Tumors leaky vasculature

Cancer Therapy Nanoparticles were first prepared with the concept of targeting colloidal carriers of nanosize to tumor tissues via the leaky vasculature in tumor regions. Since then nanoparticulate drug carriers have been associated with cancer therapy through passive and active targeting to cancer cells. Thus, amphiphilic CD nanoparticles were mainly focused on cancer therapy and its different aspects. 

Small pegylated liposomes have been shown to extravasate into tumors with leaky vasculature, and the prolonged circulation half-life has a positive effect on the extravasation. Passive tumor targeting of liposomes was visualized in a study of radio-labeled PEG-liposomes in patients with locally advanced cancers, and whole body gamma camera imaging was used to monitor biodistribution and tumor localization. Of 17 patients treated with In-DTPA (Diethylenetri-aminepentaacetic acid) labeled PEG-liposomes, tumor... 

Passive accumulation and physiological effects have been exploited for disease treatment in preclinical models for inflammation and cancer ° without surface modification or active targeting by ligand attachment. This may reflect the neovasculature associated with these conditions and the enhanced permeability and retention effect in tumors in which nanoscale particles migrate and accumulate across leaky vasculature in disease tissue. Relying on physiological conditions, however, limits the capability to control the location and dose and results in widespread biodistrihution commonly associated with unmodified nanoparticles that... 

Figure 4.2. Passive (a) and active (b) targeting. In passive targeting, the non-functionalized micelles extravasate in tissues presenting leaky vasculatures (e.g. tumors) and accumulate through the EPR effect. In active targeting, the micelles bind to specific receptors expressed on the surface of the target cells, after which they are internalized. The entrapped drug should be able to escape from the endosomes in order to reach to the cytoplasm and/or nucleus (the solid lines).

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. 

Most gene therapy applications require extravasation of the DNA carriers so that only relative small DNA complexes can pass through the blood vessels and interact directly with parenchymal cells after vascular administration [2]. Under pathophysiological conditions, the structure of the vasculature can change. This phenomenon - termed the enhanced permeation effect - has been utilized to passively target macromolecules to tumors, since blood vessels in tumors are relatively more leaky. 

A triggered release of an anticancer drug at tumor pHg (target tumor sites. In general, stable nanocarriers stay in the vicinity of a leaky tumor vasculature after extravasation because of their size (93). Their location can form an obstacle to other nanoparticles, and further accumulation may be prevented. It is assumed that if the nanoparticles disintegrate completely by the time of the subsequent administration, a multiple dose scheme may result in effective tumor targeting. 

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