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A peer-reviewed article of this preprint also exists.
This version is not peer-reviewed
Receptor targeting | Carrier formulation | Ligand modification/coating | Cargo | Purpose | Result | Ref. |
Mannose receptor | Liposomes | Mannose | DNA | Stimulation of immune response | Mannosylated cationic liposomes exhibited improved DNA delivery | [147] |
Polymeric micelles | siRNA | TAMs repolarization | Modified micelles could selectively deliver efficacious amounts of functional siRNA into TAMs | [148] | ||
Liposomes | 64Cu | PET imaging of TAMs | High selective accumulation of the liposomes in TAMs was observed | [149] | ||
Selenium NPs | Isoniazid | Treatment of tuberculosis | The NPs preferentially entered macrophages and accumulated in lysosomes releasing Isoniazid | [150] | ||
Galactose receptor | Dextran NPs | Galactose | CpG, anti-IL-10 and anti-IL-10 receptor oligonucleotides | TAMs repolarization | NPs accumulated in the tumor and was taken up predominantly by TAMs | [151] |
Chitosan-cysteine NPs | siRNA | Treatment of ulcerative colitis | Galactose modification significantly facilitated the uptake by macrophages and targeting ability of the NPs | [152] | ||
Poly(lactic-co-glycolic acid) NPs | Dexamethasone | Developing of the strategy to catch macrophages during intestinal inflammation | NPs were effectively captured by macrophages | [153] | ||
Dectin-1 | Polymer-lipid hybrid NPs | Yeast cell wall microparticles, containing β-1,3-D-glucan | Cabazitaxel | Developing of oral targeted drug delivery | The microparticles were rapidly and efficiently taken up by macrophages | [154] |
Mesoporous silica NPs | Doxorubicin | Developing of anti-tumor therapy | Drug delivery to macrophages was enhanced compared to uncoated silica NPs | [155] | ||
Fc receptor | Alginate NPs | Tuftsin | DNA | Developing of anti-inflammatory agents | Tuftsin-modified NPs were rapidly internalized in murine macrophages | [156] |
Folate receptor-β (FRβ) | - | Anti-mouse FRβ monoclonal antibody | Pseudomonas exotoxin A | TAMs depletion | Direct eliminating of TAMs was attained | [157] |
Poly(amidoamine) dendrimers | Folic acid | Methotrexate | Alleviating of the inflammatory disease of arthritis | High degree of specific binding and internalization of the dendrimers into macrophages was observed | [158] | |
Human serum albumin nanocapsules | - | Evaluating targeting ability of folic acid-modified agents | The internalization of nanocapsules was enhanced via FR specificity | [159] | ||
CD44 | Hyaluronic acid-tocopherol succinate micelles | Hyaluronic acid | Rifampicin | Developing of tuberculosis treatment | Micelles exhibited a significant phygocytosis and CD44-dependent uptake in comparison to free drug | [160] |
Liposomes | Prednisolone | Developing of rheumatoid arthritis therapy | Enhanced cellular uptake, mainly mediated by caveolae- and clathrin-dependent endocytosis, was acheived | [161] | ||
Poly(lactic-co-glycolic acid) NPs | Curcumin | Alleviating of ulcerative colitis | Enhanced drug delivery to intestinal macrophages and selective accumulation in inflamed colitis tissue with minimal accumulation in healthy colon tissue was observed | [162] | ||
Siglec-1 | Liposomes | Sialic acid | Epirubicin | Tumor therapy | The tumor targeting efficiency and the accumulation of epirubicin in monocytes was improved | [163] |
Zoledronic acid | TAMs depleting and repolarization | Good targeting ability was observed | [164] |
Utilization of living cells | ||||||
Method of binding to macrophages | Source | Carrier formulation | Cargo | Loading efficiency | Cell viability | Ref. |
Incubation (engulfment) | RAW264.7 | - | Doxorubicin (400 µg/ml) | ≈14% (after 10 s of incubation) | 79% at 72 h after incubation | [63] |
- Liposomes |
AuNRs (150 µg/ml) + Doxorubicin (25 µg/ml) |
13.34% (after 6 h of incubation) 35.2% |
85% after 6 h of incubation | [61] | ||
- | Bioengineered Salmonella typhimurium | 220 ± 13 CFU /100 cells (after 60 min of incubation) | >90% after 60 min of incubation | [79] | ||
Mouse peritoneal macrophages | - | Doxorubicin (1-200 µg/ml) | No data | about 30-60% after 12 h of incubation | [80] | |
Liposomes | Doxorubicin (1-200 µg/ml) | No data | about 80-90% at 12 h after incubation | |||
BMM | Polymeric NPs (100 µg/mL) | Nitric oxide | ≈77% (after 2 h of incubation) | ≈100% for incubation period of 24 h and 48 h | [70] | |
Human monocyte-derived macrophages | Liposomes (100 μM) | Indinavir | 85% (after 4 h of incubation) | No effect of drug encapsulation on macrophage viability was observed | [81] | |
Hypotonic dialysis | THP-1 | - | Catalase (osmolality of 75.67 mOsm/L during 15 min of dialysis) |
53% | 89% after encapsulation | [52] |
Electroporation | J774 | - | Doxorubicin (20mg/mL) | 5% (after <20 s of electroporation) | Drug-loading significantly decreased cell viability | [53] |
Adhesion | Raw 264.7 | Multilayer microfilm (“backpack”) | Catalase (2.3 µU/cell backpack) | 80% (after a brief incubation with the “backpacks”) | Attachment of cell backpacks to macrophages did not alter their major functions | [82] |
J774 | Multilayer microfilm (“backpack”) | Bovine serum albumin | ≈95% (after incubation with the “backpacks” for 4 h) | “Cellular backpacks” didn’t affect macrophage biological functions | [83] | |
Utilization of macrophage-derived membrane structures | ||||||
Source | Carrier formulation | Cargo | Method of encapsulation | Detected proteins | Ref. | |
Cellular membranes | J774 | Polymeric NPs | - | Sonication | CD126, CD130, CD120, CD119, CD14 and TLR4 | [54] |
Mouse peritoneal macrophages | Polymeric NPs | Paclitaxel | Sonication | No data | [84] | |
RAW264.7 | - | Methyltransferase like 14 + RS09 | Coextrusion | No data | [85] | |
RAW 264.7 | Bi2Se3 hollow mesoporous NPs | Quercetin | Coextrusion | α4 integrin, CCR2 | [86] | |
Vesicles | RAW264.7 | - | Paclitaxel | Sonication | Alix, TSG101, CD9, iNOS, Arg-1 | [87] |
J774A.1 | Liposomes | Doxorubicin | Vortexing, sonication and coextrusion | CD81, CD63 and CD9 | [88] | |
RAW 264.7 | Polymeric NPs | - | Sonication | CD45, CD14, CD44, CD18, Mac-1 etc. | [56] | |
RAW264.7 | - | Brain derived neurotrophic factor | Simple mixing | Alix, Tsg 101, LAMP 2 and cytosolic protein β-actin | [89] |
Vehicle | Carrier formulation | Cargo | Target | Highlighted features of macrophage-like particles | Therapeutic effect | Ref. |
Macrophage membrane | Chitosan NPs | - | Tumor cells: HeLa, MCF7 and MDA-MB-231 (in vitro) | Stability Biocompatibility and hemocompatibility Triggering apoptosis due to the presence of TNFα in macrophage membrane |
Dose-dependent anti-tumor proliferative properties and triggering of apoptosis | [109] |
Macrophage | - | Doxorubicin | 4T1 mouse breast cancer cells (in vivo) | Meaningful content of the drug High targeting ability |
Significant inhibition of tumor growth and increasing the survival rate among tumor-bearing mice | [63] |
Macrophage | Poly(D,L-lactide-co-glycolide) micelles and Pluronic block copolymer micelles | Paclitaxel | Human glioma cell line U87 (in vitro) | Main biological functions of macrophages were preserved Anti-tumor effect was enhanced compared to nano-Paclitaxel |
Significant tumor cell growth inhibition | [110] |
Macrophage | Poly(D,L-lactide-co-glycolide) NPs | Tirapazamine | 4T1 mouse breast cancer cells (in vivo) | Targeting ability Enhanced accumulation in hypoxic areas of tumor |
Inhibition of tumor growth and extension in the median survival time, especially in the synergetic chemotherapy | [111] |
Macrophage | - | siRNA lipoplexes | MDA-MB-468 breast cancer model (in vivo) | Ability for horizontal gene transfer of siRNA in tumor site Anti-tumor effect was enhanced compared to pure siRNA Results indicated that exosomal secretion via M2 activation is involved with gene transfer |
A significant reduction in the tumor spheres growth | [112] |
Macrophage | N-methacryloyl mannosamine (conjugated to macrophage surface) | Nucleic acid aptamers | CCRF-CEM tumor cells (in vitro) | Surface modification didn’t affect macrophage phenotype and viability The capture of tumor cells was improved |
Enhanced anticancer immune response via macrophages | [113] |
Macrophage | - | Oncolytic adenovirus | Human prostate tumor model (in vivo) | Targeting ability Accumulation in hypoxic/perinecrotic areas of the tumor |
A lasting antitumor effect with negligible metastatic frequency | [114] |
Macrophage membrane | Gold nanoshells (AuNSs) | Cy7 | 4T1 cancer cells (in vivo) | Active targeting ability High tumoritropic accumulation Good biocompatibility Prolonged circulation time Membrane coating didn’t affect NIR optical properties of AuNSs |
Effective inhibition of tumor growth and its complete eradication after 25 days of photothermal therapy | [115] |
Macrophage | - Liposomes |
AuNRs + Doxorubicin |
4T1 mouse breast cancer cells (in vivo) | High targeting ability Effective infiltration into the tumor tissue High thermal sensitivity Controlled drug release via photothermal perfomance |
Synergetic chemo- and phototherapy allowed enhanced tumor growth inhibition | [61] |
Macrophage | Liposomes | ICG (photothermal agent) + Resveratrol (anti-inflammatory drug) |
4T1 post-operative model (in vivo) | tumor-targeting ability good inflammatory tropism release of the liposomes was enhanced due to membrane destruction via phototherapy excellent photothermal performance |
Ablation of residual tumor tissues, inhibiting tumor postoperative relapse and reduction of the postoperative inflammation | [116] |
Method | Applications | Brief description | References |
FTIR spectroscopy | Macrophage CD206 receptor – ligand interaction studies on the example of ConA model and mannosylated polymers | The use of a model receptor protein allows for rapid primary screening of ligands and selection of the most affine ones, and it is not necessary to isolate hard-to-reach CD206 | [253,260] |
Drug – delivery system (to macrophages) interactions | Registration of FTIR spectra of drug complexes with different polymer ratios and calculation of dissociation constants, entrapment efficiency. Study of molecular details of binding ( functional groups) | [258,260,261] | |
Cells – drug formulation interactions. The effect of the drug on the cells. Selection of the optimal composition of the drug formulation | Provide information about the main components of the cell interacting with the drug. Using this technique, efflux and its inhibition on bacterial and cancer cells were demonstrated | [252,258] | |
Quantification of living cells | Centrifugation of cell suspension and registration of the FTIR spectra of sediment. Low analysis time: does not require seeding of bacteria on a Petri dish | [255] | |
Characterization of polymeric drug delivery systems | The presence of all components, and the success of crosslinking. Molecular architecture | [172,253,255,256,257,258,260,261,262,263] | |
NMR spectroscopy | Drug interaction with the delivery system | The NMR spectrum provides valuable information about the functional groups involved | [261] |
Characterization of polymer drug delivery systems | The presence of all components, and the success of crosslinking | [172,255,260] | |
Fluorescence spectroscopy | Macrophage CD206 receptor – ligand interaction studies on the example of ConA model and mannosylated polymers | Quenching of tryptophan fluorescence in the receptor protein and an increase in fluorescence anisotropy during ligand binding. An alternative is using a FITC-labeled ligand | [254] |
Inclusion of fluorophores-drugs in polymer particles | Change of fluorescent properties: the position and intensity of the maximum, as well as FRET | [264] | |
Interaction of ligands with cells, adsorption and permeability over time, and the effect of efflux inhibitors on drug permeability and retention | |||
UV spectroscopy | Macrophage CD206 receptor – ligand interaction studies on the example of ConA model and mannosylated polymers | Change in protein uptake during ligand binding and change in secondary structure | [254] |
Loading and release of drugs from polymer carriers | Absorption characterizes the amount of drug loaded or released from nanoparticles | [253,256] | |
Antibacteril activity | A600 correlates with the number of colony-forming units | [255,256,261] | |
Circular dichroism spectroscopy | Secondary structure of macrophage CD206 receptor (or its model protein on the example of ConA model) during ligand binding | Changing the circular dichroism sometimes with a cardinal reversal of the spectrum | [265] |
Loading of chiral drugs into polymeric particles | [266] | ||
Isothermal titration calorimetry | Study of macrophage CD206 receptor – ligand interaction studies on the example of ConA model and mannosylated polymers | Thermodynamic parameters (enthalpy, entropy and Gibbs energy) of ligand–receptor complex formation | [267,268,269,270] |
Atomic force microscopy, SEM and TEM | Study of the morphology of nanoparticles, simulating epitops of pathogenic microoragnisms recognized by macrophages. Study of the morphology of bacterial and macrophage cells with adsorbed polymers | High-quality images providing information about the structure of nanoparticles and their effect on bacteria | [257,264,266] |
Nanoparticle tracking analysis (NTA) | Characterization of macrophage terget drug delivery system (nanoparticles) | The rate of particle movement is related to a sphere equivalent hydrodynamic radius as calculated through the Stokes–Einstein equation | [256] |
Dynamic light scattering | Detection of polymeric nanoparticles interaction with cells surface by changing of zeta potential of bacteria and macrofages cells during polymer adsorption | The zeta potential characterizes the stability of nanoparticles. For cells, there is a recharge during the adsorption of polymers | [172,257,264] |
Confocal laser scanning microscopy | Interaction of drug formulations with bacterial and eukaryotic (macrophage and cancerous) cells | Images from multiple cells at the micro and nanoscale. Inhibition of efflux (reverse release of drugs from cells) has been demonstrated | [172,252,271] |
Microbiological studies | Study of the antibacterial effect of drugs including effect on bacteria inside macrophage | The strengthening and prolonged (in vitro) of antibacterial drugs due to the addition of adjuvants to them has been demonstrated | [172,253,255,256,260,261] |
Pharmacokinetics studies | Testing the macrophage terget drug delivery system in terms od the drug circulation time in the bloodstream and bio-distribution | A multiple increase in the half-life of the drug is shown, especially for covalent pro-drugs, and accumulation in the lungs | [255,256,260] |
Flow cytometry | The existence of fluorescent nanoparticles with the drug (not debris) | [257] | |
Nanoparticles adsorption on E. coli cells, and quantification of living cells by DAPI staining | |||
Computer modeling | Molecular dynamics and neural network analysis of macrophage CD206-ligand and drug-polymer interaction | The study of ligands does not require synthesis in the laboratory and complex experiments - as the primary stage of selecting candidates for drug delivery systems to macrophages. Molecular architecture of complexes, binding sites and prediction of binding energy. | [251,272] |
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Submitted:
10 August 2023
Posted:
11 August 2023
You are already at the latest version
A peer-reviewed article of this preprint also exists.
This version is not peer-reviewed
Submitted:
10 August 2023
Posted:
11 August 2023
You are already at the latest version
Receptor targeting | Carrier formulation | Ligand modification/coating | Cargo | Purpose | Result | Ref. |
Mannose receptor | Liposomes | Mannose | DNA | Stimulation of immune response | Mannosylated cationic liposomes exhibited improved DNA delivery | [147] |
Polymeric micelles | siRNA | TAMs repolarization | Modified micelles could selectively deliver efficacious amounts of functional siRNA into TAMs | [148] | ||
Liposomes | 64Cu | PET imaging of TAMs | High selective accumulation of the liposomes in TAMs was observed | [149] | ||
Selenium NPs | Isoniazid | Treatment of tuberculosis | The NPs preferentially entered macrophages and accumulated in lysosomes releasing Isoniazid | [150] | ||
Galactose receptor | Dextran NPs | Galactose | CpG, anti-IL-10 and anti-IL-10 receptor oligonucleotides | TAMs repolarization | NPs accumulated in the tumor and was taken up predominantly by TAMs | [151] |
Chitosan-cysteine NPs | siRNA | Treatment of ulcerative colitis | Galactose modification significantly facilitated the uptake by macrophages and targeting ability of the NPs | [152] | ||
Poly(lactic-co-glycolic acid) NPs | Dexamethasone | Developing of the strategy to catch macrophages during intestinal inflammation | NPs were effectively captured by macrophages | [153] | ||
Dectin-1 | Polymer-lipid hybrid NPs | Yeast cell wall microparticles, containing β-1,3-D-glucan | Cabazitaxel | Developing of oral targeted drug delivery | The microparticles were rapidly and efficiently taken up by macrophages | [154] |
Mesoporous silica NPs | Doxorubicin | Developing of anti-tumor therapy | Drug delivery to macrophages was enhanced compared to uncoated silica NPs | [155] | ||
Fc receptor | Alginate NPs | Tuftsin | DNA | Developing of anti-inflammatory agents | Tuftsin-modified NPs were rapidly internalized in murine macrophages | [156] |
Folate receptor-β (FRβ) | - | Anti-mouse FRβ monoclonal antibody | Pseudomonas exotoxin A | TAMs depletion | Direct eliminating of TAMs was attained | [157] |
Poly(amidoamine) dendrimers | Folic acid | Methotrexate | Alleviating of the inflammatory disease of arthritis | High degree of specific binding and internalization of the dendrimers into macrophages was observed | [158] | |
Human serum albumin nanocapsules | - | Evaluating targeting ability of folic acid-modified agents | The internalization of nanocapsules was enhanced via FR specificity | [159] | ||
CD44 | Hyaluronic acid-tocopherol succinate micelles | Hyaluronic acid | Rifampicin | Developing of tuberculosis treatment | Micelles exhibited a significant phygocytosis and CD44-dependent uptake in comparison to free drug | [160] |
Liposomes | Prednisolone | Developing of rheumatoid arthritis therapy | Enhanced cellular uptake, mainly mediated by caveolae- and clathrin-dependent endocytosis, was acheived | [161] | ||
Poly(lactic-co-glycolic acid) NPs | Curcumin | Alleviating of ulcerative colitis | Enhanced drug delivery to intestinal macrophages and selective accumulation in inflamed colitis tissue with minimal accumulation in healthy colon tissue was observed | [162] | ||
Siglec-1 | Liposomes | Sialic acid | Epirubicin | Tumor therapy | The tumor targeting efficiency and the accumulation of epirubicin in monocytes was improved | [163] |
Zoledronic acid | TAMs depleting and repolarization | Good targeting ability was observed | [164] |