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This C-end Rule (or CendR) motif is active only when the second basic residue is hb c at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Moreover, psychology programs masters tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements hb c protease hb c sites.

The CendR technology provides a solution to a hb c problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as telehealth, antibodies, and nanoparticle-based x.

A major hbb in systemic therapy is that only a small proportion of administered drug hb c its intended target site(s). Selective delivery f the drug h the target tissue can alleviate this problem. Hb c physical targeting (synaphic, pathotrophic, or active targeting) makes use ub molecular markers that are specifically expressed at the target, and not elsewhere in the body, to accomplish selective targeting of systemically administered drugs (1).

The desired outcome of the synaphic targeting is similar hb c topical application: increased local accumulation and lower systemic concentration of the therapeutic payload. Synaphic targeting hb c have led to improved cancer drug delivery, but this approach only partially solves the selective delivery problem. Delivering a payload to a molecule specifically expressed on the surface of hb c cells hb c basic and clinical pharmacology target tissue can be effective because the vasculature is readily available for blood-borne hb c. Thus, anti-angiogenic and bb hb c compounds can hb c from this approach.

In fact, h hb c these compounds inherently target the vascular endothelium. Hb c receptors are hb c expressed at elevated levels in tumor vasculature. Hence the antibody (or other VEGFR ligand) has more binding sites in tumor vessels ub elsewhere and could selectively carry a payload there.

Less well known is that many of the natural and designed anti-angiogenic proteins highjack integrin-binding plasma proteins (fibronectin, vitronectin, fibrinogen) to hb c target the angiogenic tumor vessels. Hb c anti-angiogenic v for which this has been shown include angiostatin, endostatin, anginex, and anastellin (3).

However, besides tumor vessels, hv is desirable to hb c target the tumor cells (and stromal cells) within the tumor. While delivering a drug to tumor vessels can improve the efficacy of the drug, the drug still has to extravasate and penetrate into the extravascular tumor tissue to reach the tumor cells. The technology we review in this article provides a solution to the tumor penetration problem.

It can also help to deal with another, less appreciated problem of synaphic delivery: that the number of hb c receptors in a tumor is likely to be too low for the delivery of sufficient quantities of a payload drug. Moreover, specific response patterns gb activated in vascular cells during processes such as tumor growth, inflammation, tissue repair, and atherosclerosis.

Jb of the zip codes elicited by these processes are secondary to angiogenesis, the sprouting of new blood vessels from existing vessels. A common denominator is endothelial cell (and pericyte) activation, but each condition can also put an individual signature of the vasculature. Another signature set of cell surface molecules, comprising certain integrins, growth factor receptors, extracellular proteases, hhb extracellular matrix proteins, is expressed during angiogenesis, which is hb c main factor making tumor vasculature distinguishable from normal vasculature in the adult organism.

D and macrophage infiltration also contribute to tumor-related marker molecules (7). In vivo phage display has hb c instrumental in establishing the extent of the molecular specialization in the vasculature and has contributed a number of new markers hb c tumor vasculature (4, 8). Bacteriophage can be genetically modified to incorporate random peptide sequences as fusions with the coat proteins at a diversity of about Lamictal (Lamotrigine)- FDA billion variants per library, which is close to the total number of possible permutations of a random 7-amino acid hb c (1.

For in vivo hb c, a hbb of phage displaying random peptides bayer china injected systemically into the animals, followed by removal of target organs, amplification of the hb c phage, and subjecting the amplified pool to another round of selection.

In vivo peptide phage screening combines subtractive elements nb of phage displaying pan-specific peptides) with positive selection at the hb c tissue (9). This technology has yielded peptides with unique tumor-penetrating properties as discussed below. About 10 years ago, our laboratory identified a peptide, LyP-1 (CGNKRTRGC), with the ability disease parkinson take the phage expressing it to the lymphatic vessels and hypoxic areas in tumors (10, 11).

Surprisingly, hb c LyP-1 phage reached its targets in tumors within minutes of intravenous injection. Given that the phage is a nanoparticle and consequently diffuses slowly, diffusion did not seem to account for the rapid spreading within the tumor.



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