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Our previous studies demonstrated that topic application of recombinant human acid fibroblast growth factor (aFGF) significantly, but still not completely, improved in diabetic ulcer healing. To obtain a maximal therapy for diabetic ulcer healing, a combined protocol containing aFGF, anti-oxidative reagent zinc (Zn) and stem cell stimulator granulocyte colony-stimulating factor (G-CSF), i.e.: aFGF/G-CSF/zinc sulphate (ZnSO 4 ), was explored in the present study. Diabetes was induced by a single dose of streptozotocin (STZ, 55 mg/kg) in Sprague Dawley rats, and full thickness skin wound was made in diabetic rats at 2 months after diabetes onset. Diabetic ulcer rats were treated with aFGF, G-CSF, ZnSO 4 , aFGF/G-CSF/ZnSO 4 or vehicle control, respectively and 3, 6, 9, 12, 15, 18, 21 and 28 days later, therapeutic effects were evaluated by calculating ulcer area. On day 7, 14, 21 after treatment, rats were sacrificed to collect 2 pieces of dorsal skin from 3 different sites (wound center, edge and healed area) to perform histopathological examination. Results showed that treatment with aFGF/G-CSF/ZnSO 4 significantly enhanced ulcer healing compared with single drug treatment groups at different time points. Healing times for 100% of the wound in the aFGF/G-CSF/ZnSO 4 group was 20.00 ± 1.15 days, and significantly shorter than those in single treatment groups (p < 0.05). Histopathological and immunohistochemical analysis disclosed significant increases in capillary density, proliferating cells, the expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and the ratios of TIMP-1 to matrix metalloproteinase 1 (MMP-1) in aFGF/G-CSF/ZnSO 4 group as compared to other single treatments. Collectively, the combinative protocol of aFGF/G-CSF/ZnSO 4 significantly enhanced the therapeutic effect on diabetic ulcer wound, probably through the promotion of fibroblast proliferation and differentiation, enhancement of blood vessel regeneration, and up-regulation of TIMP-1 and down-regulation of MMP-1 expression in diabetic ulcer healing process.

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As the most numerous inflammatory cell group in tumor microenvironment, tumor-associated macrophages (TAMs) have an essential effect in tumor therapy and are potential therapeutic targets. M2 type tumor-associated macrophages (M2-TAMs) were involved in the entire process of tumor development, invasion, and metastasis, obstructing the anti-tumor effect of chemotherapy drugs and nano-medicine. This study aimed to construct a mannose modified co-loaded zoledronic acid and doxorubicin liposomes (Man-LP@ZOL/DOX) for improving the anti-tumor effect by suppressing M2-TAMs on triple-negative breast cancer (TNBC). The size, PDI, and Zeta-potential of Man-LP@ZOL/DOX liposomes were determined to be 212.80±7.74 nm, 0.1413±0.0232, -33.63±0.49 mV, respectively. The Man-LP@ZOL/DOX's EE% and DL% of ZOL as measured were 17.21±2.26% and 1.56±0.21%, while for DOX, they were 84.42±2.05% and 5.12±0.14%. The uptake of Man-LP into cells was increased when it was modified with a TAMs target ligand. The liposomes inhibited the invasion of MDA-MB-231 cells induced by M2-TAMs, and expression of biomarkers on M2-TAMs (Arg1 and CD206 in vitro, CD68, and CD206 in vivo) was apparent. Moreover, co-loaded drugs liposome system remarkably enhanced anticancer effects both in vitro and vivo combined with ZOL. In conclusion, all these results established that Man-LP@ZOL/DOX could enhance anti-tumor effect of DOX via depleting M2-TAMs on TNBC.