LHRH-Conjugated Drugs as Targeted Therapeutic Agents for the Specific Targeting and Localized Treatment of Triple Negative Breast Cancer

J D Obayemi,V O Uzonwanne,C E Onyekanne,S M Jusu,S C Eluu,O Ojelabi,W O Soboyejo,L Payne,C M Moore,A A Salifu,C C Nwazojie,J A King

doi:10.1038/s41598-020-64979-1

Abstract

Bulk chemotherapy and drug release strategies for cancer treatment have been associated with lack of specificity and high drug concentrations that often result in toxic side effects. This work presents the results of an experimental study of cancer drugs (prodigiosin or paclitaxel) conjugated to Luteinizing Hormone-Releasing Hormone (LHRH) for the specific targeting and treatment of triple negative breast cancer (TNBC). Injections of LHRH-conjugated drugs (LHRH-prodigiosin or LHRH-paclitaxel) into groups of 4-week-old athymic female nude mice (induced with subcutaneous triple negative xenograft breast tumors) were found to specifically target, eliminate or shrink tumors at early, mid and late stages without any apparent cytotoxicity, as revealed by in vivo toxicity and ex vivo histopathological tests. Our results show that overexpressed LHRH receptors serve as binding sites on the breast cancer cells/tumor and the LHRH-conjugated drugs inhibited the growth of breast cells/tumor in in vitro and in vivo experiments. The inhibitions are attributed to the respective adhesive interactions between LHRH molecular recognition units on the prodigiosin (PGS) and paclitaxel (PTX) drugs and overexpressed LHRH receptors on the breast cancer cells and tumors. The implications of the results are discussed for the development of ligand-conjugated drugs for the specific targeting and treatment of TNBC.

Highlights

triple negative breast cancer (TNBC) is an aggressive and immunopathology subtype of breast cancer that usually does not respond to drugs that target ER, PR and HER26
We only focus on targeting triple negative breast cancer cells that have been shown to overexpressed Luteinizing Hormone-Releasing Hormone (LHRH) receptors[11,12,15,20,21,24]
We have successfully developed specific LHRH-conjugated PGS drug that target overexpressed LHRH receptors on TNBC cells/tissue under in vitro and in vivo conditions

Summary

Introduction

TNBC is an aggressive and immunopathology subtype of breast cancer that usually does not respond to drugs that target ER, PR and HER26. The challenges associated with TNBCs. Recent efforts indicate that breast cancer cells can exhibit or acquire intrinsic resistance to chemotherapeutic drugs[13]. In most cases, targeted cancer drug delivery systems can attach to antibodies, peptides and hormonal receptors that have been developed for the treatment of tumors that overexpress these receptors[16,17,18,19,20]. Prior work has shown that LHRH receptors are expressed in over 50% of human breast cancer specimens obtained from a non-selected patient cohort characterized by TNBC21,22 as well as in MDA-MB-231 cell lines[11,20]. The effects of the LHRH-conjugated prodigiosin and paclitaxel drugs (on cancer cells/tissue) are elucidated under in vitro (experiments with MDA-MB-231 TNBC cell line) and in vivo conditions (using an athymic nude mouse model induced with TNBC xenograft tumors).

Methods

Results

Conclusion