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Tumor-associated macrophages (TAMs) play a crucial role in the proliferation and metastasis of cancer cells in solid tumors. TAMs-cancer cell co-culture models provide the opportunity to study the impact of TAMs on the efficiency of therapeutic agents in combination with drug delivery systems. In this study, we aimed to investigate the impact of M0 and M2 phenotypes of TAMs on the cytotoxicity of doxorubicin-loaded poly (n-butyl cyanoacrylate) nanoparticles on hepatocellular carcinoma cells using a co-culture model. In this study, THP-1 cells were polarized into M0 and M2 phenotypes and co-cultured with the cancer cells. The results indicated that M2 cells represented a higher expression of CD14, CD16, CD80, and CD86 markers compared to M0 cells. Moreover, NPs demonstrated higher cytotoxicity in the co-culture model compared to the conventional 2D culture model. Besides, the proliferation of the cancer cells significantly declined following treatment with the serum-free supernatant of the NPs-treated M2 cells after incubation of 48 h, while the supernatant of untreated cells promoted the proliferation of the cancer cells. In addition, the intracellular cytokines levels of TAMs did not significantly change following treatment by the NPs. In conclusion, TAMs play a determinant role in the cytotoxicity aspect of the NPs for hepatocellular carcinoma cells.

The physical properties of I-131 may be suboptimal for the delivery of therapeutic radiation to bone marrow metastases, which are common in the natural history of neuroblastoma. In vitroand preliminary clinical studies have implied improved efficacy of I-125 relative to I-131 in certain clinical situations, although areas of uncertainty remain regarding intratumoral dosimetry. This prompted our study using human neuroblastoma multicellular spheroids as a model of metastasis. 3D dose calculations were made using voxel-based Medical Internal Radiation Dosimetry (MIRD) and dose-point-kernel (DPK) techniques. Dose distributions for I-131 and I-125 labeled mIBG were calculated for spheroids (metastases) of various sizes from 0.01 cm to 3 cm diameter, and the relative dose delivered to the tumors was compared for the same limiting dose to the bone marrow. Based on the same data, arguments were advanced based upon the principles of tumor control probability (TCP) to emphasize the potential theoretical utility of I-125 over I-131 in specific clinical situations. I-125-mIBG can deliver a higher and more uniform dose to tumors compared to I-131 mIBG without increasing the dose to the bone marrow. Depending on the tumor size and biological half-life, the relative dose to tumors of less than 1 mm diameter can increase several-fold. TCP calculations indicate that tumor control increases with increasing administered activity, and that I-125 is more effective than I-131 for tumor diameters of 0.01 cm or less. This study suggests that I-125-mIBG is dosimetrically superior to I-131-mIBG therapy for small bone marrow metastases from neuroblastoma. It is logical to consider adding I-125-mIBG to I-131-mIBG in multimodality therapy as these two isotopes could be complementary in terms of their cumulative dosimetry.