Table 1 Drug delivery systems tested in BBB in vitro models

1

hCMEC/D3 brain endothelial cell line

Lipid nanocapsules

Nonpsychotropic cannabinoids

This system outperformed G-Technology by sixfold crossing the in vitro BBB, a sustained drug delivery system to the brain currently in the last stage of clinical trials

[48]

hIPSCs-derived brain endothelial cells

None

Immunoglobulin G

The antibody transport across the in vitro barrier is increased in the presence of amyloid-b and neuroinflammatory cytokines, proving to be a plausible therapy for Alzheimer’s disease

[49]

Primary human microvascular endothelial cells

None

Anti-amyloid-b monoclonal antibody

Anti-amyloid-b N-terminal antibodies allow clearance of amyloid-b across the BBB unlike Anti-amyloid-b C-terminal, due to a RAGE-based process

[50]

Bovine primary brain endothelial cells

Phage display-based HAIYPRH sequence containing peptides

None

MALDI-TOF allowed a more sensitive analysis of the BBB crossing peptides, allowing highly sensitive and low sample assays for peptide selection

[51]

hIPSC’s derived brain endothelial cells

None

Cyclosporine A

Evaluation of Cyclosporine A time and concentration dependent toxicity using a simple in vitro BBB model

[52]

hIPSC’s derived brain endothelial cells

None

Mannitol

The miniaturized in vitro model of BBB allows the visualization and characterization of the hyperosmotic permeability enhancement caused by mannitol dosages

[53]

hCMEC/D3 brain endothelial cell line

Recombinant human apoferritin nanoparticles

Anti-CTX and anti- TZ monoclonal antibodies

Using a glioblastoma cell line and a well plate insert BBB model, ferritin-based nanocarriers of monoclonal antibodies show BBB crossing capacity and posterior glioblastoma targeting

[54]

hCMEC/D3 brain endothelial cell line

Spheric and rod-shaped polystyrene particles

None

Rod-shaped particles overcome the BBB more easily than spherical particles of the same material

[41]

2

Primary rat endothelial cells and astrocytes

Phage display derived peptides

None

The two selected peptides show particularly high BBB permeability as compared to control ones with 3.3 × 10⁻⁷ cm/s for GLHTSATNLYLH and 1.5 × 10⁻⁶ cm/s for VAARTGEIYVPW

[41]

GLHTSATNLYLH and VAARTGEIYVPW for primary rat endothelial cells

Human CD34 + endothelial cells derived from hematopoietic stem cells

None

Methotrexate

Levofloxacin

Indomethacin

Atenolol

Diazepam

Metoprolol

Lamotrigine

Verapamil

Bupropion

The blood/cerebrospinal fluid (CSF) ratio for each of the used drugs matched the values acquired for this ratio in human patients with a correlation factor R² = 0.88

[55]

Murine immortalized endothelial cells and murine astrocytes

Transferrin and cell penetrating peptide PFVYLI modified liposomes

Doxorubicin and erlotinib

Dually modified liposomes showed significantly higher BBB crossing ability and glioblastoma cells’ death than controls

[56]

3

hIPSCs derived brain microvascular endothelial cells and primary brain pericytes and astrocytes

100–400 nm fluorescent polystyrene and 100 nm rhodamine-labeled polyurethane nanoparticles

None

The BBB vascularized microfluidic model allows rapid nanoparticle testing, concluding that both the commercial polystyrene and the custom-made polyurethane nanoparticles have similar BBB permeability

[57]

hIPSCs derived brain microvascular endothelial cells and primary brain pericytes and astrocytes

None

Digoxin

Colchicine

Quinidine

Vinblastine

Glibenclaide

Caffeinem

Bupropion

Gabapentin

Lamotrigine

Tacrine

Thioridazine

Topiramate

Verapamil

Higher correlation of in vitro human BBB model crossing with human in vivo models of standard drugs than rat BBB and Caco-2 models

[58]

Immortalized human brain endothelial, brain pericytes and astrocytes

None

Propranolol

Pyrilamine

Memantine

Diphenhydramine

Sodium fluorescein

Lucifer yellow

Immortalized BBB recreated the in vivo permeation profile of BBB permeable and non-permeable drugs

[59]