A reduction-sensitive lipophilic dihydroartemisinin prodrug in a self-microemulsifying drug delivery system for treating breast cancer lung metastasis via intestinal lymphatic transport.

The eradication of cancers within the lymphatic system is a key treatment goal for cancer metastasis and an important determinant of patient prognosis. Therefore, efficient delivery of chemotherapy drugs to the lymphatic system with minimal side effects holds potential for improved treatment options in aggressive breast cancer. In contrast to the invasive administration routes, oral nanocarriers, particularly self-microemulsifying drug delivery system (SME) has attracted increasing attention to treating lymphatic disorders by exploiting intestinal lymphatic transport. In this study, an optimized SME formulation loaded with a reduction-sensitive lipophilic dihydroartemisinin (DHA) prodrug (DSC) was developed for oral delivery and the treatment of breast cancer metastasis by harnessing intestinal lymphatic transport. Compared with parent DHA, DSC exhibited higher affinity with the oil phase of SME, improving the molar drug loading (1.83-fold) and sustained-release behavior of the SME formulation. DSC also exhibited reduction-triggered release of DHA under high reducing condition, which may reduce unnecessary systemic exposure while improving antitumor efficacy. In vitro cell studies revealed that DSC-SME was internalized into intestinal epithelial cells primarily via caveolae/lipid raft- and clathrin-mediated endocytosis, rather than macropinocytosis. Following internalization, it was subsequently trafficked across cells via the chylomicron pathway. After oral administration, DSC-SME enhanced intestinal retention and promoted drug accumulation in mesenteric lymph nodes. Its oral bioavailability was 8.91- and 2.14-fold higher than that of free DHA and DHA-SME, respectively. Both in vitro and in vivo studies indicated that DSC-SME exhibited favorable antitumor efficacy against murine orthotopic 4 T1 breast tumors and lung metastases, with no significant gastrointestinal or systemic toxicity observed under the current experimental conditions. The proposed mechanism of action involved glutathione depletion, apoptosis induction, proliferation inhibition, and amelioration of the immunosuppressive tumor microenvironment. Collectively, these findings suggest that integrating a reduction-responsive lipophilic prodrug with a convenient SME formulation may offer a promising oral platform for inhibiting cancer metastasis, warranting further preclinical evaluation.