Table 5.
Summary of recently developed PLGA-based NP surfaces functionalized with targeting ligands. 5-FU: 5-fluorouracil; CPP: cell-penetrating peptide; DSPE-PEG: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)]; ICG: indocyanine green (fluorophore); PSMA: prostate-specific membrane antigen; RGD: arginine-glycine-aspartic acid.
| Targeting Ligand | Ligand Attachment Technique | Preparation Method | Stabilizer | Other Surface Modifications | Mean Size (nm) | Therapeutic Agent | Application/Experiments Performed | References |
|---|---|---|---|---|---|---|---|---|
| Antibodies | ||||||||
| Anti-CD133 | Carbodiimide chemistry | Double emulsion solvent evaporation | Tween® 20/PVA | PEG | ≈175 | Methioninase/pemetrexed | Gastric carcinoma/In vitro | [119] |
| Anti-CD44 | Maleimide chemistry | Emulsification solvent evaporation | PVA (30 to 70 kDa) | Lipid film (phosphatidylcholine, DSPE, cholesterol)/ PEG |
≈140 | Salinomycin | Prostate cancer cells/In vivo | [120] |
| Anti-EGFR protein | Maleimide chemistry | Nanoprecipitation | – | PEG | ≈335 | Paclitaxel | Breast cancer/In vivo | [121] |
| Cetuximab | Carbodiimide chemistry | Emulsification solvent evaporation | PVA (30 to 50 kDa) | – | ≈130 | Docetaxel | Lung cancer/In vitro and in vivo | [122] |
| Anti-PD-1 | Carbodiimide chemistry | Emulsification solvent evaporation | PVA (30 to 70 kDa) | PEG | ≈270 | SD-208 (inhibitor of TGF-β kinase) | Immunotherapy—CD8+ T cells targeting/In vitro and in vivo | [123] |
| PSMA antibody | Maleimide chemistry | Emulsion solvent diffusion | PVA | PEG | ≈250 | Toremifene | Prostate cancer cells/In vitro and in vivo | [124] |
| Trastuzumab | Carbodiimide chemistry | Nanoprecipitation | PVA (9 to 10 kDa) | CS | ≈125 | Cisplatin | Ovarian cancer/In vitro | [125] |
| Click chemistry | Nanoprecipitation | – | PEG | ≈100 | Doxorubicin | Breast cancer/In vitro | [126] | |
| Physical electrostatic adhesion | Emulsion solvent diffusion | PVA (13 to 23 kDa) | Polyethylenimine/phosphatidylcholine | ≈220 | Docetaxel | Breast cancer/In vitro | [127,128,129,130] | |
| Biotin | Carbodiimide chemistry | Emulsification solvent evaporation | PVA (20 to 30 kDa) | PEG | ≈180 | SN-38 | Breast cancer/In vitro | [131] |
| Carbodiimide chemistry | Emulsification solvent evaporation | PVA | PEG | ≈180 | 15,16-Dihydrotanshinone I | Cervical cancer/In vitro | [132] | |
| Carbodiimide chemistry | Nanoprecipitation | PVA (30 to 70 kDa) | CS | ≈220 | Epirubicin | Breast cancer/In vitro and in vivo | [133] | |
| Not mentioned | Emulsification solvent evaporation | PVA (30 to 70 kDa) | PEG | ≈210 | Lutein | Delivery to the posterior segment of the eye/In vitro | [134,135] | |
| Bisphosphonates | ||||||||
| Alendronate | Carbodiimide chemistry | Nanoprecipitation | Pluronic® F-68 | – | ≈200 | N/A | Osteolytic bone metastases/In vitro | [136] |
| Carbodiimide chemistry | Emulsification solvent evaporation | Pluronic® F-68 | – | ≈245 | doxorubicin | Bone cancer/In vitro and in vivo | [137] | |
| Physical adhesion | Emulsification solvent evaporation | PVA (30 to 70 kDa) | – | ≈235 | Curcumin/bortezomi | Bone cancer/In vitro and in vivo | [138] | |
| Zoledronic acid | Carbodiimide chemistry | Nanoprecipitation | Pluronic® F-68 | PEG | ≈130 | Docetaxel | Bone cancer/In vitro and in vivo | [139] |
| Carbodiimide chemistry | Nanoprecipitation | Pluronic® F-68 | – | ≈190 to 245 | Gemcitabine/epirubicin | Bone cancer/In vitro and in vivo | [140] | |
| Pamidronate | Physical adhesion | Emulsification solvent evaporation | Brij® 78 | – | ≈155 | Curcumin | – | [141,142] |
| Folic acid | Carbodiimide chemistry | Nanoprecipitation | PVA | PEG | ≈190 | 5-FU | Colon and breast cancer/In vitro | [143] |
| Physical incorporation of DSPE-PEG-FA | Nanoprecipitation | – | Phospholipids/PEG | ≈200 | Pheophorbide | Gastric cancer/In vitro and in vivo | [144] | |
| Physical adhesion using a folic acid–dodecylamine conjugate | Emulsification solvent evaporation | PVA (30 to 70 kDa) | – | ≈230 | Docetaxel | Breast adenocarcinoma/In vitro and in vivo | [145] | |
| Carbodiimide chemistry | Emulsification solvent evaporation | PVA (13 to 23 kDa) | PEG | ≈200 | Oxaliplatin | Colorectal cancer/In vitro and in vivo | [146] | |
| Carbodiimide chemistry | Emulsion solvent diffusion | PVA | PEG | ≈280 | ICG | Breast cancer/In vivo | [147] | |
| Physical incorporation of DSPE-PEG-FA | Nanoprecipitation | – | Lecithin/DSPE-PEG | ≈100 | ICG | Tumor diagnosis and targeted imaging/In vitro and in vivo | [148] | |
| Carbodiimide chemistry | Emulsification solvent evaporation | Pluronic® F-68 | PEG/polypeptide K237 | ≈105 to 130 | Technetium-99 (99mTc, radiolabeled) | Ovarian cancer/In vitro and in vivo | [149] | |
| Lectins | ||||||||
| Wheat germ agglutinin | Maleimide chemistry | Emulsification solvent evaporation | Sodium cholate | PEG | ≈120 to 135 | Curcumin | Enhanced transcellular transport/In vitro | [150,151] |
| Odorranalectin | Maleimide chemistry | Double emulsion solvent evaporation | Sodium cholate | PEG | ≈115 | Urocortin peptide | Nose-to-brain delivery-Parkinson’s disease/In vivo | [152,153] |
| Solanum tuberosum | Maleimide chemistry | Emulsification solvent evaporation | Sodium cholate | PEG | ≈125 | – | Nose-to-brain delivery/In vitro and in vivo | [154] |
| Concanavalin-A | Carbodiimide chemistry | Nanoprecipitation | Pluronic® F-68 | – | ≈550 to 700 | Clarithromycin/acetohydroxamic acid | Helicobacter pylori infection/In vitro and ex vivo bioadhesion | [155] |
| Mannan | Carbodiimide chemistry | Emulsion solvent diffusion | Carbopol® 940 | PEG-PE | ≈215 | Plasmide DNA | Targeted gene delivery/In vitro and in vivo | [156] |
| Carbodiimide chemistry | Nanoprecipitation | Carbopol® 940 | PE | ≈190 | Plasmide DNA | Targeted gene delivery/In vitro and in vivo | [157] | |
| Physical adsorption or carbodiimide chemistry | Double emulsion solvent evaporation | PVA (30 to 50 kDa) | – | ≈300 to 500 | – | Vaccine formulations/In vitro | [158] | |
| Carbodiimide chemistry | Double emulsion solvent evaporation | PVA (30 to 50 kDa) | – | ≈405 | Ovalbumin | Antigen-specific T-cell responses/In vitro and in vivo | [159] | |
| Aptamers | ||||||||
| Heparanase | Carbodiimide chemistry | Nanoprecipitation | TPGS | PEG | ≈145 | Paclitaxel | Breast cancer/In vitro and in vivo | [160,161] |
| CD133 aptamers | Carbodiimide chemistry | Emulsification solvent evaporation | Sodium cholate | PEG | ≈150 | Salinomycin | Osteosarcoma cancer stem cells targeting/In vitro and in vivo | [162] |
| RNA aptamer specific for Ets1 | Carbodiimide chemistry | Emulsification solvent evaporation | PVA | – | Not specified | Gefitinib | Lung cancer/In vitro and in vivo | [163] |
| Gint4.T aptamer (anti-PDGFRβ) | Carbodiimide chemistry | Double emulsion solvent evaporation | Sodium cholate | PEG | ≈50 | Dactolisib | Glioblastoma/In vitro and in vivo | [164] |
| Peptides | ||||||||
| S2P | Maleimide chemistry | Emulsification solvent evaporation | PVA (30 to 70 kDa) | PEG | ≈185 | Imatinib | Atherosclerotic plaques/None | [165] |
| DWSW and NGR | Maleimide chemistry | Nanoprecipitation | - | PEG/erythrocyte membranes | ≈150 | Euphorbia factor L1 | Glioblastoma/In vitro and in vivo | [166] |
| SP94 | Maleimide chemistry | Nanoprecipitation | RH40 | PEG | ≈145 | Cryptotanshinone | Hepatocellular carcinoma/In vitro and in vivo | [167] |
| Penetratin, end-binding protein 1, MPG, and MPGΔNLS CPP | Carbodiimide and maleimide chemistries | Emulsification solvent evaporation | PVA | Avidin-palmitate/ DSPE-PEG |
≈325 to 390 | – | Cellular uptake enhancement/In vitro | [168,169] |
| Tat | Carbodiimide and maleimide chemistries | Emulsification solvent evaporation | Polysorbate 80 | – | ≈60 | – | Cellular uptake enhancement/In vitro | [170] |
| CPPs (Tat, pAntp4, G2) | Physical adhesion | Nanoprecipitation | PVA | PEG | ≈150 to 170 | Fluorometholone | Ocular inflammatory disorders/In vitro and in vivo | [171] |
| CPPs, e.g., Tat, penetratin, and poly(arginine) 8 | Physical adhesion | Emulsification solvent evaporation | PVA (31 kDa) | CS/PEG/Pluronic F127 | ≈150 | – | Inner-ear therapy/In vitro and in vivo | [172] |
| CPPs (R8, Tat, penetratin), and a secretion peptide | Physical adhesion | Emulsification solvent evaporation | Sugar Ester S-1670 | – | ≈115 to 160 | Insulin | Enhanced oral bioavailability of insulin/In vitro and in vivo | [173] |
| Angiopep-2 | Maleimide chemistry | Nanoprecipitation | Pluronic® F-127 | PEG | ≈165 to 180 | – | Brain targeting/In vivo | [174] |
| Cyclic-RGD peptide | Maleimide chemistry | Double emulsion solvent evaporation | Pluronic® F-127 | PEG | ≈310 to 330 | – | Angiogenic endothelium targeting/In vitro | [175,176] |
| RGD peptides | Covalent conjugation to Pluronic® F-127 via vinylsulfone-tiol reaction, and surface adhesion | Microfluidics-based nanoprecipitation | Pluronic® F-127 | PEG | ≈140 to 160 | – | Ovarian carcinoma and glioma/In vitro | [177] |
| Cyclo-(1,12)- PenITDGEATDSGC |
Carbodiimide chemistry | Solvent displacement | Pluronic® F-127 | – | ≈285 to 305 | Doxorubicin | Lung cancer/In vitro | [178] |
| Sialic acid | Carbodiimide chemistry | Nanoprecipitation | Pluronic® F-68 | – | ≈125 | Lycopene | Kidney injury/In vitro | [179,180,181,182] |
| Electrostatic adsorption | Emulsification solvent evaporation | PVA | CS | ≈195 | Doxorubicin | Non-Hodgkin’s lymphoma/In vitro and in vivo | [183] | |
| Carbodiimide chemistry | Nanoprecipitation | Pluronic® F-68 | Similopioid peptide (BBB-penetrating peptide) | ≈180 | Loperamide | Central nervous system targeting/In vitro and in vivo | [184] | |
| Binds to sialic acid | Emulsification solvent evaporation | PVA (30 to 70 kDa) | Doxorubicin/Phloretin | – | [185] | |||
| Transferrin | Physical adsorption | Emulsification solvent evaporation | PVA (30 to 70 kDa) | – | ≈465 | Paclitaxel/Superparamagnetic NP | Breast cancer, brain glioma/In vitro | [186,187] |
| Carbodiimide chemistry | Emulsification solvent evaporation | PVA | – | ≈210 | Docetaxel | Breast cancer/In vitro | [188] | |
| Physical adsorption | Emulsification solvent evaporation | Pluronic® F-127 | – | ≈200 | Bortezomib | Pancreatic cancer/In vitro | [189] | |
| Physical adsorption | Double emulsion solvent evaporation | PVA | Lipid coat (lecithin/DSPE-PEG) | ≈110 | Doxorubicin | Lung cancer/In vitro and in vivo | [190] | |
| Carbodiimide chemistry | Nanoprecipitation | PVA | PEG | ≈110 | Thymoquinone | Lung cancer/In vitro and in vivo | [191] | |
| Carbodiimide chemistry | Emulsification solvent evaporation | PVA | PEG | ≈150 | Temozolomide | Brain glioma/In vitro and in vivo | [192] | |
| Physical adsorption | Nanoprecipitation | – | – | ≈90 | – | Brain glioma/In vitro and in vivo | [193] | |
| Carbodiimide chemistry | Double emulsion solvent evaporation | – | – | ≈150 | Doxorubicin/paclitaxel | Brain glioma/In vitro and in vivo | [194] | |