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Stealth Attraction Free 18

Abstract:Nanoparticles (NPs) have emerged as a powerful drug-delivery tool for cancer therapies to enhance the specificity of drug actions, while reducing the systemic side effects. Nonetheless, NPs interact massively with the surrounding physiological environments including plasma proteins upon administration into the bloodstream. Consequently, they are rapidly cleared from the blood circulation by the mononuclear phagocyte system (MPS) or complement system, resulting in a premature elimination that will cause the drug release at off-target sites. By grafting a stealth coating layer onto the surface of NPs, the blood circulation half-life of nanomaterials can be improved by escaping the recognition and clearance of the immune system. This review focuses on the basic concept underlying the stealth behavior of NPs by polymer coating, whereby the fundamental surface coating characteristics such as molecular weight, surface chain density as well as conformations of polymer chains are of utmost importance for efficient protection of NPs. In addition, the most commonly used stealth polymers such as poly(ethylene glycol) (PEG), poly(2-oxazoline) (POx), and poly(zwitterions) in developing long-circulating NPs for drug delivery are also thoroughly discussed. The biomimetic strategies, including the cell-membrane camouflaging technique and CD47 functionalization for the development of stealth nano-delivery systems, are highlighted in this review as well.Keywords: nanoparticles; polymer; stealth; drug delivery; opsonization; phagocytosis

Stealth Attraction Free 18


I had already made the decision to part with my $69.95 before realizing the package also includes 14-days free access to the Master Pickup Artist University program (which would be valued at an additional $69.95 if purchased separately). So that was a MASSIVE bonus.

Our appearance is also a part of stealth attraction because it is vital to how people perceive us. Our looks matter, and this is exactly why conventionally beautiful people succeed in life. Appearances mean facial symmetry and a good body, but they also mean how we present ourselves.

On the beachThe prime viewing location for the Chicago Air and Water Show is near the water. If you want to be in the center of the action, bring chairs or a blanket and stake out a spot on the sand or grass anywhere on North Avenue Beach from Fullerton Avenue to Oak Street. You can also see the show from iconic lakefront attraction Navy Pier and the Miller Lite Beer Garden.

Regarding MPS uptake, Blume et al have found that the increased blood circulation time is due to a reduced interaction with plasma proteins and cell-surface proteins (Blume 1993; Vert and Domurado 2000), although other studies have found no direct evidence of this reduced interaction with plasma components (Johnstone et al 2001). One possible explanation for the reduced interaction is the steric hindrance effect, which is generated by the surface-grafted methoxy-PEG molecules. Complement fixation on PEG-bearing liposomes thus appears to occur in a cryptic location inaccessible to ligation to complement receptors. Another possible contributor to the stealth behavior of such vesicles is competition for CR3 between surface-bound and free-complement proteins iC3b. Furthermore, degradation of surface-bound C3b to fragments inhibiting recognition by phagocytic complement receptors might also explain the anti-phagocytic effect. Studies with freshly isolated macrophages have also indicated the presence of unidentified serum factors (called dysopsonins) that act synergistically with the steric barrier of long circulating particles, thereby further suppressing particle recognition by phagocytic cells (Moghimi et al 1993; Johnstone et al 2001).

Stealth liposomes are important in cancer treatment for their passive targeting effect, which may lead to preferential accumulation in tumor tissue, but this phenomenon is not fully understood: Stealth liposomes are able to lodge in the interstitial spaces among tumor cells but, once in the tumor area, they locate in the extracellular fluid surrounding the tumor cell without entering it. Thus, to deliver the active form of an anticancer agent, such as doxorubicin or cisplatin, the drug must be released from the liposomes into the tumor extracellular fluid and then diffuse into the cell (Harrington et al 2000a, 2000b). As a result, the ability of liposomes to carry the anticancer agent to the tumor (which depends on their stability) and to release it into the tumor extracellular fluid (depending on membrane composition and fluidity) are equally important factors in determining the anti-tumor effect of liposome-encapsulated anticancer agents. Unfortunately, little is known of the kinetics of drug release from liposomes into the interstitial space: only the free drug can penetrate into the solid tumor, and it is difficult to determinate the ratio between free/liposome-encapsulated drug in the tumor extracellular fluid (Zamboni et al 2004).

Recently, S-CKD602 (Alza Corporation), a PEGylated stealth liposomal formulation of CKD-602, which is a semi-synthetic analog of camptothecin, was submitted for a Phase I trial. After administration of S-CKD602 at doses of 0.5 mg/m2, the plasma AUC was 50-fold that of non-liposomal CKD-602; S-CKD602 showed minimal toxicity and interesting activity (Zamboni et al 2005).

In order to behave in this fashion, immunoliposomes are built so as to be long-circulating and non-immunogenic, using the stealth technique. Briefly, a PEG (MW 3400) derivative of PE or DSPE containing a maleimide group at the end of the PEG chain is mixed into the liposome formulation (Figure 2). After liposome preparation, reduced thiol groups of Fab or scFv fragments are joined via surface linkage to the maleimide group of the aforementioned PEG-liposome, obtaining a stable thioether bond. This method for preparing immunoliposomes starting from preformed liposomes is the most widely used. Alternatively, commercially available doxorubicin-loaded long-circulating liposomes (DOXIL) have been modified by post-insertion of a monoclonal antibody. MAb, modified with DSPE-PEG conjugate, in which the free PEG terminus is activated with the p-nitrophenylcarbonyl group, has been inserted into preformed liposomes (Lukyanov et al 2004). Therapeutic targets and immunoliposomal compositions are reported in Table 2.

Other ligands have been used to specifically target stealth liposomes to receptors over-expressed in cancer cells. Folic acid, which has been used for liposome-specific targeting of DXR, daunorubicin, cisplatin, and other drugs, is one of the most extensively studied (for a recent review (Stephenson et al 2004)) and it has been proposed for boron neutron capture therapy (Stephenson et al 2003). Transferrin is a popular ligand for specific delivery of anticancer drugs, proteins and genes to malignant cells (Ishida et al 2001) as well as for boron neutron capture therapy (Maruyama et al 2004).

Sigma receptors (subtype of opioid receptor) have recently been proposed as an interesting target for different malignancies (breast, melanoma, prostate). An anisamide-derivatized stealth liposomal formulation (DXR) showed high specific toxicity and superior therapeutic effect versus untargeted liposomes (Banerjee et al 2004) and recently haloperidol-associated stealth liposomes can efficiently target genes to sigma receptor overexpressing breast cancer cells (Mukherjee et al 2005). 350c69d7ab


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