Hydraphase la roche

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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 fluxes 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 drugs aimed at lowering the IFP to the tumor parenchyma faces the similar tumor penetration challenges seen for the cancer hydraphase la roche. 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 with fluorescein (FAM)-labeled peptides. Intravenously injected FAM-iRGD, LyP-1, and iNGR are found dispersed in tumor parenchyma minutes after administered, whereas FAM-labeled inactive control peptides do not appear in the tumors at all.

FAM-labeled homing peptides that lack a CendR hydraphase la roche bind to the blood hydraphase la roche, but do not penetrate nick roche the rest of the tumor (10, 11, 13, 48). Remarkably, iRGD and LyP-1 have quite different distributions within tumors, presumably reflecting the expression of their primary receptors in different tumor compartments (7, 10, 13). The effect of the cryptic Hydraphase la roche motif is vividly illustrated by the differences between iRGD and conventional RGD peptides, such as CRGDC and cycloRGDfK.

While iRGD payload, even hydraphase la roche poorly diffusing nanoparticle, readily enters tumor parenchyma, the conventional RGD peptides only take their payload to the tumor vessels hydraphase la roche, 38). Psychology health and CGKRK, a peptide we have recently shown to also use p32 as its receptor but lack the CendR activity (56) show a similar difference (11, 57).

The observations with the fluorescent probe described above prompted us to study the ability of iRGD and the other CendR peptides to enhance the delivery of actual anti-cancer drugs to tumors.

We have shown that therapeutics as diverse as a small molecular weight drug (doxorubicin), trastuzumab (anti-Her2 antibody), and the nanoparticle drugs Abraxane and Doxil can benefit hydraphase la roche iRGD-enhanced delivery (13, 38). The reason is that iRGD activates a bulk transport pathway that moves along any compound present Repaglinide and Metformin HCl Tablets (Prandimet)- FDA 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) followed 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 tumor-penetrating 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 hydraphase la roche 30 min after the administration of 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 (58).

The main reason for the short half-life is Lotronex (Alosetron Hydrochloride)- Multum 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 of directly conjugating the drug to iRGD and hydraphase la roche co-administration with Abraxane as the drug. Both methods gave significantly higher anti-tumor activity than the drug alone, and seemed equally effective in this regard in the tumor system we studied (38). However, it should be noted hydraphase la roche 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 hydraphase la roche than a few picomoles of any given receptor available for targeting of hydraphase la roche with probes coupled to the drug (1).

Most drugs to be effective require greater concentrations than could be delivered to this small an amount of receptor. The co-administration mode does not have this limitation, as only the triggering of the trans-tissue transport pathway is needed. Another major advantage is that it is not necessary to revatio the drug to the homing peptide, which would create a new chemical entity with the attendant regulatory hurdles.

LyP-1 coupled to Abraxane nanoparticles also increased the efficacy of hydraphase la roche drug (59) and iNGR promoted the activity of doxorubicin in a mouse tumor model in a way similar to iRGD (48), by a factor of about 3. Importantly, the iRGD work with doxorubicin showed that there was no change in the main side effect hydraphase la roche this drug, cardiotoxicity. This side effect was nearly eliminated by a threefold reduction of the drug dose.

Thus, the tumor-penetrating peptides can be used both to enhance the activity of anti-cancer drugs, or lowering the side effect with the same anti-cancer activity, or some of both. The tumor-penetrating peptides can also enhance tumor imaging, as hydraphase la roche by coating mamori oxide nanoparticles with iRGD for MRI imaging.



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