Besides various side effects caused by platinum anticancer drugs, they are not efficiently absorbed by the tumor cells. Two Pt-peptide conjugates; cyclic mPeg-CNGRC-Pt (7) and cyclic mPeg-CNGRC-Pten (8) bearing the Asn-Gly-Arg (NGR) targeting sequence, a malonoyl linker and low molecular weight miniPEG groups have been synthesized. The platinum ligand was attached to the peptide via the carboxylic end of the malonate group at the end of the peptide. The pegylated peptide is non toxic and highly soluble in water. Platinum conjugates synthesized using the pegylated peptides are also water soluble with reduced or eliminated peptide immunogenicity. The choice of carboplatin as our untargeted platinum complex was due to the fact that malonate linker chelates platinum in a manner similar to carboplatin. Cell toxicity assay and competition assay on the PC-3 cells (CD13 positive receptors) revealed selective delivery and destruction of PC-3 cells using targeted Pt-peptide conjugates 7 and 8 significantly more than untargeted carboplatin. Platinum uptake on PC-3 cells was 12-fold more for conjugate 7 and 3-fold more for conjugate 8 compared to the untargeted carboplatin indicating selectively activation of the CD13 receptors and delivery of the conjugates to CD13 positive cells. Further analysis on effects of conjugates 7 and 8 on PC-3 cells using caspase-3/7, fluorescence microscopy and DNA fragmentation confirmed that the cells were dying by apoptosis.
The matrix metalloproteinases (MMPs) exhibit a broad array of activities, some catalytic and some non-catalytic in nature. An overall lack of selectivity has rendered small molecule, active site targeted MMP inhibitors problematic in execution. Inhibitors that favor few or individual members of the MMP family often take advantage of interactions outside the enzyme active site. We presently focus on peptide-based MMP inhibitors and probes that do not incorporate conventional Zn2+ binding groups. In some cases, these inhibitors and probes function by binding only secondary binding sites (exosites), while others bind both exosites and the active site. A myriad of MMP mediated-activities beyond selective catalysis can be inhibited by peptides, particularly cell adhesion, proliferation, motility, and invasion. Selective MMP binding peptides comprise highly customizable, unique imaging agents. Areas of needed improvement for MMP targeting peptides include binding affinity and stability.
Pancreatic ductal adenocarcinomas are invariably lethal, and developing effective treatments that have minimal side effects is a challenge. Previous studies from our laboratory have shown that conjugates of cell membrane disrupting lytic peptides and luteinizing hormone releasing hormone (LHRH) target and destroy human prostate and breast cancer cells in xenografts in the nude mouse model (Hansel et al., Mol Cell Endocrinol 2007;260-262:183-9; Hansel et al., Mol Cell Endocrinol 2007;269:26-33), which express LHRH receptors. The objectives of our study were to synthesize a bioconjugate of LHRH analog ([DLys 6 ]-LHRH) and a dietary microchemical (curcumin) and test the hypothesis that [DLys 6 ]-LHRH-curcumin targets and inhibits pancreatic cancer cell growth in vitro and in vivo. In in vitro studies, we determined by confocal microscopy, flow cytometry analysis and reverse transcriptase-polymerase chain reaction that MIAPaCa-2, Panc-1 and BxPC-3 pancreatic cancer cell lines express LHRH receptors. [DLys 6 ]-LHRH-curcumin inhibited cell proliferation of pancreatic cancer cell lines and induced apoptotic cell death (p < 0.05). Apoptosis was induced by cleavage of polyadenosine-5 0 -diphosphate-ribose-polymerase and caspase-3. The activity of [DLys 6 ]-LHRH-curcumin was equal to free curcumin at equimolar concentrations in vitro. Unlike curcumin itself, the [DLys 6 ]-LHRH-curcumin conjugate is water soluble which allows its intravenous administration. In two in vivo studies, [DLys 6 ]-LHRH-curcumin given intravenously caused a significant (p < 0.01) reduction in tumor weights and volumes, and free curcumin given by gavage at an equal dose failed to cause a significant reduction in tumor weights and volumes in the nude mouse pancreatic cancer model. [DLys 6 ]-LHRH-curcumin treatment enhanced apoptosis compared to [DLys 6 ]-LHRH and vehicle-treated controls in tumor tissue. In conclusion, [DLys 6 ]-LHRH-curcumin may be useful in treating pancreatic cancer.Pancreatic cancer is a highly lethal disease with extremely poor prognosis. It has been estimated that 42,470 new cases and 35,240 deaths in United States were due to pancreatic cancer in 2009. 1 The 5-year relative survival rate for all stages is approximately 4%. Current treatments, such as radiation, surgery, chemotherapy or a combination of these modalities have had little impact on survival rate in pancreatic cancer patients. One of the major problems in cancer chemotherapy is the severe toxic side effects of anticancer drugs designed to destroy rapidly dividing cells, including those found in healthy tissues. These severe side effects often result in dose reduction, treatment delay or discontinuance of therapy. To overcome these limitations, various systems have been developed to deliver anticancer drugs used in chemotherapy to increase solubility, decrease adverse side effects and limit nonspecific activity. 2,3 Targeted anticancer drug delivery systems are an advanced approach for delivering the anticancer drugs. Cancer cell targeting can be achieved by...
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