Table 1.
Summary of research articles that investigated active targeting NPs delivering chemotherapeutic drugs in cancer therapy
| Ligand | Receptor/antigen | Drug-NP platform | Types of study | Outcome
|
References | |
|---|---|---|---|---|---|---|
| Compared to non-targeted | Side effect | |||||
| Proteins/peptides | ||||||
| H2009.1 peptide | Integrin αvβ6 | Doxorubicin-liposome | In vivo: human non-small cell lung cancer cell lines (H2009) xenograft | No difference in tumor targeting and tumor growth inhibition rate | No significant change in body weight | 12 |
| IL-13 peptide | IL-13Rα2 receptor | Docetaxel-PEG-PCL | In vitro: human glioblastoma cell lines (U87) In vivo: cell lines U87 orthotopic xenograft |
Higher cellular uptake; 1.1-fold higher cellular apoptosis Higher tumor growth inhibition rate; 1.73-fold higher tumor targeting |
Not evaluated | 13 |
| AP-1 peptide | IL-4 receptor | Paclitaxel-cyclodextrin | In vivo: human breast adenocarcinoma cell lines MDA-MB-231 xenograft | Specifically targeting tumor site; higher tumor growth inhibition rate | Low nonspecific toxicity | 14 |
| Peptide CVKTPAQSC | CD133+ receptor | Docetaxel-PLA | In vitro: human lung cancer cell lines (A549) In vivo: cell lines A549 xenograft |
30.5% higher cellular uptake ratio Higher anti-metastatic efficacy |
No significant change in body weight | 15 |
| Transferrin | Transferrin receptor | Hydroxycamptothecin-PEG | In vivo: murine sarcoma cell lines (S180) xenograft | 9.03-Fold higher tumor accumulation; 1.85-fold higher tumor growth inhibition rate | No significant change in body weight | 16 |
| Transferrin | Transferrin receptor | Paclitaxel-PEG-chitosan | In vitro: non-small cell lung cancer cell lines (HOP-62) | Higher cellular uptake; 6.67-fold higher cytotoxicity | Not evaluated | 17 |
| cRGDyK | Integrin αvβ3 | Paclitaxel-PEG-PTMC | In vitro: human glioblastoma – astrocytoma, epithelial-like cell lines (U87MG) | 36.6% higher cellular uptake; 2.3-fold higher cytotoxicity; higher cellular apoptosis | Not evaluated | 18 |
| RGDS | Integrin αvβ3 | Doxorubicin-PEG-MIONP | In vitro: human cervical carcinoma cell lines (HeLa) | 11-Fold higher cellular uptake; higher cytotoxicity | Not evaluated | 19 |
| cRGDyK | Integrin αvβ3 | Paclitaxel-micelle | In vitro: human prostate cancer cell lines (PC-3) In vivo: cell lines PC-3 xenograft |
1.93-Fold higher cellular uptake; 1.26-fold higher cytotoxicity Higher tumor growth inhibition rate |
No significant change in body weight | 20 |
| RGD | Integrin αvβ3 receptor | Doxorubicin-dendritic poly-L-lysine-gelatin | In vitro: mouse mammary breast tumor cell lines (4T1) In vivo: cell lines 4T1 xenograft |
Higher cytotoxicity 1.18-Fold higher tumor accumulation; 10.6% higher tumor growth inhibition rate |
No significant change in body weight | 21 |
| Bombesin peptide | Gastrin-releasing peptide receptor | Docetaxel-PLGA | In vitro: human breast adenocarcinoma cell lines (MDA-MB-231) | 4-Fold higher cytotoxicity | Not evaluated | 22 |
| NR7 peptide | EGFR | Doxorubicin-PLGA-PEG | In vitro: human ovarian carcinoma cell lines (SKOV3) In vivo: cell lines SKOV3 xenograft |
3-Fold higher cellular uptake; 62.4-fold higher cytotoxicity 2.6-Fold higher tumor accumulation |
Low nonspecific toxicity | 23 |
| LHRH peptide | LHRHR | Methotrexate-HSA | In vitro: human breast carcinoma cell lines (T47D) | 71.5% higher cellular uptake; 8.5-fold higher cytotoxicity | Not evaluated | 24 |
| Angiopep-2 | LRP | Doxorubicin-dendritic poly-L-lysine-gelatin NP | In vitro: mouse mammary breast tumor cell lines (4T1) In vivo: cell lines 4T1 xenograft |
Higher cellular uptake; higher cellular apoptosis Higher accumulation of NP in tumor; higher tumor growth inhibition rate |
Low side effect to normal tissue | 25 |
| TbFGF peptide | FGFR | Paclitaxel-micelle | In vitro: murine Lewis lung carcinoma cell lines (LL/2), human hepatocellular liver carcinoma cell lines (HepG2), human lung cancer cell lines (A549), murine colorectal cancer cell lines (C26) | 18-Fold higher cytotoxicity to LL/2; higher cellular uptake by 6.6-fold for HepG2, 6.2-fold for A549, 2.9-fold for C26, and 2.7-fold for LL/2 | Not evaluated | 26 |
| Hyaluronic acid | ||||||
| Hyaluronic acid | CD44 receptor | Topotecan hydrochloride-dendrimer | In vitro: human colorectal cancer cell lines (HCT-116) In vivo: cell lines HCT-116 xenograft |
Higher cellular uptake; 3-fold higher cytotoxicity compared to free drug Higher tumor growth inhibition rate; 3.6-fold and 1.7-fold higher drug accumulation in tumor compared to kidney and liver | Not evaluated | 8 |
| Hyaluronic acid | CD44 receptor | Paclitaxel-micelle | In vitro: human breast adenocarcinoma cell lines (MCF-7) In vivo: murine hepatic carcinoma cell lines (Heps) xenograft |
4.1-Fold higher cellular uptake 2.80-Fold higher tumor accumulation; 31.89% higher tumor growth inhibition rate; higher median survival time |
No significant change in body weight | 27 |
| Hyaluronic acid | CD44 receptor | Cisplatin-chitosan | In vitro: human lung cancer cell lines (A549) | Higher cellular uptake; 8-fold higher cytotoxicity | Not evaluated | 28 |
| Hyaluronic acid | CD44 receptor | Rapamycin-LbL-LCNP | In vitro: human breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) | Higher cytotoxicity, 1.35-fold for MDA-MB-231, and 1.1-fold lower cytotoxicity to MCF-7 | No significant change in body weight | 29 |
| Hyaluronic acid | CD44 receptor | Doxorubicin-PBLG | In vivo: Ehrlich ascites tumor-bearing mice | Higher tumor growth inhibition rate; higher survival time | Not evaluated | 30 |
| Hyaluronic acid | CD44 receptor | Methotrexate-lipid-based NP | In vivo: murine melanoma cell lines (B16F10) xenograft | Higher tumor accumulation; higher tumor growth inhibition rate | Not evaluated | 31 |
| Hyaluronic acid | CD44 receptor | Doxorubicin hydroxylapatite | In vitro: human hepatocellular carcinoma cell lines (HepG2) In vivo: cell lines HepG2 xenograft |
Higher cellular uptake; 46.3% higher cytotoxicity compared to free drug Higher in tumor targeting; lower tumor volume | No significant change in body weight | 32 |
| Hyaluronic acid | CD44 receptor | Doxorubicin-HACE-PEG | In vitro: murine squamous cell carcinoma cell lines (SCC7) and mouse embryo fibroblast cell lines (NIH3T3) In vivo: cell lines SCC7 xenograft |
Higher cellular uptake in CD44 overexpressing (SCC7) compared to CD44 negative (NIH3T3); no difference in cellular uptake compared to free drug 30% higher tumor growth inhibition rate compared to free drug |
No significant change in body weight | 33 |
| Hyaluronic acid | CD44 receptor | Doxorubicin hyaluronic acid-Lys-LA10 | In vitro: doxorubicin-resistant human breast adenocarcinoma cell lines (MCF-7/ADR) In vivo: cell lines MCF-7/ADR xenograft |
Higher cellular uptake compared to free drug; no difference in cytotoxicity Lower relative tumor volume; higher median survival time |
No significant change in body weight and low nonspecific toxicity | 34 |
| Hyaluronic acid | CD44 receptor | Doxorubicin-PBLG-LA | In vitro: human breast adenocarcinoma cell lines (MCF-7) In vivo: cell lines MCF-7 xenograft |
10-Fold higher in cellular DOX level; higher cytotoxicity No difference in tumor growth inhibition rate; higher survival time |
No significant change in body weight and low nonspecific toxicity | 35 |
| Folate | ||||||
| Folic acid | Folate receptor | Docetaxel-PEG-PLGA | In vitro: human cervical carcinoma cell lines (HeLa) In vivo: cell lines HeLa xenograft |
26.7-Fold higher cellular uptake; 12-fold higher cytotoxicity compared to free drug Higher tumor targeting; higher tumor growth inhibition rate |
Not evaluated | 36 |
| Folic acid | Folate receptor | Doxorubicin-dendrimer | In vitro: human epidermal carcinoma cell lines (KB) | 1.4-Fold higher cellular uptake; 2.2-fold higher cytotoxicity | Not evaluated | 37 |
| Folic acid | Folate receptor | Gemcitabine-BSA | In vitro: human ovarian cancer cell lines (Ovcar-5) and human breast adenocarcinoma cell lines (MCF-7) In vivo: Ehrlich ascites carcinoma tumor cell-bearing mice |
2-Fold higher cellular uptake by MCF-7; higher cytotoxicity – 1.4-fold for MCF-7 and 1.6-fold for Ovcar-5; higher cellular apoptosis Higher tumor growth inhibition rate |
No significant change in body weight | 38 |
| Folic acid | Folate receptor | Carboplatin-PLGA-chitosan | In vitro: human cervical carcinoma cell lines (HeLa) | Higher cellular uptake in time-dependent manner; 1.67-fold higher cytotoxicity; higher cellular apoptosis | Not evaluated | 39 |
| Folic acid | Folate receptor | Doxorubicin-polymeric NP | In vivo: human epidermal carcinoma cell lines (KB) xenograft | 1.6-Fold higher tumor growth inhibition rate | Not evaluated | 7 |
| Folic acid | Folate receptor | Doxorubicin-PEG | In vitro: human epidermal carcinoma cell lines (KB), human lung cancer cell lines (A549) and human hepatocellular carcinoma cell lines (HepG2) In vivo: cell lines KB xenograft |
Higher cellular uptake by KB cell; higher cytotoxicity – 1.2-fold for A549, 3.5-fold for KB, and 2.1-fold for HepG2 Higher tumor targeting; higher tumor growth inhibition rate; higher survival time |
No significant change in body weight and less cardiotoxicity | 40 |
| Folic acid | Folate receptor | Cisplatin-PEG-MSN | In vitro: human cervical carcinoma cell lines (HeLa) | Higher cellular uptake | Not evaluated | 41 |
| Folic acid | Folate receptor | Doxorubicin-β-cyclodextrin | In vitro: human placenta choriocarcinoma cell lines (JAR), human colon adenocarcinoma cell lines (HT-29), human breast adenocarcinoma cell lines (MCF-7), and mouse fibroblast cell lines (3T3) | Higher cellular uptake – 2.09-fold by HT-29, 1.98-fold by MCF-7, and 7.31-fold by JAR; higher cytotoxicity – 12.39-fold for JAR, 6.73-fold for HT-29, and >1.5-fold for 3T3 | Not evaluated | 42 |
| Folic acid | Folate receptor | Paclitaxel-PEG-PLGA | In vitro: human endometrial carcinoma cell lines (HEC-1A) In vivo: cell lines HEC-1A xenograft |
Higher cellular uptake; 2.6-fold higher in cytotoxicity; 12% higher cellular apoptosis 16.48% higher tumor growth inhibition rate |
Not evaluated | 43 |
| Antibody | ||||||
| Anti-Fas mAb | Fas receptor | Camptothecin-PLGA | In vitro: human colorectal cancer cell lines (HCT116) | Higher cellular uptake; 58.9-fold higher cytotoxicity compared to free drug | Not evaluated | 44 |
| Anti-CD20 mAb | CD20 receptor | Doxorubicin-DSPE-PEG2000 | In vitro: human Burkitt’s lymphoma cell lines (Raji) | Selectively targeting CD-20-overexpressing cells (Raji) | Low nonspecific toxicity | 45 |
| Anti-CD47 mAb | CD47 receptor | Gemcitabine-MIONP | In vitro: human pancreatic ductal adenocarcinoma primary cells (Panc215 and Panc354) | Higher cellular uptake; higher cytotoxicity | Not evaluated | 46 |
| EGFR antibody | EGFR | Rapamycin-PLGA | In vitro: human breast adenocarcinoma cell lines (MCF-7) | 13-fold higher cellular uptake; higher cytotoxicity; 2.4-fold higher cellular apoptosis | Not evaluated | 47 |
| PR81 mAb | MUC1 receptor | 5-fluorouracil-BSA | In vitro: human breast adenocarcinoma cell lines (MCF-7) | Higher cytotoxicity | Not evaluated | 48 |
| Aptamer | ||||||
| Aptamer AS1411 | Nucleolin receptor | Doxorubicin-HPAEG | In vitro: human breast adenocarcinoma cell lines (MCF-7) | 2-fold higher cellular uptake; 1.7-fold higher cytotoxicity | Not evaluated | 6 |
| Aptamer AS1411 | Nucleolin receptor | Gemcitabine-PEG-PLGA | In vitro: human lung cancer cell lines (A549) | 36% higher cellular uptake; 5.9-fold higher cytotoxicity | Not evaluated | 49 |
| Aptamer AS1411 | Nucleolin receptor | Methotrexate-UnTHCPSi-PEI | In vitro: human breast adenocarcinoma cell lines (MDA-MB-231) | 1.6-fold and 4.7-fold higher cellular uptake for 3 h and 12 h, respectively; higher cytotoxicity | Not evaluated | 50 |
| Aptamer AS1411 | Nucleolin receptor | Docetaxel-mannitol-PLGA-TPGS | In vitro: human cervical carcinoma cell lines (HeLa) In vivo: cell lines HeLa xenograft |
Higher cellular uptake; 20-fold higher cytotoxicity 24.44% life time extended |
Not evaluated | 51 |
| Aptamer AS1411 | Nucleolin receptor | Doxorubicin-polymersome | In vitro: human breast adenocarcinoma cell lines (MCF-7) In vivo: cell lines MCF-7 xenograft |
1.73-fold higher cellular uptake compared to mutated aptamer conjugates; 1.75-fold higher cytotoxicity compared to mutated aptamer conjugates 1.75-fold higher tumor targeting; 21.8% higher tumor growth inhibition rate compared to mutated aptamer conjugated |
No significant change in body weight | 52 |
| Carbohydrates/polysaccharides | ||||||
| Lactose | ASGPR | Doxorubicin-lactose | In vitro: human hepatocellular carcinoma cell lines (SMMC-7721) In vivo: cell lines SMMC-7721 xenograft |
No difference in cytotoxicity and cellular apoptosis; higher cellular uptake in time-dependent manner Higher tumor targeting; no difference in tumor growth inhibition rate | Low nonspecific toxicity | 53 |
| Galactose | ASGPR | Doxorubicin-LPL | In vitro: human liver cancer cell lines (SK-HEP-1) In vivo: cell lines SK-HEP-1 orthotopic xenograft |
Higher cellular uptake; higher cytotoxicity in dose-dependent manner; higher cellular apoptosis Higher tumor growth inhibition rate |
No significant change in liver enzyme | 54 |
| Galactose | ASGPR | 5-Fluorouracil-pectin | In vitro: human hepatocellular carcinoma cell lines (HepG2) | Higher cellular uptake; 2.6-fold higher cytotoxicity compared to free drug | Not evaluated | 55 |
| Galactosamine | ASGPR | Paclitaxel-γ-PGA-PLA | In vitro: cell lines HepG2 | Higher cytotoxicity | Not evaluated | 56 |
| Galactose | Lecithin receptor | Doxorubicin solid lipid NP | In vitro: human lung cancer cell lines (A549) | 1.5-Fold higher cellular uptake; higher cytotoxicity | Not evaluated | 57 |
| Other molecules | ||||||
| EGF | EGFR | Gemcitabine-stearoyl | In vitro: human breast adenocarcinoma cell lines (MDA-MB-468, MDA-MB-231, and MCF-7) In vivo: cell lines MDA-MB-468 xenograft Ex vivo: MDA-MB-468 tumor |
Higher cellular uptake in MDA-MB-468; higher cytotoxicity Higher tumor growth inhibition rate; higher survival time Higher tumor accumulation |
Not evaluated | 58 |
| EGa1 | EGFR | Doxorubicin-micelle | In vitro: human mouth squamous cell carcinoma cell lines UM-SCC 14C In vivo: cell lines UM-SCC 14C xenograft |
Higher cellular uptake; higher cytotoxicity Higher tumor targeting; higher tumor growth inhibition rate; higher median survival time |
Not evaluated | 59 |
| CSA | CD44 receptor | Doxorubicin chondroitin sulfate A-deoxycholic acid | In vitro: human breast adenocarcinoma cell lines (MDA-MB-231) | Higher cellular uptake compared to free drug; 1.67-fold higher cytotoxicity compared to free drug | Not evaluated | 60 |
| Folic acid and bovine serum albumin | Folate receptor and SPARC | Paclitaxel-lipid | In vitro: human breast adenocarcinoma cell lines (MCF-7) | 1.9-Fold higher cellular uptake | No significant change in body weight | 61 |
| Hyaluronic acid and glycyrrhetinic acid | CD44 and glycyrrhetinic acid receptor | Paclitaxel glycyrrhetinic acid-graft-hyaluronic acid | In vitro: human hepatocellular carcinoma cell lines (HepG2) and murine melanoma cell lines (B16F10) | Higher cellular uptake compared to free drug; higher cytotoxicity to HepG2 | Not evaluated | 62 |
Abbreviations: ASGPR, asialoglycoprotein receptor; BSA, bovine serum albumin; cRGDyK, cyclic arginine-glycine-aspartic acid-tyrosine-lysine; DSPE-PEG2000, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy polyethylene glycol-2000; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; HACE, hyaluronic acid-ceramide; HSA, human serum albumin; HPAEG, hyperbranched poly(2-((2-(acryloyloxy) ethyl)disulfanyl)ethyl 4-cyano-4-(((propylthio)-carbonothioyl)-thio)-pentanoate-co-polyethylene glycol methacrylate; IL, interleukin; LbL-LCNP, layer-by-layer-liquid crystalline nanoparticle; LHRH, luteinizing hormone-releasing hormone; LHRHR, luteinizing hormone-releasing hormone receptor; LPL, lithocholic acid-polyethylene glycol-lactobionic acid; LRP, low density lipoprotein-receptor related protein; Lys-LA10, L-lysine methyl ester-lipoic acid; mAb, monoclonal antibody; MIONP, magnetic iron oxide nanoparticle; MSN, mesoporous silica nanoparticle; NP, nanoparticle; γ-PGA-PLA, poly(gamma-glutamic acid)-poly(lactic acid); PBLG, poly(γ-benzyl L-glutamate); PBLG-LA, G-poly(c-benzyl-L-glutamate)-lipoic acid; PCL, polyethylene glycol-poly(ε-caprolactone); PEG; polyethylene glycol; PEI, polyethylenimine; PLGA, poly(lactic-co-glycolic acid); PTMC, poly(trimethylene carbonate); RGD, arginine–glycine–aspartic acid peptide; RGDS, arginine–glycine–aspartic acid–serine peptide; SPARC, secreted protein, acidic and rich in cysteine; TbFGF, truncated basic fibroblast growth factor; TPGS, tocopheryl polyethylene glycol 1000 succinate; UnTHCPSi, undecylenic acid modified, thermally hydrocarbonized porous silicon.