Macrophages have a leading position in the tumor microenvironment (TME) which paves the way to carcinogenesis. Initially, monocytes and macrophages are recruited to the sites where the tumor develops. Under the guidance of different microenvironmental signals, macrophages would polarize into two functional phenotypes, named as classically activated macrophages (M1) and alternatively activated macrophages (M2). Contrary to the anti-tumor effect of M1, M2 exerts anti-inflammatory and tumorigenic characters. In progressive tumor, M2 tumor-associated macrophages (TAMs) are in the majority, being vital regulators reacting upon TME. This review elaborates on the role of TAMs in tumor progression. Furthermore, prospective macrophage-focused therapeutic strategies, including drugs not only in clinical trials but also at primary research stages, are summarized followed by a discussion about their clinical application values. Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.

In this study, doxorubicin (DOX) was conjugated to a lipophilic triphenylphosphonium (TPP) that is selectively taken up by the mitochondrial membrane of cells. This new derivative of DOX, i.e., TPP-DOX, was characterized by infrared spectroscopy (IR), nuclear magnetic resonance ((1)H NMR, (13)C NMR), and mass spectrometry. The effect of TPP modification on DOX cell uptake, intracellular trafficking, eventual DOX induced cytotoxicity, and the level of cleaved caspase 3 and PARP in wild type MDA-MB-435/WT and DOX resistant MDA-MB-435/DOX cells was then evaluated and compared to that for free DOX. In general, free DOX cellular uptake appeared to be significantly higher in MDA-MB-435/WT than MDA-MB-435/DOX cells. Moreover, free DOX was able to enter the nucleus of MDA-MB-435/WT cells, but in MDA-MB-435/DOX cells, it was confined within the cytoplasm. The TPP-DOX, on the other hand, was localized in the cytoplasm of both cell phenotypes and showed preferential distribution to the mitochondria. Correspondingly, in MDA-MB-435/DOX cells, an enhanced cytotoxicity was observed for TPP-DOX (IC50 of 33.6 and 21.0 μM at 48 and 72 h incubation, respectively) in comparison to free DOX (IC50 of 126.7 and 77.96 μM at 48 and 72 h incubation, respectively). This observation was accompanied by the increased level of cleaved caspase 3 and PARP indicating enhanced apoptosis in both cell lines, particularly that of MDA-MB-435/DOX, for TPP-DOX compared to free DOX following 24 h treatment. The present study highlights promising application of TPP-DOX in reversing drug resistance in tumor cells.

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