Institutes for Life Sciences and School of Medicine , South China University of Technology , Guangzhou , Guandong 510006 , P. R. China.
National Engineering Research Center for Tissue Restoration and Reconstruction , Guangzhou , Guangdong 510006 , P. R. China.
Mol Pharm. 2018 Sep 4;15(9):3642-3653. doi: 10.1021/acs.molpharmaceut.7b00997. Epub 2018 Jan 26.
Accumulating evidence has confirmed that malignant tumors have a complex microenvironment, which consists of a heterogeneous collection of tumor cells and other cell subsets (including the full gamut of immune cells). Tumor-associated macrophages (TAMs), derived from circulating Ly6C monocytes, constitute the most substantial fraction of tumor-infiltrating immune cells in nearly all cancer types and contribute to tumor progression, vascularization, metastasis, immunosuppression, and therapeutic resistance. Interrupting monocyte recruitment to tumor tissues by disturbing pivotal signaling pathways (such as CCL2-CCR2) is viewed as one of the most promising avenues for tumor microenvironment manipulation and cancer therapy. One critical issue for monocyte-based therapy is to deliver therapeutic agents into monocytes efficiently. In the present study, we systematically investigated the relationship between the surface potential and the biodistribution of polymeric nanoparticles in monocytes in vivo, aiming to screen and identify an appropriate delivery system for monocyte targeting, and we found that cationic nanoparticles have a higher propensity to accumulate in monocytes compared with their neutral counterparts. We further demonstrated that siCCR2-encapsulated cationic nanoparticle (CNP/siCCR2) could modify immunosuppressive tumor microenvironment more efficiently and exhibit superior antitumor effect in an orthotopic murine breast cancer model.
越来越多的证据证实，恶性肿瘤具有复杂的微环境，由异质性的肿瘤细胞和其他细胞亚群（包括各种免疫细胞）组成。肿瘤相关巨噬细胞（TAMs）来源于循环 Ly6C 单核细胞，在几乎所有癌症类型中构成肿瘤浸润免疫细胞的最大部分，并促进肿瘤进展、血管生成、转移、免疫抑制和治疗耐药。通过干扰关键信号通路（如 CCL2-CCR2）干扰单核细胞向肿瘤组织的募集，被认为是肿瘤微环境调控和癌症治疗最有前途的途径之一。基于单核细胞的治疗的一个关键问题是如何有效地将治疗剂递送到单核细胞中。在本研究中，我们系统地研究了体内聚合物纳米颗粒表面电势与单核细胞生物分布之间的关系，旨在筛选和鉴定一种用于单核细胞靶向的合适递药系统，我们发现阳离子纳米颗粒比中性纳米颗粒更倾向于在单核细胞中积累。我们进一步证明，包载 siCCR2 的阳离子纳米颗粒（CNP/siCCR2）能够更有效地修饰免疫抑制性肿瘤微环境，并在原位乳腺癌模型中表现出更好的抗肿瘤效果。
