Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases.
TL;DR: The low density lipoprotein receptor related protein (LRP) is the most adapted for such use with the engineered peptide compound (EPiC) platform incorporating the Angiopep peptide in new therapeutics the most advanced with promising data in the clinic.
About: This article is published in Neurobiology of Disease.The article was published on 2010-01-01. It has received 735 citations till now. The article focuses on the topics: Drug delivery to the brain & Nanoparticles for drug delivery to the brain.
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TL;DR: Two important aspects of nanomedicine, drug delivery and tissue engineering are discussed, highlighting the advances the authors have recently experienced, the challenges they are currently facing, and what they are likely to witness in the near future.
Abstract: The application of nanotechnology in medicine, referred to as nanomedicine, is offering numerous exciting possibilities in healthcare. Herein, we discuss two important aspects of nanomedicine, drug delivery and tissue engineering, highlighting the advances we have recently experienced, the challenges we are currently facing, and what we are likely to witness in the near future.
1,377 citations
TL;DR: This review will discuss the barrier issue from a biological and pathological perspective to provide a better insight to the challenges and opportunities associated with the BBB.
772 citations
TL;DR: The key issues in translating BDNF biology into synaptic repair therapies are reviewed, which pave the way for a 'synaptic repair' therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis.
Abstract: Synaptic dysfunction is a key pathophysiological hallmark in several neurodegenerative disorders. In this Review, Lu and colleagues consider a 'synaptic repair'-based therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis and discuss BDNF as a potential synaptic repair molecule.
589 citations
TL;DR: Recent evidence supporting important roles for astrocytes in neuropathological conditions such as neuroinflammation, amyotrophic lateral sclerosis and Alzheimer's disease is discussed and the potential for neuroprotective therapeutics based on the modulation of astroCytic functions is explored.
575 citations
TL;DR: The delivery of drugs, which usually are not able to cross the BBB, into the brain was confirmed by the biodistribution studies and pharmacological assays in rodents, and the presence of nanoparticles in the brain parenchyma was visualized by electron microscopy, suggesting that this technology holds great promise for non-invasive therapy of the CNS diseases.
558 citations
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TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
14,026 citations
TL;DR: This work has shown that the blood-brain barrier provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences.
Abstract: The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain ∼100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the brain capillary endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences.
2,226 citations
"Approaches to transport therapeutic..." refers background or methods or result in this paper
...○ Using the antibody approach against TR, the receptor specific mAb binds to the receptoron theendothelial cells, andallows theassociated therapeutic agent to cross the BBB via receptor-mediated transcytosis (Pardridge, 2003; Zhang and Pardridge, 2005)....
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...This result is similar to a slow intravenous infusion rather than a direct administration of drugs into the brain (Pardridge, 2005)....
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...Since almost every neuron in the brain is perfused by its own capillary as a result of the small distance separating capillaries (on average 40 μm) and the brain's very high perfusion rate (Pardridge, 2005 and 2007c)....
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TL;DR: Overall, a transporter has been developed that is superior to Tat(49-57), protease resistant, and more readily and economically prepared and suggest that the guanidinium groups of Tat( 49-57) play a greater role in facilitating cellular uptake than either charge or backbone structure.
Abstract: Certain proteins contain subunits that enable their active translocation across the plasma membrane into cells. In the specific case of HIV-1, this subunit is the basic domain Tat(49-57) (RKKRRQRRR). To establish the optimal structural requirements for this translocation process, and thereby to develop improved molecular transporters that could deliver agents into cells, a series of analogues of Tat(49-57) were prepared and their cellular uptake into Jurkat cells was determined by flow cytometry. All truncated and alanine-substituted analogues exhibited diminished cellular uptake, suggesting that the cationic residues of Tat(49-57) play a principal role in its uptake. Charge alone, however, is insufficient for transport as oligomers of several cationic amino acids (histidine, lysine, and ornithine) are less effective than Tat(49-57) in cellular uptake. In contrast, a 9-mer of l-arginine (R9) was 20-fold more efficient than Tat(49-57) at cellular uptake as determined by Michaelis-Menton kinetic analysis. The d-arginine oligomer (r9) exhibited an even greater uptake rate enhancement (>100-fold). Collectively, these studies suggest that the guanidinium groups of Tat(49-57) play a greater role in facilitating cellular uptake than either charge or backbone structure. Based on this analysis, we designed and synthesized a class of polyguanidine peptoid derivatives. Remarkably, the subset of peptoid analogues containing a six-methylene spacer between the guanidine head group and backbone (N-hxg), exhibited significantly enhanced cellular uptake compared to Tat(49-57) and even to r9. Overall, a transporter has been developed that is superior to Tat(49-57), protease resistant, and more readily and economically prepared.
1,710 citations
"Approaches to transport therapeutic..." refers background in this paper
...Poly-arginines (9 mer of L-Arg, R9) showed a very efficient cellular uptake 20× superior than TAT4957 and D-Arg oligomers (r9)N100 fold superior (Wender et al., 2000)....
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TL;DR: By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.
Abstract: For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules 111In-labeled transferrin (111In-Tf; M(r), 80,000) and [14C]sucrose (M(r), 359) over centimeter distances by maintaining a pressure gradient during interstitial infusion into white matter to generate bulk flow through the brain interstitium. The volume of distribution (Vd) containing > or = 1% concentration of infusion solution increased linearly with the infusion volume (Vi) for 111In-Tf(Vd/Vi, 6:1) and [14C]sucrose (Vd/Vi, 13:1). Twenty-four hours after infusion, the distribution of 111In-Tf was increased and more homogeneous, and penetration into gray matter had occurred. By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.
1,400 citations
"Approaches to transport therapeutic..." refers methods in this paper
...In contrast to the mm distances obtained with simple diffusion, CED has been shown in laboratory experiments to deliver high molecular weight proteins 2 cm from the injection site in the brain parenchyma after as little as 2 h of continuous infusion (Bobo et al., 1994)....
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TL;DR: The blood-brain barrier can be consistently opened with focused ultrasound exposures in the presence of a US contrast agent and MR imaging signal intensity changes may be useful in the detection of blood- brain barrier opening during sonication.
Abstract: PURPOSE: To determine if focused ultrasound beams can be used to locally open the blood-brain barrier without damage to surrounding brain tissue and if magnetic resonance (MR) imaging can be used to monitor this procedure. MATERIALS AND METHODS: The brains of 18 rabbits were sonicated (pulsed sonication) in four to six locations, with temporal peak acoustic power ranging from 0.2 to 11.5 W. Prior to each sonication, a bolus of ultrasonographic (US) contrast agent was injected into the ear vein of the rabbit. A series of fast or spoiled gradient-echo MR images were obtained during the sonications to monitor the temperature elevation and potential tissue changes. Contrast material–enhanced MR images obtained minutes after sonications and repeated 1–48 hours later were used to depict blood-brain barrier opening. Whole brain histologic evaluation was performed. RESULTS: Opening of the blood-brain barrier was confirmed with detection of MR imaging contrast agent at the targeted locations. The lowest power leve...
1,188 citations