Table 1.
Summary of descriptive characteristics of the included studies.
| Study | Population | Intervention | Outcomes | |||
|---|---|---|---|---|---|---|
| Authors, year (reference)/country | Animal model a | Treatment regimen b | Dose; route | Nanostructure platform | Antitumor activity | Toxicity analysis |
| Shukla et al. (25)/India | Balb/c mice/n = 3/ | Ten days from tumor inoculation; | 100 mg/kg; | Lipid based CPC-SNEDDS NPs (Phospholipid, castor oil, Tween 80, PEG 400); | 1) Cur-NP ↓TV (58.9%); free Cur ↓TV (29.5%); p<0.001 | (ND) |
| 4T1/mouse/ | Daily for 28 days | Oral | HD: 83.27 nm/PDI: 0.151; | |||
| (1 x 106 cells)/ | - Free Cur vehicle: | ZP: −16 mV/EE: 29.1% | ||||
| subcutaneously on back skin | gum acacia (1%, w/v). | |||||
| Chen et al. (26)/China | Balb/c nude mice/n = 5/ | TV of 200 mm3 | 5 mg/kg; | Micelles NPs [POCA4C6 (phosphorylated calixarene) micelles—PM]; | 1) Cur-NP ↓TV (~60%) and ↓ TW (~80%); free Cur: ↓TV (~34%) and ↓ TW (~60%); p<0.05 | No damage in major organs; |
| BT-549/human/ | Fourteen days at every 2 days | Intratumoral | HD: 3.86 nm/PDI: 0.125; | 2) Cur-NP ↑TNC and ↑TAP | No WL; hematological indices: ~ control | |
| (2 x 106 cells)/ | - Free Cur vehicle: (NM) | ZP: −25.18 mV/EE: 95.4% | 3) Cur-NP ↓CD44+ CD133+ cancer stem cells | |||
| Subcutaneously on the upper right thigh | p<0.05 | |||||
| Mahalunkar et al. (27)/India, Germany, and Norway | Balb/c mice/n = 6/ | First day of treatment: (NM) | 10 mg/kg; | Metal gold NPs (CurAu-PVP) with folic acid (FA) (HAuCl4 and PVP polymer). | 1) Cur-NP-FA ↓TV (~51%); free Cur: no ↓TV; p<0.006 | (ND) |
| 4T1/mouse/ | Twice a week for 2 weeks | Intratumoral | HD: 358.7 nm/PDI: 0.6 | 2) Cur-NP-FA ↓TW (~44%); free Cur: no TV↓; p<0.05 | ||
| (1 x 105 cells)/ | - Free Cur vehicle: (NM) | ZP: −12.5 mV/EE: (NM) | ||||
| Mammary fat pad | ||||||
| Alizadeh et al. (28)/Iran | Balb/c mice/n = 8/ | 14 days after tumor induction; | Dose: (NM); | Micelles/polymersomes NPs (PNP) [monomethoxy-PEG (mPEG 2000), oleic acid (OA)] | 1) Cur-NP ↓TV (~80%); p<0.05 | 31.25 mg/Kg of PNP-CUR: no damage in major organs; |
| Transplantation of spontaneous mouse mammary tumor/ | Daily for 24 days | Intraperitoneal | HD: 99.44 nm/PDI: 0.182; | 2) Cur-NP ↑TAP; ↓ANG (CD31); ↓PROL (Ki-67); p<0.05 | Hematological and biochemical indices: ~ control | |
| Pieces < 0.3 cm3/ | ZP: −29.3 mV mV/EE: 64% | p<0.05 | ||||
| Subcutaneous on the left flank | ||||||
| Jung et al. (29)/Republic of Korea | Balb/c nude mice/n = 4/ | TV of 50 mm3; | 10 mg/kg; | Micelle NPs (DSPE-PEG micelle with or without EGFR specific targeting—EGF-Cur-NP) | 1) Cur-NP-EGFR ↓TV (~59.1%); Cur-NP no ↓TV; p<0.05 | No WL |
| MDA-MB-468/human/ | Three times a week; total of eight injections | Intraperitoneal | Cur-NP and EGF-Cur-NP: HD: 248.9 and 229.3 nm/PDI: 0.170 and 0.200, respectively | p<0.05 | ||
| (5 x 106 cells)/ | Cur-NP and EGF-Cur-NP: ZP: −3.6 and −1.73 mV, respectively/EE: (NM) | |||||
| Right shoulder | ||||||
| Wang et al. (30)/China | Nuke mice/n = (NM)/ | Two months after tumor induction; | 1 × 10−3 M; | Polymeric NPs (MPEG-PCL); | 1) Cur-NP ↓TV (~82%); free Cur:↓TV (~49%); p<0.01 | (ND) |
| MDA-MB-231/human/ | Daily for 2 weeks | Intravenous | HD: 139 nm/PDI: (NM); | 2) Cur-NP ↑TAP | ||
| (1.5 x 106 cells)/ | - Free Cur vehicle: (NM) | ZP and EE: (NM) | ||||
| Subcutaneous | ||||||
| Laha et al. (31)/India and USA | Balb/c mice/n =6/ | Ten days after tumor induction; | 2 mg/kg (*unclear); | Metal organic frameworks NPs (IRMOF-3) with or without folic acid (FA) [(Zn (NO3)2; NH2-H2BDC] | 1) Cur-NP-FA ↓TV (~61%); Cur-NP↓TV (~44%); p<0.05 | Biochemical markers for liver and kidney: ~ control |
| 4T1/mouse/ | Every 5 days for 4 times | Route of administration: (NM) | HD: 371,7 nm/PDI: 0.397 | 2) Cur-NP ↓TW (~74%); Cur-NP-FA ↓TW (~85%); p<0.05 | p<0.05 | |
| (NM)/ | ZP: −10.9 mV/EE: 98% | 3) Cur-NP and Cur-NP-FA ↓ tumor cell density | ||||
| Mammary fat pad | ||||||
| Vakilinezhad et al. (32)/Iran | Sprague Dawley rats/n = 6/ | Four months after tumor induction; | 2.5 mg; | Polymeric NPs (PLGA-PVA) | 1) Cur-NP ↓TV (~20%); Free Cur: ↓TV (~16%); p<0.05 | (ND) |
| Chemically induced mammary tumors (MNU) | Once a week for 4 weeks | Intravenous | HD: 92.4 nm/PDI: 0.150 | |||
| - Free Cur vehicle: aqueous suspension | ZP: −5.12 mV/EE: 89.4% | |||||
| Yuan et al. (33)/China | Balb/c nude mice/n = 6/ | TV of 100 mm3; | 2.5 mg/kg; | Polymeric NPs (mPEG- PLGA-Pglu) | 1) Cur-NP ↓TV (~28.0%); p<0.05 | No damage in major organs; |
| MCF-7/human/ | Every other day 4 times; total 18 d | Intravenous | HD: 228.5 nm/PDI: (NM) | 2) Cur-NP ↓TW (~22.5%); p<0.05 | No WL | |
| (3 x 106 cells)/ | ZP: −23.8 mV/EE: 76.9% | 3) Cur-NP ↓breast cancer stem cells (~62%); p<0.05 | p<0.05 | |||
| Right flank | ||||||
| Sahne et al. (34)/Iran | Balb/c mice/n = 4/ | TV of 50–100 mm3; | 4 mg/kg; | Graphene oxide NPs (GO NPs with CMC, PVP, PEG, FA); | 1) Cur-NP-FA↓TV (~86%); p<0.05 | No damage in major organs; |
| 4T1/mouse/ | Daily for a total 3 weeks | Intravenous | HD: ~60 nm/PDI: (NM) | 2) Cur-NP-FA ↓TW (~76%); p<0.05 | No WL | |
| (NM)/ | ZP: −48 mV/EE: 94% | 3) Cur-NP-FA ↑ ST and ↓ metastasis; p<0.05 | p<0.05 | |||
| Subcutaneous on the flank | 4) Cur-NP-FA: ↑TNC; ↓ cell density; ↓ANG (CD31, CD34); ↑ pro-inflammatory response in the tumor microenvironment; p<0.05 | |||||
| Ji et al. (35)/China | Balb/c mice/n = 5/ | First day of treatment: (NM); | 5 mg/kg; | Nanocrystals NPs with or without HA | 1) Cur-NP-HA ↓TV (~86%); Cur-NP↓TV (~39%); free Cur: ↓TV (~21%); p<0.05 | No damage in major organs; no WL; |
| 4T1/mouse/ | Every 2 days for a total 10 days | Intravenous | Cur-NP and HA-Cur-NP: HD: 101.4 and 161.9 nm/PDI: ~0.330 and 0.250, respectively | 2) Cur-NP-HA ↓TW (~75%); Cur-NP↓TW (~37.5%); Free Cur: ↓TW (~25%); p<0.05 |
No hemolysis (<5%); | |
| (1 x 106 cells)/ | - Free Cur vehicle: (NM) | HA-Cur-NP: ZP: −25.0 mV, respectively/EE: (NM) | 3) ↑ ST: Cur-NP-HA > Cur-NP > Free Cur; p<0.05 | Hematological and biochemical indices: ~ healthy control | ||
| Subcutaneous on the right flank | p<0.05 | |||||
| He et al. (36)/China | Balb/c mice/n = 6/ | TV of 100 mm3 | 5mg/kg; | Polymeric micellar NPs [amphiphilic diblock copolymer— mPEG-b-PLG (Se)-TP]; | 1) Cur-NP ↓TV (~65%); Free Cur: ↓TV (~49%); p<0.05 | No damage in major organs; no WL |
| 4T1/mouse/ | Every 4 days, for 4 times; total 21 days | Intravenous | HD: 136 nm/PDI: 0.071 | 2) Cur-NP ↓TW (~82%); free Cur: ↓TW (~62%); p<0.05 | p<0.05 | |
| (1 x 106 cells)/ | - Free Cur vehicle: (NM) | ZP: (NM)/EE: ~ 68% | 3) Cur-NP ↑TNC and ↑TAP; ↓ANG (CD31); ↓PROL (Ki-67); p<0.05 | |||
| Subcutaneous on the right back | ||||||
| Jin et al. (37)/China and USA | Balb/c nude mice/n = 5/ | 7 days after tumor induction; | 5 mg/kg; | Polymeric NPs with or without EGFR-targeting peptides (GE11) (PLGA-PEG); | 1) Cur-NP-GE11 and Cur-NP ↓TV (~80%); free Cur: no TV↓; p<0.05 | Inflammatory cytokine levels: ~ healthy mice |
| MCF-7/human/ | Every 24 h for 20 times | Intravenous | HD: 210 nm/PDI: 0.112; | 2) Cur-NP-GE11↓TW (~56%); Cur-NP ↓TW (~48%); free Cur: no TW↓; p<0.05 | p<0.05 | |
| (1 x 107 cells)/ | ZP: −22 mV/EE: 92.3 | 3) Cur-NP-GE11and Cur-NP ↑TAP | ||||
| Subcutaneous on the dorsal flank | - Free Cur vehicle: (NM) | |||||
| Abd-Ellatef et al. (38)/Italy and Egypt | Balb/c mice/n = 8/ | TV of 50 mm3; | 5 mg/kg; | Solid lipid nanoparticles (SLN) with or without chitosan (CS) coating (cholesterol; trilaurin, butyl lactate, Epikuron®200, Cremophor®RH60, sodium taurocholate, Pluronic® F68); | 1) Cur-NP-CS and Cur-NP ↓TV (~35%); Free Cur: no TV↓; p<0.01 | Biochemical indices: ~ control |
| JC/mouse/ | Thrice (on day 1st, 7th, 14th) | Intravenous | HD: < 200 nm/PDI: (NM) | p<0.05 | ||
| (1 x 107 cells)/ | - Free Cur vehicle: 10% v/v DMSO suspension |
ZP: (NM)/EE: 70–75% | ||||
| Mammary fat pad | ||||||
| Li et al. (39)/China | Balb/c mice/n = 4/ | Tumor diameter of 4 mm; | 8 mg/kg; | Mesoporous silica nanoparticles with hyaluronan (MSN-HA) or polyethyleneimine-folic acid (MSN-PEI-FA). | 1) Cur-NP-PEI-HA ↓TV (~50%); Free Cur: no TV↓; p<0.01 | No damage in major organs; no WL; |
| MDA-MB-231/human/ | Every 3 days for a total of six times | Intravenous | HD: < 300 nm/PDI: (NM)/ | 2) Cur-NP-PEI-HA ↓TW (~70%); free Cur: no TW↓; p<0.01 | Hemolysis (<5%); | |
| (1 x 107 cells)/ | - Free Cur vehicle: (NM) | ZP: ~ −20 mV (MSN-HA); ~ +40 mV (MSN-PEI-FA) |
Biochemical indices: ~ healthy control | |||
| Subcutaneous | p<0.05 | |||||
| Kundu et al. (40)/India | Swiss albine mice/n = 6/ | Ten days after induction; | 10 mg/kg; | Metal NPs [Zinc oxide nanoparticles (ZnO) with PBA]; | 1) Cur-NP↓TV (~77%); free Cur: ↓TV (~66%); p<0.05 | No damage in the liver and kidney; |
| Ehrlish ascites carcinoma cells/ | Alternate days for 14 days. | Intravenous | HD: 413.63 nm/PDI: (NM) | 2) Cur-NP ↓TW (~72%); free Cur: ↓TW (~50%); p<0.05 | Biochemical markers: ~control; ↓ tumor-induced splenomegaly | |
| (1.0 x 107/ml) | - Free Cur vehicle: (NM) | ZP: −16.4 mV/EE: 27% | 3) Cur-NP and free Cur: ↑TAP; p<0.05 | p<0.05 | ||
| Left flank | ||||||
| Lv et al. (41)/China | Kunming (mice)/n = 6/ | TV of 300 mm3; | 10 mg/kg; | Polymeric NPs (PEG-PCDA) with or without biotin; | 1) Cur-NP ↓TV (~69%); Cur-NP-biotin ↓TV (~79%); free Cur: ↓TV (~32%); p<0.05 | no WL |
| EMT6/mouse/ | Daily for 9 days; total 14 days | Intravenous | PEG-PCDA and biotin-PEG-PCDA: HD: 94.2 and 125.1 nm/PDI: 0.170 and 0.08, respectively | 2) Cur-NP ↓TW (~70%); Cur-NP-biotin ↓TW (~85%); free Cur: ↓TW (~25%); p<0.05 | p<0.05 | |
| (1.0 x 107/ml) | - Free Cur vehicle: cremophor EL: dehydrated alcohol (1:1, v/v) and diluted with physiological saline | PEG-PCDA and biotin-PEG-PCDA: ZP: −9.56 and −12.86 mV/EE: (NM) | 3) Cur-NP and Cur-NP-biotin: ↑TNC and ↑TAP; ↓ANG (CD31; VEGF; COX-2); ↓PROL (Ki-67); p<0.05 | |||
| Subcutaneously | ||||||
| Yang et al. (42)/China | Balb/c nude mice/n = 5 | TV of 200 mm3 | 10 mg/kg; | Micelle NPs (triblock copolymer PPBV); | 1) Cur-NP ↓TV (~58.5%, day 12); ↓TV (~28.9%, day 20); p<0.05 | No WL |
| MCF-7/human/ | Every other day for 5 times; total 20 days | Intravenous | HD: 6.7 nm/PDI: 0.117 | 2) Cur-NP ↓TW (~22%, day 20); p<0.05 | p<0.05 | |
| (1 x 107 cells)/ | ZP: −1.42 mV/EE: 68.5% | |||||
| Subcutaneous on the flank | - Free Cur vehicle: (NM) | |||||
| Yang et al. (43)/China | Balb/c nude mice/n = 5/ | TV of 200 mm3 | 15 mg/kg; | Hybrid NPs [PLGA NPs coated with a modified hialuronic acid (HA-hybrid)] | 1) Cur-NP-HA ↓TV (~43.8%, day 12); ↓TV (~24%, day 20); p<0.05 | No WL |
| MCF-7/human/ | Every other day for 5 times; total 20 days | Intravenous | HD: 350 nm/PDI: (NM) | 2) Cur-NP-HA ↓TW (~22%, day 20); p<0.05 | p<0.05 | |
| (1 x 107 cells)/ | ZP: −22 mV/EE: 32% | 3) Cur-NP-HA ↓tumor cell density; p<0.05 | ||||
| Subcutaneous on the flank | - Free Cur vehicle: (NM) | |||||
| Greish et al. (44)/Bahrain | Balb/c mice/n = 5/ | TV of 100 mm3; | 10 and 20 mg/kg; | Micelles (curcumin–metal complex and SMA) | 1) Cur-NP-10mg/Kg ↓TV (~61%); Cur-NP-20mg/Kg ↓TV (~92%); p<0.05 |
(ND) |
| 4T1/mouse/ | frequency of treatment: unclear; total 10 days | Intravenous | HD: 248 nm/PDI: 0.274; | |||
| (1 x 106 cells)/ | ZP: −11 mV/EE: 80% | |||||
| Bilaterally on the flanks | ||||||
| Mukerjee et al. (45)/USA | Balb/c nude mice/n = 8/ | TV of 70 mm3; | 20 mg/kg; | Polymeric NPs [PLGA/PVA with or without antibody targeting (AnxA2)] | 1) Cur-NP- AnxA2 ↓TV (~44.0%); Cur-NP ↓TV (~33.5%); p<0.05 | No WL |
| MCF10CA1a/human/ | Thrice week for a total 30 days | Intravenous | Cur-NP and AnxA2-Cur-NP: HD: 150 and 157 nm/PDI: ~0.240 and 0.200, respectively | 2) Cur-NP- AnxA2 ↓TW (~53.0%); Cur-NP ↓TW (~30%); p<0.05 | p<0.05 | |
| (3 x 106 cells)/ | Cur-NP and AnxA2-Cur-NP: ZP: −27.5 and −28.5 mV, respectively/EE: 89.2% | 3) Cur-NP- AnxA2 and Cur-NP: ↓ANG; ↓ NFkβ; ↓PROL (Ki-67); p<0.05 | ||||
| Flank | ||||||
| Mukhopadhyay et al. (46)/India | Balb/c nude mice/n = 5/ | 8 days after induction; | 20 mg/kg | Polymeric NPs [PLGA/PVA with or without folate (F)] | 1) Cur-NP-F ↓TV (~90%); Cur-NP↓TV (~75%); p<0.05 | No damage in major organs |
| MDA-MB-231/human/ | Thrice week for a total 21 days | Route of administration: unclear | HD: 170 nm/PDI: 0.186; | 2) Cur-NP-F ↓TW (~92%); Cur-NP↓TW (~61.5%); p<0.05 | p<0.05 | |
| (5 x 106 cells)/ | ZP: −28.2 mV/EE: 68.6% | 3) Cur-NP-F and Cur-NP ↓ cell density | ||||
| Right flank | ||||||
| Yu et al. (47)/China | Balb/c nude mice/n = 5/ | TV of 100–400 mm3; | 40 mg/kg | Micelles NPs (MPEG-PLA with or without PAE) | 1) Cur-NP-PAE ↓TV (~65.6%); Cur-NP ↓TV (~47.1%); p<0.05 | no WL |
| MCF-7/human/ | Every other day for 5 times for a total 24 days | Intravenous | HD: 128.4 nm to 171.0 nm/ PDI: 0.118 to 0.134 |
2) Cur-NP-PAE ↓TW (~76%); Cur-NP ↓TW (~53%); p<0.05 |
p<0.05 | |
| (3 x 106 cells)/ | ZP: −2.0 to +4.0 mV/ EE: 96.5 to 98.8% |
|||||
| Subcutaneously right flank | ||||||
| Huang et al. (48)/China | Balb/c mice/n = 5/ | TV of 40–50 mm3/ | 50 mg/kg | Polymeric NPs (HA-CHEMS); pH-sensitive | 1) Cur-NP ↓TV (~38%); p<0.05 | ↓ Damage in major organs |
| 4T1/mouse/ | Every 2 days for a total of 5 times | Intravenous | HD: 144 nm/PDI: (NM); | 2) Cur-NP ↑ ST; | no WL | |
| (NM)/ | ZP: −21.25 mV/EE: (NM) | 3) Cur-NP ↑TNC and ↑TAP | p<0.05 | |||
| Flank | ||||||
| Shiri et al. (49)/Iran | Balb/c mice/n = 9/ | Third day after tumor induction/ | 40 mg/kg or 80 mg/kg | Dendrosome NPs (DNC) [composition: not mentioned (patent number: 71753)] | 1) NP-40mg/Kg ↓TV (~72%); NP-80mg/Kg ↓TV (~76%); p<0.05 | no WL |
| 4T1/mouse/ | daily for 35 consecutive days | Route of administration: (NM) | HD; PD; ZP; EEI: (NM) | 2) NP-40mg/Kg ↓TV (~61%); NP-80mg/Kg ↓TV (~64%); p<0.05 | No change in food intake and behavior | |
| (1 x 106 cells)/ | 3) NP ↑ ratio of M1/M2 macrophages | p<0.05 | ||||
| left flank | ||||||
| Lin et al. (50)/China | Balb/c nude mice/n = 6/ | First day of treatment: (NM)/ | Dose: (NM)/ | Lipid based NPs (NLC) with or without folate (FA) coating (PEG-DSPE, soya lecithin, castor oil, Tween 80, Precirol ATO-5); | 1) Cur-NP-FA ↓TV (~83%); Cur-NP ↓TV (~66%); free Cur: ↓TV (~31%); | No WL |
| MCF-7/human/ | once every 3 days for 15 days | Intravenous | HD: 126.8 nm/PDI: 0.16 | p<0.05 | ||
| (NM)/ | ZP: +12.6 mV/EE: 82.7% | |||||
| Subcutaneous in the right armpit | - Free Cur vehicle: (NM) | |||||
a
Animal type/replicates/cell type injected/source/cell concentration/local of cell insertion;
b
First day of treatment (or tumor volume)/treatment frequence and total experiment time; ANG, angiogenesis; CHEMS, cholesteryl hemisuccinate; CMC, carboxymethyl cellulose; CPC-SNEDDS, curcumin-phospholipid complex self-nanoemulsifying drug delivery systems; Cur, curcumin; d, days; DSPE, distearoyl phosphatidyl- ethanolamine; EGFR, epidermal growth factor receptor; FA, folic acid; HA, hyaluronic acid; MNU, N-methyl nitroso urea; mPEG-b-PLG (Se)-TP, poly-(ethylene glycol)-b-poly(L-glutamic acid)-two-photon AIE fluorophores [mPEG-b-PLG (Se)-TP] amphiphilic copolymer with selenide group (Se) conjugated and a two-photon AIE fluorogen (TP) on the terminal group of PLG segments.; MPEG-PCL, methoxypoly(ethylene glycol)-polycaprolactone; NF-κB, nuclear factor kappa b; NH2-H2BDC, 2-amino terephthalic acid; (ND), not determined; (NM), not mentioned; NPs, nanoparticles; PAE, poly (b-aminoester; PBA, phenyl boronic acid; PCDA, pentacosadiynoic acid; PEG, poly(ethylene glycol); PGlu, poly L-glutamic acid; PLA, polylactic-co-glycolic acid; PPBV, mPEG-PBLA-PVIm triblock copolymer; PROL, tumor proliferation; PVA, polyvinyl alcohol; PVP, polyvinylpyrrolidone; SMA, poly(styrene)-co-maleic acid; ST, survival time; TAP, tumor apoptosis; TNC, tumor necrosis; TV, tumor volume; TW, tumor weight; WL, weight loss.