Understanding the Crossing of Blood–Brain Barrier Using Nanocarriers: Current Trends and the Role of Physiologically Based Pharmacokinetic Modeling

Drug delivery to the brain across the blood-brain barrier (BBB) has been a challenge for drugs unable to passively diffuse through it. Various parameters of the drugs contribute to the potency to cross the barrier made up of tight junctions of the epithelial cell membrane. For drugs with low permeability, novel nanoscale drug carriers have been developed to enhance delivery into the brain by circumventing the BBB. The carriers are fabricated in nanoscale for better penetration of the tight junctions in BBB. Understanding the physiology of the blood-brain barrier and the mechanism of molecular transport across it is crucial for designing effective drug carriers. Physiologically based pharmacokinetics (PBPK) modeling is a powerful tool for simulating the permeability of drugs and drug carriers across the BBB. The perfusion-limited kinetics and permeability-limited kinetics are two key equations that describe the transport of the drug into the brain and aiding in the determination of whether surface modifications to the drug carrier are necessary to improve the permeability. This review discusses the mechanisms of molecule transfer across the BBB, the parameters that filter drugs from the blood, the role of nanocarriers in enhancing permeability, the significance of PBPK modeling in extrapolating ${\boldsymbol {i}n}~\boldsymbol {vivo}$ permeability data of the drugs, and the recommended surface modifications to optimize drug delivery to the brain.