Aberrant Vasculature

Tumor neovasculature is a promising site for targeting nanoparticles for both diagnosis and therapy. Once a tumor reaches a size of greater than ~ 1 cm3, vascular assistance to deliver oxygen and

Macropage

Macropage

Macropage

Cell division

FIGURE 3.4 Effect of chronic pro-inflammatory stimulus on epithelial barrier patency. (a) A variety of stimuli can incite the release of pro-inflammatory cytokine (e.g., TNFa and IFNy) from macrophages and other cells. Genetic predisposition can enhance these responses. (b) Released pro-inflammatory cytokines act to open tight junction (TJ) structures (□), allowing entry of additional activating stimuli that, in turn, attract more cells associated with inflammation. (c) Chronic inflammation leads to breakdown of basement membrane, loss of TJ function, and disorganization of the epithelia characteristic with a pre-neoplastic state.

remove by-products is required for cell survival. Cancer cells secrete a variety of growth factors that stimulate the formation of nascent blood and lymph vessels. Tumor-associated vascular beds have unique surface properties that are associated with their rapid growth characteristics, resulting in aberrant vascular beds that have been used to design a combined vascular imaging and therapy approach using nanoparticles.94 Non-specific targeting of nanoparticles (10-500 nm in diameter) to solid tumors through this EPR capacity of solid tumors47 can provide a means to enrich the localization of an anti-neoplastic agent to a tumor when it is coupled to a nanoparticle compared to its free form.95 The EPR effect has also been used to increase localization through inherent targeting96 of long-circulating liposomes.97

PAMAM dendrimers useful for boron neutron capture therapy (BNCT) of cancers have been targeted to tumor vasculature by attachment of vascular endothelial growth factor (VEGF) that acts to target VEGF receptors that are frequently overexpressed on tumor neovasculature.98 Targeting VEGF receptors Flk or Flt on tumor-associated endothelial cells could also be effective; this has been done with a complex material composed of anti-Flk-1 antibody-coated 90Y-labeled nanoparticles99. PECAM (or CD31) is highly expressed on the surface of endothelial cells present in immature vasculature. Platelet endothelial cell adhesion molecule (PECAM) up-regulation occurs following VEGF stimulation of endothelial cells. The presence of such endothelial surface markers also provides the opportunity to target nanoparticles that contain DNA for gene therapy applications,100 release anti-angiogenesis agents as well as chemotherapeutics,101 and antigens/agents to stimulate an anti-cancer cell immune response.101'102 Vascular cell adhesion molecule-1 (VCAM-1) is a marker for inflammation of the endothelial and has been used to target nanoparticles to these sites for magento-optical imaging.103

Differences in tissue-specific endothelial surface properties might be used for targeting nanoparticles.104 In one such example, a peptide that binds to membrane dipeptidase on lung endothelial cells can be used to target nanocrystals to the lung.105 Doxorubicin-loaded nanoparticles have been targeted to tumor vasculature by surface decoration with a cyclic arginine-glycine-aspartic acid (RGD) peptide that binds to the cell adhesion molecule integrin avb3 on the surface of endothelial cells.106 A peptide that interacts with the lymphatic vessel marker podoplanin can be used to target nanocrystals to lymph vessels and some tumor cells.105 Cationic nanoparticles, containing genes that can block endothelial cell signaling that were selectively targeted to tumor vasculature by coupling to an integrin avb3 ligand, were shown to produce endothelial apoptosis and tumor

regression.

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