Blood-Brain Barrier Drug Targeting: The Future of Brain Drug Development

Pardridge, William M.

doi:10.1124/mi.3.2.90

Cited by 642 publications

(467 citation statements)

References 47 publications

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“…This barrier, which is formed by the anatomical and biochemical properties of brain endothelium, prevents all large-molecule agents and even most smallmolecule agents from being delivered to the brain (Pardridge 2003). It is arguably the principle impediment to the use of therapeutics for CNS disease.…”

Section: Introductionmentioning

confidence: 99%

Blood-Brain Barrier Disruption Induced by Focused Ultrasound and Circulating Preformed Microbubbles Appears to Be Characterized by the Mechanical Index

McDannold

Vykhodtseva

Hynynen

2008

Ultrasound in Medicine & Biology

246

199

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This work investigated the effect of ultrasonic frequency on the threshold for blood-brain barrier (BBB) disruption induced by ultrasound pulses combined with an ultrasound contrast agent. Experiments were performed in rabbits using ultrasound pulses at 2.04 MHz using sonications with peak pressure amplitudes ranging from 0.3 to 2.3 MPa. BBB disruption was evaluated using contrastenhanced magnetic resonance imaging. The threshold for BBB disruption was estimated using probit regression. Representative samples with similar amounts of contrast enhancement were examined in light microscopy. Results from these experiments were compared to data from previous studies that used ultrasound frequencies between 0.26 and 1.63 MHz. We found that the BBB disruption threshold (value where the probability for disruption was estimated to be 50%) expressed in terms of the peak negative pressure amplitude increased as a function of the frequency. It appeared to be constant, however, when the exposures were expressed as a function of the mechanical index (peak negative pressure amplitude estimated in situ divided by square root of frequency). Regression of data from all frequencies resulted in an estimated mechanical index threshold of 0.46 (95% confidence intervals: 0.42-0.50). Histological examination of representative samples with similar amounts of blood-brain barrier disruption found that the number of regions containing extravasated red blood cells per unit area was substantially lower on average for lower ultrasound frequencies. This data suggests that the mechanical index is a meaningful metric for ultrasound-induced blood-brain barrier disruption, at least for when other parameters that are not taken into account by the mechanical index are not varied. It also suggests that lower frequency sonication produces less red blood cell extravasation per unit area.

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Section: Introductionmentioning

confidence: 99%

Blood-Brain Barrier Disruption Induced by Focused Ultrasound and Circulating Preformed Microbubbles Appears to Be Characterized by the Mechanical Index

McDannold

Vykhodtseva

Hynynen

2008

Ultrasound in Medicine & Biology

246

199

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“…However, these large molecule drugs do not cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo (Pardridge, 2001). Certain large molecules in blood, such as insulin, do cross the BBB via a process of receptor-mediated transcytosis (RMT).…”

Section: Introductionmentioning

confidence: 99%

Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier

Boado

Zhang

et al. 2006

Biotech & Bioengineering

186

138

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A murine monoclonal antibody (MAb) to the human insulin receptor (HIR) has been engineered for use as a brain drug delivery system for transport across the human blood-brain barrier (BBB). The HIRMAb was humanized by complementarity determining region (CDR) grafting on the framework regions (FR) of the human B43 IgG heavy chain and the human REI kappa light chain. A problem encountered in the humanization process was the poor secretion of the CDR-grafted HIRMAb by myeloma cells. This problem was solved by the production of human/mouse hybrids of the engineered heavy chain variable region (VH), which led to the replacement of five amino acids in the FR3 of the VH with original murine amino acids. No replacement of FR amino acids in the light chain variable region (VL) was required. The affinity of the humanized HIRMAb for the HIR was decreased 27% relative to the murine HIRMAb. The humanized HIRMAb avidly bound to the HIR of isolated human brain capillaries, which are used as an in vitro model system of the human BBB. The HIRMAb cross reacts with the HIR of Old World primates such as the Rhesus monkey. The humanized HIRMAb was radiolabeled with 125-iodine, and injected intravenously into an adult, anesthetized Rhesus monkey. Brain scanning showed the humanized HIRMAb was rapidly transported into all parts of the primate brain after intravenous administration. The humanized HIRMAb may be used as a brain drug and gene delivery system for the targeting of large molecule therapeutics across the BBB in humans.

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“…Due to their poor stability in biological fluids, rapid enzymatic degradation, unfavorable pharmacokinetic properties, and lack of diffusion toward the CNS, they may be advantageously formulated in brain-targeted protective nanocontainers. 5 Compared with conventional drugs, they possess a high intrinsic pharmacological activity. The small dose requested for therapeutic efficiency could easily fit the loading capacity of nanoparticles and would not require the administration of large amount of potentially toxic nanoparticle excipient.…”

Section: Introductionmentioning

confidence: 99%

Drug transport to brain with targeted nanoparticles

2005

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Summary: Nanoparticle drug carriers consist of solid biodegradable particles in size ranging from 10 to 1000 nm (50 -300 nm generally). They cannot freely diffuse through the bloodbrain barrier (BBB) and require receptor-mediated transport through brain capillary endothelium to deliver their content into the brain parenchyma. Polysorbate 80-coated polybutylcyanoacrylate nanoparticles can deliver drugs to the brain by a still debated mechanism. Despite interesting results these nanoparticles have limitations, discussed in this review, that may preclude, or at least limit, their potential clinical applications. Long-circulating nanoparticles made of methoxypoly(ethylene glycol)-polylactide or poly(lactide-co-glycolide) (mPEG-PLA/ PLGA) have a good safety profiles and provide drug-sustained release. The availability of functionalized PEG-PLA permits to prepare target-specific nanoparticles by conjugation of cell surface ligand. Using peptidomimetic antibodies to BBB transcytosis receptor, brain-targeted pegylated immunonanoparticles can now be synthesized that should make possible the delivery of entrapped actives into the brain parenchyma without inducing BBB permeability alteration. This review presents their general properties (structure, loading capacity, pharmacokinetics) and currently available methods for immunonanoparticle preparation.

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Blood-Brain Barrier Drug Targeting: The Future of Brain Drug Development

Cited by 642 publications

References 47 publications

Blood-Brain Barrier Disruption Induced by Focused Ultrasound and Circulating Preformed Microbubbles Appears to Be Characterized by the Mechanical Index

Blood-Brain Barrier Disruption Induced by Focused Ultrasound and Circulating Preformed Microbubbles Appears to Be Characterized by the Mechanical Index

Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier

Drug transport to brain with targeted nanoparticles

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