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Review
. 2014 May 22:9:2539-55.
doi: 10.2147/IJN.S47129. eCollection 2014.

Nanomedicine for drug targeting: strategies beyond the enhanced permeability and retention effect

Hayley Nehoff  1 , Neha N Parayath  1 , Laura Domanovitch  1 , Sebastien Taurin  1 , Khaled Greish  2
Affiliations
Review

Nanomedicine for drug targeting: strategies beyond the enhanced permeability and retention effect

Hayley Nehoff et al. Int J Nanomedicine. .

Abstract

The growing research interest in nanomedicine for the treatment of cancer and inflammatory-related pathologies is yielding encouraging results. Unfortunately, enthusiasm is tempered by the limited specificity of the enhanced permeability and retention effect. Factors such as lack of cellular specificity, low vascular density, and early release of active agents prior to reaching their target contribute to the limitations of the enhanced permeability and retention effect. However, improved nanomedicine designs are creating opportunities to overcome these problems. In this review, we present examples of the advances made in this field and endeavor to highlight the potential of these emerging technologies to improve targeting of nanomedicine to specific pathological cells and tissues.

Keywords: cancer treatment; inflammation; nanomedicine; permeability and retention effect; tissue targeting.

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Figures

Figure 1
Figure 1
Enhanced permeability and retention effect results from loose endothelial junctions allowing extravasation of macromolecules and nonfunctional lymphatics, resulting in prolonged retention of macromolecules within the pathological tissue, in this representation tumor tissue. This tissue also shows a high interstitial fluid pressure and a lack of a functional smooth muscle layer surrounding the blood vessels.
Figure 2
Figure 2
Gross tissue level targeting. (A) Convection enhanced delivery utilizes a positive pressure gradient to cause the dispersion of the active agent through the interstitial space. (B) Magnetic targeting is utilized in order to facilitate the extravasation of magnetic nanoparticles specifically into target tissues using magnetic stimulation. (C) pH-dependent release of drug from nanoconstructs allows specificity of drug release in regions with low pH such as hypoxic tumor regions. (D) Enzyme-mediated release allows release of the active agent from the encapsulating agent specifically in tissue with elevated levels of these enzymes confering a degree of specificity to the site of release. (E) Increased blood pressure, due to the lack of a functional smooth muscle layer and AT-II receptors in tumor blood vessels, allows specific increases in blood flow and subsequently nanomedicine delivery in pathological tissue. Abbreviation: AT-II, angiotensin II.
Figure 3
Figure 3
Effect of inflammation on the development of the EPR effect in inflammatory tissue. Inflammatory tissue will release a range of mediators that will induce the EPR effect. Inflammation will cause the vessel to dilate resulting in a higher blood flow. Furthermore, the contraction of endothelial cells will allow the penetration of nanoparticles into the tissue. The major difference between inflammatory tissue and tumor tissues in relation to macromolecular targeting is the presence of a functional lymphatic system in inflammation. Retention of nanomedicine in this case can be attributed to macrophage uptake. Abbreviation: EPR, enhanced permeability and retention.
Figure 4
Figure 4
Specific cellular delivery. (A) Receptor-mediated endocytosis involves the use of a specific ligand to a receptor that is preferentially expressed in the pathological tissue. (B) Inflammatory mediators can be utilized in order to cause degradation of the carrier in the region of the inflammation and release the payload. (C) Antibody targeting involved the use of a specific antibody directed against a protein of interest that is specifically expressed in pathological cells but not in nonpathological cells. Abbreviations: siRNA, small interfering RNA; ROS, reactive oxygen species
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