Signaled drug delivery and transport across the blood–brain barrier

Abstract

We use a mathematical model to describe the delivery of a drug to a specific region of the brain. The drug is carried by liposomes that can release their cargo by application of focused ultrasound (US). Thereupon, the drug is absorbed through the endothelial cells that line the brain capillaries and form the physiologically important blood-brain barrier (BBB). We present a compartmental model of a capillary that is able to capture the complex binding and transport processes the drug undergoes in the blood plasma and at the BBB. We apply this model to the delivery of levodopa (L-dopa, used to treat Parkinson's disease) and doxorubicin (an anticancer agent). The goal is to optimize the delivery of drug while at the same time minimizing possible side effects of the US.

Dynamic control of neurochemical release with ultrasonically-sensitive nanoshell-tethered liposomes

“…An acoustic pressure threshold of~0.2 MPa was observed to elicit CF release. This is considerably lower than that previously observed for sonosensitive liposomes containing DOPE under identical ultrasound conditions 30 , without the need for membrane-compromising additives. In addition, release appears to occur in a primarily non-destructive manner, with evidence of intact HGN-tethered liposomes after the application of ultrasound visible by TEM.…”

Scaling behavior of drug transport and absorption in in silico cerebral capillary networks

“…The pressure difference and the parameter ranges for the transport of L-Dopa across the BBB are listed in Table 1 . The transport and metabolism parameters for L-Dopa were derived from sources in the literature in [ 8 ] and we use them here again.…”

“…Mathematical modeling and computational simulation are essential tools to further our understanding of transport phenomena in biology and biomedical engineering in general [ 6 ]. In the particular area of drug delivery, among the various topics that have been addressed are the optimization of properties of drug carrier particles [ 7 ] and the effects of physical triggers such as ultrasound [ 8 ] or elevated local temperature [ 9 – 11 ].…”

“…Recent work [ 8 ] proposed a compartmental mathematical model for liposomes that encapsulate a drug and release their cargo by a focused transcranial ultrasound signal. The model includes the release of the cargo from the liposomes as a function of the sound pressure, interactions of the free drug with plasma proteins [ 12 ], passive as well as nonlinear active transport mechanisms across the BBB [ 13 ] and the drug metabolism in the brain tissue [ 14 ].…”

“…The model also accounts for the temporary opening of the BBB in response to focused ultrasound [ 15 ]. However, for sake of simplicity, the model in [ 8 ] considered only a single blood vessel. Sample simulations were performed for the dopamine precursor L-Dopa and the anticancer drug doxorubicine.…”