In-vivo antitumour effect of daunorubicin–GnRH-III derivative conjugates on colon carcinoma-bearing mice

Abstract

Targeted cancer chemotherapy is a novel approach developed for the specific delivery of anticancer drugs. Tumour targeting can be achieved by combining a chemotherapeutic agent with a targeting moiety that recognizes tumour-specific or highly expressed receptors on cancer cells. We used the gonadotropin-releasing hormone-III (GnRH-III) as a targeting moiety to which the chemotherapeutic agent daunorubicin (Dau) was attached through an oxime bond either directly or by inserting a GFLG tetrapeptide spacer. The in-vivo toxicity of Dau-GnRH-III derivative conjugates was evaluated on healthy BDF-1 female mice, and their tumour growth inhibitory effect was determined on C26 murine and HT-29 human colon carcinoma-bearing mice. Both oxime bond-containing conjugates were well tolerated and exerted significant antitumour activity on C26 colon carcinoma-bearing mice at a dose of 30 mg Dau content in conjugate/kg body weight. Furthermore, the conjugates inhibited the tumour growth more than the free drug at a dose that was still not toxic. Similar tumour growth inhibitory effects were obtained on HT-29 human colon carcinoma-bearing mice using three treatments with 15 mg Dau content in conjugate/kg. The tumour growth inhibitions according to the tumour volume and the tumour weight were 44/41% and 58/50%, respectively. Considering the results, both of the investigated Dau-GnRH-III derivative conjugates were well tolerated and had significant antitumour effect on colon carcinoma-bearing mice.

Drug delivery and release systems for targeted tumor therapy

“…This compound displayed an efficient release after disulfide reduction and exerted potent in vitro toxicity, although no comparative results with an only oxime-connected conjugate were presented [104]. However, because of the high stability, combined with a moderate toxic activity, the oxime-linked conjugate [Lys 8 (DAU = Aoa)]- GnRH-III (Aoa is aminooxyacetyl) was evaluated in vivo using healthy and colon carcinoma-bearing mice [105]. The conjugate showed significant tumor growth inhibition and no toxicity in healthy mice, in contrast to an unselective effect observed for free DAU.…”

<em>In Vitro</em> Imaging and Quantification of the Drug Targeting Efficiency of Fluorescently Labeled GnRH Analogues

“…The high expression of GnRH-I-R on several malignant tumor cells compared with healthy tissues provides an opportunity for targeted therapy 5,6 . Many gonadotropin-releasing hormone (GnRH) analogues have been developed in the last few decades, which could be used as targeting moieties 7,8,9 . These peptides are able to deliver anticancer agents with high selectivity into malignant tumor cells which over-express GnRH-I-R 6 .…”

“…These peptides are able to deliver anticancer agents with high selectivity into malignant tumor cells which over-express GnRH-I-R 6 . Several GnRH conjugated anti-tumor drugs with higher selectivity and better efficiency than the corresponding unconjugated free drug have been reported 7,8,9 . Previous publications about GnRH peptides and their receptors reported that the GnRH-I-R can assume various conformations which have different selectivity for GnRH analogues 10 .…”

Protein Expression Profile of HT-29 Human Colon Cancer Cells after Treatment with a Cytotoxic Daunorubicin-GnRH-III Derivative Bioconjugate

“…In our previous work, various anthracycline-GnRH-III derivative bioconjugates have been designed, synthesized and biochemically characterized [10]–[12]. One of the most promising drug delivery systems developed to date in our laboratories consists of the anticancer drug daunorubicin (Dau) attached via an oxime bond to a GnRH-III derivative in which Ser in position 4 was replaced by Lys(Ac) [13].…”

“…Despite its clinical benefits, the administration of free Dau is followed by toxic side effects, the most severe one being cardiotoxicity [14], [15]. Therefore, the attachment of Dau to GnRH-based targeting moieties should provide increased selectivity and decreased systemic toxicity [12]. We have recently shown that the bioconjugate GnRH-III[ 4 Lys(Ac), 8 Lys(Dau = Aoa)] (Figure 1B) exerted in vitro cytostatic/cytotoxic effect on human breast, prostate and colon cancer cells, with IC 50 values in low μM range.…”