Nanodiamond-Protein hybrid Nanoparticles: LHRH receptor targeted and co-delivery of doxorubicin and dasatinib for triple negative breast cancer therapy

Triple Negative Breast Cancer (TNBC) is an aggressive type of breast cancer that is difficult to treat with conventional therapies. This study aimed to develop a novel therapeutic approach using a multifunctional proteinnanodiamond nanocomposite to co-deliver doxorubicin (DOX) and dasatinib (DAS) to cancer cells via luteinising hormone-releasing hormone receptors. Nanodiamonds help retain DOX in targeted cells, while alpha-lactalbumin efficiently encapsulates DAS, reducing side effects. We successfully formulated the nanocomposite with over 80 % drug loading efficiency for both drugs. The imine Schiff-base bond in the nanocomposite hydrolyzes in the acidic pH tumor environment, triggering approximately 65 % drug release after 72 h, compared to less than 20 % in neutral pH. In vitro studies showed enhanced uptake of DOX and DAS in TNBC cell lines, potentially overcoming drug resistance. The combined delivery showed enhanced synergistic cytotoxic effects in drug-resistant TNBC cell models. For example, in the MDA-MB-231 cell line, the IC50 of DOX dropped to 45.63 ng/ml, while in MDA-MB-468, DAS decreased to 35.85 ng/ml with nanoparticle therapy. In vivo experiments utilizing a TNBC mouse model demonstrated the therapeutic effectiveness of the nanocomposite, leading to a 55 % reduction in tumor growth and enhanced survival rates. All mice given the nanocomposite survived after 44 days, but most treated with the DOX/DAS mixture died by day 28. This research showcases multifunctional nanocomposites as targeted drug delivery systems for TNBC, improving drug uptake and cytotoxicity. This strategy presents a promising method for treating drug-resistant breast cancer, with potential clinical applications and synergy with other therapies.