Table 2.
Targeting ligands used for directing therapies for different cell types in the brain
| Targeting Ligand | Target Cell Type | Target Receptor | Target Receptor and Tissue specificity | Delivery System | Reference |
|---|---|---|---|---|---|
|
Transferrin Transferrin antibody (OX26, 8D3, R17217) |
Endothelial cells of the BBB | Transferrin receptor | Low tissue specificity; enriched in endothelial cells, bone marrow cells, and monocytes. In the brain is mostly expressed in microvasculature, neurons, and oligodendrocytes. |
PLGA Liposomes |
[30, 80–84] + HPA* |
|
ApoE Angiopep-2 |
Endothelial cells of the BBB | Low Density Lipoprotein Receptor (LDLR) | Tissue enriched: adrenal gland; in the brain is mostly expressed in excitatory neurons and endothelial cells of the BBB. |
PBCA Human serum albumin-based NPs |
[85–89] + HPA* |
|
Insulin Insulin antibody (29B4) |
Endothelial cells of the BBB | Insulin receptor | Low tissue specificity; in the brain is mostly expressed in oligodendrocytes. | Human serum albumin-based NPs | [90] + HPA* |
| Choline | Endothelial cells of the BBB | Choline transporter (SLC5A7) | Tissue enriched: brain and intestine; in the brain is mainly expressed in endothelial cells and some subtypes of neurons. | Dendrigraft poly-L-lysin-based NPs | [91, 92] + HPA* |
| CRM197 |
Endothelial cells of the BBB Neurons |
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) |
Tissue enriched: urinary bladder; increased in endothelial cells |
PBCA PLGA |
[93] + HPA* |
| TGN | Endothelial cells of the BBB | N.T. | N.A. | PLA | [94] |
| VCAM-1 antibody | Endothelial cells of the BBB | VCAM-1 | Tissue enriched: lymphoid tissue; increased in vascular endothelium and T-cells; in brain is mostly expressed in microglia. | Lipid nanoparticles | [95] + HPA* |
| ICAM1 antibody | Endothelial cells of the BBB | ICAM1 | Tissue enriched: lung and urinary bladder; in the brain is mainly expressed in microglia. | Lipid nanoparticles | [95] + HPA* |
| Neurotensin | Neurons | Neurotensin receptor | Tissue enriched: intestine; in brain: 3-fold increased expression in neurons. | Graphene oxide NPs | [96, 97] + HPA* |
| Tet-1 | Neurons | N.T. | N.A. | PEI | [98] |
| C4-3 | Neurons | Tropomyosin receptor kinase B (TrkB) | Tissue enriched: skeletal muscle and tongue; in brain: 3-fold increased expression in neurons. | N.T. | [99] + HPA* |
| IKRG | Neurons | Tropomyosin receptor kinase B (TrkB) | Tissue enriched: skeletal muscle and tongue; in brain: 3-fold increased expression in neurons. | PCL | [100] + HPA* |
| Non-toxic carboxylic fragment of the tentanus neurotoxin | Neurons | N.T. | N.A. |
Chitosan PEI |
[101–103] |
|
Mel kFGF PasR8 |
Neurons, Astrocytes, Endothelial cells of the BBB | N.A. | N.A. | Liposomes | [104] |
|
pVec QL TAT |
Neurons, Astrocytes, Endothelial cells of the BBB | N.A. | N.A. | Liposomes | [105] |
| Glycoprotein g7 | Neurons | Opioid receptor delta 1 | Tissue enriched: brain; in brain: 6-fold increased expression in neurons. | PLGA | [106, 107] + HPA* |
| RVG (RVG-9r, RVG29) | Neurons | nAChR | Tissue enriched: adrenal glands and gastrointestinal tract; in the brain is increased in inhibitory neurons. |
Liposomes Human serum albumin-based NPs |
[108, 109] + HPA* |
| AQP4 antibody | Astrocytes | AQP4 channel | Tissue enriched: brain and lung; in brain: specific marker of astrocytes. | PGMA | [110] + HPA* |
| D4 (GFAP) antibody | Astrocytes | GFAP | Tissue enriched: brain; in brain: specific marker of astrocytes. | Liposomes | [111] + HPA* |
| Bradykinin B2 antibody | Astrocytes | Bradykinin B2 receptor | Tissue enriched: urinary bladder; increased in excitatory neurons and glial cells. | Chitosan | [112] + HPA* |
| CD11b antibody | Microglia | CD11b (Integrin subunit α M) | Tissue enriched: bone marrow; increased in brain and immune system tissues; brain marker of microglia and macrophages. | Ceria-zirconia | [113] + HPA* |
| NG-2 antibody | Oligodendrocyte progenitor cells | NG-2 receptor | Tissue enriched: intestine; increased in the brain, namely in oligodendrocyte progenitors. | PLGA | [114] + HPA* |
| Myaptavin-3064 | Oligodendrocytes | N.T. | N.A. | Streptavidin | [115] |
| LJM-3064 | Oligodendrocytes | N.T. | N.A. | Exosomes | [116] |
|
QTRFLLH VPTQSSG |
Neural progenitor cells | N.T. | N.A. | Wild-type adenoviral capsid | [117, 118] |
| NFL-TBS.40–63 | Neural stem cells | N.T. | N.A. | Lipid nanocapsules | [119, 120] |
| Transferrin | Neural stem cells | N.T. | N.A. | Gold NPs and gold nanorods | [121] |
N.A.: not available information; NPs: nanoparticles; N.T.: not tested; PLGA: poly(lactic-co-glycolic acid); PLA: poly(lactic acid); PGMA: poly(glycidyl methacrylate); PC: Polycaprolactone; PEI: Polyethylenimine; PBCA: poly(n-butyl cyanoacrylate); nAChR: nicotinic acetylcholine receptor. *data from Human Protein Atlas (https://www.proteinatlas.org/)