Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are two of the major players involved in the inhibition of anti-tumor immune response in cancer patients, leading to poor prognosis. Selective targeting of myeloid cells has therefore become an attractive therapeutic strategy to relieve immunosuppression and, in this frame, we previously demonstrated that lipid nanocapsules (LNCs) loaded with lauroyl-modified gemcitabine efficiently target monocytic MDSCs in melanoma patients. In this study, we investigated the impact of the physico-chemical characteristics of LNCs, namely size and surface potential, towards immunosuppressive cell targeting. We exploited myeloid cells isolated from glioblastoma patients, which play a relevant role in the immunosuppression, to demonstrate that tailored nanosystems can target not only tumor cells but also tumor-promoting cells, thus constituting an efficient system that could be used to inhibit their function. The incorporation of different LNC formulations with a size of 100 nm, carrying overall positive, neutral or negative charge, was evaluated on leukocytes and tumor-infiltrating cells freshly isolated from glioblastoma patients. We observed that the maximum LNC uptake was obtained in monocytes with neutral 100 nm LNCs, while positively charged 100 nm LNCs were more effective on macrophages and tumor cells, maintaining at low level the incorporation by T cells. The mechanism of uptake was elucidated, demonstrating that LNCs are incorporated mainly by caveolae-mediated endocytosis. We demonstrated that LNCs can be directed towards immunosuppressive cells by simply modulating their size and charge thus providing a novel approach to exploit nanosystems for anticancer treatment in the frame of immunotherapy.

中文翻译：

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通过调节脂质纳米胶囊的大小和表面电荷，靶向胶质母细胞瘤患者免疫抑制性髓样细胞

髓样来源的抑制细胞（MDSC）和肿瘤相关的巨噬细胞（TAM）是参与抑制癌症患者抗肿瘤免疫反应的两个主要因素，导致预后不良。因此，对髓样细胞的选择性靶向已成为缓解免疫抑制的有吸引力的治疗策略，在此框架下，我们先前证明了载有月桂酰修饰的吉西他滨的脂质纳米胶囊（LNC）有效靶向黑色素瘤患者的单核MDSC。在这项研究中，我们调查了LNCs的物理化学特征（即大小和表面电位）对免疫抑制细胞靶向的影响。我们利用从胶质母细胞瘤患者中分离的骨髓细胞，这些细胞在免疫抑制中起着重要的作用，证明定制的纳米系统不仅可以靶向肿瘤细胞，而且可以靶向促进肿瘤的细胞，从而构成可以用来抑制其功能的有效系统。在新鲜分离自胶质母细胞瘤患者的白细胞和肿瘤浸润细胞上，评估了带有总正，中性或负电荷的大小为100 nm的不同LNC制剂的掺入。我们观察到，在具有中性100 nm LNC的单核细胞中获得了最大的LNC摄取，而带正电的100 nm LNC对巨噬细胞和肿瘤细胞更有效，将T细胞的掺入保持在较低水平。阐明了摄取的机制，表明LNC主要通过小窝介导的胞吞作用而被掺入。