Table 2.
Recent research on liposomes to overcome BBB in the treatment of CNS diseases.
| Surface modify | Targeting ligands | Receptors | Model drug | Use | Others | Refs |
|---|---|---|---|---|---|---|
| glucose-functionalized liposome @TMZ&PAP(gLTP) | glucose | glucose transporter 1 (GLUT1) | TMZ and pro-apoptotic peptide (PAP) | GBM | gLTP can easily penetrate the BBB and effectively deliver drugs to brain tumors, significantly improving overall survival. | [142] |
| n-Butylidenephthalide (BP)/polycationic liposomal polyethylenimine and polyethylene glycol PEG complex (LPPC) | / | / | BP | GBM | LPPC transported BP through the BBB, and uptake through clathrin-dependent, caveolae-mediated and macropinocytosis led to the accumulation of large amounts of BP in tumors and triggered strong anticancer activity. | [143] |
| muscone/RI7217 co-modified docetaxel (DTX) liposomes | RI7217 | TfR | DTX | glioma | The RI7217 monoclonal antibody recognizes TfR through receptor-mediated transendocytosis, which facilitates BBB penetration to the tumor site and enhances brain targeting. muscone modification increased BBB permeability. Therefore, the constructed musk/RI7217 co-modified long-circulating DTX liposomes not only increased the drug concentration in the brain, but also enhanced the anti-glioma effect of DTX. | [144] |
| transferrin-modified Ost liposomes (Tf-Ost-Lip) | Tf | TfR | Osthole(Ost) | AD | Tf-Ost-Lip increased the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and improved the efficiency of BBB delivery. It has a protective effect on APP-SH-SY5Y cells. The retention time of Ost in mice was prolonged, and the concentration of Ost in brain was increased. | [145] |
| Paclitaxel-loaded Rg3- based liposomal system (Rg3-PTX-LiPs) | glucosyl residues of Rg3 | GLUTs | PTX | glioma | Ginsenoside Rg3 can be used as a better substitute for cholesterol in the preparation of liposomes. In addition to improving the stability and mobility of liposomes, ginsenoside Rg3 can also enhance the BBB penetration ability, tumor targeting ability, tumor cell killing activity, TME remodeling ability and PTX chemotherapy effect. | [109] |
| T7-modified liposomes/vincristine (T7-LS/VCR) | T7 | TfR | VCR | glioma | T7-LS/VCR enhanced BBB permeability and showed high anti-glioma effect by promoting cytotoxicity and apoptosis in vitro. | [146] |
| DCDX liposomes (HSPC/cholesterol/PEG2000-DSPE/DCDX -PEG3400-DSPE (52/43/3/2, molar ratio)) | D-type polypeptide (DCDX) | Nicotinic acetylcholine receptors (nAChRs) | / | glioma | DCDX liposomes in the cells of the transport is very complex, involving a variety of ways, such as the endocytic pathways and organelles. This study optimized the structure of the brain-targeted drug delivery system and improved the efficiency of drug delivery. | [147] |
| RVGMAN and PenMAN liposomes encapsulating ApoE2/chitosan complex | mannose (MAN), rabies virus glycoprotein peptide | glut-1; acetylcholine receptor | plasmid encoding ApoE2 (pApoE2) | AD | RVGMAN and PenMAN liposomes encapsulation of ApoE2/chitosan complexes enhanced BBB penetration and brain targeting, resulting in efficient delivery of ApoE2 encoding plasmid DNA. | [148] |
| DOX-terpolymer-lipid-hybrid nanoparticle (DOX-TPLN) | polysorbate 80 (PS 80) | Low-density lipoprotein receptor (LDL-R) | DOX | GBM | The efficacy of DOX was better than that of TMZ. However, the application of DOX in GBM is limited due to its difficulty in penetrating the BBB. The DOX-TPLN formulation enables the penetration of DOX, a brain-impermeable anticancer drug, across the BBB for the treatment of GBM. | [149] |
| Brain derived neurotrophic factor AntagoNAT (BDNF AT) cationic liposomes | / | / | / | PD | BDNF is the most intensively studied target for PD, which can reverse the progression of the disease. BDNF AT is able to up-regulate BDNF expression, so it can be targeted to increase endogenous BDNF expression to treat PD. However, BDNF AT cannot cross the BBB, and BDNF AT cationic liposomes can overcome this problem. | [150] |
| Ost liposomes with modified CXCR4 on the surface (CXCR4-Ost-Lips) | Stromal cell-derived factor-1 (SDF-1) | CXCR4 | Ost | AD | Although Ost can improve AD, its neuroprotective effect is limited by various limitations, such as poor solubility, poor stability, poor brain targeting, and low bioavailability. In addition, SDF-1 is highly expressed in the brain of AD patients and is the only ligand of CXCR4, which has the potential to become a brain-targeting molecule. The results showed that CXCR4-Ost-Lips was able to enhance brain targeting, increase cellular uptake, and prolong the blood circulation time of the drug. | [151] |
| Lf and muscone dual‐modified DTX long‐circulating liposomes (Lf‐LiP‐Mu‐DTX) | Lf | Lactoferrin receptors (LfR) | DTX | glioma | Lf was modified to actively target LfR, and muscone was modified to increase BBB permeability on the liposome surface. Thus, LF-LiP-MU-DTX can increase cellular uptake, enhance BBB penetration, and enhance brain targeting and anti-glioma efficacy in vitro and in vivo. | [152] |
| PenTf-Liposomes Containing Chitosan–plasmid nerve growth factor (pNGF) | Tf | TfR | pNGF | AD | PenTf-Liposomes Containing chitosan-PNGF can protect pNGF from enzymatic degradation, promote NGF transfection, and overcome BBB, which has the potential to treat AD. | [153] |
| GSH-ApoE-Cur-QU-EGCG-RA-PC-liposomes | GSH; ApoE | glutathione receptors (GSHR); LDL-R | Cur; Quercitin (QU); Epigallocatechin gallate (EGCG); Rosmarinic acid (RA) | AD | GSH and ApoE on the liposomes enhanced BBB penetration, and ApoE and PC recognized Aβ in the delivery of the four drugs. | [154] |
| Aniopep-2- icariin/tanshinone IIA liposomes (Ang2-ICA/TSIIA liposomes) | Angiopep-2 (A2) | Low-density lipoprotein receptor-related protein-1 (LRP1) | Icariin (ICA) and tanshinone IIA (TSIIA) | AD | Ang2-ICA/TSIIA liposomes have brain targeting ability and are able to cross the BBB. | [155] |
| SNA-Liposome-ApoE/RVG | ApoE; rabies virus glycoprotein (RVG) | LDL-R; nAChRs | oligonucleotide miRNA inhibitors (OMIs); | GBM | Compared with Sn-liposome-RVG, SN-liposome-apoe is more likely to advance mirNA-based GBM therapies as well as the transformation of other CNS diseases. | [156] |
| Epirubicin (EPI) plus resveratrol (RES) liposomes modified with p-aminophenyl-α-D-manno-pyranoside (MAN) and wheat germ agglutinin (WGA) | MAN; WGA | GLUT; WGA receptors | EPI; RES | glioma | The EPI plus RES liposomes modified with MAN and WGA can significantly improve the transport of EPI and RES across the blood-brain barrier and the survival of brain tumor animals with multifunctional targeting. | [157] |
| ApoE- artesunate-phosphatidylcholine (ARTPC)@TMZ | ApoE | LDLR | artesunate (ART); TMZ | GBM | The ApoE-ARTPC@TMZ nanoplatform enhances BBB penetration for effective delivery of ART and TMZ chemotherapy drugs. ART and TMZ synergistically reduced the tumor burden and prolonged the survival of mice, indicating that they could improve the prognosis of patients with CNS tumors treated with TMZ chemotherapy. | [158] |
| polyethylene glycol-cyclic Arg-Gly-Asp- emodin liposomes (PEG-cRGD-Em-Lip) | cRGD | αvβ3 receptor | Em | Ischemic Stroke | PEG-cRGD-Em-Lip achieves brain-targeted delivery of Em and significantly improves the therapeutic effect of Em in ischemic stroke. | [159] |
| Tf- Vitamin B12 (VB12)- liposomes | Tf | TfR | VB12 | AD | The NPs were stable under storage conditions for 2 months and sustained release of VB12 for up to 9 days. | [160] |
| ApoE- resveratrol/salidroside (Res/Sal)- liposomes | ApoE | LDL-R | Res/Sal | AD | ApoE-Res/Sal-Lips can alleviate AD pathological symptoms, reduce learning and memory impairment, and improve brain function. | [161] |
| RVG29-nAChR-liposomes | RVG29 | nAChR | Quercetin | AD | RVG29-nAChR-liposomes can improve Quercetin permeability through BBB and inhibit amyloid β aggregation. | [162] |
| PTX-CHO-RVG15-Lipo | RVG15 | nAChR | PTX | glioma | PTX-CHO-RVG15-Lipo improved BBB penetration and anti-glioma efficacy of the drug. | [163] |
| novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties | The PEGylated glucose modified ligand (Chol-TPG) | GSHR | doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND) | glioma | Lip-TPGS release is a combination of SDOX and LND to effectively treat glioma. | [164] |
| MAN/CPP- vgf-liposomes | glucose transporter-1 targeting ligand and brain targeted cell-penetrating peptide (CPP) | GLUT-1 | plasmid encoding vgf | AD | MAN/CPP-vgf-liposomes promote the brain targeting ability, transfection efficiency and biocompatibility of plasmacyto-encoding vgf. | [165] |
| Tf-Pep63-Lip | Tf | TfR | Pep63 | AD | Tf-Pep63-Lip can bypass the BBB to enter the brain and rescue cognitive impairment in AD mice. | [166] |
| PTX-Bio2+Glu3-Lip | Glu3-Chol; biotin 2 (Bio2)-Chol | GLUTR; SMVT receptor | PTX | glioma | Multi-target ligands can significantly enhance the tumor targeting ability of liposomes. | [167] |
| PEG-Lip-DOX/CB | / | / | DOX, carboplatin (CB) | GBM | Peg-lip-dox/CB can penetrate the BBB and enhance the cytotoxic effect of the drug on rat glioma cells, and PEG is more effective in increasing the therapeutic effect and reducing the side effects of the drug. | [168] |
| WGA-Lep-AS-IV-NF-1-PS-Lip | WGA; Leptin (Lep); Phosphatidylserine (PS) | N-acetyl-D-glucosamine and sialic acid; Lep receptor (LEPR); α-synuclein (α-Syn); | Astragaloside IV (AS-IV); Nesfatin-1 (NF-1) | PD | WGA-Lep-AS-IV-NF-1-PS-Lip increased BBB permeability of AS-IV and NF-1 and showed promising effects in reducing neurotoxicity. | [169] |
| Angiopep-2-modified calcium arsenite liposome (A2-PEG-Lip@CaAs) | A2 | LRP | arsenic trioxide (ATO) | glioma | A2-PEG-Lip@CaAs has high drug loading, high embedding efficiency, and can effectively target anti-glioma. | [170] |
| pH-sensitive multi-targeted liposomes (Lip-CTPP) | p-hydroxybenzoic acid (p-HA) | dopamine/sigma receptors | DOX and LND | glioma | Lip-CTPP has a good pharmacokinetic behavior, can cross the BBB, and has a strong tumor cell targeting ability. Moreover, the synergism of the two drugs increased the anti-tumor efficacy. | [171] |
| cisplatin- (Cispt) loaded PEGylated liposomes, targeted with OX26 monoclonal antibody | OX26 | TfR | Cispt | GBM | In this study, encapsulation of drugs into liposome nanoparticles can reduce nephrotoxicity, hearing toxicity and neurotoxicity, and enhance the anti-tumor activity of drugs. | [172] |
| Caffeic acid (CA)-Tf-Lip | Tf | TfR | CA | AD | Ca-tf-lip can promote the sustained release of CA. | [173] |
| Tf-functionalized liposomes for the delivery of gallic acid (GA) | Tf | TfR | GA | AD | The liposome prepared in this study can improve the ability to penetrate the BBB, enhance the colloidal stability, promote the sustained slow and stable release of drugs, and have neuroprotective effects. This indicated that the liposome could enhance the anti-tumor activity of the carried GA. | [174] |
| temozolomide magnetic temperature-sensitive liposomes (TMZ/Fe-TSL) | / | / | TMZ | GBM | TMZ/Fe-TSL exposed to an alternating magnetic field (AMF) could significantly induce GBM cell death and promote ROS production. | [175] |
| A2-Sal/Ica-Lip | A2 | LRP | Salidroside (Sal) and Icariin (Ica) | AD | A2-Sal/Ica-Lip can cross the BBB to increase drug accumulation in the brain and increase cellular uptake. In addition, it can reverse neuronal and synaptic damage, inhibit neuroinflammation and oxidative stress, and improve learning and cognitive function. | [176] |
| folate-modified TPGS-transfersomes containing DTX (TF-DTX-FA) | FA | folic acid receptor (FAR) | DTX | GBM | Transfersomes are different from traditional liposomes, They are ultradeformable (ultra-flexible) vesicles that consist of at least one inner water core wrapped in a lipid bilayer composed of phospholipids and surfactants (edge activators). | [177] |
| atorvastatin-loaded PEGylated liposomes (PEGylated LipoStatin) | / | / | atorvastatin | acute ischemic stroke | PEGylated LipoStati can be effectively delivered to the ischemic brain and has a significant neuroprotective effect. | [178] |
| folic acid (FA) derivatives and mitochondria-targeting berberine (BBR) derivatives co-modified liposome coated with Tween 80 loading paclitaxel (PTX-Tween 80-BBR + FA-Lip) | FA | FAR | PTX | glioma | PTX-Tween 80-BBR + FA-Lip can be aggregated in tumor tissues and targeted to mitochondria. | [179] |
| Lep/RES-EGCG-PA-liposomes (PA: cholesterol and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate) | Lep | Lep receptor | RES and epigallocatechin gallate (EGCG). | PD | Lep/RES-EGCG-PA-liposomes increased the drug loading rate and decreased the drug release rate. | [84] |
| Functionalized nanoparticles for brain targeted BDNF gene | MAN | GLUT1 | plasmid encoding BDNF | AD | Liposomes were surface-functionalized with brain targeting ligand, MAN, and cell-penetrating peptides (CPP) (rabies virus-derived peptide or penetratin). CPP, rabies virus-derived peptide (RDP) or penetratin (Pen), was used in combination with MAN | [180] |
| RVG-Lf-AZD5582-SM-164-liposomes | Lf; RVG | LfR; nAChR | AZD5582; SM-164 | GBM | This liposome improved the embedding efficiency of AZD5582 and SM-164 and reduced the release rate. Moreover, it promotes the synergistic activity between AZD5582 and SM-164 to facilitate its transit through the BBB. | [181] |
| α5β1 integrin selective liposomes of RGDK-lipopeptide | RGDK | α5β1 integrin receptors | WP1066 (a small-molecule STAT3 inhibitor) and STAT3siRNA | GBM | Intravenous administration of liposomes containing coencapsulated STAT3siRNA and WP1066 resulted in a significant increase in the overall viability of orthotopic established glioblastoid-bearing mice. | [182] |
| neurotransmitter-modified liposomes (NTs-LIP): tryptamine (Tryp) + Camptothecin (CPT) + Cur | / | / | CPT; CUR | glioma | The introduction of Tryp promotes the delivery efficiency of CPT and CUR across the BBB | [74] |
| procaine-loaded liposome modified with cRGDyK (Pro/cRGDyK-L) | pentapeptide cyclic (arginine-glycine-aspartic acid-tyrosine-lysine) (cRGDyK) | αvβ3 receptor | procaine | glioma | The cRGDyK peptide significantly facilitated the ability of liposomes to transfer procaine across the BBB and improved the cellular uptake of procaine by glioma cells. | [183] |
| gH625-lipoPACAP | / | / | pituitary adenylate cyclase-activating polypeptide (PACAP) | PD | PACAP neuroprotective effects when delivered by gH625-liposome on MPP-damaged SH-SY5Y spheroids gh625 (Liposome-delivered PACAP provides neuroprotection in MPP-injured SH-SY5Y spheres). | [184] |
| FA-modified lidocaine-carrying liposome (Lid-FA-Lip) | FA | FAR | lidocaine-carrying | glioma | Lid-FA-Lip is a promising liposomal preparation of lidocaine, which can be mediated through the PI3K/AKT pathway to improve the therapeutic effect on glioma. | [185] |