Passive accumulation

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. 

Chronic copper poisoning in domestic sheep is first characterized by a period of passive accumulation of copper in the tissues. This period varies from a few weeks to more than a year. During this time the animal appears outwardly normal although the liver may contain more than 1000 mg Cu/kg DW and plasma activities of aspartate transaminase, sorbitol dehydrogenase, lactic... 

Growth reduction of 30% (Gonzalez-Murua etal. 1985) Photosynthesis reduced 30%, but no effect on growth (Lay et al. 1984) Growth reduction 90% of atrazine passively accumulated within 1 h (Veber et al. 1981)... 

Stuer-Lauridsen, F. 2005. Review of passive accumulation devices for monitoring organic micro-pollutants in the aquatic environment. Environ. Pollut. 136 503-524. 

The nucleation of a calcitic or aragonitic form is species specific, and they grow where conditions are also favorable for abiotic carbonate deposition. The filamentous cyanobacterial mats may passively accumulate and bind local sedimentary particles that become entombed through cementation with additional calcium carbonate. 

Decreased lymphatic drainage keeps the carriers in the tumor. This passive targeting mechanism has been called the enhanced permeation and retention (EPR) effect and was first identified by Maeda et al. [98,99]. Numerous studies have shown that the EPR effect results in passive accumulation of macromolecules and nanosized particulates (e.g., polymer conjugates, polymeric micelles, dendrimers, and liposomes) in solid tumor tissues, increasing the therapeutic index while decreasing side effects. Figure 4 describes the concept of passive tumor targeting by EPR effects. 

Tumor cells have an increased vascular permeability and a decrease in their lymphatic drainage system, which leads to the passive accumulation of macromo-lecular drugs in these neoplastie cells. The macromolecules may also contain groups that are preferentially taken up by cancer cells. For example, the presence of folate ions on the surface of boron eontaining hposomes greatly enhances the boron uptake in human KB squamous epithelial cancer cells, which have overexpressed foliate acceptors. " Other examples are the reconstituted LDLs, whieh stiU retain their ability to bond to LDL speeifie sites on the tumor cells. These liposomes and modified LDLs have the ability to deliver massive amounts of to cancer eells and have been... 

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... 

Dendrimers are small (typically less than lOnm in diameter) in comparison to other drug-delivery vehicles such as linear polymers, micelles (50-200 nm), and liposomes (100-1000nm). The small size results in rapid renal filtration and elimination via the urine compared to larger carriers. To reach an effective therapeutic concentration of the drug in the tumor tissue, a dendritic drug carrier needs to balance kidney clearance and elimination via the fiver and reticuloendothelial system (RES) against the passive accumulation resulting from the EPR effect. RES clearance is more pronoimced for... 

High-pressure safety injection water is provided by separate high-head pumps while lower pressure injection water is supplied by the RHRS pirnips. Passive accumulator tanks are inside the containment to provide for fast injection of water after a LCXZA. Figure 2.19 shows the injection phase of the SIS and is the configuration for a four-loop plant. The configurations for two- and three-loop plants differ only in the size of the components and the number of branch injection lines to the RCS. 

It is one thing to design micelles with targeted properties and behavior yet another to evidence their in vitro and in vivo applicability. To our benefit, there are numerous instances where the formulation of drugs as PM reduced their cytotoxity, increased the maximum tolerated dose (MTD) or permitted passive accumulation at target sites while accounting for improved therapeutic effects compared to control formulations. Some PM and PICM systems are summarized in Tables 4.3 and 4.4, respectively, and their performance discussed below. 

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