Macrophages associated with tumors as potential targets and therapeutic intermediates

Abstract

Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mϕ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs.

Keywords: biodistribution of nanoparticles; cancer stem cell; eradication of cancer cells; macrophage; nanocarrier; phagocytosis; reprogramming of macrophages; tumor-associated macrophage; tumor-supporting function; ‘Trojan horses’.

Figure 1. Principle functions of tumor-associated macrophages and major factors released during tumor development

MMP: Matrix metallopeptidase; NO: Nitrogen oxide; PGE: Prostaglandin; ROS: Reactive oxygen species; TAM: Tumor-associated macrophage.

Figure 2. Putative role of TAMs in metastasis and tumorigenesis and potential application of TAMs for drug delivery in tumor volume

(A,i) Mobilization of healing M2 Mφ to lesion site, (A,ii) lesion seeding with cancer cell spheroid-containing CSCs, and (A,iii) conversion of Mφ to TAMs; the latter assists in (A,iv) cancer cell proliferation and tissue penetration. (B) Release of angiogenic factors by TAMs induces growth of neovasculature. (C) Monocyte activation and Mφ conversion into TAMs in growing tumor. (D) Accumulation of nanodrugs in tumor via neovasculature (enhanced permeability and retention effect) and the potential route of their intratumoral distribution by TAMs, which can capture nanodrugs to carry them into the hypoxic area. Dashed lines show release of modifying/activating factors. Solid lines show cell movement. Yellow cells are CSCs. Blue ovals are neovascular endothelial cells. CSC: Cancer stem cell; Mφ: Macrophage; TAM: Tumor-associated macrophage.

Figure 3. Effect of an immunostimulatory CpG oligonucleotide and antisense oligonucleotide against IL-10 and the IL-10 receptor encapsulated in specially designed nanoparticles on reprogramming of tumor-associated macrophages in murine tumor model

Galactosylated cationic dextran was used to pack these oligonucleotides (GDO), and it was then encapsulated in acid-sensitive PEG–histidine-modified alginate NPs (PDO). After injection in mouse and accumulation in tumors, NPs were stripped off PEG in the acidic tumor environment, which made them recognizable by TAMs via MGL. The release of active oligonucleotides initiated M2-to-M1 conversion and subsequent tumor growth inhibition. (A) Shows accumulation of PDO NPs in murine tumor by fluorescent (Cy5.5) bioimaging. (B) Shows confocal images of fluorescently labeled oligonucleotides (red) and TAMs (green F4/80 marker). Oligonucleotides were effectively colocalized with the TAMs. GDO: Glycerol dioleate; iv.: Intravenous; MGL: Macrophage galactose-type lectin; NP: Nanoparticle; ODN: Oligodeoxynucleotide; PDO: Polyethylene glycol-histidine-modified alginate nanoparticles; PEG: Polyethylene glycol; PHA: Polyhydroxyalkanoate; TAM: Tumor-associated macrophage. Reproduced with permission from [75].