Abstract
Objective Pt-Mal-LHRH is a newly synthesized chemotherapeutic agent that was designed to selectively target the luteinizing hormone-releasing hormone (LHRH) receptor expressed by triple negative breast cancer (TNBC). The aim of this study was to evaluate the therapeutic dosing, tumor reduction efficacy, and selective distribution of Pt-Mal-LHRH in-vivo. Methods and results LHRH tissue expression levels in-vivo were investigated using western blotting and LHRH was found to be increased in reproductive tissues (mammary, ovary, uterus). Further, Pt-Mal-LHRH was found to have increased TNBC tumor tissue platinum accumulation compared to carboplatin by inductively coupled plasma mass spectrometry analysis. The platinum family, compound carboplatin, was selected for comparison due to its similar chemical structure and molar equivalent doses were evaluated. Moreover, in-vivo distribution data indicated selective targeting of Pt-Mal-LHRH by enhanced reproductive tissue accumulation compared to carboplatin. Further, TNBC tumor growth was found to be significantly attenuated by Pt-Mal-LHRH compared to carboplatin in both the 4T1 and MDA-MB-231 tumor models. There was a significant reduction in tumor volume in the 4T1 tumor across Pt-Mal-LHRH doses (2.5–20 mg/kg/wk) and in the MDA-MB-231 tumor at the dose of 10 mg/kg/wk in models conducted by an independent contract testing laboratory. Conclusion Our data indicates Pt-Mal-LHRH is a targeting chemotherapeutic agent towards the LHRH receptor and reduces TNBC tumor growth in-vivo. This study supports drug conjugation design models using the LHRH hormone for chemotherapeutic delivery as Pt-Mal-LHRH was found to be a more selective and efficacious than carboplatin. Further examination of Pt-Mal-LHRH is warranted for its clinical use in TNBCs, along with, other reproductive cancers overexpressing the LHRH receptor.
| Original language | English |
|---|---|
| Article number | e0287151 |
| Journal | PLoS ONE |
| Volume | 18 |
| Issue number | 10 October |
| DOIs | |
| State | Published - Oct 2023 |
Bibliographical note
Publisher Copyright:© 2023 Ndinguri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding
Funding: Authors: Lindsay Cormier (LC), Margaret Ndinguri (MN); Kentucky Biomedical Research Infrastructure Network (KBRIN) grants (P20GMI04489 and P20GM103436); https:// louisville.edu/research/kbrin/kbrin-cores/researchcore Yes, Lindsay Cormier: study design, data collection and analysis, decision to publish, and manuscript preparation. Yes, Margaret Ndinguri: study design, data collection and analysis, decision to publish, and manuscript preparation. Authors: Lindsay Cormier (LC), Margaret Ndinguri (MN); Lisa Middleton (LM); KYNETIC grant funding National Institutes of Health U01 HL152392 funded by NCI, NEI, NHGRI, NIDCR, the Commonwealth of Kentucky and administered by NHLBI. https:// louisville.edu/research/researchers/innovationcommercialization/translational-grants/kynetic Yes, Lindsay Cormier: study design, data collection and analysis, decision to publish, and manuscript preparation. Yes, Margaret Ndinguri: study design, data collection and analysis, decision to publish, and manuscript preparation. Yes, Lisa Middleton: study design, data analysis, decision to publish, and manuscript preparation.
| Funders | Funder number |
|---|---|
| Kentucky Biomedical Research Infrastructure Network Bioinformatics Core | P20GM103436, P20GMI04489 |
| Margaret Ndinguri | |
| National Institutes of Health (NIH) | U01 HL152392 |
| National Heart, Lung, and Blood Institute (NHLBI) | |
| National Human Genome Research Institute | |
| National Eye Institute (NEI) | |
| National Childhood Cancer Registry – National Cancer Institute | |
| National Institute of Dental and Craniofacial Research |
ASJC Scopus subject areas
- General
