Targeting a ruthenium complex to the nucleus with short peptides

Abstract

In an effort to develop octahedral metal complexes as chemotherapeutic and diagnostic agents targeted to DNA, it is critical to optimize the properties of their cellular uptake. Appending Doctaarginine has been found to improve both the uptake and nuclear localization efficiency of these complexes, but the increased positive charge interferes with selective DNA binding and hence activity. Herein, we evaluate the nuclear entry of a series of luminescent ruthenium peptide conjugates of shorter sequence and lower charge. As is the case for the D-octaarginine conjugate (Ru-D-R8), the tetrapeptide RrRK (where r = D-arginine) facilitates nuclear localization of the ruthenium complex above a threshold concentration, though the threshold is higher for this conjugate (Ru-RrRK) than for Ru-D-R8. Furthermore, appended fluorescein, which lowers the threshold concentration for Ru-D-R8, does not improve nuclear entry of Ru-RrRK, indicating that fluorescein conjugation is not a general strategy for modulating the distribution of cell-penetrating peptides. Similarly, the concentration required for nuclear entry of Ru-RrRK is much higher than has been reported for a thiazole orange RrRK conjugate, demonstrating the influence of payload on the efficiency of uptake and localization of cell-penetrating peptides.

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

“…25 In recent years, several coordination or organometallic complexes have also been conjugated to carrier molecules such as receptor-binding peptides or known delivery peptides to improve both cellular uptake to cancer cells and cytotoxic activity of the metal-based drug. 26,27,28,29,30,31,32,33 Herein we report on the use of conjugates between octreotide and several metal complexes as new chemotherapeutic agents. In particular, the synthesis of hybrid compounds between the dicarba analogue of octreotide (2) and platinum(II), ruthenium(II) and osmium(II) metal complexes has been accomplished by efficient solid-phase procedures (compounds 3-6 in Chart 1).…”

Peptide-mediated vectorization of metal complexes: conjugation strategies and biomedical applications

“…Taking advantage of these cellular uptake studies, Barton group evaluated the cell-penetrating properties of luminescent Ru(II) dppz complexes conjugated to D-octaarginine or to RrRK, and compared them with those of the corresponding fluorescein-labeled metallopeptides (Figure 4b). 49,50 This work emphasizes the importance of exploring the fluorophore effect, since it was noticed that the cellular uptake properties of the non-labeled metallopeptide differed significantly from those of the labeled one.…”

“…In support to these targeted delivery works, Keyes group exploited the capacity of Ru(II) polypyridyl peptide conjugates as probes for cell imaging. 54,55 Metallopeptides incorporating other CPPs such as Tat [47][48][49][50][51][52][53][54][55][56][57] , sC18 or Penetratin have also been described. For instance, Keppler group reported the conjugation of a Pt(IV) analogue of oxaliplatin prodrug to the Tat 47-57 peptide (YGRKKRRQRRR-NH 2 ).…”

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

“…[15][16] Among such modifications, derivatization of non-leaving ligands with a carrier molecule has tremendous potential to generate selective, less toxic metallodrugs. The potential of this targeted strategy is particularly promising when metal complexes, either organometallic or classical coordination compounds, are attached to biomolecules [17][18][19][20][21][22][23][24] whose receptors are overexpressed on the membrane of tumoral cells [25][26][27][28] or to organic molecules with high affinity with a given biological target (proteins or nucleic acids). 29 Such differences in cytotoxic activity for each compound in a particular cell line, either normal or tumoral, could be interpreted in terms of cell uptake and accumulation efficiency.…”

“…15,16 Moreover, modification of the non-leaving ligands allows the metal complex to be anchored to a "tumor-targeting device" such as receptor-binding peptides, folic acid or estrogens. [17][18][19][20][21][22][23][24] This targeted strategy has a tremendous potential in the development of more efficient, less toxic, selective metallodrugs in chemotherapy because receptors for these carrier molecules are over-expressed in the membrane of tumoral cells. [25][26][27][28] Another strategy to improve efficiency of a metal-based drug is to increase its affinity with its ultimate biological target.…”