Design, Synthesis, and In Vitro Activity of Novel Drug Delivery Systems Containing Tuftsin Derivatives and Methotrexate

Abstract

During the past decade, biodegradable polymers or oligopeptides recognized by cell-surface receptors have been shown to increase drug specificity, lowering systemic drug toxicity in contrast to small-size fast-acting drugs. The goal of the present study was to develop anticancer bioconjugates based on chemotactic drug targeting (CDT). These constructs are composed of methotrexate (Mtx) attached to a tuftsin-like peptide carrier through an enzyme-labile pentapeptide spacer (GFLGC) and several copies of a chemotactic targeting moiety (H-TKPR, For-TKPR, H-TKPKG, and Ac-TKPKG). Carriers with targeting moieties in the branches were prepared by solid-phase synthesis using mixed Boc and Fmoc strategies. The drug molecule connected to an enzyme-labile spacer was attached to the branched oligopeptide in solution. In vitro chemotaxis, cellular uptake, and cytotoxicity assays were carried out on the MonoMac6 cell line. The most effective conjugates with H-TKPR or Ac-TKPKG targeting moieties in the branches, which have the most advantageous chemotactic properties, can be internalized rapidly, and these conjugates trigger higher toxic effect than the free drug (Mtx). The results suggest that our tuftsin-based drug delivery systems might be potential candidates for targeting cancer chemotherapy.

Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH‐III derivatives in Tetrahymena and human leukemia cell line

“…It is well known that the efficient chemotactic drug delivery requires a suitable conjugate of at least three components: a carrier, a chemotactic ligand, and a drug molecule. In respect of the basic concept of CDT design, the GnRH-III derivatives are rather special as they fulfill the function of both the carrier and the trigger of chemotactic response in the target cell [1,3,4]. Furthermore, GnRH-III and some of its derivatives have own antiproliferative effect.…”

Comparative analysis of internalisation, haemolytic, cytotoxic and antibacterial effect of membrane-active cationic peptides: aspects of experimental setup

“…Tuftsin is a receptor binding peptide produced by the enzymatic cleavage of the Fc-domain of the heavy chain of immunoglobulin G. Based on the canine tuftsin sequence, [TKPKG]4 (OT20) peptide was developed in our laboratory (Bai et al 2008;Horvati et al 2012;Mezo et al 2004). …”

Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models

“…oligotuftsin derivatives consisting of a pentapeptide unit TKPKG 6,7 . In this study, the TKPKG peptide was elongated with palmitic acid to enhance the lipophilicity, membrane affinity and encapsulation efficacy.…”