New drug delivery strategies targeting the GnRH receptor in breast and other cancers

Abstract

Cancer is the uncontrolled division of abnormal cells in a specific organ. Globally, about 1 in 6 deaths is due to cancer. Despite the plethora of research being undertaken worldwide to find a cure for cancer, it remains a significant challenge. Cancer targeting via agents designed to interfere with some specifically or highly expressed molecules in cancer cells has been a shift in the treatment of various forms of cancers. The development of drug delivery systems, specifically to cancer cells, is a common approach that succeeded in increasing the efficacy and reducing the side effects of different anticancer agents. Gonadotropin-releasing hormone (GnRH) is a naturally occurring hormone with receptors overexpressed in many types of cancers related or unrelated to the reproductive system. Several drug delivery systems were developed using GnRH derivatives as targeting agents. In this review, we first discuss the role of GnRH and its receptors in cancer. Then, we provide a detailed insight into different delivery systems developed using GnRH derivatives as targeting agents in various types of GnRH receptor overexpressing cancers. Some promising findings from these studies indicate that GnRH receptor targeting is a potential strategy to efficiently guide anticancer therapeutics, diagnostic agents, and nucleic acids directly to cancer cells. Lastly, some limitations of the current research and suggestions for more successful outcomes in clinical trials of these delivery systems are highlighted.

Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic

“…Additionally, crizotinib (anaplastic lymphoma kinase (ALK) inhibitor was also conjugated with [ d -Lys6]-GnRH-I targeting peptide to study the GnRH-receptor mediated internalization into nonsmall cell lungs cancer (NSCLC) tissues to exert potent c-Met kinase inhibitory effect . Other famous examples of PDCs consist of GnRH agonists conjugated with chemotherapeutic drugs via covalent linkage are shown in Figure d. , …”

“…The amino acids sequences of GnRG-2 and GnRH-3 are Glp-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH 2 and Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH 2 , respectively. 118 The GnRH-R is also a type of GPCR that plays a key role in cellular growth, and proliferation through the activation of mitogen-activated protein kinase (MAPK) cascade, and apoptosis. This receptor is also highly overexpressed in the reproductive system related to different endocrine cancers including breast (50%), prostate (86%), endometrial and ovarian adenocarcinomas (80%), renal (80%), and pancreatic cancers (50%).…”

“…Up until now, over 20 isoforms of GnRH were found in protochordate and vertebrae speciesamong them, three isoforms such as GnRH-1, GnRH-2, and GnRH-3 are commonly expressed in most vertebrae. The amino acids sequences of GnRG-2 and GnRH-3 are Glp-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH 2 and Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH 2 , respectively …”

Targeting Breast Cancer: An Overlook on Current Strategies

“…GnRH-R is a G-protein coupled receptor, which activates the mitogen-activated protein kinase (MAPK) cascade leading to growth and proliferation of the cells. GnRH-R is overexpressed in cancers that are dependent on gonadal steroids such as breast cancer, representing the 50% of the cases [ 103 ]. GnRH agonists bind GnRH-R in the pituitary gland, resulting in the secretion and initial surge of FSH and LH, thus stimulating the production of serum testosterone or estrogen.…”

Learn from antibody–drug conjugates: consideration in the future construction of peptide-drug conjugates for cancer therapy

“…This might be attributed to the release of free DOX from the PDC in the blood by enzymatic cleavage or hydrolysis. Though proved to be effective and of low toxicity in women with GnRH-R-positive endometrial cancer in phase II trials, AN-152 did not improve overall survival, progression-free survival, overall response rate, clinical benefit rate, or adverse events compared to free DOX for advanced endometrial cancers in phase III clinical trials [ 83 , 84 ]. Obayemi et al conjugated D-Lys 6 -modified GnRH with prodigiosin (PGS) and paclitaxel (PTX) respectively for the treatment of triple-negative breast cancer (TNBC) cells in in vitro studies and both PDCs exhibited stronger antitumor activities than free PTX and in TNBC models [ 85 ].…”