Engineering a facile and versatile nanoplatform to facilitate the delivery of multiple agents for targeted breast cancer chemo-immunotherapy

• Published in: Biomedicine & pharmacotherapy Vol. 163; p. 114789
• Main Authors: Bahreyni, Amirhossein, Mohamud, Yasir, Zhang, Jingchun, Luo, Honglin
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.07.2023; Elsevier
• Subjects: Animals; B7-H1 Antigen; Breast cancer; Cancer chemotherapy; Cancer immunotherapy; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems - methods; Immunotherapy; Mice; Nanoparticle; Nanoparticles; Neoplasms - drug therapy; Targeted delivery; Tumor Microenvironment; Breast cancer; Cancer chemotherapy; Cancer immunotherapy; Nanoparticle; Targeted delivery
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114789

There is growing evidence showing that single administration of immunotherapeutic agents has limited efficacy in a number of cancer patients mainly due to tumor heterogeneity and immunosuppressive tumor microenvironment. In this study, a novel nanoparticle-based strategy was applied to achieve efficient tumor-targeted therapy by combining chemotherapeutic agents, i.e., doxorubicin (Dox) and melittin (Mel), with an immune checkpoint inhibitor (PD-L1 DsiRNA). The proposed nanoparticle was prepared by the formation of a complex between Mel and PD-L1 DsiRNA (Dicer-substrate short-interfering RNA), followed by the loading of Dox. The surface of the resultant particles (DoxMel/PD-L1 DsiRNA) was then modified with hyaluronic acid (HA) to increase their stability and distribution. In addition, HA can also act as a tumor-targeting agent through binding to its receptor CD44 on the surface of cancer cells. We demonstrated that the surface engineering of DoxMel/PD-L1 DsiRNA with HA significantly enhances its specificity towards breast cancer cells. Moreover, we observed a noticeable reduction in PD-L1 expression together with a synergistic effect of Dox and Mel on killing cancer cells and inducing immunogenic cell death, leading to significantly diminished tumor growth in 4T1-breast tumor bearing Balb/c mice, improved survival rate and extensive infiltration of immune cells including cytotoxic T cells into the tumor microenvironment. Safety analysis revealed that there is no significant toxicity associated with the developed nanoparticle. All in all, the proposed targeted combination treatment strategy can be considered as a useful method to reduce cancer-associated mortality. •A novel nanoparticle-based chemo-immunotherapy (DoxMel/PD-L1 DsiRNA@HA) for breast cancer was developed.•DoxMel/PD-L1 DsiRNA@HA significantly suppressed both primary and distant breast tumors in tumor-bearing Balb/c mice.•Induction of ICD along with suppression of PD-L1 expression by DoxMel/PD-L1 DsiRNA@HA led to a robust systemic immunity against cancer cells.•DoxMel/PD-L1 DsiRNA@HA has high potential for future clinical translation due to its high safety profile and strong anti-tumor efficacy.