Abstract
The presence of a high number of macrophages within solid tumors is often significantly associated with poor prognosis and predict treatment failure for chemotherapy and radiotherapy. Macrophages are innate immune cells capable of performing diverse functions depending on the different signals from the microenvironment. The classically activated macrophage is commonly present during the early stages of tumor development while alternatively activated macrophages are associated with more advanced tumors. The distinction of the antitumoral macrophages from the pro-tumoral macrophages is not absolute. However, they have different cell surface markers such as mannose receptor (MRC1 or CD206) abundantly expressed by macrophages treated with interleukin-4 (IL-4). The important roles of macrophages in cancers suggest that it is important to develop novel therapies that target these cells. In the present study, we designed a probe using Polyamidoamine (PAMAM) fifth-generation (G5) dendrimers conjugated with mannose, Cyanine 7 (Cy7), and hydrazinonicotinamide (HYNIC) for target macrophages with high expression of MRC1 in the tumor. The intracellular uptake of 99mTc-HYNIC-dendrimer-mannose-Cy7 through the interaction with MRC1 in bone marrow-derived macrophages (BMDMs) untreated or treated with lipopolysaccharides (LPS) + interferon (IFN)γ or IL-4 was analyzed. Our results show that high-density mannose dendrimers are preferentially bound by macrophages treated by IFNγ and LPS that express lower levels of MRC1 than for macrophages treated by IL-4 that express high levels of MRC1. Furthermore, the intracellular 99mTc-HYNIC-dendrimer-mannose-Cy7 uptake in BMDMs was not inhibited in the presence of free mannose or glucose. This result suggests that 99mTc-HYNIC-dendrimer-mannose-Cy7 is not internalized via macrophage MRC1. Based on these findings, we concluded that MRC1 expression does not determine the uptake of high-density mannose dendrimers.
Highlights
Macrophages are components of the innate immune system
PAMAM G5 dendrimer-mannose-Cyanine 7 (Cy7)-HYNIC-Tfa was prepared through three steps (Fig 1)
The results suggest that the average number of terminal groups introduced in each step was approximate, 47 mannose, 16 Cy7, and 8 HYNIC-Tfa conjugated per dendrimer (Fig 2)
Summary
Macrophages are components of the innate immune system They play different roles in the maintenance of homeostasis, protection during infection, organ development, and contribute to some pathologic processes as chronic inflammatory diseases and cancer [1]. Macrophages are found in all tissues and display high functional diversity and plasticity [1,2,3]. Macrophages derived from the yolk sac and fetal liver precursors are seeded throughout tissues, persisting in the adulthood as resident macrophages. They are long-lived and self-maintain independently of the hematopoietic stem cells. Bone marrowderived monocytes can replenish tissue-resident macrophages following injury, inflammation, and infection [4]
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