Cancer cell surface induced peptide folding allows intracellular translocation of drug

Abstract

Many lead molecules identified in drug discovery campaigns are eliminated from consideration due to poor solubility and low cell permeability. These orphaned molecules could have clinical value if solubilized and delivered properly. SVS-1 is a de novo designed peptide that preferentially folds at the surface of tumor cells, adopting a β-hairpin conformation that rapidly translocates into the cytoplasm, and ultimately nucleus, of cells. SVS-1 is stable in serum and small molecules attached to the peptide are effectively delivered to cancer cells via mechanisms involving physical translocation and, to a lesser extent, clathrin-dependent endocytosis. For example, ligating the model hydrophobic drug Paclitaxel (PTX) to SVS-1 improved its aqueous solubility by ~1000-fold and successfully delivered and released PTX to cancer cells in vitro and tumors in vivo without toxic adjuvants. These results suggest SVS-1 can serve as a simple, effective delivery platform for molecules with poor solubility and permeability.

Glycan Alteration Imparts Cellular Resistance to a Membrane-Lytic Anticancer Peptide

“…Results show both small molecular drugs led to potent A549 RES cell killing, with nanomolar IC 50 values. Previous results from our lab show the reverse is also true, that cells (OVCAR-3 and NCI/ADR-RES) which have gained resistance to chemotherapy are sensitive to the lytic action of SVS-1 with equal potency as drug-susceptible lines (Medina and Schneider, 2015). …”

“…In addition, we show that cancer cells which have gained resistance to the SVS-1 peptide retain their sensitivity towards standard chemotherapeutic agents (Figure S4). Conversely, we have also previously shown that cells resistant to small molecule chemotherapeutics can be effectively killed with oncolytic peptides (Medina and Schneider, 2015). This suggests combinatorial treatments using ACPs and anti-cancer drugs may be a potentially successful strategy in the clinic to limit resistance.…”

An amphipathic lytic peptide for enhanced and selective delivery of ellipticine

“…34,35 Some recent studies using CLPs, conjugating or complexing with hydrophobic anticancer drugs as drug delivery platforms, also showed selective and fast cellular uptake of drugs, which could have a similar mechanism. 26,36 This ''therapeutic drug carrier'' strategy could provide several unique benefits. The enhancement of anticancer efficacy would allow a lowered dosage of anticancer agent, reducing the side effect; the selectivity could further limit the cytotoxicity towards normal tissues.…”

Anticancer Peptides: Prospective Innovation in Cancer Therapy

“…Short linear ACPs fold into amphipathic conformations upon membrane interaction Schweizer 2009), depending on hydrophobicity, amphipathicity, net charge, secondary structure, and oligomerization at the membrane level (Harris et al 2013;Hoskin and Ramamoorthy 2008). Uncovering the details of the molecular mechanisms underlying each ACP mode of action is a technically challenging but rewarding task because the information gathered from these studies can be successfully applied in the development of innovative approaches in cancer treatment (Medina and Schneider 2015). There are ACPs with high specificity and selectivity for their targets.…”

“…Adapted from references Sinthuvanich et al (2012) and Gaspar et al (2015) folding is the membrane net negative charge but full membrane neutralization is not mandatory for cell death . It was recently found that SVS-1 is able to translocate across the cell membrane into the cytoplasm and into the nucleus when present in concentrations below the minimal inhibitory concentration (MIC 50 ) necessary for lytic action (Medina and Schneider 2015). The combination of SVS-1 with paclitaxel improves SVS-1 aqueous solubility and the peptide is capable of delivering and releasing paclitaxel into cancer cells and tumors in vivo without any adjuvant (Medina and Schneider 2015).…”