Table 1.
Internalization pathways of major nanocarriers for drug delivery
| Nanocarrier | Drug | Main internalization pathways | In vitro models | In vivo models | Remarks | References |
|---|---|---|---|---|---|---|
| PSt-based nanoparticles | ||||||
| – | Phagocytosis | Rat/mouse Mac, Acanthamoeba | – | Nanoparticle size and shape influence phagocytosis. | [19, 56] | |
| – | CME, CvME | Mouse melanoma B16 cells | – | CME predominant for nanoparticles below 200 nm, CvME involved above | [95] | |
| PACA-based nanoparticles | ||||||
| Conventional | Doxorubicin | Phagocytosis (Mac) or non-endocytotic (cancer cells) | MDR cancer cells | Metastasis-bearing mice | Liver Kupffer cells act as a drug reservoir. Transdrug® in phase II/III clinical trials for hepatocarcinoma | [57–63] |
| Conventional | Azidothymidine | Phagocytosis | Human Mo/Mac | Rats | Targeting of Mac of the RES. Uptake is increased by cell infection by HIV | [20, 75–77] |
| PEGylated | Doxorubicin | RME via LDL receptors | Rat brain endothelial cells | Glioblastoma-bearing rats | Preferential accumulation in brain after BBB crossing | [118, 120–124, 171] |
| Polyester-based nanoparticles | ||||||
| PLA, PLGA | Plasmid DNA | Various, including CME | Vascular smooth muscle cells, MCF-7 and PC-3 cancer cells | – | Uptake and endosomal escape are influenced by surface-associated surfactants | [104] |
| PLA-PEG | – | CME, macropinocytosis | MDCK epithelial cells | – | Cationic surface avoid lysosomal degradation | [97, 100] |
| PLGA-PEG-Tf | Paclitaxel | TfR-mediated endocytosis | MCF-7 cancer cells | Solid tumor-bearing mice | Greater uptake and reduced exocytosis result in paclitaxel increased activity | [139, 140] |
| Chitosan-based/coated nanoparticles | ||||||
| Proteins | CME, adsorptive endocytosis | Caco-2, mucus-secreting MTX-E12, A-549 epithelial cells | Rats | Chitosan confers mucoadhesive properties to nanoparticles | [98, 99, 114, 207] | |
| Liposomes | ||||||
| Conventional | – | Phagocytosis | Mouse Mac | Rats | Uptake influenced by liposome size, composition, and rigidity | [23, 24, 29] |
| SUV | Amphotericin B | Phagocytosis | Mac, Langerhans cells, fungi | Mice and rabbits infected by fungi and leshmania | AmBisome® is marketed for the treatment of leshmaniasis and various intracellular fungal infections | [41, 66, 67] |
| pH-Sensitive | ODN | Endocytosis followed by endosomal escape | CV-1, psi2neo, 3T3 cells | Mice | Cytosolic delivery | [101–107] |
| Polyplexes | ||||||
| PEI-based | DNA, ODN, siRNA | Endocytosis followed by endosomal escape | 3T3, HepG2, COS-7, HeLa, neurons | Mice | Polyplexes escape endosomes through “proton sponge” effect. Phase I/II clinical trials | [111-113, 186, 188] |
BBB blood-brain barrier, CME clathrin-mediated endocytosis, CvME caveolae-mediated endocytosis, Mac macrophage, MDR multi-drug resistant, Mo monocyte, ODN oligonucleotide, PACA poly(alkylcyanoacrylate), PEG poly(ethyleneglycol), PEI poly(ethyleneimine), PLA poly(lactic acid), PLGA poly(lactic-co-glycolic acid), PSt polystyrene, SUV small unilamellar vesicle, Tf transferrin, TfR transferrin receptor