Nanomedicine Strategies to Target Tumor-Associated Macrophages

Abstract

In recent years, the influence of the tumor microenvironment (TME) on cancer progression has been better understood. Macrophages, one of the most important cell types in the TME, exist in different subtypes, each of which has a different function. While classically activated M1 macrophages are involved in inflammatory and malignant processes, activated M2 macrophages are more involved in the wound-healing processes occurring in tumors. Tumor-associated macrophages (TAM) display M2 macrophage characteristics and support tumor growth and metastasis by matrix remodeling, neo-angiogenesis, and suppressing local immunity. Due to their detrimental role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer may prove to be beneficial in the treatment of cancer. Due to the plastic nature of macrophages, their activities may be altered to inhibit tumor growth. In this review, we will discuss the therapeutic options for the modulation and targeting of TAM. Different therapeutic strategies to deplete, inhibit recruitment of, or re-educate TAM will be discussed. Current strategies for the targeting of TAM using nanomedicine are reviewed. Passive targeting using different nanoparticle systems is described. Since TAM display a number of upregulated surface proteins compared to non-TAM, specific targeting using targeting ligands coupled to nanoparticles is discussed in detail.

Progress on Modulating Tumor‐Associated Macrophages with Biomaterials

“…However, for macrophage‐targeted therapies, their high phagocytic capability can be utilized for targeting and drug delivery. In particular, macrophages in the liver and spleen, the primary clearance organs, rapidly sequester and degrade 30–99% of injected nanoparticles immediately after injection . Passive targeting, preferential accumulation due to physical properties like size and charge, and the rate and extent of macrophage uptake, are significantly affected by NP modifications .…”

“…Worth noting is the passive targeting strategy that relies on the “enhanced permeation and retention” (EPR) effect which is believed to enhance NP accumulation in tumors due to leaky vasculature. This targeting strategy dominated cancer nanomedicine principles for years, yet the benefits of the EPR effect varies considerably between patients and tumor types . As the importance of TAM‐tumor interactions gained appreciation, TAMs have been explored as drug targets of interest that can be reached through the passive targeting methods described in this section.…”

“…In particular, macrophages in the liver and spleen, the primary clearance organs, rapidly sequester and degrade 30-99% of injected nano particles immediately after injection. [37][38][39] Passive targeting, preferential Adv. Mater.…”

“…This targeting strategy dominated cancer nanomedicine principles for years, yet the benefits of the EPR effect varies considerably between patients and tumor types. [38,41] As the importance of TAM-tumor interactions gained appreciation, TAMs have been explored as drug targets of interest that can be reached through the passive targeting methods described in this section.…”

Metabolism and TAM functions—it takes two to tango

“…All these observations, together with the evidence that this pathway is deregulated in human diseases such as cancer and type 2 diabetes, have prompted scientists to not only investigate the mechanism of its activation but also to exploit it pharmacologically. mTOR Abbreviations 2-OG, 2-oxoglutarate; 3-HAA, 3-hydroxyanthranilic acid; AC, adenylate cyclase; ACLY, ATP citrate lyase; AhR, aryl hydrocarbon receptor; AKT, serine/threonine-specific protein kinase; AMPc, cyclic adenosine monophosphate; AMPK, adenosine monophosphate-activated protein kinase; ARG1, arginase-1; C/EBP, CCAAT-enhancer-binding proteins; CCL13, chemokine (C-C motif) ligand 13; CCL17, chemokine (C-C motif) ligand 17; CCL22, chemokine (C-C motif) ligand 22; CD163, cluster of differentiation 163; CD206, cluster of differentiation 206; CD209, cluster of differentiation 209; CIC, citrate carrier; COX2, cyclooxygenase-2; CREB, cAMP response element-binding protein; CSF1R, colony-stimulating factor 1 receptor; CXCR4, C-X-C chemokine receptor type 4; EAAT, excitatory amino acid transporter; EP4, prostaglandin E2 receptor subtype EP4; ERK, extracellular signal-regulated kinase; FAO, fatty acid oxidation; FAS, fatty acid synthase; Foxp3, forkhead box P3; GABA, c-aminobutyric acid; GCN2, general control nonderepressible 2; Gln, glutamine; GLS, glutaminase; Gpr132, G protein-coupled receptor 132; GS, glutamine synthetase; GSK, glycogensynthase kinase; HIF-α, hypoxia-inducible factor 1α; HSF1, heat shock transcription factor 1; IDO, indoleamine 2,3 dioxygenase; IFN-γ, interferon-γ; IL-4/10/13, interleuchin-4/10/13; iNOS, inducible nitric oxide synthase; IRF4, interferon regulatory factor 4; JNK, c-Jun N-terminal kinase; LDH, lactate dehydrogenase; LLC, Lewis lung carcinomas; LOC, mitochondrial lactate oxidation complex; LPS, lipopolysaccharide; MBT-2, mouse bladder tumor line-2; M-CSF, macrophage colony-stimulating factor; MCT, monocarboxylate transporter; MEK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; MRC1, mannose receptor C-type 1; MSO, methionine sulfoximine; MSR1, macrophage scavenger receptor 1; mTOR, mammalian target of rapamycin; NAD, nicotinamide adenine dinucleotide; NFκB, nuclear factor Kappa light-chain enhancer of activated B cells; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PD-L1, programmed death ligand 1; PDPK1, 3phosphoinositide-dependent protein kinase 1; PGE2, prostaglandin E2; PI3Ks, phosphatidylinositol 3-kinases; PKA, protein kinase A; PKC, phosphorylates protein kinase C; PKM2, pyruvate kinase isozymes M2; PPAR, peroxisome proliferator-activated receptor; PtdInsP3, phosphatidylinositol (3,4,5)trisphosphate; PTEN, phosphatase and tensin homolog; PUFAs, polyunsaturated fatty acids; qRT-PCR, quantitative real-time reverse transcription-PCR; RAF, rapidly accelerated fibrosarcoma; RAS, family of retrovirus-associated DNA sequences; RCC, renal cell carcinoma; REDD1, regulated in development and DNA damage response 1; rhGM-CSF, recombinant human granulocyte/macrophage colony-stimulating factor; SGK1, serum and glucocorticoid-regulated kinase 1; Sp1, specificity protein 1; TAMs, tumor-associated macrophages; TCA cycle, tricarboxylic acid cycle; TCR, T-cell receptor; T eff , effector T cell; TGF-β, transforming growth factor-β; TLR, Toll-like receptor; TME, tumor microenvironment; T reg cells, regulatory T cell; TSC1/2, tuberous sclerosis complex 1/2; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; VEGF, vascular endothelial growth factor. inhibitors (rapamycin and its analogs) are currently used for the treatment of solid tumors, rheumatoid arthritis and during organ transplantation.…”