Table 2.
The strategies of overcoming the transport barriers of NDDSs to codeliver two different drugs.
| Delivery barriers | Physiological basis | Strategies | Feature | Nanocarrier type | Nanocarrier composition | Drug | Ref |
|---|---|---|---|---|---|---|---|
| (1) Blood circulation | (1) The mononuclear phagocyte system (MPS) | (1) Hydrophilic polymer nanoparticles | PEG-modified | Liposome | DSPE-PEG 2000 | Adriamycin + quercetin | [42] |
| PEG-modified | Micelles | mPEG-PCL | Doxorubicin + curcumin | [43] | |||
| (2) Electrostatic interaction | (2) RBC cloak nanoparticles | PEG-modified | Nanoparticles | PEG-b-PLL | Doxorubicin + triptolide | [44] | |
| PEG-MSN | Mesoporous silica nanoparticle (MSN) | PEG-MSN | Paclitaxel + curcumin | [45] | |||
| PEG-modified | Lipid-coated polymeric nanoparticle | PEG2k-DSPE/PLGA | Doxorubicin + curcumin | [46] | |||
| PEG-MNPs | Magnetic nanocomposite | Fe3O4/HAPA/β-CD | Doxorubicin + curcumin | [47] | |||
|
| |||||||
| (2) Drug accumulation and penetrtion | (1) ECM | (1) EPR effect | RGD peptide-targeted | Liposome | DSPE-PEG 2000 | Paclitaxel + curcumin | [48] |
| (2) Vascular endothelial barrier | (2) Vascular targeting for accumulation | RGD peptide-targeted | Mesoporous silica nanoparticle | PAA-chitosan | Topotecan + quercetin | [49] | |
| RGD peptide-targeted | Lipid-coated nanoparticles | DSPE-PEG-NHS, PLGA | Sorafenib + quercetin | [50] | |||
| (3) Thick stroma | (3) Antivascular targeting by inhibiting tumor angiogenesis | EPR | Liposome | SPC : Chol : DOPE/EPG | Doxorubicin + biochanin A | [51] | |
| (4) Proteolytic enzymes in the tumor | EPR | Lipid-polymer hybrid nanoparticles (Lpns) | DOPE/EPG | Cisplatin + curcumin | [33] | ||
| Smaller and compacted scale nanoparticles | Self-assembled nanoparticle | PEG-VES | Sorafenib + curcumin | [52] | |||
|
| |||||||
| (3) Drug internalization into the targeted cells | (1) Electric interaction needed to stride over the cell membrane to enter inside the cells | (1) P-gp inhibitors combining nanoparticles | P-gp inhibitor (curcumin) | Amphiphilic polymeric micelle | PEG(2k)-PLA(5k) | Doxorubicin + curcumin | [53] |
| P-gp inhibitor (tetrandrine) | Lipid polymer hybrid nanosystem | MAL-PEG-DSPE, PLGA | Paclitaxel + Tetrandrine | [54] | |||
| (2) Receptor-targeted nanocarriers | Transferrin-targeted, pH-sensitive | Polymer-drug conjugate | Tf-PEG-CUR | Doxorubicin + curcumin | [55] | ||
| FA-targeted | Planetary ball-milled (Pbm) nanoparticles | FA-PCL-PEG | Docetaxel + resveratrol | [56] | |||
| FA-targeted | Lipid nanoparticles | GMS-TPGS-SA-FA | Paclitaxel + curcumin | [57] | |||
| GLUT1-targeted | Polymeric micelles | PEG2000–DSPE | Doxorubicin + curcumin | [58] | |||
| Transferrin-targeted | Polymeric micelles | PEG-PE | Paclitaxel + curcumin | [36] | |||
|
| |||||||
| (4) Drug release | (1) Acidic environment and specific enzymes present in CSCs in the tumor | (1) PH-sensitive nanoparticles | pH-sensitive | Micellar nanoparticles | DSPE-PEG-imine-MTX | Methotrexate + curcumin | [59] |
| pH-sensitive | Nanoparticles | PEG-lipid/PAA/CaCO3 | Doxorubicin + curcumin | [60] | |||
| (2) Enzyme-sensitive nanparticles | pH-sensitive, CSCs-targeted | Micellar system | PPBV | Paclitaxel + curcumin | [61] | ||
| pH-sensitive | Nanoparticle | TPGS-PAE | Doxorubicin + curcumin | [62] | |||
| (3) Temperature-responsive | pH-sensitive | Copolymer | PCL-St-POX | Terminator + curcumin | [63] | ||
| Pe-targeted, EPR | Peptosome | PePm/PS | Pe + curcumin | [64] | |||
| Thermosensitive copolymer | Nanogels | Heparin-pluronic F127 (Hep-F127) | Cisplatin + curcumin | [65] | |||
| Near-infrared (NIR)-responsive | Gold nanocages | Biotin-PEG-SH | Doxorubicin + quercetin | [66] | |||
|
| |||||||
| (5) Drug response | (1) Based on summarized pathophysiological basis | (1) Directly target and kill CSCs | pH-sensitive, CSCs-targeted | Polymeric nanoparticle | mPEG-PLGA-pglu | Doxorubicin + curcumin | [67] |
| pH-sensitive, CSCs-targeted | Core-shell nanoparticle | VES-g-e-PLL/γ-PGA-Dopa | Doxorubicin + curcumin | [68] | |||
| (2) Synergistic combination of two or more drugs | Combination of chemotherapeutic and plants extracts | Nanoliposomes | mPEG2000-DSPE, DOPA | Cisplatin + curcumin | [69] | ||
| Phytosome | Quercetin and phospholipid (lecithin) | Doxorubicin + quercetin | [70] | ||||
| Lipid nanoparticles | Glyceryl distearate,triglycerides medium-chain, soybean lecithin/polyoxyl 40 hydrogenated castor oil, glycerin | Doxorubicin + curcumin | [71] | ||||
| Polymeric micelles | PCL-b-ABPA-b-POEGMEA | Platinum drugs + curcumin | [72] | ||||
| Nanoparticle | mPEG-PCL | Temozolomide + resveratrol | [73] | ||||
| Liposomal | Egg sphingomyelin/cholesterol/PEG2000 ceramide | Quercetin + vincristine | [74] | ||||
| Polymeric micelles | PGS2000/PEG2000-DSPE | Doxorubicin + curcumin | [75] | ||||
| Lipid nanoparticles | PEG-DSPE | Etoposide + curcumin | [76] | ||||
| Lipid-polymer hybrid nanoparticles (Lpns) | DSPE-mPEG5000/DSPE-PEG5000 FITC | Paclitaxel + triptolide | [77] | ||||
| Liposomes | Egg phosphatidylcholine/DSPE-PEG | Doxorubicin + resveratrol | [78] | ||||
| Nanoemulsion (NE) | PEG400-DOCA, HP-beta-CD | Pemetrexed + quercetin | [79] | ||||
| Bottlebrush copolymer-Based micelle | PEG-PNB-TC | Paclitaxel + curcumin | [35] | ||||
| Lipid-polymeric nanocarriers | PLGA, PEG2000-DSPE | Vincristine + quercetin | [80] | ||||
| Niosomes | Tween-60: cholesterol:DPPC : DOTAP : DSPE-PEG2000 | Doxorubicin, quercetin + sirna | [81] | ||||
| Polymer-lipid nanoparticles | DSPE-PEG2000, POPC,DOPAC | Paclitaxel + curcumin | [82] | ||||
| (3) Multifunctional targeted delivery | pH-responsive, CRGDK-targeted, EPR | Nanoparticles | CRGDK-PEG-PCL | Doxorubicin + curcumin | [83] | ||
| Magnetic-guided targeting, T7-mediated targeting | Nanoparticles | PLGA-PEG-T7 | Paclitaxel + curcumin | [84] | |||
| Lactoferrin- (Lf-) tethered magnetic-targeted | Magnetic micelle | PVA/PAA | Doxorubicin + curcumin | [37] | |||
| pH-responsive, Folate receptor-targeted | Nanoplates | PEG methacrylate, PEG | Daunorubicin + curcumin | [85] | |||
| EGFR peptide (GE11)-targeted, pH-sensitive, EPR | Prodrug nps | PLGA-PEG-Mal, PLGA-PEG-NH2, PEG-NH2 | Docetaxel + curcumin | [86] | |||
| Magnetic targeting, biotin receptors-targeted | Magnetic nanoparticles | Biotin-PEG-PCDA | Paclitaxel + curcumin | [87] | |||
|
| |||||||
| (6) Mutidrug resistance (MDR) | (1) Based on summarized pathophysiological basis | (1) Reverse transporter-mediated MDR (Inhibition of P-p, LRP, MRPs,BCRP) | PEGylation | Prodrug nanopaticle | PEG-curcumin | Docetaxel + curcumin | [88] |
| PAMAM dendrimer | Copolymer nanopaticle | PEG-PAMAM | Paclitaxel + Borneol | [89] | |||
| PEGylated | Liposome | DSPE-mPEG2000, PC | Paclitaxel + resveratrol | [90] | |||
| 2) Reverse apoptosis gene-mediated MDR | EPR | PLGA-lipid nanoparticles | DSPE-PEG2000, PLGA | Docetaxel + gambogic acid | [32] | ||
| Anisamide- (AA-) targeted | Nanoparticles | PLGA, CHO-hyd-PEG-AA | Doxorubicin + resveratrol | [91] | |||
|
| |||||||
| (7) Immunoregulation | (1) Oxidative and enzymatic environment | (1) Anti-inflammatory effects | CD44-targeted | Nanohydrogel | FA-HA | Rapamycin + quercetin | [92] |
| PEGylated | Long-circulating liposomes | DPPC, PEG-2000-DSPE | Docetaxel + curcumin | [93] | |||
|
| |||||||
| (8) Antagonize/reduce toxicity and side effects | (1) Reactive oxygen species (ROS) environment | 1) ROS-sensitive nanoparticles | ROS-cavenger: curcumin | Polymeric micelles | mPEG-PCL | Docetaxel + curcumin | [94] |
DSPE-PEG: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol); PLGA: poly(lactic-co-glycolic acid); mPEG-PCL: methoxy poly(ethylene glycol)-poly caprolactone; PEG-b-PLL: poly(ethylene glycol)-b-poly(L-lysine); HAPA: hydroxyapatite; β-CD: β-cyclodextrin; PEIIPDI-PEA: branched polyethylenimine-isophorone diisocyanate-poly(L-lactide)-PEI; PAA: polyacrylic acid; DSPE-PEG-NHS: distearoyl-L-a-phosphatidylethanolamine-polyethylene glycol-N-hydroxysuccinimide; SPC: soy phosphatidylcholine, Chol: cholesterol, EPG: egg phosphatidylglycerol, and DOPE: 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine; PEG-VES: polyethylene glycol derivative of vitamin E succinate; MAL: maleimide; Tf: transferrin; FA: folate; GMS-TPGS-SA-FA: glyceryl monostearate-D-alpha tocopherol acid polyethylene glycol succinate-stearic acid and folate; PEG2000–PE: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; PPBV: poly(ethylene glycol)-benzoic imine-poly(gamma-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer; TPGS-PAE: d-alpha-tocopheryl polyethylene glycol 1000-block-poly(beta-amino ester); PCL-St-POX: poly caprolactone-starch-poly(2-ethyl 2-oxazoline); PePm: TFIIATVEGVLLFLILVVVVGILIKRRGPLGVRGC, PS: peptosomes; mPEG-PLGA-PGlu: monomethoxy (polyethylene glycol)-b-P (D,L-lactic-coglycolic acid)-b-P (L-glutamic acid); VES-g-e-PLL: RRR-a-tocopheryl succinate-grafted-e-polylysine conjugate; γ-PGA-Dopa: poly-γ-glutamic acid-dopamine; DOPA: 1,2-dioleoyl-sn-glycerol-3-phosphate; PABPA: 3-((tert-Butoxycarbonyl)amino)propyl acrylate; POEGMEA: polymerisation of oligo(ethyleneglycol)methyl ether acrylate; DSPE-PEG5000-FITC: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[(polyethylene glycol)-5000]-fluorescein isothiocyanate; DOCA: deoxycholic acid, HP-beta-CD: 2-hydroxypropyl-beta-cyclodextrin; PEG-PNB-TC: polyethylene glycol-polynorbornene-thiocresol; DPPC: 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine phospholipid, DOTAP: 1, 2-dioleoyl-3-trimethylammonium-propane; POPC: 1-palmitoyl-2oleoyl-sn-glycero-3-phosphocholine; CRGDK: Cys-Arg-Gly-Asp-Lys; T7: sequence HAIYPRH.