Cancer therapy requires not only inhibition of cancer cells themselves, but also specific treatments with stroma. Cancer cells communicate with cancer microenvironment, and cancer microenvironment provides corresponding matrix for cancer cells. Among them, tumor-associated macrophages are a set of macrophages in tumor stroma, which play crucial roles in mediating tumor growth, angiogenesis and tumor metastasis; and matrix metalloproteinases are important enzymes overexpressed in tumor microenvironment that degrade extracellular matrix. The degradation of extracellular matrix in cancer enables cancer cells to escape from their original location and results in metastasis. In this study, we designed a matrix metalloproteinases responsive, tumor-associated macrophages targeting drug delivery system for cancer therapy. We employed matrix metalloproteinases sensitive drug carrier to delivery Bletilla striata polysaccharidebisphosphonate conjugate that has been proven strong affinity to macrophages and high inhibition effects on them in our previous study. We synthesized and characterized the polymer and prepared liposomal nanocarrier for drug delivery. Physicochemical characterization, cytotoxicity and cellular uptake of the nanocarrier were tested as well. The nanocarrier showed sensitivity in the matrix metalloproteinases triggered drug release. Cytotoxicity of the nanocarrier on different cells showed specific inhibition on macrophages. Cellular uptake also demonstrated the matrix metalloproteinases stimulus sensitivity of the nanocarrier. Taking together, we designed a cancer environment responsive, tumor-associated macrophages targeting drug delivery system for cancer therapy.

腫瘤的治療不僅需要抑制腫瘤細胞自身，也需要對腫瘤細胞所處的基質採取治 療措施。腫瘤細胞與其所在的基質發生信息交換，而腫瘤微環境為腫瘤細胞提 供相應的細胞基質。其中，腫瘤相關巨噬細胞就是一類存在於腫瘤微環境，在 介導腫瘤生長，腫瘤血管新生以及腫瘤遷移過程發揮重要作用的細胞，而基質 金屬蛋白酶又是一類在腫瘤微環境中過量表達，可以降解腫瘤細胞外基質從而 令腫瘤細胞脫離原位置，造成腫瘤遷移的重要酶類。 在本研究中，我們設計了一種基質金屬蛋白酶響應的，靶向腫瘤相關巨噬細胞 的藥物遞送系統。我們採用基質金屬蛋白酶敏感的載體包載白芨多糖－雙膦酸 鹽複合物。這種白芨多糖－雙膦酸鹽複合物在我們之前的研究中被證實具有很 強的巨噬細胞親和性並對巨噬細胞有很強的殺傷效果。我們合成並表徵了用於 製備該脂質體型納米載體的高分子化合物。同時研究了該納米載體的物理化學 性質，細胞毒性以及細胞對其的攝取。結果表明，該納米載體在基質金屬蛋白 酶觸發的藥物釋放中展現出預期的敏感性。其對不同細胞的毒性試驗證明其對 巨噬細胞的特異性殺傷。同時，細胞攝取實驗也證明了該納米載體的基質金屬 蛋白酶敏感性。綜上所述，我們成功設計並製備了一種腫瘤微環境響應的，靶 向腫瘤相關巨噬細胞的納米給藥系統。