Improved In Vivo Anti-Tumor and Anti-Metastatic Effect of GnRH-III-Daunorubicin Analogs on Colorectal and Breast Carcinoma Bearing Mice

Abstract

Among various homing devices, gonadotropin-releasing hormone-III (GnRH-III) peptide represents a suitable targeting moiety for drug delivery systems. The anti-tumor activity of the previously developed GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)] conjugate and the novel synthesized GnRH-III-[2ΔHis,3d-Tic,4Lys(Bu),8Lys(Dau=Aoa)] conjugate, containing the anti-cancer drug daunorubicin, were evaluated. Here, we demonstrate that both GnRH-III-Dau conjugates possess an efficient growth inhibitory effect on more than 20 cancer cell lines, whereby the biological activity is strongly connected to the expression of gonadotropin-releasing hormone receptors (GnRH-R). The novel conjugate showed a higher in vitro anti-proliferative activity and a higher uptake capacity. Moreover, the treatment with GnRH-III-Dau conjugates cause a significant in vivo tumor growth and metastases inhibitory effect in three different orthotopic models, including 4T1 mice and MDA-MB-231 human breast carcinoma, as well as HT-29 human colorectal cancer bearing BALB/s and SCID mice, while toxic side-effects were substantially reduced in comparison to the treatment with the free drug. These findings illustrate that our novel lead compound is a highly promising candidate for targeted tumor therapy in both colon cancer and metastatic breast cancer.

In Vivo Tumor Growth Inhibition and Antiangiogenic Effect of Cyclic NGR Peptide-Daunorubicin Conjugates Developed for Targeted Drug Delivery

“…A variety of synthetic therapeutics have been used which target receptors, and hence revealed a significant tumor growth inhibition in vitro and in vivo. Thus, HT-29 human colon tumors were implanted to the intestine of immunodeficient SCID mice [75][76][77].…”

Energy‐resolved HCD fragmentation of daunorubicin‐peptide conjugates

“…Daunorubicin was used for the development of a large number of peptide-drug conjugates in our laboratory that showed efficient antitumor activity not only in vitro, but also in vivo. 4,5 Daunorubicin consists of an anthraquinone aglycon part and a daunosamine sugar moiety linked to the tetracycline by a glycosidic bond. Due to the complex structure of PDCs, tandem mass spectrometry is an indispensable tool for verification of the structure and purity of synthetic products.…”

“…Mass spectrometry is widely used to determine the release of drugs from PDCs, and to identify their metabolites. [4][5][6][7][8] In the case of anthracycline containing PDCs, however, mass spectrometric analysis is hindered by the degradation of the compounds during electrospray ionization (ESI). ESI is a soft ionization technique, producing intact, singly or multiply protonated molecules from peptides.…”

Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer

“…Usually, they are not toxic up to 30 mg Dau content/kg body weight, while the free Dau can be applied at 1–2 mg/kg dose as maximum tolerated dose (MTD) [ 28 ]. Furthermore, the conjugates usually show similar or higher tumor growth inhibition at 10 mg Dau content/kg than the free drug at MTD with significantly less toxic side effects [ 27 , 29 ]. According to our observations the oxime linked Dau-peptide conjugates prevent better also the cell proliferation and metastases in mice models.…”

“…The Balb/c mice and immunodeficient SCID mice used in these studies were kept as described previously [ 27 ] and cared for according to the “Guiding Principles for the Care and Use of Animals” based upon the Helsinki Declaration, and they were approved by the local ethical committee. The permission license for breeding and performing experiments with laboratory animals: PEI/001/1738-3/2015 and PEI/001/2574-6/2015.…”