time, would stay correlated until the combined system is disturbed by measurement. Two principles of fundamental importance are assumed in this analysis  

without in any way disturbing a system, the value of a physical quantity in that system can be predicted with certainty (with probability equal to one), then there exists an element of reality corresponding to the physical quantity. 

Consider an arbitrary observable A with a set of eigenfunctions, ipa, belonging to a series of eigenvalues denoted by o. According to the first assumption there is an element of reality corresponding to observable A in the system. Next, consider another observable B which does not commute with A, so that there exists no wave function for which A and B have simultaneously definite values. If every element of physical reality must have a counterpart in a complete physical theory, the previous conclusion implies that A and B cannot exist simultaneously. 

In other words, for a pair of observable properties characterized by noncommuting operators, AB BA, precise knowledge of property A precludes any knowledge of B. 

---

In cancer treatment, passive targeting of macromolecular carriers to tumors is a commonly used approach. This passive targeting is based on the enhanced permeability and retention (EPR) effect, which leads to an accumulation of the high molecular weight carrier in the tumor tissue. The EPR effect arises from the different physiology of tumor vasculature, where the vessel walls are highly porous and lack the tight junctions that are present in healthy tissue. As a result, macromolecular carriers extravasate and accumulate preferentially in tumor tissue relative to normal tissues [63, 64]. 

Micellar nanocarriers have already been applied successfully for delivery of hydro-phobic drugs [86]. These carriers are usually the product of self-assembled block copolymers, consisting of a hydrophilic block and a hydrophobic block. Generally, an ELP with a transition temperature below body temperature is used as hydrophobic block and the hydrophilic block can be an ELP with a transition temperature above body temperature or another peptide or protein. The EPR effect also directs these types of carriers towards tumor tissue. 

Fig. 5 Polypeptide vesicles demonstrate the ability to utilize the EPR effect, (a) Chemical structure of the amphiphilic block polypeptide PSar-b-PMLG. (b) Fluorescence image using fluorescently labeled PEG. Fluorescence is not observed in the cancer site although accumulation is observed in the bladder, (c) Fluorescence image using ICG-labeled vesicles, showing evidence of vesicle accumulation due to the EPR effect. Adapted from [41] with permission. Copyright 2008 American Chemical Society...

Shielded polyplexes with improved blood circulating properties are interesting tools for systemic cancer therapy (see Sect. 4.2). Nanoparticles can take advantage of the enhanced permeability and retention (EPR effect) [89] for passive tumor targeting. The EPR effect is based on the leakiness of tumor vasculature, due to neovascularization in growing tumors, combined with an inadequate lymphatic drainage. Nanoparticles with an elongated plasma circulation time can extravasate and passively accumulate at the tumor site. 

Hatakeyama H, Akita H, Harashima H (2011) A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect a strategy for overcoming the PEG dilemma. Adv Drug Deliv Rev 63 152-160... 

Maeda, H., Greish, K. and Fang, J. The EPR Effect and Polymeric Drugs A Paradigm Shift for Cancer Chemotherapy in the 21st Century. Vol. 193, pp. 103-121. 

Maeda H, Wu J, Sawa T, Matsumara Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics a review. J Control Rel 2000 65 271. 

In addition to the passive targeting of tumors due to the EPR effect, active targeting of PEGylated liposomes has also been successful. A study by Huwyler and coworkers (1996), for example, showed that coupling a monoclonal antibody to the surface of PEGylated liposomes resulted in significant transfer of the liposomes across the blood-brain barrier, which is difficult to achieve otherwise. The attached... 

Maeda H, Greish K, Fang J (2006) The EPR effect and polymeric drugs a paradigm shift for cancer chemotherapy in the 21st century. Adv Polym Sci 193 103-121... 

Another example of passive targeting is the exploitation of the EPR effect to deliver a dmg to a site of inflammation, or a tumor site. This form of passive targeting, also called selective targeting , requires two conditions to be satisfied ... 

SMANCS has been shown to retain nearly all the in vitro activity of NCS, with much improved pharmacokinetic properties. Tumor uptake has been shown to increase in animal models, presumably by the EPR effect. Clinical successes have been reported with SMANCS in Lipiodol (a lymphographic vehicle) after intra-arterial administration in patients with unresectable hepatocellular carcinomas. 

Long circulating liposomes can exploit the EPR effect to accumulate at sites where pathological reactions occur. For example, the commercial product Doxil (marketed as Caelyx in Europe) consists of smallsized PEGylated liposomes, encapsulating the cytostatic doxorubicin. The resulting long circulation times and small size of the vesicles facilitate their accumulation in tumor tissue via the EPR effect. 

Micelles used as DDTS must be sufficiently stable in the blood circulation and should not disintegrate upon contact with blood components. This means that their CMC should be very low. The diameter of the micelles can be chosen so that it is in the range where the EPR effect is observed (<0.2 //m) to allow accumulation of the drag in, for example, tumor tissue or sites of inflammation. 

The size of the polyplex is also crucial to its function. The threshold for first-pass elimination by the kidneys is approximately lOnm in diameter defining a rough lower size limit for nanoparticles (21). Upper size limits are more difficult to establish as they depend on a variety of factors that are variable within tumors including penetration of capillary endothelium, diffusion rates in tumor interstitium and intracellular spaces (22). Macromolecular complexes preferentially accumulate in tumors through the enhanced permeability and retention (EPR) effect (23). Ideally, a nanoparticle would be in a size window such that it could take advantage of the EPR effect. The size of the polyplex can be readily modified during complexation by altering the DNA to polymer ratio (24). 

Because of the EPR effect quantum systems that have interacted before remain correlated even when the interaction no longer persists. The experiments have shown that, even when all interaction comes to an end, information about the second of a pair of particles can be obtained by performing a measurement on the first. The conclusion is that the physical world cannot be correctly described by a realistic local theory. It is necessary either to abandon the criterion of reality or to accept the possibility of action at a distance. The latter occurs because each particle is described by a wave function which is, in general, a non-local entity that collapses when a measurement is made. This collapse is instantaneous and complete. It occurs everywhere, also at the position of a particle not involved in the measurement and therefore predicts the correlation of distant events. Most particles or aggregates of particles, usually regarded as separate objects, have interacted in the past with other objects and must hence remain correlated and to constitute an indivisible entangled whole. This observation represents the scientific rediscovery [45] of holism [46]. 

Maeda H, Sawa T, Konno T (2001) Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. J Control Release 74 47-61... 

---