Innovative Hybrid Nanocarriers of <scp>GnRH</scp> Peptide‐Modified Chitosan‐Coated Lipid Nanoparticles as a Targeted Chemotherapy for Reproductive‐Related Cancers

Cancer stands as a primary contributor to worldwide mortality, especially reproductive-related cancers (e.g., breast/cervical cancers among females and prostate cancer among males). Chemotherapy is the most common systemic therapy for cancer, but its adverse effects are concerning. Developing effective and new strategies against cancer is necessary to increase their efficacy and minimize their adverse effect. In this work, the novel core-shell structure of lipid nanoparticle (LNP) was fabricated via a high-throughput microfluidic for chemotherapy drug delivery. A gonadotropin-releasing hormone (GnRH), a targeting moiety for the overexpressed GnRH receptors (GnRHR) in cancer cells, was conjugated on chitosan (GnRH-CS) as a shell and used to modify the surface of LNP with doxorubicin loading to form a complex of LNP-dox-GnRH (≤ 150 nm, PDI ~0.2). The modified surface enhances the binding affinity of the LNP to the breast and prostate cancer cells. For an in vitro study, we found that LNP-dox-GnRH can specifically target the GnRHR-overexpressing cancer cells (i.e., MCF-7 and PC-3) compared with non-targeted LNP-dox. Conversely, there was no difference in the targetability between LNP-dox-GnRHR and non-targeted LNP to MDA-MB-436, a low GnRHR-expressing cancer cell. Furthermore, the enhanced anticancer activity of LNP-dox-GnRH was observed in both monolayer and spheroid cell cultures. This study highlights the advantages of easy customization of payloads and targeting peptides, requiring only a simple coating process that doesn't need specialized expertise. Its flexibility and efficiency enhance the potential for precision therapies, making it ideal for translational applications in treating reproductive-related cancers, GnRH-associated diseases, and other conditions.