PDF(Pubmed)
Abstract：
BACKGROUND: Melanoma is a highly aggressive form of skin cancer with increasing incidence and mortality rates. Chemotherapy, the primary treatment for melanoma, is limited by hypoxia-induced drug resistance and suppressed immune response at the tumor site. Modulating the tumor microenvironment (TME) to alleviate hypoxia and enhance immune response has shown promise in improving chemotherapy outcomes.
METHODS: In this study, a novel injectable and in situ forming hydrogel named MD@SA was developed using manganese dioxide (MnO2) nanosheets pre-loaded with the chemotherapy drug doxorubicin (DOX) and mixed with sodium alginate (SA). The sustainable drug delivery, oxygen generation ability, and photothermal property of MD@SA hydrogel were characterized. The therapeutic efficacy of hydrogel was studied in B16F10 in vitro and B16F10 tumor-bearing mice in vivo. The immune effects on macrophages were analyzed by flow cytometry, real-time quantitative reverse transcription PCR, and immunofluorescence analyses.
RESULTS: The MD@SA hydrogel catalyzed the tumoral hydrogen peroxide (H2O2) into oxygen, reducing the hypoxic TME, down-regulating hypoxia-inducible factor-1 alpha (HIF-1α) and drug efflux pump P-glycoprotein (P-gp). The improved TME conditions enhanced the uptake of DOX by melanoma cells, enhancing its efficacy and facilitating the release of tumor antigens. Upon NIR irradiation, the photothermal effect of the hydrogel induced tumor apoptosis to expose more tumor antigens, thus re-educating the M2 type macrophage into the M1 phenotype. Consequently, the MD@SA hydrogel proposes an ability to constantly reverse the hypoxic and immune-inhibited TME, which eventually restrains cancer proliferation.
CONCLUSIONS: The injectable and in situ forming MD@SA hydrogel represents a promising strategy for reshaping the TME in melanoma treatment. By elevating oxygen levels and activating the immune response, this hydrogel offers a synergistic approach for TME regulation nanomedicine.
METHODS: In this study, a novel injectable and in situ forming hydrogel named MD@SA was developed using manganese dioxide (MnO2) nanosheets pre-loaded with the chemotherapy drug doxorubicin (DOX) and mixed with sodium alginate (SA). The sustainable drug delivery, oxygen generation ability, and photothermal property of MD@SA hydrogel were characterized. The therapeutic efficacy of hydrogel was studied in B16F10 in vitro and B16F10 tumor-bearing mice in vivo. The immune effects on macrophages were analyzed by flow cytometry, real-time quantitative reverse transcription PCR, and immunofluorescence analyses.
RESULTS: The MD@SA hydrogel catalyzed the tumoral hydrogen peroxide (H2O2) into oxygen, reducing the hypoxic TME, down-regulating hypoxia-inducible factor-1 alpha (HIF-1α) and drug efflux pump P-glycoprotein (P-gp). The improved TME conditions enhanced the uptake of DOX by melanoma cells, enhancing its efficacy and facilitating the release of tumor antigens. Upon NIR irradiation, the photothermal effect of the hydrogel induced tumor apoptosis to expose more tumor antigens, thus re-educating the M2 type macrophage into the M1 phenotype. Consequently, the MD@SA hydrogel proposes an ability to constantly reverse the hypoxic and immune-inhibited TME, which eventually restrains cancer proliferation.
CONCLUSIONS: The injectable and in situ forming MD@SA hydrogel represents a promising strategy for reshaping the TME in melanoma treatment. By elevating oxygen levels and activating the immune response, this hydrogel offers a synergistic approach for TME regulation nanomedicine.
摘要：
背景：黑色素瘤是一种高度侵袭性的皮肤癌，发病率和死亡率都在增加。化疗,黑色素瘤的主要治疗方法，受到缺氧诱导的耐药性和肿瘤部位免疫反应抑制的限制。调节肿瘤微环境（TME）以减轻缺氧并增强免疫反应已显示出改善化疗结果的希望。
方法：在本研究中，使用预先装载有化疗药物多柔比星(DOX)并与海藻酸钠(SA)混合的二氧化锰(MnO2)纳米片开发了一种名为MD@SA的新型可注射原位形成水凝胶。可持续的药物输送，产氧能力，并对MD@SA水凝胶的光热性能进行了表征。在体外B16F10和体内B16F10荷瘤小鼠中研究了水凝胶的治疗功效。通过流式细胞术分析对巨噬细胞的免疫作用,实时定量逆转录PCR,和免疫荧光分析。
结果：MD@SA水凝胶催化肿瘤过氧化氢（H2O2）转化为氧气，减少缺氧TME，下调缺氧诱导因子-1α（HIF-1α）和药物外排泵P-糖蛋白（P-gp）。改善的TME条件增强了黑色素瘤细胞对DOX的摄取，增强其功效并促进肿瘤抗原的释放。在NIR照射下，水凝胶的光热效应诱导肿瘤凋亡以暴露更多的肿瘤抗原，从而将M2型巨噬细胞重新教育成M1表型。因此,MD@SA水凝胶提出了一种不断逆转缺氧和免疫抑制的TME的能力，最终抑制了癌症的扩散。
结论：可注射和原位形成的MD@SA水凝胶代表了在黑色素瘤治疗中重塑TME的有希望的策略。通过提高氧气水平和激活免疫反应，这种水凝胶为TME调节纳米医学提供了一种协同方法。
方法：在本研究中，使用预先装载有化疗药物多柔比星(DOX)并与海藻酸钠(SA)混合的二氧化锰(MnO2)纳米片开发了一种名为MD@SA的新型可注射原位形成水凝胶。可持续的药物输送，产氧能力，并对MD@SA水凝胶的光热性能进行了表征。在体外B16F10和体内B16F10荷瘤小鼠中研究了水凝胶的治疗功效。通过流式细胞术分析对巨噬细胞的免疫作用,实时定量逆转录PCR,和免疫荧光分析。
结果：MD@SA水凝胶催化肿瘤过氧化氢（H2O2）转化为氧气，减少缺氧TME，下调缺氧诱导因子-1α（HIF-1α）和药物外排泵P-糖蛋白（P-gp）。改善的TME条件增强了黑色素瘤细胞对DOX的摄取，增强其功效并促进肿瘤抗原的释放。在NIR照射下，水凝胶的光热效应诱导肿瘤凋亡以暴露更多的肿瘤抗原，从而将M2型巨噬细胞重新教育成M1表型。因此,MD@SA水凝胶提出了一种不断逆转缺氧和免疫抑制的TME的能力，最终抑制了癌症的扩散。
结论：可注射和原位形成的MD@SA水凝胶代表了在黑色素瘤治疗中重塑TME的有希望的策略。通过提高氧气水平和激活免疫反应，这种水凝胶为TME调节纳米医学提供了一种协同方法。
