421ISSN 2041-599010.4155/TDE.13.8 © 2013 Future Science Ltd Ther. Deliv. (2013) 4(4), 421–423

Keywords: cancer n drug delivery n nanomedicine n tumor microenvironment

Editorial

Delivery of nanomedicines to solid tumors depends on the abnormal tumor microenviron-ment and the physicochemical properties of the nanoparticle. The enhanced permeability and retention (EPR) effect characterizes in large part the tumor microenvironment, but it is not ade-quate to cause effective delivery of nano particle formulations. The effect of the nanoparticle properties, and particularly its size, has to be considered in order to optimize drug delivery and therapeutic outcome.

EPR effect & currently approved nanomedicinesThe EPR effect was introduced more than two decades ago [1,2], and since then it has given great promise to the use of nanoparticle formu-lations for the detection and treatment of solid tumors. The EPR effect is based on the hyper-permeability of the tumor vessels, which allows particles to enter the tumor interstitial space, as well as on the absence of functional lymphatics in the tumor interior, which enables them to stay there for a long time. The hyper-permeability of tumor vasculature is mainly due to the large inter cellular openings between endothelial cells that comprise the neoplastic tumor vessel wall [3]. These openings might be hundreds of nano-meters in size, contrary to the openings of the normal vessel wall, whose size is less than 10 nm [4,5]. Therefore, the rationale for employing the EPR effect to treat cancer is that therapeutic particles with sizes larger than 10 nm will not be able to extravasate to normal tissues – reduc-ing adverse effects – and would selectively pass through the openings of the tumor vessels.

Nowadays, three nanoparticle formulations have been widely approved for the treatment of solid tumors: Doxil® (or Caelyx®) is a pegylated liposomal doxorubicin that has been approved

for the treatment of HIV-related Kaposi’s sarco-mas, metastatic ovarian cancers and metastatic breast cancers; DaunoXome® is a liposomal dau-norubicin, approved for HIV-related Kaposi’s sarcomas; and Abraxane® is an albumin-bound paclitaxel, which has been given approval for metastatic breast cancers. The size of these nano-drugs is in the range of 50 to 150 nm. Despite the fact that these drugs are associated with significantly less adverse effects compared with conventional chemotherapy, presumably due to the EPR effect, the increase in overall survival is modest in many cases [3,6–8]. The efficacy of the treatment is largely determined by the amount of drugs that are delivered to the tumor. Therefore, it seems that even though current nanomedicines have succeeded in preventing delivery to normal tissues, they cannot ensure effective delivery in tumors.

EPR effect & barriers to the delivery of nanomedicinesEffective delivery of nanoparticles is hindered by heterogeneity of EPR within and between tumor types. All blood vessels within a single tumor are not equally hyperpermeable. There is a large distribution of intercellular openings, which might cause heterogeneous delivery of nanoparticles. Furthermore, vascular perme-ability might vary significantly among different tumor types [4].

The hyperpermeability of the tumor vessels results in excessive fluid passing from the vas-cular to the interstitial space of the tissue. Due to the lack of functional lymphatics, this fluid cannot be drained effectively and accumulates in the tumor interstitium, causing a uniform elevation of the interstitial f luid pressure – a hallmark of solid tumor pathophysiology [9]. Indeed, interstitial fluid pressure can be as high

EPR-effect: utilizing size-dependent nanoparticle delivery to solid tumors

“The rationale for employing the enhanced permeability and retention effect to treat cancer is that therapeutic particles with sizes larger than 10 nm will not be able to extravasate to normal tissues – reducing adverse effects – and would selectively

pass through the openings of the tumor vessels.”

Triantafyllos StylianopoulosDepartment of Mechanical & Manufacturing Engineering, University of Cyprus, Nicosia, 1678, Cyprus E-mail: tstylian@ucy.ac.cy

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Editorial | Stylianopoulos

Ther. Deliv. (2013) 4(4)422 future science group

as the vascular pressure, eliminating pressure gradients across the vessel wall. As a result, diffu-sion rather than convection is the main mecha-nism of nanoparticle transport, which is a slow process and inversely related to the size of the particles. Therefore, size-dependent delivery of nanoparticle formulations has to be taken into account in order for the potential of EPR to be fully exploited in cancer patients.

Utilizing size-dependent delivery The ability of nanoparticles to effectively travel across the tumor vessel wall to the interstitial space depends on the ratio of particle size to the size of the openings [10]. On one hand, if this ratio is small, the transport of the particle through the pores of the wall is unhindered. On the other hand, if the size of the nanoparticle is comparable to the size of the openings, the particle will interact with the pores and the transport might be severely hindered. Moreover, large nanoparticles (>40 nm in diameter), even if they manage to cross the vessel wall, might not be able to penetrate the dense extracellular matrix of the tumor interstitial space [11]. Indeed, in many tumors, a desmoplastic response might occur that can lead to excessive production of extracellular fibers resulting in limited penetration of nanoparticles [9].

In general, the smaller the nanoparticle the better the transport across the tumor vessel wall. Nanoparticles, however, should be large enough so that they will not extravasate to nor-mal tissues and cause adverse effects. Given that the openings in normal vessels can be as large as 10 nm, particles of that size are the small-est that can take advantage of the EPR effect. Apart from the ability to cross the vessel wall, other parameters that need to be considered for optimal delivery of cancer nanomedicines are clearance from the kidneys and the reticuloen-dothelial system, along with transport through the tumor interstitial space, as mentioned previ-ously. Renal clearance is very rapid for particles smaller than 6 nm in diameter, while reticu-loendothelial clearance is usually avoided with PEGylation [12,13]. Therefore, PEGylated par-ticles with sizes 10–40 nm should, in general, ensure long circulation times, effective transport across the tumor vessel wall and deep penetra-tion into the tumor interstitium. However, an exact optimal size is difficult to define given the continuously evolving and highly heteroge-neous nature of tumors, as well as the differences among tumor types.

Future perspectiveSize plays a crucial role in the delivery of nanopar-ticles to solid tumors, but it is not the only param-eter that affects transport. Nano particle shape and charge might also be of equal importance and further studies are required to elucidate the effect of these two physical properties. Elongated particles (e.g., nanorods) have shown superior transvascular flux compared with spherical parti-cles of equal hydrodynamic radius [14]. It has also been shown that cationic nanoparticles can more effectively cross the tumor vessel wall compared with their neutral or anionic counterparts [15,16]. Therefore, it might be more beneficial if we uti-lize not only the size-dependence, but also the shape- and charge-dependence of nanoparticle accumulation solid tumors.

Recently, multistage nanoparticle formula-tions have been developed whose size can change in response to the properties of the micro-environment. pH-responsive nanoparticles aim to utilize the acidic microenvironment of many tumors [17]. However, the decrease in pH is rela-tively small and occurs at a distance of several hundreds of micrometers from the blood vessels [3]. Therefore, effective interstitial transport is an important parameter that has to be considered. More promising appear to be multistage parti-cles whose size decreases in response to activated enzymes, such as MMPs that are abundant in the interstitial space of most tumors [18].

Currently, clinically approved nanoparticle formulations exploit the EPR effect and passive delivery. Active delivery of nanoparticles with targeting ligands on their surface is another approach that enables specific binding to cancer cells. Even though addition of targeting ligands has often failed to improve intratumoral pen-etration, there are cases where targeted nanopar-ticles have been shown to significantly increase delivery and therapeutic outcome [19,20]. There-fore, the field of active delivery of cancer nano-medicines is promising and further studies will be beneficial.

Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t estimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

EPR-effect: utilizing size-dependent nanoparticle delivery to solid tumors | Editorial

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