The high incidence of postoperative recurrence and metastasis has a serious effect on survival in breast cancer patients. Moreover, it is still a great challenge to prevent the postoperative recurrence and metastasis through traditional implantable devices due to their inability to control multiple drug release. Herein, an implantable hierarchical structured ultrafine fiber device with a time-programmed drug release function for the local postoperative adjuvant chemotherapy of breast cancer is developed. The structure is obtained through a co-axial electrospinning technology by the formation of the periodically arranged chambers inside a fiber matrix. The Doxorubicin hydrochloride in these chambers is released rapidly, killing the residual tumor cells to prevent tumor recurrence; while the matrix metalloproteinases-2 (MMP-2) inhibitor disulfiram in the fiber matrix is released in a sustained manner, inhibiting tumor invasion to prevent its metastasis. The fiber device implanted in tumor-bearing mice after a surgical tumor reduction displays excellent therapeutic efficacy by preventing both recurrence and metastasis. The mechanism investigation of tumor invasion through the type-II collagen immunofluorescence analysis reveals that the decrease of the activity of MMP-2 plays a key role in this process.
Combining photodynamic therapy (PDT) with natural killer (NK) cell-based immunotherapy has shown great potential against cancers, but the shedding of NK group 2, member D ligands (NKG2DLs) on tumor cells inhibited NK cell activation in the tumor microenvironment. Herein, we assembled microenvironment-/light-responsive bio-nanosystems (MLRNs) consisting of SB-3CT-containing β-cyclodextrins (β-CDs) and photosensitizer-loaded liposomes, in which SB-3CT was considered to remodel the tumor microenvironment. β-CDs and liposomes were linked by metalloproteinase 2 (MMP-2) responsive peptides, enabling sequential release of SB-3CT and chlorin e6 triggered by the MMP-2-abundant tumor microenvironment and 660 nm laser irradiation, respectively. Released SB-3CT blocked tumor immune escape by antagonizing MMP-2 and promoting the NKG2D/NKG2DL pathway, while liposomes were taken up by tumor cells for PDT. MLRN-mediated photo-immunotherapy significantly induced melanoma cell cytotoxicity (83.31%), inhibited tumor growth (relative tumor proliferation rate: 1.13% of that of normal saline) in the xenografted tumor model, and enhanced tumor-infiltrating NK cell (148 times) and NKG2DL expression (9.55 and 16.52 times for MICA and ULBP-1, respectively), achieving a synergistic effect. This study not only provided a simple insight into the development of new nanomedicine for programed release of antitumor drugs and better integration of PDT and immunotherapy but also a novel modality for clinical NK cell-mediated immunotherapy against melanoma.
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