Exosome-liposome hybrid nanoparticle codelivery of TP and miR497 conspicuously overcomes chemoresistant ovarian cancer.

BACKGROUND: Although cisplatin-based chemotherapy has been used as the first-line treatment for ovarian cancer (OC), tumor cells develop resistance to cisplatin during treatment, causing poor prognosis in OC patients. Studies have demonstrated that overactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is involved in tumor chemoresistance and that overexpression of microRNA-497 (miR497) may overcome OC chemotherapy resistance by inhibiting the mTOR pathway. However, the low transcriptional efficiency and unstable chemical properties of miR497 limit its clinical application. Additionally, triptolide (TP) was confirmed to possess a superior killing effect on cisplatin-resistant cell lines, partially through inhibiting the mTOR pathway. Even so, the clinical applications of TP are restricted by serious systemic toxicity and weak water solubility. RESULTS: Herein, whether the combined application of miR497 and TP could further overcome OC chemoresistance by synergically suppressing the mTOR signaling pathway was investigated. Bioinspired hybrid nanoparticles formed by the fusion of CD47-expressing tumor exosomes and cRGD-modified liposomes (miR497/TP-HENPs) were prepared to codeliver miR497 and TP. In vitro results indicated that the nanoparticles were efficiently taken up by tumor cells, thus significantly enhancing tumor cell apoptosis. Similarly, the hybrid nanoparticles were effectively enriched in the tumor areas and exerted significant anticancer activity without any negative effects in vivo. Mechanistically, they promoted dephosphorylation of the overactivated PI3K/AKT/mTOR signaling pathway, boosted reactive oxygen species (ROS) generation and upregulated the polarization of macrophages from M2 to M1 macrophages. CONCLUSION: Overall, our findings may provide a translational strategy to overcome cisplatin-resistant OC and offer a potential solution for the treatment of other cisplatin-resistant tumors.

pH and redox dual response nano-suppository for the treatment of ulcerative colitis.

To improve treatment compliance and reach sustained and controlled drug release in the colon, we developed a hollow mesoporous silica nano-suppository that responded to both pH and redox stimuli. Firstly, we prepared hollow mesoporous silica nanoparticles containing disulfide bonds (HMSN-SS) and loaded them with 5-ASA. Secondly, we modified the surface of HMSN-SS with polydopamine (PDA) and chitosan (CS) and molded the suppository, which we named 5-ASA@HMSN-SS-PDA-CS (5-ASA@HSPC). By administering 5-ASA@HSPC rectally, it acted directly on the affected area. CS helped the nanoparticles adhere to the colon's surface, while PDA dissociates from HMSN-SS due to protonation in the acidic environment of the ulcerative colon. The disulfide bonds were destroyed by the reducing environment of the colon, leading to a stable and slow release of encapsulated 5-ASA from the pores of HMSN. Finally, in vitro release experiments and in vivo pharmacokinetic and pharmacodynamic experiments had demonstrated that 5-ASA@HSPC exhibited a slow and steady action at the colonic site, with an excellent safety profile. This novel approach showed great potential in the treatment of ulcerative colitis.