Passive extravasation

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... 

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. 

Docebenone has shown anti-inflammatory effects in several animal models following local dosing phorbol ester-induced oedema and neutrophil influx in mouse skin [208,209], arachidonate-induced plasma extravasation in rabbit skin [210], the pleural reversed passive Arthus reaction in rats [211], and GPB [212], An oral dose of 80 mg/kg reduced infarct size, LTB4 levels and neutrophil infiltration in a rat myocardial infarction model [213,214], and in a rat brain ischaemia-reperfusion model oedema and LTC4 levels were reduced at 200 mg/kg [107]. Significant, but not dramatic, improvement in nasal symptoms was seen in humans following 150 mg of docebenone twice daily for 8 weeks [215], but there was no effect on bronchial hyperresponsiveness to acetylcholine in asthmatics [216]. 

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. 

Passive targeting occurs due to extravasation of the nanoparticles at the diseased site where the microvasculature is leaky. Passive delivery refers to nanoparticle s transport through leaky tumor capillary fenestrations into the tumor interstitium and cells by passive diffusion or convection (Haley and Frenkel 2008). What is important to understand, passive targeting proceeds based on natural developed... 

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).

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