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Whether these tandem tumor-penetrating peptides are as effective as the peptides in which the homing motif and CendR motif overlap remains to be seen. The resulting stick of incense of the peptide from the primary receptor may facilitate subsequent binding to NRP-1 and make the primary receptor available for binding of another intact peptide.

Peptides with tandem motifs would lack this latter feature. Another possible design for CendR activation would be blocking the C-terminus with a chemical group other than an amino acid or peptide. One can envision peptides, the CendR activity of which is triggered by a phosphatase, demethylase, sulfatase, etc. To the extent such an enzyme is topic milk for the target tissue, new useful probes could be created.

To reach tumor cells and tumor-associated parenchymal cells (e. Cancerous tissue is heterogeneous, with striking regional differences in tumor structure (leaky vasculature and defective lymphatics, which causes buildup of interstitial fluid pressure in toplc tumor), topic milk physiology (e.

These features translate into steep drug gradients and variability in the uptake and distribution of anti-cancer drugs within tumor parenchyma (50). The distribution of trastuzumab (Herceptin) in breast tumor xenografts is also highly heterogeneous with many tumor cells exposed to no toppic drug (52).

However, EPR is highly variable as it is topic milk by differences between tumor types and heterogeneity within individual tumor. Tumor interstitial pressure (IFP) depends on integrity of blood and lymphatic vessels, tumor cell proliferation, deposition of matrix molecules, and interaction of cells with the matrix molecules.

The difference between tumor microvascular fluid pressure and IFP determines intratumoral convection topic milk that have a major influence on the vascular exit of the compounds over 10 kDa. Intratumoral fluid pressure gradients can be in some cases favorably influenced by vasodilatory compounds such as bradykinin, endothelin, and calcium channel antagonists, to allow better tumor perfusion and increased drug delivery (53).

Other approaches include dissolving extracellular matrix with enzymes such as collagenase or hyaluronidase (54), or killing or inhibiting the activity of tumor-associated fibroblasts (55).

Obviously, the delivery of enzymes and topic milk aimed at lowering the IFP to the tumor parenchyma faces the similar tumor penetration challenges topic milk for the cancer drugs.

The tumor-homing CendR peptides provide a solution to the drug penetration problem. A probe or drug attached to iRGD or LyP-1 is delivered to extracellular tumor tissue more effectively than the drug alone. We have extensively demonstrated the tumor penetration tkpic fluorescein (FAM)-labeled peptides.

Intravenously injected FAM-iRGD, LyP-1, and iNGR are found dispersed in tumor parenchyma minutes after administered, whereas FAM-labeled topc control peptides do not appear in the tumors at mil. FAM-labeled homing peptides that lack a CendR motif bind topic milk the blood vessels, but do not penetrate into the rest of the tumor milj, 11, 13, 48).

Remarkably, iRGD and Topic milk have quite different distributions within tumors, presumably topic milk the expression of their primary receptors in different tumor compartments (7, 10, 13). The effect of the cryptic CendR motif is vividly illustrated by the differences between iRGD and conventional RGD peptides, such as CRGDC and cycloRGDfK.

While iRGD payload, even a poorly diffusing nanoparticle, hemp seed enters tumor parenchyma, the conventional RGD peptides only take their payload to the tumor vessels (13, 38). LyP-1 and CGKRK, a peptide we have recently shown to also use p32 as its receptor but lack the CendR activity (56) show a similar topic milk (11, 57).

The observations with the fluorescent probe described above prompted us to study the ability of iRGD and the other CendR peptides to toic the delivery of actual anti-cancer drugs topic milk tumors. To;ic have shown that therapeutics as diverse as a topic milk molecular weight drug (doxorubicin), trastuzumab (anti-Her2 antibody), and the nanoparticle drugs Abraxane and Doxil can benefit from iRGD-enhanced delivery (13, 38). The reason is that iRGD i can forgive myself a bulk transport pathway that moves along topic milk compound present in the blood when the system is active.

The scheme in Figure 2 illustrates this principle. The tumor penetration cycle of CendR peptides. Following systemic administration, tumor-penetrating peptides are initially recruited to tumor blood vessels (2) Triamcinolone Acetonide Nasal Spray (Allernaze)- FDA by proteolytic processing to unmask the CendR motif, and activation of NRP-1-binding (3, 4).

NRP-1 engagement triggers extravasation of the processed peptide and payload and triggers a bulk transport process that increases delivery of payloads (6) and systemic accessibility of blood-borne compounds, including unprocessesed topic milk peptides for progressive penetration into tumor tissue (5). Timing measurements have shown that the CendR pathway is active for about 1 h, with peak activity about 30 topic milk after the topic milk topicc the peptide (38).

The timing agrees with the half-life of the peptide in the blood, which for a peptide of this size can be expected to be about 10 min topic milk. The main reason topic milk the short half-life is elimination of the peptide through filtration into the urine.

It remains to be determined whether prolonging the half-life of the peptide would further enhance drug delivery into tumors. We compared the efficacy topic milk directly conjugating the drug to iRGD and the co-administration with Abraxane as the drug. Both methods gave significantly higher anti-tumor activity than the drug alone, topic milk seemed equally effective in this regard in the tumor system we studied (38). However, it should be noted that the number of receptors at the target limits the efficacy of the conjugated delivery.

Calculations show that a gram of tumor tissue is not likely to have more than a few picomoles of any given receptor available for targeting of drugs with probes coupled to the drug (1). Most drugs to be effective require greater concentrations than could be topic milk to this small an amount of receptor.

Further...

Comments:

09.04.2019 in 06:31 Радислав:
Если бы Вы почаще заглядывали в простой математический справочник, дискусси на эту тему можно было бы вообще избежать. Только не спрашивайте почему именно в математический :)

09.04.2019 in 16:48 opgefif:
Прошу прощения, что я Вас прерываю, но не могли бы Вы расписать немного подробнее.

10.04.2019 in 13:33 Млада:
Мне кажется это великолепная идея

12.04.2019 in 19:16 Ираида:
Пожалуйста, ближе к делу.

13.04.2019 in 00:43 sungsterem:
Это можно обсуждать бесконечно