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Table 3 Active targeted drug delivery systems of norcantharidin

From: Review targeted drug delivery systems for norcantharidin in cancer therapy

Drug delivery system

Ligand/antibody

Receptor/antigen

Composition

Efficacy

Ref., year

2E8-NCTD-liposomes

A murine anti-human CD19 monoclonal antibody 2E8

CD19

SPC/CHO/mPEG2000-PE/Mal-PEG2000-DSPE (molar ratio of 2: 1: 0.08: 0.02), 2E8-Mal-PEG2000-DSPE

Targeting efficiency: Nalm-6, Raj cells (CD19+): 2E8-NCTD-liposomes > NCTD-liposomes; Molt-3, K562 cells (CD19–): 2E8-NCTD-liposomes ≈ NCTD-liposomes; cell viability (10–50 µmol/L 2E8-NCTD-liposomes): Nalm-6 cells < Molt-3 cells; cell viability (Nalm-6 cells): 2E8-NCTD-liposomes < NCTD-liposomes < free NCTD

[111], 2010

Hm2E8b-NCTD-liposomes

A humanized anti-human CD19 monoclonal antibody, Hm2E8b

CD19

SPC/CHO/mPEG2000-PE/Mal-PEG2000-DSPE (molar ratio of 2: 1: 0.08: 0.02), Hm2E8b-Mal-PEG2000-DSPE

Targeting efficiency: HAL-01 cells (CD19+): Hm2E8b -NCTD-liposomes > NCTD-liposomes; Molt-3 cells (CD19–): Hm2E8b-NCTD-liposomes ≈ NCTD-liposomes; inhibition rate (2E8-NCTD-liposomes): HAL-01 cells > Molt-3 cells; inhibition rate (HAL-01 cells): Hm2E8b-NCTD-liposomes > NCTD-liposomes > free NCTD; cell apoptosis ↑; HLF-SLUG, NFIL3, c-myc, p-STAT5, STAT5 ↓, caspase-3/-6/-7/-9, P53, p-P53 ↑

[112], 2018

Anti-carbonic anhydrase IX (CA IX) NCTD nano-micelle

An anti-CA IX monoclonal antibody

CA IX

NCTD, DSPE-PEG2000-Mal, DTT, EDTA, anti-CA IX

A549 cell viability: anti-CA IX NCTD nano-micelle < NCTD nano-micelle < NCTD; A549 tumor inhibition rate (iv., once daily, 8 days): NCTD (1.0 mg/kg) = 54.78%, NCTD nano-micelle (0.5, 1.0 mg/kg) = 45.22%, 64.35%, anti-CA IX NCTD nano-micelle (0.5, 1.0 mg/kg) = 67.82%, 75.65%

[115], 2017

NCTDloaded liposome modified with stearyl glycyrrhetinate (SG) (SG-NCTD-LIP)

SG

Glycyrrhetinic acid (GA) receptor

1: 5 NCTD‑phospholipid mass ratio, EPC (0.4%),

1: 7 cholesterol-phospholipid mass ratio, SG (0.04%), 2 mL absolute ethanol, 15 mL PBS (pH 7.0)

HepG2 cells: SG‑NCTD‑LIP (IC50 = 16.93 µg/mL) < NCTD‑LIP (IC50 = 24.03 µg/mL) < free NCTD (IC50 = 49.79 µg/mL)

[117], 2018

mPEG-PCL-PEI-GA (MPG)/NCTD nanoparticles (AT NPs)

GA

GA receptor

NCTD (6–20 mg),

MPG copolymer (94−80 mg), 1 mL DMSO, 1 mL methyl alcohol, 10 mL deionized water

HepG2 cells: cell viability: free NCTD > NAT NPs > AT NPs; cellular uptake ↑; H22 tumor inhibition rate and median survival time (iv., 2.5 mg/kg, every 2 days, 4 times): free NCTD (44 days) < NAT NPs (56 days) < AT NPs (68 days); tumor/muscle (T/M) ratio: free NCTD > NAT NPs > AT NPs; cell apoptosis and cell cycle (G2 and S phase): free NCTD < NAT NPs < AT NPs; Ki-67, microvessel density (MVD): free NCTD > NAT NPs > AT NPs; CD31: free NCTD < NAT NPs < AT NPs

[118], 2018

NCTD-loaded liposome modified with GA and (trans-activator of transcription, TAT)

GA and TAT

GA receptor

NCTD, lecithin, cholesterol, DSPE-PEG5000-GA, DSPE-PEG2000-TAT

HepG2 cells: cell viability: NCTD-loaded liposome < NCTD solution

[119], 2020

Lac-NCTD-NPs

Lactosyl

Asialoglycoprotein receptor (ASGPR)

0.1 g CS, 0.2% aqueous acetic acid solution, 0.1 g Lac-NCTD, 21 mL 1.2 g/L TPP water solution

HepG2, SMMC-7721 cells: IC50 (48 h): Lac-NCTD-NPs < Lac-NCTD; H22 tumor inhibition rate (ip., once daily, 8 days): Lac-NCTD (3.3, 6.6, 13.8 mg/kg) = 27.1%, 41.7%, 53.5% < Lac-NCTD-NPs (3.3, 6.6, 13.8 mg/kg) = 31.9%, 63.9%, 70.1%; thymus and spleen index: Lac-NCTD < Lac-NCTD-NPs

[122, 123], 2009, 2010

Lactosyl-NCTD N-Trimethyl chitosan (TMC) nanoparticles (Lac-NCTD-TMC-NPs)

Lactosyl

ASGPR

0.15 g TMC, 50 mL distilled water containing 0.03 g Lac-NCTD, 25 mL 1.2 g/L TPP water solution

HepG2 cells: IC50: Lac-NCTD-TMC-NPs < Lac-NCTD-CS-NPs < Lac-NCTD; induce cell apoptosis; Cellular uptake (HepG2 cells) ↑; H22 tumor inhibition rate (ip., once daily, 9 days): NCTD (2.0 mg/kg) = 31.2% < Lac-NCTD (6.6 mg/kg) = 38.3% < Lac-NCTD-CS-NPs (6.6 mg/kg) = 51.06% < Lac-NCTD-TMC-NPs (6.6 mg/kg) = 69.5%; spleen coefficient and thymus coefficient ↑

[96], 2012

NCTD-associated galactosylated chitosan (GC) nanoparticle (NCTD-GC-NPs)

GC

ASGPR

100 mg GC, 50 mL 0.2% aqueous acetic acid solution, 20 mg NCTD, 1.2 g/L TPP water solution

Cellular uptake (HepG2, SMMC-7721 cells) ↑; in vitro cytotoxicity (HepG2, SMMC-7721 cells): NCTD < NCTD-CS-NPs < NCTD-GC-NPs

[124], 2009

NCTD-GC-NPs

GC

ASGPR

GC, 0.2% aqueous acetic acid solution, NCTD, 1.2 g/L TPP water solution

Cellular uptake (Bel-7402, HL-7702 cells) ↑; in vitro cytotoxicity (Bel-7402, HL-7702 cells): NCTD < NCTD-CS-NPs < NCTD-GC-NPs;

H22 tumor inhibition rate (ip., once daily, 8 days): NCTD (2.0 mg/kg) = 28.97% < NCTD-CS-NPs (0.5, 2.0, 4.0 mg/kg) = 25.71%, 37.86%, 56.87% < NCTD-GC-NPs (0.5, 2.0, 4.0 mg/kg) = 26.42%, 43.56%, 59.52%

[125], 2010

Gal-GAOStNC-LP

Stearin glycyrrhetinic acid ester-3-O-galactosidase, Gal-GAOSt

Galactose receptor

NCTD, soy lecithin, cholesterol, sodium ursodeoxycholate, Gal-GAOSt

Targeting index: liver (5.213 ± 1.320) > 1, spleen (1.980 ± 1.375) > 1, heart (0.496 ± 0.837) < 1, lung (0.871 ± 0.659) < 1, kidney (0.468 ± 0.914) < 1

[126], 2009

Galactose-cholesterol modified NCTD liposomes (Gal-NCTD-Lips)

Galactose

ASGPR

Phospholipid/galactosylated cholesterol = 3: 1 (weight ratio), lipid/drug = 12: 1 (weight ratio)

-

[127], 2019

Arabinogalactan-anchored polymeric micelles of NCTD (NCTD-M)

Arabinogalactan (AG)

ASGPR

N-(4-methylimidazole)-hydroxyethyl-chitosan (MHC): AG = 1: 3 (mass ratio), 5 mg NCTD

A significant liver-targeting effect; HepG2 cells: enhance cellular uptake of NCTD, promote the lysosomal escape, inhibit cell invasion and induce cell apoptosis; H22 tumor inhibition rate (iv., once every 3 days, 15 days): NCTD (2.0 mg/kg) < NCTD-M (2.0 mg/kg)

[128], 2018

NCTD/Galactosamine- hyaluronic acid-Vitamin E succinate micelles (NCTD/Gal-HA-VES micelles)

Gal, HA

CD44, ASGPR

20 mg Gal-HA-VES, NCTD

Cellular uptake (HepG2 and MCF-7 cells) ↑; inhibit P-gp expression (MCF-7/Adr cells); IC50 (HepG2 and MCF-7 cells, MCF-7/Adr cells): NCTD/Gal-HA-VES < NCTD/HA-VES < NCTD; cell apoptosis ↑; the micelles accumulated in liver, spleen, tumors ↑ and in kidneys ↓; HepG2 tumor inhibition rate (iv., every 3 days for 6 times, 18 days, 10 mg/kg): NCTD = (44.01 ± 5.78) % < NCTD/HA-VES = (68.74 ± 2.72) % < NCTD/Gal-HA-VES = (77.87 ± 3.36) %

[129], 2018

NCTD-loaded RGD-lipid-polymer hybrid (LPH) nanoparticles (RGD-LPH-NCTD)

RGD (Arg-Gly-Asp)

Integrin α5 (ITGA5) receptor

Lecithin (2 mg), PEG-DSPE (18 mg), RGD-PEG-DSPE (2 mg), NCTD (1.25 mg), PEI10 K (375 µg), PLGA (1.875 mg)

Cellular uptake (LM2 cells) ↑; LM2, MDA-MB-231, SUM159 cells: cell viability: free NCTD > LPH-NCTD > RGD-LPH-NCTD; reduce colony formation ↑;

inhibit cancer stem cell-like property ↑; reduce both active (non-phospho-β-catenin) and total β-catenin protein levels; the targeting capability in primary mammary tumor and metastatic lung tumor ↑; inhibit LM2 tumor growth and lung metastasis (iv., 3 times a week for 5 consecutive weeks), reduce β-catenin level and its nuclear localization, increase E-cadherin expression

[135], 2019

Folate acid (FA)-conjugated NCTD-loaded stealth niosomes

FA

FA receptor

FA-PEG-chol, F127-chol, Span-80, 3.8 mg NCTD, 0.15 mL absolute ethanol, 0.05 mL ethyl acetate, 5 mL PBS

Hela cells: cellular uptake ↑; IC50 (12 h): FA-conjugated NCTD-loaded stealth niosomes (46 µg/mL) < FA + FA-conjugated NCTD-loaded stealth niosomes (91 µg/mL) < NCTD-loaded stealth niosomes (148 µg/mL) < NCTD (261 µg/mL)

[137], 2013

Diacid metabolite (DM)-NCTD-loaded, FA-modified, polyethylene glycolated (DM-NCTD/FA-PEG) liposomes

FA

FA receptor

DSPC, cholesterol, DSPE-PEG2000, DSPE-PEG2000-FA = 2: 1: 0.11: 0.017 (molar ratio), DM-NCTD

H22 cells: IC50 (48 h): DM-NCTD (30.0 ± 1.73) µg/mL < DM-NCTD/FA-PEG liposomes (50.1 ± 1.04) µg/mL < DM-NCTD/PEG liposomes (92.5 ± 1.31) µg/mL; tumor-targeting efficiency: DM-NCTD/PEG liposomes [relative intake rate 4.86, tissue/tumor-targeting efficacy 12.81%, relative targeting efficiency 2.36, peak concentration ratio 4.78] < DM-NCTD/FA-PEG liposomes (9.25, 24.44%, 4.50, and 9.24); H22 tumor inhibition rate (iv., once daily, 9 days, 2.0 mg/kg): DM-NCTD = 30.14% < DM-NCTD/PEG liposomes = 40.41% < DM-NCTD/FA-PEG liposomes = 67.81%; tumor-cell apoptosis ↑

[138], 2016

FA receptor-targeted NCTD/tetrandrine (Tet) dual-drug loaded lipid nanoparticles [(FA-LP@Tet/(MSNs@NCTD)]

FA

FA receptor

FA-DSPE-PEG2000 (0.18 mg), DSPE-PEG2000 (0.72 mg), DSPC (6.3 mg), cholesterol (2.8 mg),

Tet (2 mg), 5 mL dichloro-

methane, 10 mL anhydrous ethanol, PBS buffer (10 mL,

pH 7.4) containing 2 mg of MSNs@NCTD

HepG2 cells: cellular uptake ↑; IC50 (HepG2, HepG2/Adr, MCF-7, LO2 cells): FA-LP@Tet/(MSNs@NCTD) < LP@Tet/(MSNs@NCTD) < LP/(MSNs@NCTD) < NCTD; induce cell apoptosis: HepG2 cells < HepG2/Adr cells; inhibit P-gp expression

[182], 2019

FA-LB(ABT-737)-(DM-NCTD@CHMSN)

FA

FA receptor

DSPC, cholesterol, DSPE-PEG2000, DSPE-PEG2000-FA = 2: 1: 0.11: 0.017 (molar ratio), CHMSN/DM-NCTD = 2.5: 1

(weight ratio), ABT-737/ DM-NCTD = 1: 10 (mol ratio), DM-NCTD@CHMSN/lipid = 0.02: 1 (weight ratio)

In vitro cytotoxicity, cell apoptosis (H22 cells): DM-NCTD < ABT-737 < DM-NCTD + ABT-737 

< LB(ABT-737)-(DM-NCTD@CHMSN) < FA-LB(ABT-737)-(DM-NCTD@CHMSN); mitochondrial membrane potential ↓; cellular uptake ↑; H22 tumor inhibition rate (14 days): ABT-737 (ip., 50 mg/kg) = 21.0% < DM-NCTD (iv., 2 mg/kg) = 34.6% < DM-NCTD (iv., 2 mg/kg) + ABT-737 (ip., 50 mg/kg) = 45.8% < FA-LB(ABT-737)-(DM-NCTD@CHMSN) (iv., 2 mg/kg) = 69.6%; tumor-cell apoptosis and Cytochrome C expression ↑

[184], 2020