Tumor vasculature

Arap W, Pasqualini R, Ruoslahti E (1998) Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279 377-380... 

In cancer treatment, passive targeting of macromolecular carriers to tumors is a commonly used approach. This passive targeting is based on the enhanced permeability and retention (EPR) effect, which leads to an accumulation of the high molecular weight carrier in the tumor tissue. The EPR effect arises from the different physiology of tumor vasculature, where the vessel walls are highly porous and lack the tight junctions that are present in healthy tissue. As a result, macromolecular carriers extravasate and accumulate preferentially in tumor tissue relative to normal tissues [63, 64]. 

Shielded polyplexes with improved blood circulating properties are interesting tools for systemic cancer therapy (see Sect. 4.2). Nanoparticles can take advantage of the enhanced permeability and retention (EPR effect) [89] for passive tumor targeting. The EPR effect is based on the leakiness of tumor vasculature, due to neovascularization in growing tumors, combined with an inadequate lymphatic drainage. Nanoparticles with an elongated plasma circulation time can extravasate and passively accumulate at the tumor site. 

The neoangiogenic tumor vasculature overexpresses certain integrins and other surface markers, which can also be used for targeting of polyplexes. The RGD peptide motif has been successfully applied for integrin-targeted pDNA [125-128] and siRNA [129, 130] delivery. In many cases, the PEG motif-containing peptide was attached to the polycation via a PEG spacer. For RGD-PEG-PEI/pDNA polyplexes, an optimum grafting with RGD-PEG was required because transfection... 

Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41 189-207... 

NGR-TNF MolMed TNF fused to CNGRCG, a tumor vasculature-targeting (CD13) peptide Advanced solid tumors... 

Jain RK. Normalization of tumor vasculature an emerging concept in antian-giogenic therapy. Science 2005 307 58-62. 

Fig. 7. Bar graph of blood flow vs time following irradiation. Radiation-induced destruction of tumor vasculature resolves following irradiation, except when SU5416 is administered concurrently.

Staba MJ, Mauceri HJ, Kufe DW, et al. Adenoviral TNF-a gene therapy and radiation damage tumor vasculature in a human malignant glioma xenografts. Gene Ther 1998 5 293-300. 

Mauceri HJ, Hanna NN, Wayne JD, et al. Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature. Cancer Res 1996 56 4311-4314. 

As is implied by its name, the first TNF-a-dependent mechanism described was the induction of tumor necrosis in vivo through its role in tumor vasculature. However the mechanisms of the in vitro toxicity of TNF-a to tumor cells imply apoptosis rather than necrosis [97], Tumor necrosis in SCID (severe combined immuno-deficiency) mice treated with LPS does not lead to the rejection of tumors [98], Furthermore, necrosis and tumor regression must be dissociated since anti-IFN-y antibodies inhibit LPS-induced regression of Meth A sarcoma in mice, but not the necrotic hemorrhage attributed to TNF-a. It is now accepted that the antitumoral effect of TNF-a is indirect and dependent on acquired immune response. Matsumoto et al. [99] reported that, while TNF-a itself has no effect on hepatoma KDH-8 tumor cells in vitro, the antitumoral effect of the lipid A ONO-4007 against KDH-8 tumors in vivo is inhibited by anti-TNF-a antibodies in WKAH rat, showing an indirect effect of TNF-a. 

Pasqualini, R., W. Arap, and D.M. McDonald. 2002. Probing the structural and molecular diversity of tumor vasculature. Trends Mol Med 8 563. 

Zhong H, Bowen JP. Antiangiogenesis drug design multiple pathways targeting tumor vasculature. Curr Med Chem. 2006 13 849-862. 

Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature, Science 275 547-550 (1997). 

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