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

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. Breast cancer is the most commonly diagnosed cancer and the second most frequent cause of death in women 1. In general, breast tumors are intrinsically heterogeneous in nature, making them difficult to detect and treat 2. Approximately, 75-80% of breast cancers are hormone receptor-positive 2,3. Also, these overexpressed receptors are usually estrogen and/or progesterone receptors 2,3. However, Triple Negative Breast Cancer (TNBC) (which represents approximately 10-17% of all breast cancers) does not express estrogen receptors (ER), or progesterone receptors (PR), or the human epidermal growth factor receptor 2 gene (HER2) 4-8. In addition, TNBCs also exhibit distinctive clinical features 7,8 and are more common in younger patients 6 and African American/African women 9. TNBC is an aggressive and immunopathology subtype of breast cancer that usually does not respond to drugs that target ER, PR and HER2 6. Furthermore, since the most common and conventional breast cancer diagnosis and treatment techniques tend to focus and target ER, PR and HER2, it is often difficult to detect 10 and treat 11 TNBCs with conventional targeted hormonal therapy and chemotherapy. The challenges associated with TNBCs

Drug-encapsulated blend of PLGA-PEG microspheres: in vitro and in vivo study of the effects of localized/targeted drug delivery on the treatment of triple-negative breast cancer

“…Targeted drug-loaded microspheres (PGS-LHRH-loaded PLGA-PEG and PTX-LHRH-loaded PLGA-PEG blend microspheres) and non-targeted drug-loaded microspheres (PGS-loaded PLGA-PEG and PTX-loaded PLGA-PEG blend microparticles) were prepared, respectively, using the emulsion solvent evaporation technique, described in prior work by Obayemi et al . 24 , 76 . Although, in this study physical blends consisting of PLGA and PEG polymer in the ratio of 1:1 were dissolved in an organic solvent (DCM) to form a primary system.…”

Microbial transglutaminase nanoflowers as an alternative nanomedicine for breast cancer theranostics

“…9 However, proven disadvantages such as side effects, inability to adjust the dosage, failure to reach the desired region effectively, and efficiency loss before the targeted area is reached are associated with the conventional chemotherapeutic drugs. 10,11 Nevertheless, the relapse oen occurs, which is the major drawback in the usual course of action following a diagnosis of BC. 5,11 Besides, they damage healthy cells and tissues, thereby limiting the treatment responses.…”

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

“…While both PDCs showed stronger antitumor activities than free PTX and PGS in TNBC models, GnRH-conjugated PGS was more potent than GnRH-conjugated PTX in MDA-MB-231 cells. Mice treated with conjugates had healthy primary organs with no observable physiological changes (Obayemi et al 2020). In another study, GnRH was conjugated to PGS or PTX to yield a PDC, which was then encapsulated in poly lacticco-glycolic acid-PEG (PLGA-PEG) polymer microspheres.…”