A cyclic-RGD-BioShuttle functionalized with TMZ by DAR_inv “Click Chemistry” targeted to α_vβ₃ integrin for therapy

Abstract

Clinical experiences often document, that a successful tumor control requires high doses of drug applications. It is widely believed that unavoidable adverse reactions could be minimized by using gene-therapeutic strategies protecting the tumor-surrounding healthy tissue as well as the bone-marrow. One new approach in this direction is the use of “Targeted Therapies” realizing a selective drug targeting to gain effectual amounts at the target site, even with drastically reduced application doses. MCF-7 breast cancer cells expressing the αvβ3 [alpha(v)beta(3)] integrin receptor are considered as appropriate candidates for such a targeted therapy. The modularly composed BioShuttle carrier consisting of different units designed to facilitate the passage across the cell membranes and for subcellular addressing of diagnostic and/or therapeutic molecules could be considered as an eligible delivery platform. Here we used the cyclic RGD-BioShuttle as a carrier for temozolomide (TMZ) at the αvβ3 integrin receptor realizing local TMZ concentrations sufficient for cell killing. The IC50 values are 12 µMol/L in the case of cRGD-BioShuttle-TMZ and 100 µMol/L for underivatized TMZ, which confirms the advantage of TMZ reformulation to realize local concentrations sufficient for cell killing.Our paper focuses on the design, synthesis and application of the cRGD-BioShuttle conjugate composed of the cyclic RGD, a αvβ3 integrin-ligand, ligated to the cytotoxic drug TMZ. The ligation was carried out by the Diels Alder Reaction with inverse electron demand (DARinv).

A small-molecule RGD-integrin antagonist inhibits cell adhesion, cell migration and induces anoikis in glioblastoma cells

“…In MCF-7 breast cancer cells expressing αvβ3 integrin, the integrin antagonist cyclic-RGD-bioshuttle functionalized with the antitumoral drug temozolomide (TMZ) displayed a 10-fold decrease in the IC 50 when compared to the underivatized TMZ (27). The co-administration or chemical coupling of these inhibitors with clinically relevant drugs deserves further testing first in different in vitro models and warrants additional in vivo studies in animal experimental models.…”

SPPS Resins Impact the PNA-Syntheses' Improvement

“…They are designed for use as a cargo of genetic material 38, 39, highly pharmacologically active substances like temozolomide (TMZ) 40, 41 or components for imaging of morphologic structures and metabolic processes in PET, SPECT 42, MRT 43, and CT 44 as well as for optical imaging (OI) 45-48. In case of theranostic agents 13, 49-51 both groups of cargos (therapeutic and diagnostic) may be combined and a monitoring of the therapeutic success is much easier.…”

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“…The synthesis of further diene building blocks improved the variability of the "Click Chemistry" for fluorescence imaging as exemplarily documented here by the coupling of 5-(dimethylamino)-naphthalene-1-sulfonyl (dansyl) 28 and bis2,6-[5-carboxylic acid-pyrid-2-yl]-tetrazine 29 62,63 .…”