Somatostatin (sst) is one such protein that has been under study. Sst receptor antagonists have been proven to be more effective than agonists for tumors expressing certain sst receptors [8]. When the highly-expressed sst receptors on cancer cells were targeted by the antagonists, the growth hormone somatotropin was inhibited and the cancer cells did not receive the protein that allows them to proliferate for survival. The study of sst receptors indicated a viable route by which cancer cells could be targeted for drug delivery [6]. iRGD, a Tumor Penetrating Peptide Once peptides bind to cell receptors, the next step is to enter the tumor. Tumor penetrating peptides are vehicles for drugs to enter and accumulate [5].   iRGD is one tumor penetrating peptide that has been studied extensively [3]. The peptide has several components that define its function. The RGD (arginylglycylaspartic acid) motif recognizes integrin, a protein on the tumor cell surface, and allows binding. Another motif is defined for the C-end Rule (CendR) effect by which the drug is taken up by the tumor cell, a process known as endocytosis. In addition, one site on iRGD binds to a protease, a type of enzyme, which works to expose and prepare the CendR motif [5]. Drugs have various ways of entering tumor cells. Conjugation is a method that involves the attachment of the drug to the tumor penetrating peptide. Several issues arise, however. Conjugation requires a proper molecular design and reduces drug activity when the peptide and drug are coupled [3]. Moreover, since the number of cell receptors is limited, a sufficient amount of drug cannot reach the tumor [5]. One method under analysis for rectifying such issues is the separate administration of the iRGD peptide and cancer drug [3]. The CendR effect is defined by bulk transport: once the peptide is bound to the receptor, the drug is taken in by the tumor in large quantities, even if it is not attached to the peptide. Other targeting molecules, in comparison to the iRGD peptide are not as effective [5]. Conjugate Entry Mechanisms Diffusion Molecular Retention (DMR) Tumor Targeting Tumor targeting mechanisms must be tracked closely to ensure that they successfully deliver the drug to the tumor. In effective mechanisms, low doses of the drug are needed for minimal toxicity. The DMR tumor targeting mechanism is designed to overcome the delivery barriers that exist between vascular areas, or blood vessels, and the tumor itself. Its efficiency is measured by tumor surface fluorescence [11]. The DMR tumor targeting mechanism is effective under specific conditions. The RGD probe, a peptide, contains fluorochrome to observe diffusion. Polyethylene glycol (PEG)fluorochrome shielding prevents non-specific binding, which can be caused by the fluorochrome. The RGD probe should theoretically only bind to the integrin on the tumor cell. The probe must move slowly in vivo since PEG is both bulky and hydrophilic. As the probe moves from the interstitial space to the vascular areas, sufficient diffusion can occur [11]. The DMR method requires several steps from when the conjugate is first administered to when it reaches the tumor. The probe is inserted into the body by a peritumoral (PT) injection, which is preferred over an IV injection for specific
Peptides are useful for targeting cancer cells and the endothelial cells that form the tumor vasculature...they are favored for their high stability during delivery and high affinity to the target receptors. Their low molecular weight also allows them to successfully enter the tumor tissue. targeting (Figure 2). The probe diffuses within the tissue interstitium and is retained in the tumor where integrin, the molecular target, exists on the cell surface.
Figure 2 Note the “Probe:Target Complex,� in which the probe is the peptide and the target is the receptor on the tumor cell. With IV molecular targeting, the drug enters normal tissue in addition to tumor tissue. DMR targeting is more specific to the tumor tissue [11].
EPR Effect vs. CendR Penetration Effect The molecular interactions in the tumor microenvironment can result in the enhanced permeability and retention (EPR) and CendR penetration effects. EPR is a passive targeting method [2]. The extent of EPR depends on tumor-specific characteristics [5]. Tumor capillaries are permeable such that the designed drugs can pass through and reach the tumor tissue by EPR. Since lymphatic drainage is inadequate, the drug molecule is not able to be removed from the tumor site. Consequently, the drug is retained to accumulate [12]. In the CendR penetration effect, the drug is linked to a tumor-homing peptide, such as iRGD (Figure 3). The effect is receptor-mediated, and thus is more effective and has quicker results when compared to EPR [3]. The tumor targeting process is also more active and produces better results for apoptosis [2].
Figure 3 The process by which tumor penetrating peptides undergo the CendR penetration effect [5].
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