Enhanced In Vitro Antitumor Activity of GnRH-III-Daunorubicin Bioconjugates Influenced by Sequence Modification

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Gonadotropin-releasing hormone (GnRH) receptors are prevalent in various human cancers, including breast, ovarian, endometrial, prostate, and colorectal cancers.
• GnRH analogues like GnRH-III are being explored as drug delivery systems for targeted cancer therapy.

Purpose of the Study:

• To synthesize and evaluate novel oxime bond-linked daunorubicin GnRH-III conjugates with unnatural amino acids for targeted cancer therapy.
• To assess the cytostatic effects, cellular uptake, drug release, stability, and receptor binding affinity of these new conjugates.

Main Methods:

• Synthesis of 14 novel oxime bond-linked daunorubicin GnRH-III conjugates incorporating unnatural amino acids.
• In vitro evaluation of cell viability on ERα-positive and ERα-negative cancer cells.
• Flow cytometry and fluorescence microscopy for cellular uptake studies.
• Assessment of drug-metabolite release by lysosomal enzymes and stability in human blood plasma.
• Receptor binding studies to determine affinity for the GnRH-receptor.

Main Results:

• All synthesized conjugates demonstrated reduced cell viability across tested cancer cell lines.
• The lead conjugate, GnRH-III-[²ΔHis,³d-Tic,⁴Lys(Bu),⁸Lys(Dau=Aoa)], exhibited enhanced cancer cell growth inhibition compared to the previous lead compound.
• Cellular uptake was significantly improved, leading to accelerated drug delivery to the site of action.
• Amino acid substitution did not impede lysosomal enzyme-mediated drug release and maintained high stability in human blood plasma.
• High binding affinity for the GnRH-receptor was confirmed for the lead conjugate.

Conclusions:

• The novel daunorubicin GnRH-III conjugates are potent anticancer agents with improved cellular uptake and targeted delivery capabilities.
• GnRH-III-[²ΔHis,³d-Tic,⁴Lys(Bu),⁸Lys(Dau=Aoa)] represents a highly promising drug delivery system for targeted cancer therapy due to its efficacy, stability, and receptor binding affinity.