Table 8.
Various liposomal active targeting ligands for active components of CHMs targeted to cancer cells and the TME
| Targeting ligands | Targeting site | Entrapped components | Drug loading | Cancer model | Main results | Reference |
|---|---|---|---|---|---|---|
| Over-expressed receptors on the surface of cancer cells | ||||||
| β-Galactose | Asialoglycoprotein receptors | Glycyrrhetinic acid (GA) | Film dispersion method |
In vivo Kunming mice In vitro HepG2 cells |
In vivo Galactosylated GA-liposomes (Gal-GA-LP) showed long-circulating profile in Kunming mice with the MRT of Gal-GA-LP being 1.48- and 1.3-fold increasement when compared with GA solution and nontargeting GA-loaded liposomes, respectively. In vitro Gal-GA-LP showed 1.4-fold higher drug concentration in cells than that of GA-liposomes. |
[420] |
| Oridonin (ORI) | Ethanol injection method |
In vivo Kunming mice |
In vivo The MRT of ORI-loaded liposomes modified with galactose (NOH-ORI-LP) was 5.56-fold longer than that of ORI solution in mice, with lower clearance from liver. |
[421] | ||
| Lactose | Matrine (MA) | Reversed-phase evaporation method |
In vivo Kunming mice In vitro HepG2 cells |
In vivo The accumulation of MA in targeting liposomes in the mice liver was 2.7 times higher than in the spleen, 3 times higher than in the lung, 6.6 times higher than in the kidney, and 8.5 times higher than in the heart. In vitro Inhibitory rate of targeting liposomes of MA was 1.6- and 1.83-fold higher than those of conventional MA liposomes and MA solution at 0.5 mg/mL concentration, respectively. |
[422] | |
| Transferrin (Tf) | Transferrin receptors | Tetrandrine and Vincristine | Film dispersion method |
In vivo Glioma-bearing ICR mice model In vitro C6 cells, C6/ADR cells and murine brain microvascular endothelial cells (BMVECs) |
In vivo Tf targeting liposomes improved accumulation in brain tumor tissue with fluorescent signal maintained up to 48 h and animals exhibited prolonged survival time (42.67 ± 3.56 days) compared with the saline group. In vitro The targeting liposomes showed significantly prolonged circulation time and increased accumulation in tumors. |
[423] |
| Lactoferrin (Lf) | Honokiol and Daunorubicin | Film dispersion plus ammonium sulfate gradient methods |
In vivo Glioma-bearing ICR mice model In vitro C6 cells and BMVECs |
In vivo The targeting liposomes improved accumulation in brain tumor tissue indicated by fluorescence probe and conferred prolonged survival time. In vitro Lf modified daunorubicin plus honokiol liposomes enhanced drug transportation across the blood-brain barrier, inhibited C6 cells invasion, and destroyed vasculogenic mimicry channels. |
[424] | |
| Folic acid | Folate receptors (FR) | Curcumin (Cur) | Film dispersion method |
In vitro KB, Hela, and A549 cells |
In vitro FR-positive cells endocytosed more FR-targeting liposomes than nontargeted liposomal Cur. Targeted liposomes more effectively inhibited cellular proliferation and caused higher dose- and time-dependent apoptosis. KB cells were more sensitive to FR-targeting liposomal Cur than Hela cells. |
[425] |
| Baicalin (Bai) | Film hydration and homogenization |
In vitro HeLa cells |
In vitro Cytotoxicity and cellular uptake of Bai-loaded FR-targeting liposomes were higher than that of non-targeted liposomes. |
[426] | ||
| Ursolic acid (UA) | Film hydration and extrusion |
In vivo Balb/c nude mice xenografted oral cancer (KB cells) In vitro KB cells |
In vivo Compared with passive targeting liposomes, FA-PEG modified UA liposomes significantly inhibit oral tumor growth. In vitro The EE% of UA was more than 85%. FR targeting UA PEGylated liposomes showed improved tumor cell uptake, proliferation inhibition, and apoptotic effects as compared with nontargeting PEGylated liposomes. |
[427] | ||
| Glycyrrhetinic acid (GA) | GA receptors | Ginsenoside Rh2 | Film hydration method |
In vitro SMMC-7721 cells |
In vitro IC50 of GA-modified liposomes in SMMC-7721 cells increased by 0.5- and 0.6-fold compared with Rh2 solution and Rh2-loaded liposomes, respectively. |
[428] |
| Baicalin | Film hydration and ethanol injection methods | \ | The size of GA modified baicalin liposomes was 150 nm with EE% at 41.8%. | [429] | ||
| Brucine | Ethanol injection method | \ | The formulation of GA modified brucine liposomes was optimized with a lipid to cholesterol (w/w) ratio of 6, lipid to drug (w/w) ratio of 15, and lipid to GA (w/w) ratio of 35 (g/g). The size of targeted liposomes was 147.2 nm and the EE% of brucine was 82.8%. | [430] | ||
| Wogonin | Reversed-phase evaporation method |
In vivo ICR mice xenografted liver cancer (HepG2 cells) In vitro HepG2, L-02 and LX-2 cells |
In vivo GA modified liposomes rapidly and highly accumulated in the tumor and liver shortly after administration. The tumor inhibitory ratio of targeted liposomes was 1.7-fold higher than that of nontargeted liposomes. In vitro GA-modified liposomes showed 1.46-fold higher growth inhibition than that of non-targeted liposomes in HepG2 cells. |
[428] | ||
| Cur | Ethanol injection method |
In vitro HepG-2 and H22 cells |
In vivo GA modified liposomes loaded with Cur inhibited tumor growth, reduced tumor microvascular density and regulated the expression of Caspases3 and VEGF proteins in H22 tumor tissues. In vitro GA modified liposomes induced more HepG2 cellular apoptosis and tumor growth inhibition. |
[431] | ||
| Epigallocatechin 3-gallate (EGCG) | 67LR | Doxarubicin | Film hydration method |
In vivo C57BL/6 mice melanoma (B16F10 cells) |
In vivo Targeting liposomes showed superior anti-tumor effect without observed side effects. |
[432] |
| Targeting cytoplasmic organelles | ||||||
| Mitochondrion | Dequalinium (DQA) | Resveratrol | Film dispersion and extrusion |
In vivo Balb/c nude mice xenografted resistant lung cancer (A549/cDDP cells) In vitro A549 cells and A549/cDDP cells |
In vivo The combination administration of targeting resveratrol liposomes with vinorelbine liposomes exhibited superior prohibition of tumor growth. In vitro The increased mitochondrial uptake and solubility of resveratrol in targeting liposomes promoted inhibitory cell activity by triggering cytochrome C release. |
[433] |
| Berberine | Film dispersion and extrusion |
In vivo Balb/c nude mice xenografted breast cancer (MCF-7 dissociated cancer stem cells) In vitro MCF-7 cells |
In vivo The synergistic effect of targeting berberine liposomes and paclitaxel liposomes exhibited the strongest anti-tumor effect. In vitro Targeting berberine liposomes (1, 5, and 10 μM) could synergistically enhance the toxicity of paclitaxel liposomes in a dose-dependent manner, while achieving selective mitochondrial accumulation. |
[434] | ||
| 4-Carboxybutyl triphenylphosphonium bromide (TPP) or DQA | Resveratrol | Film dispersion and extrusion |
In vitro B16F10 cells |
In vitro TPP and DQA conjugated with DSPE-PEG liposomes carrying resveratrol caused better cellular uptake and selective accumulation in mitochondria. |
[435] | |
| Targeting the TME | ||||||
| Hyaluronic acid (HA) | CD44 and the receptor for hyaluronan-mediated motility | Curcumin (Cur) | Reversed-phase evaporation method |
In vitro HepG2 and A549 cells |
In vitro The binding rate of HA-lipid to Cur-liposomes was 72%. The IC50 values were found to be 0.054, 0.032 and 0.021 mol/ml for free Cur, nontargeted Cur liposomes and modified Cur liposomes, respectively, after incubation with A549 cells overexpressing the CD44 receptor. |
[436] |
| Matrine | Film dispersion, reversed-phase evaporation and ethanol injection methods |
In vivo Balb/c mice xenografted liver cancer (H22 cells) |
In vivo The inhibition rate of HA-modified MA liposomes on H22 hepatocarcinoma was similar to that of cyclophosphamide, and 2.0- and 1.4- fold higher than that of MA solution and MA conventional liposomes, respectively. |
[437] | ||
| Surface modification with antibodies | ||||||
| Anti-CD44 antibody | CD44 receptors | Timosaponin AIII (TAIII) | Film evaporation and ultrasonic methods |
In vivo Balb/c nude mice xenografted liver cancer (HepG2 cells) In vitro HepG2 cells |
In vivo CD44 targeting liposomes showed significantly inhibition on tumor growth, which was 7.2- and 1.3- fold greater than that of free drug and non-targeted liposomes, respectively. In vitro Targeting liposomes were more toxic to tumor cells with lower IC50 than non-targeting liposomes. |
[438] |
| Trastuzumab | Human epidermal growth factor receptor-2 (HER2) | Curcumin and Resveratrol | Film evaporation and extrusion method |
In vitro JIMT1 an MCF-7 cells |
In vitro The immunoliposomes of curcumin and resveratrol showed notably higher cytotoxicity, compared to free drugs. The finding was more prominent for curcumin than resveratrol. |
[439] |
| Surface modification with peptides | ||||||
| T7 (HAIYPRH) peptide | Transferrin receptors | Quercetin | Film hydration method |
In vivo Balb/c nude mice with orthotopic lung cancer (A549-Luc cells) In vitro A549-Luc cells |
In vivo T7 modified liposomes significantly delayed tumor growth and enhanced the lifespan of mice following pulmonary administration. In vitro T7 modified liposomes showed higher cellular uptake and significantly higher tumor-spheroid growth inhibition. |
[440] |
| NGR (Asn-Gly-Arg) | CD13 | Triptolide | Film hydration method |
In vitro Human umbilical vein endothelial cells (HUVEC) |
In vitro Triptolide-loaded liposomes modified with NGR showed stronger cellular toxicity with lowest IC50 on HUVECs at 11 μM. |
[441] |
| Brucine | Ammonium sulfate gradient method |
In vivo Balb/c nude mice xenografted fibrosarcoma (HT1080 cells) In vitro HT1080 cells and HUVEC |
In vivo The highest fluorescence signals in tumors were found in animals treated with NGR-modified liposomes with HSPC and SPC together than that with HSPC or SPC used alone. In vitro The composition of lipids did not exhibit significant influence on EE% of brucine. The cellular uptake of NGR-modified liposomes was about 1.5-fold higher than that of non-targeted liposomes. |
[442] | ||
| RGD (Arg-Gly-Asp) | Integrins | Tetrandrine and Vinorelbine | Film dispersion followed by ammonium sulfate gradient method |
In vivo Glioma-bearing ICR mice model (Doxorubicin-resistant C6 cells) In vitro C6 cells and BMVECs |
In vivo RGD modified vinorelbine and tetrandrine liposomes prolonged elimination half-life compared with free drug, and extended survival times. Strong fluorescent signals of targeting liposomes were observed in tumors within 24 h after administration, while the signals of free drugs was in the liver. In vitro Targeted liposomes significantly enhanced transportation across the BBB and uptake in tumor cells. |
[443] |
| Matrine | Film dispersion followed by pH-gradient method |
In vitro Bcap-37, HT-29 and A375 cells |
In vitro RGD-PEG-DSPE was employed to obtain matrine liposomes with an EE% of 83.13%. Compared with free matrine, targeting liposomes induced stronger inhibition of proliferation and induced more apoptosis in tumor cells. |
[444] | ||
| Shikonin (SHK) | Film hydration method |
In vitro MDA-MB-231 cells |
In vitro RGD modified SHK-loaded liposomes with EE% of 94.9% greatly induced cellular apoptosis by increasing the ratio of Bcl-2-associated X protein (Bax)/Bcl-2, and inhibited cellular proliferation, migration and invasion, as compared with nontargeted SHK-loaded liposomes. |
[445] | ||
| Octaarginine (R8) | Syndecan 4 | Dihydroartemisinin and Epirubicin | Film dispersion method |
In vitro A549 cells |
In vivo R8 modified liposomes increased the selective drug accumulation at tumor sites and showed a targeting capable of reducing tumor volume. In vitro R8 modified liposomes exhibited powerful cytotoxicity on A549 cells, effectively suppressed vasculogenic mimicry channels, and regulated metastasis related proteins. |
[446] |
| R8GD (RGD and R8) | Integrins | Emodin | Film dispersion method |
In vivo Balb/c nude mice xenografted breast cancer (MDA-MB-435S cells) In vitro MDA-MB-435S cells |
In vivo Strong fluorescence signals of R8GD modified liposomes were found in tumors within 24 h after administration. R8GD modified daunorubicin liposomes significantly inhibited tumor growth with the combination of R8GD modified emodin liposomes. Their efficacy was 3-fold stronger than that of nontargeting liposomes combination. In vitro The cellular uptake was increased for targeting liposomes. |
[447] |
| HIV protein transactivator of transcription (TAT) together with HA | Syndecan 4 | Curcumin and Celecoxib | Film hydration method |
In vivo Balb/c mice with orthotopic breast cancer (4T1 cells) In vitro RAW264.7, HUVEC and 4T1 cells |
In vivo NF-κB essential modulator-binding domain (NBD) fused with TAT peptide modified liposomes co-delivering curcumin and celecoxib were coated with HA (HA/TN-CCLP). HA/TN-CCLP could prolong circulation time, increase tumor accumulation, and block lung metastasis. In vitro HA/TN-CCLP improved cytotoxicity, inhibited migration, and enhanced anti-inflammation effect, when compared to nontargeted liposomes. |
[448] |
| tLyp-1 (sequence CGNKRTR) | Neuropilin-1 | Ginsenoside CK and Parthenolide | Film hydration method |
In vivo Balb/c nude mice xenografted lung cancer (A549 cells) In vitro A549 cells |
In vivo Targeting liposomes with hydrophilic PEG shell demonstrated stronger antitumor effect than free drugs combination without observed toxicity. In vitro The cellular uptake of targeted liposomes was through micropinocytosis and the liposomes were escaped from lysosome in a time-dependent manner. |
[449] |
| Surface modification with polymers | ||||||
| D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) | \ | Luteolin | Film-dispersion method |
In vivo Balb/c nude mice xenografted lung cancer (A549 cells) In vitro A549 cells |
In vivo TPGS coated liposomes loaded with luteolin were significantly accumulated in tumor sites. The modified liposomes exhibited higher tumor inhibition rate to 51.7% than that of free luteolin. In vitro TPGS coated liposomes improved cytotoxicity in A549 cells by increasing the Bax/Bcl-2 ratio. |
[450] |
| \ | Ginsenoside compound K | Film hydration method |
In vivo Balb/c nude mice xenografted lung cancer (A549 cells) In vitro A549 cells |
In vivo Targeted liposomes delivered ginsenoside compound K into tumor sites, enhanced its permeability and retained it in tumor cells. In vitro The EE% of targeted liposomes was 98.4%, and the size was (119.3±1.4) nm at the ratio of 7:3 (phospholipid: TPGS). The IC50 of targeted liposomes was significantly reduced to 25% of that of free drugs. |
[451] | |