Nanotechnology-mediated targeting of tumor angiogenesis

Abstract

Angiogenesis is disregulated in many diseased states, most notably in cancer. An emerging strategy for the development of therapies targeting tumor-associated angiogenesis is to harness the potential of nanotechnology to improve the pharmacology of chemotherapeutics, including anti-angiogenic agents. Nanoparticles confer several advantages over that of free drugs, including their capability to carry high payloads of therapeutic agents, confer increased half-life and reduced toxicity to the drugs, and provide means for selective targeting of the tumor tissue and vasculature. The plethora of nanovectors available, in addition to the various methods available to combine them with anti-angiogenic drugs, allows researchers to fine-tune the pharmacological profile of the drugs ad infinitum. Use of nanovectors has also opened up novel avenues for non-invasive imaging of tumor angiogenesis. Herein, we review the types of nanovector and therapeutic/diagnostic agent combinations used in targeting tumor angiogenesis.

Figure 1

PLGA nanoparticles: (A) Chemical conjugation or simple encapsulation of chemotherapeutic agents in PEG-modified PLGA nanoparticles. (B) Transmission electron microscopy image of PLGA nanoparticles. Scale bar: 100 nm.

Figure 2

Effects of LY-encapsulated PLGA nanoparticles in vivo using Casper Zebrafish-breast adenocarcinoma xenograft assay. (A) Real-time imaging. Broken arrows show cancer cells. (B) Alkaline phosphatase vessel staining. Full arrows show subintestinal vessels (SIV). (C) Quantification of SIV using morphometric analyses developed in our laboratory. HNP = hybrid nanoparticles. P^# ≤ 0.05 versus wild-type and empty nanoparticle controls. (In collaboration with Dr. Richard M. White and Dr. Leonard I. Zon, Children's Hospital Boston).

Figure 3

Effects of doxorubicin (Dox)-conjugates of fullerenols and carbon nanotubes (CNT) on B16-F10 mediated angiogenesis in mouse xenograft model. Angiogenesis was assessed by immunodetection of the Von Willebrand Factor (vWF) endothelial cell marker (green) and propidium iodide counterstain (red) on treatments with: (A) control; (B) fullerenol; (C) CNT; (D) Dox alone; (E) fullerenol-Dox conjugate; and (F) CNT-Dox conjugate.

Figure 4

PEGylated Quantum Dot (QD) nanocrystals conjugated to ανβ3-specific RGD peptide for endothelial cell targeting; (A) low resolution transmission electron microscopy image showing the nanoconjugates, the arrow indicating one such nanostructure; (B and C) spinning disk confocal microscopy images showing uptake of RGD-targeted QD clusters in endothelial cells treated with cations that are known to cause integrin clustering. Incubation with the RAD-PEG-nanocrystal QD clusters showed no uptake by the cells (B), while RGD-PEG-nanocrystal QD clusters resulted in increased uptake into the cells (C).

Figure 5

Carbon nanovectors inhibit stem cell-mediated vascularization. Immunocytochemistry results show Von Willebrand Factor (vWF) endothelial cell marker (red) and DAPI counterstain (blue).