Table 3.
A detailed list of all the efficacy enhancers employed in the improvement of toxin efficacy and enhancement of endosomal escape.
| Efficacy Enhancers | Origin | Factor | Site of Action | Application | Ref. |
|---|---|---|---|---|---|
| Lysosomotropic amines | |||||
| Ammonium chloride | Inorganic | 6700 | Endosomes | Immunotoxins (RTA) | [693, 694] |
| Methylamine | Organic | 13,300 | Endosomes | Immunotoxins (RTA) | [693] |
| Dimethylamine | Organic | 3300 | Endosomes | Immunotoxins (RTA) | [693] |
| Trimethylamine | Organic | 80 | Endosomes | Immunotoxins (RTA) | [693] |
| Amantadine | Organic | 1180 | Endosomes | Immunotoxins (RTA) | [693, 695] |
| Chloroquine | Organic | 2500 | Endosomes | Immunotoxins (RTA, Gel) | [693, 696] |
| Lipopolyamines | Organic | 10 - 250 | Endosomes | Immunotoxins (Sap) | [697] |
| β-Glycylphenyl-naphthylamide (GPN) | Organic | 10 | Endosomes | Immunotoxins (PE) | [698] |
| Quinacrine | Organic | 15 | Endosomes | immunotoxins (Gel) | [696] |
| Carboxylic ionophores | |||||
| Monensin | Organic | 50,000 | Lysosomes | Immunotoxins (RTA, Gel) | [693, 696, 699] |
| Grisorixin | Organic | 25,000 | Lysosomes | Immunotoxins (RTA) | [693] |
| Lasalocid | Organic | 33,000 | Lysosomes | Immunotoxins (RTA) | [693] |
| Nigericin | Organic | 6700 | Lysosomes | Immunotoxins (RTA) | [693] |
| Calcium channel antagonists | |||||
| Verapamil | Organic | 170 | Lysosomes or other vesicular compartments | Immunotoxins (RTA, PE, Gel) | [696, 698, 700] |
| Diltiazem | Organic | 10, 40 | Lysosomes or other vesicular compartments | Immunotoxins (PE) | [698] |
| Methoxyverapamil (D-600) | Organic | 40 | Lysosomes or other vesicular compartments | Immunotoxins (PE) | [698] |
| Varapamil analogues | Organic | 2 - 70 | Lysosomes or other vesicular compartments | Immunotoxins (RTA, PE) | [700] |
| Perhexiline | Organic | 10 - 2000 | Lysosomes or other vesicular compartments | Immunotoxins (RTA) | [701] |
| SR 33557 | Organic | 540 | Lysosomes or other vesicular compartments | Immunotoxins (RTA) | [702] |
| SR 33287 | Organic | 620 | Lysosomes or other vesicular compartments | Immunotoxins (RTA) | [702] |
| Organic polymers | |||||
| Polyethylenimine (PEI) | Organic polymer | From no-effect to effect | Lysosomes | Gene transfection | [703] |
| Poly(amidoamine)s (PAAs) | Organic polymer | 100 | Endosomes and lysosomes | Toxins (RTA, Gel, Sap), Gene delivery | [704-706] |
| Poly(propylacrylic acid) (PAAP) | Organic polymer | Significant increase | Endosomes | Gene transfection | [707] |
| Fusogenic lipids | |||||
| DOPE | Organic | Significant increase | Endosomes | Gene transfection, liposomes | [708] |
| CHEMS | Organic | Significant increase | Endosomes | siRNA delivery | [709] |
| Monoolein | Organic | Significant increase | Endosomes | DNA delivery, nanoparticles | [75] |
| Other organic compounds | |||||
| Retinoic acid | Organic | 10,000 | Golgi apparatus | Immunotoxins (RTA) | [710] |
| Cyclosporin A | Organic | 100 | Vesicular compartments | Immunotoxins (RTA) | [711, 712] |
| Brefeldin-A | Organic | 1000 | Golgi apparatus | Immunotoxins (RTA) | [713] |
| Bryostatin 1 | Organic | Significant increase | Cell signalling | Immunotoxins (PE) | [714] |
| Wortmannin | Organic | Significant increase | Endosomes and lysosomes | Immunotoxins (ETA, Sap, Gel) | [715] |
| Synthetic surfactants | Organic | Significant increase | Endosomes | Gene transfection, siRNA delivery, nanoparticles | [716, 717] |
| EHCO | Organic | Significant increase | Endosomes | siRNA delivery, nanoparticles | [718] |
| Viruses and virus peptides | |||||
| Adenovirus | Adenovirus | 10,000 | Endosomes, lysosomes or other vesicular compartments | Immunotoxins (PE, RTA, Sap, Gel), gene delivery | [719-721] |
| Penton base protein (adenovirus capsid protein) | Adenovirus | 100 | Endosomes and lysosomes | Immunotoxins (PE, Gel) | [722, 723] |
| Minor capsid protein VI | Adenovirus | From no-effect to effect | Endosomes | Nanoparticles | [724, 725] |
| KFT25 (N-terminus of Protein G) | Vesicular stomatitis virus | 10 - 20 | Lysosomes or other vesicular compartments | Immunotoxins (RTA, Dia) | [309, 528] |
| HA2 (hemagglutinin HA-2) | Influenza virus | 10 - 100 | Endosomes | Immunotoxins (RTA, Sap), gene transfer | [82, 726, 727] |
| HA2 / poly (L-lysine) (PLL) | Influenza virus | Significant increase | Endosomes | Gene transfer | [728] |
| HA23 | Influenza virus | 4 - 5 | Endosomes | Immunotoxins (RTA) | [729] |
| GALA | Synthetic peptide (HIV) | From no-effect to effect | Endosomes | Gene transfection, liposomes, nanoparticles | [726, 730, 731] |
| KALA | Synthetic peptide (HIV) | From no-effect to effect | Endosomes and other membranes | Gene transfection | [732] |
| KALA/polyethylenimine (PEI) | Synthetic peptide (HIV) | Significant increase | Endosomes and other membranes | Gene transfection | [733, 734] |
| INF-7 | Influenza virus | 100 | Endosomes | Gene delivery, siRNA delivery, liposomes | [735-737] |
| Tat (transcriptional activator Tat protein) | HIV | 3340 | Endosomes | DNA delivery, PNA delivery, liposomes, nanoparticles | [738-740] |
| gp41 | HIV | Significant increase | Endosomes | Gene delivery, siRNA delivery | [741] |
| gp41/polyethylenimine (PEI) | HIV | Significant increase | Endosomes | Gene delivery, siRNA delivery | [742] |
| L2 (minor capsid protein) | Papillomavirus | From no-effect to effect | Endosomes and other membranes | Proteins (GFP) | [743] |
| Major envelope protein (E) | West Nile virus | From no-effect to effect | Endosomes | Natural process | [744] |
| VP22 (structural protein VP22) | Herpes simplex virus | From no-effect to effect | Actin-mediated endosomes | DNA delivery, proteins (GFP) | [729] |
| Synthetic analogue of glycoprotein H (gpH) | Synthetic peptide (Herpes simplex virus) | 30 | Endosomes | Gene transfection, liposomes | [745] |
| PreS2-domain of hepatitis-B virus surface antigen (TLM) | Hepatitis-B virus | 2 - 20 | Endosomes or other vesicular compartments | Immunotoxins (Sap, Ang) | [600, 746, 747] |
| Bacterial peptides | |||||
| Listeriolysin O (LLO) | Listeria monocytogenes | Significant increase | Endosomes | DNA delivery, liposomes | [748, 749] |
| Pneumococcal pneumolysin (PLO) | Pneumococcos | From no-effect to effect | Endosomes | Toxins (Granzyme B) | [750] |
| Streptococcal streptolysin O (SLO) | Streptococcos | From no-effect to effect | Endosomes | Toxins (Granzyme B) | [750] |
| T-domain of diphtheriatoxin (DT) | Corynebacterium diphtheria | From no-effect to effect | Endosomes | Immunotoxins (DT) | [751] |
| T-domain of diphtheria toxin (DT) / poly(ethylenimine) (PEI) | Corynebacterium diphtheria | Significant increase | Endosomes | Gene transfection | [752] |
| Domain II of Pseudomonas exotoxin A (ETA) | Pseudomonas aeruginosa | From no-effect to effect | Endosomes and trans-Golgi network | Immunotoxins (PE) | [753] |
| REDLK | Pseudomonas aeruginosa | From no-effect to effect | Endoplasmatic reticulum | Immunotoxins (PE) | [754] |
| Animal and human peptides | |||||
| Penetratin (homeotic transcription protein Antennapedia, Antp) | Drosophila melanogaster | From no-effect to effect | Pinocytic and other vesicular compartments | PNA delivery | [755] |
| R6-Penetratin (with arginine residues) | Synthetic (Drosophila melanogaster) | 5 - 10 | Endosmes and other vesicular compartments | PNA delivery | [756] |
| EB1 (synthetic analog of penetratin) | Synthetic (Drosophila melanogaster) | Significant increase | Endosomes | siRNA delivery | [757] |
| hCT (9-32) (human calcitonin derived peptide 9-32) | Human | From no-effect to effect | Endosomes or other vesicular compartments | Natural process | [758, 759] |
| Fibroblast growth factor-1 (FGF-1) sequence | Human | From no-effect to effect | Endosomes | Natural process | [760] |
| Melittin | Bee venom | From no-effect to effect | Endosomes | Gene delivery | [726, 761] |
| Melittin/polyethylenimine (PEI) | Bee venom | Significant increase | Endosomes | Gene delivery, siRNA delivery | [762-764] |
| Human β3 integrin signal sequence | Human | From no-effect to effect | Endosomes | Natural process | [765] |
| Heavy chain of immunoglobulin G | Caiman crocodylus | Significant increase | Cell membrane | Liposomes | [766] |
| Transportan | Synthetic peptide (neuropeptide galanin + wasp venom peptide mastoparan) | From no-effect to effect | Endosomes or other vesicular compartments | Proteins (GFP, Strep) | [767] |
| Bovine prion protein (bPrPp) | Synthetic peptide (bobine prion) | From no-effect to effect | Cell membrane, macropinosomes | Nanoparticles | [768, 769] |
| KDEL | Signal sequence | 100 - 1000 | Endoplasmatic reticulum | Immunotoxins (RTA, PE) | [770, 771] |
| Animal and human proteins | |||||
| α-Interferon (INF) | Human | Significant increase | Cell signalling | Immunotoxins (RTA) | [772] |
| Perforin | Human | From no-effect to effect | Early endosomes | Immunotoxins (GzmB) | [773, 774] |
| Rituximab | Mouse/human chimeric mAb | 80 | Cell signalling | Immunotoxins (Sap) | [587] |
| Plant saponins | |||||
| Saponinum album | Gypsophila paniculata L. | 2,500,000 | Late endosomes and lysosomes | Immunotoxins (Sap) | [599, 775, 776] |
| SA-1641 | Gypsophila paniculata L. | Significant increase | Late endosomes and lysosomes | Immunotoxins (Sap, Dia) | [83, 84] |
| SA-1657 | Gypsophila paniculata L. | From no-effect to effect | Late endosomes and lysosomes | Immunotoxins (Sap) | [52] |
| Saponaria saponins | Saponaria officinalis L. | 10, 000 | Late endosomes and lysosomes | Immunotoxins (Sap) | [52] |
| SO-1861 | Saponaria officinalis L. | 1000 | Late endosomes and lysosomes | Immunotoxins (Sap, Dia) | [52] |
| Quillaja saponins | Quillaja saponaria Mol. | 1400 | Late endosomes and lysosomes | Immunotoxins (Sap) | [775] |
| Plant proteins | |||||
| Ricin B-chain | Ricinus communis L. | From no-effect to effect | Interalization/Cell signalling | Immunotoxins (RTA) | [777] |
| Ricin B-chain immunotoxin | Ricinus communis L. | 2 - 4 | Interalization/Cell signalling | Immunotoxins (RTA) | [778] |
| Ricin B chain (piggyback) | Ricinus communis L. | 2 - 6 | Interalization/Cell signalling | Immunotoxins (RTA) | [779] |
| Synthetic peptides | |||||
| Polyarginines | Synthetic peptide | Significant increase | Late endosomes, Golgi apparatus and endoplasmatic reticulum | DNA delivery, siRNA delivery, proteins (GFP) | [780-782] |
| Polylysines | Synthetic peptide | Significant increase | Endosomes | Gene transfection | [783] |
| Histidine 10 | Synthetic peptide | 7000 | Endosomes | Gene transfection | [784] |
| (R-Ahx-R)4 | Synthetic peptide | From no-effect to effect | Late endosomes, Golgi apparatus and endoplasmatic reticulum | PNA delivery | [74, 785] |
| Poly(L-histidine) | Synthetic peptide | Significant increase | Endosomes | DNA delivery | [786, 787] |
| Sweet arrow peptide (SAP) | Synthetic peptide | Significant increase | Endosomes | Gene delivery, nanoparticles | [788] |
| Loligomer | Synthetic peptide | From no-effect to effect | Endosomes or other vesicular compartments | Peptide delivery, fluorescent probes | [789] |
| Amphiphilic model peptide | Synthetic peptide | From no-effect to effect | Endosomes or other vesicular compartments | Polar bioactive compounds | [790] |
| IRQ peptide | Synthetic peptide | Significant increase | Endosomes | siRNA delivery | [709] |
| 43E peptide | Synthetic peptide | Significant increase | Endosomes and lysosomes | Gene transfection | [791] |
| pJVE | Synthetic peptide | 2 | Endosomes | Immunotoxins (Dia) | [309] |
| RAWA | Synthetic peptide | Significant increase | Endosomes and other membranes | Gene delivery | [792] |
| Nuclear localization signals | Synthetic peptide | 150 | Cytoplasmic entrapment, nuclear membrane | Gene transfection | [793] |
| SynB1 | Synthetic peptide | 6 | Endosomes and other membranes | Peptide delivery | [78, 794] |
| Pep-1 | Synthetic peptide | From no-effect to effect | Endosomes and other membranes | Peptide delivery, proteins (GFP, β-Gal) | [795] |
| Physicochemical techniques | |||||
| Photochemical internalization | Technique | 1000 | Endosomes | Immunotoxins (Sap, Gel), gene transfection, liposomes, nanoparticles | [796-798] |
| Ultrasound | Technique | 30 | Endosomes | Gene delivery, liposomes | [799, 800] |
| Plasmonic nanobubbles | Technique | 30 | Endosomes | Nanoparticles | [801] |
| Magnetic nanoparticles | Technique | From no-effect to effect | Endosomes | Gene transfection, siRNA delivery, nanoparticles | [76, 802] |