octaarginine and Ovarian-Neoplasms

Multidrug resistance (MDR) is a major cause of chemotherapy failure in the clinic. Drugs that were once effective against naïve disease subsequently prove ineffective against recurrent disease, which often exhibits an MDR phenotype. MDR can be attributed to many factors; often dominating among these is the ability of a cell to suppress or block drug entry through upregulation of membrane-bound drug efflux pumps. Efflux pumps exhibit polyspecificity, recognizing and exporting many different types of drugs, especially those whose lipophilic nature contributes to residence in the membrane. We have developed a general strategy to overcome efflux-based resistance. This strategy involves conjugating a known drug that succumbs to efflux-mediated resistance to a cell-penetrating molecular transporter, specifically, the cell-penetrating peptide (CPP), d-octaarginine. The resultant conjugates are discrete single entities (not particle mixtures) and highly water-soluble. They rapidly enter cells, are not substrates for efflux pumps, and release the free drug only after cellular entry at a rate controlled by linker design and favored by target cell chemistry. This general strategy can be applied to many classes of drugs and allows for an exceptionally rapid advance to clinical testing, especially of drugs that succumb to resistance. The efficacy of this strategy has been successfully demonstrated with Taxol in cellular and animal models of resistant cancer and with ex vivo samples from patients with ovarian cancer. Next generation efforts in this area will involve the extension of this strategy to other chemotherapeutics and other MDR-susceptible diseases.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Line, Tumor; Cell Membrane; Disease Models, Animal; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Guanidine; Humans; Mice; Oligopeptides; Ovarian Neoplasms; Paclitaxel; Peptides; Protein Transport; RNA Interference; Solubility; Water

Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to enhance the delivery of therapeutics to tumors. Among many approaches for active tumor-targeting, arginine-rich cell penetrating peptides (AR-CPP) and ligands specific to target over-expressed receptors on cancer-cell surfaces, are popular. Earlier, we showed that the attachment of an AR-CPP octaarginine (R8) to the surface of DOXIL

Topics: Animals; Cell Line; Cell Line, Tumor; Cell-Penetrating Peptides; Doxorubicin; Drug Delivery Systems; Female; Humans; Liposomes; Mice; Mice, Nude; NIH 3T3 Cells; Oligopeptides; Ovarian Neoplasms; Polyethylene Glycols; Receptors, Transferrin; Tissue Distribution; Transferrin; Xenograft Model Antitumor Assays

Topics: A549 Cells; Acrylamides; Cell Line, Tumor; Cytoplasm; Endosomes; Female; Fluorescein-5-isothiocyanate; Gene Expression Regulation, Neoplastic; Gene Silencing; Gene Transfer Techniques; Humans; Microscopy, Confocal; Neoplasms; Oligopeptides; Ovarian Neoplasms; Peptides; Polymers; Real-Time Polymerase Chain Reaction; RNA; RNA Interference; RNA, Small Interfering; Surface Properties

Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross-resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp)-mediated drug efflux. To address this problem, new agents have been sought that are less prone to inducing resistance and less likely to serve as substrates for Pgp efflux. An alternative to this approach is to deliver established agents as molecular transporter conjugates into cells through a mechanism that circumvents Pgp-mediated efflux and allows for release of free drug only after cell entry. Here we report that the widely used chemotherapeutic agent Taxol, ineffective against Taxol-resistant human ovarian cancer cell lines, can be incorporated into a releasable octaarginine conjugate that is effective against the same Taxol-resistant cell lines. It is significant that the ability of the Taxol conjugates to overcome Taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with coelenterazine, a Pgp substrate. Although coelenterazine itself does not enter cells because of Pgp efflux, its octaarginine conjugate does so readily. This approach shows generality for overcoming the multidrug resistance elicited by small-molecule cancer chemotherapeutics and could improve the prognosis for many patients with cancer and fundamentally alter search strategies for novel therapeutic agents that are effective against resistant disease.

Topics: Biological Transport; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Oligopeptides; Ovarian Neoplasms; Paclitaxel