Tumor vasculature targeting: a generally applicable approach for functionalized nanomaterials

Abstract

The last decade has witnessed an unprecedented expansion in the design, synthesis and preclinical applications of various multifunctional nanomaterials. Efficient targeting of these nanomaterials to the tumor site is critical for delivering sufficient amount of anti-cancer drugs to suppress tumor growth, while avoiding undesired side effects. Although some nanoparticles could accumulate in the tumor tissue based on the enhanced permeability and retention effect, which may also bind to targets on the tumor cell surface after extravasation from the tumor vasculature, these strategies have many limitations. In this article, we discuss the concept of tumor vasculature targeting and summarize representative examples of in vivo targeted positron emission tomography imaging of various functionalized nanomaterials with different morphology, size and surface chemistry. The concept of targeting tumor vasculature instead of (or in addition to) tumor cells will continue to inspire the design of more advanced nanosystems for efficacious and personalized treatment of cancer in the future.

Keywords: cancer; molecular imaging; nanomaterials; positron emission tomography (PET); tumor angiogenesis; vasculature targeting.

Figure 1

Differences between normal and tumor blood vessels. (A) A scanning electron microscopy (SEM) image of polymer cast of normal microvasculature, showing simple, organized arrangement of arterioles, capillaries, and venules. (B) A SEM image of polymer cast of tumor microvasculature, showing disorganization and lack of conventional hierarchy of blood vessels. Reproduced with permission.^[4] Copyright 2003, Nature Publishing Group. Arterioles, capillaries, and venules are not identifiable. Schematic illustrations of normal endothelial cells (C) and tumor endothelial cells (D) are also shown. Normal endothelial cells form tight junctions with one another without overlapping at the margins, while tumor endothelial cells branch and sprout excessively, resulting in a defective endothelial monolayer and loss of normal barrier function. Reproduced with permission.^[7] Copyright 2012, Cold Spring Harbor Laboratory Press.

Figure 2

Representative nanomaterials with varied size and morphology that have been reported for tumor vasculature targeting. Atomic force microscopy (AFM) images of (A) QD-RGD which is sphere-shaped of ≈20 nm in diameter. Reproduced with permission.^[24] Copyright 2006, American Chemical Society. (B) SWNT-PEG which has tube-like morphology of 1–5 nm in diameter and 100–300 nm in length. Reproduced with permission.^[23] Copyright 2007, Nature Publishing Group. (D) NOTA-GO-TRC105 which has sheet-like morphology of 20–80 nm in each dimension. Reproduced with permission.^[39] Copyright 2012, American Chemical Society. Transmission electron microscopy (TEM) images of (C) NOTA-SPION-RGD which is irregularly shaped of ≈10 nm in size. Reproduced with permission.^[25] Copyright 2011, Elsevier. (E) Unimolecular micelles (NOTA-H40-DOX-RGD) which are spherically shaped of 22–31 nm in diameter. Reproduced with permission.^[26] Copyright 2012, Elsevier. (F) NOTA-MSN-TRC105 which is spherically shaped of ≈80 nm in diameter. Reproduced with permission.^[27] Copyright 2012, American Chemical Society^[25]

Figure 3

A schematic illustration showing the effect of tumor vasculature targeting to three different proteins, using differently functionalized nanomaterials. (A) PET images of ⁶⁴Cu-labeled quantum dots in U87MG tumor-bearing mice, with or without the use of RGD peptides to target integrin α_vβ₃. Reproduced with permission.^[38] Copyright 2007, Society of Nuclear Medicine and Molecular Imaging. (B) PET images of 64Cu-labeled single-walled carbon nanotubes in U87MG tumor-bearing mice, with or without the use of RGD peptides to target integrin α_vβ₃. Reproduced with permission.^[23] Copyright 2007, Nature Publishing Group. (C) PET images of ⁶⁴Cu-labeled superparamagnetic iron oxide nanoparticles in U87MG tumor-bearing mice, with or without the use of RGD peptides to target integrin α_vβ₃. Reproduced with permission.^[25] Copyright 2011, Elsevier. (D) PET images of ⁶⁴Cu-labeled nanographene oxide in 4T1 tumor-bearing mice, with or without the use of TRC105 to target CD105. Reproduced with permission.^[39] Copyright 2012, American Chemical Society. (E) PET images of ⁶⁴Cu-labeled unimolecular micelles in U87MG tumor-bearing mice, with or without the use of RGD peptides to target integrin α_vβ₃. Reproduced with permission.^[26] Copyright 2012, Elsevier. (F) PET images of ⁶⁴Cu-labeled mesoporous silica nanoparticles in 4T1 tumor-bearing mice, with or without the use of TRC105 to target CD105. Tumors were indicated by arrows or arrowheads in all cases. Reproduced with permission.^[27] Copyright 2012, American Chemical Society.