Sustained co-delivery of Parecoxib and cisplatin via a biodegradable thermosensitive hydrogel for preoperative synergistic combination chemotherapy in triple-negative breast cancer

A hydrogel system DDP-Pa@Gel was developed without altering the microstructure. • The in vivo retention times of the drugs were assessed over a period of five days. • DDP-Pa@Gel markedly improved the antitumor efficacy and overall survival duration. • DCs increased from 13.3% to 33.1%, while a 5.1-fold increase in IFN-γ + CD8 + T cells. • DDP-Pa@Gel demonstrated an 18.0% reduction in Tregs with statistical significance. Triple-negative breast cancer is getting more attention due to its unfavorable prognosis. Although the surgical resection is the first-line option in the treatment of breast cancer. But due to the poor efficacy and prognosis, now Cisplatin (DDP) based preoperative Neo-adjuvant therapy becomes the mainstay of triple-negative breast cancer. Immune cells in the tumor environment have significant impacts on the effectiveness of treatment. In this study, we observed an anti-tumor effect of combining Parecoxib with DDP in a 4T1 mouse model. Then we designed a co-delivery system based on a thermo-sensitive injectable hydrogel for preoperative Neo-adjuvant combination chemotherapy of the triple-negative breast cancer. The hydrogel system co-loaded with Parecoxib and DDP characterized by a special sol-gel transition in response to temperature and presented a sustained release in vitro and in vivo. In the tumor microenvironment (TME), we observed a synergistic anti-tumor effect and inhibition of cell proliferation, as well as a significant increase in mature Dendritic cells (mDCs) and IFN-γ + CD8 + T cells. Hydrogel loaded with Parecoxib and DDP also reduced the need for frequent administration. These findings demonstrate that the co-delivery hydrogel system DDP-Pa@Gel has great potential in the preoperative Neo-adjuvant chemotherapy of triple-negative breast cancer, that will promote the efficacy and reduce the frequency of administration as a valuable option. Triple-negative breast cancer is getting more attention due to its unfavorable prognosis. Surgical resection is the major option in the treatment of breast cancer. But due to the poor efficacy and prognosis, now preoperative neoadjuvant therapy becomes the mainstay of triple-negative breast cancer. Cisplatin (DDP) based neoadjuvant chemotherapy is the fundamental aspect of treatment. Immune cells in the tumor environment have significant impacts on the effectiveness of treatment. In this study, we observed an anti-tumor effect of combining Parecoxib with DDP in a 4T1 mouse model. Then we designed co-delivery system based on a thermo-sensitive injectable hydrogel for preoperative neoadjuvant combination chemotherapy of the triple-negative breast cancer. The hydrogel system co-loaded with Parecoxib and DDP characterized by a special sol-gel transition in response to temperature and presented a sustained release in vitro and in vivo. A synergistic anti-tumor effect and cell proliferation inhibition were observed, so as a significant increase in mature Dendritic cells (mDCs) and IFN-γ + CD8 + T cells in the tumor microenvironment (TME). The use of hydrogel co-loaded with Parecoxib and DDP benefited to fewer administration as well. These findings demonstrate that the co-delivery hydrogel system DDP-Pa@Gel has great potential in the preoperative neoadjuvant chemotherapy of triple-negative breast cancer, that will promote the efficacy and reduce the frequency of administration as a valuable option. Download: Download high-res image (286KB) Download: Download full-size image