A new look at cerebrospinal fluid circulation (original) (raw)

Delivery of peptides into the central nervous system

Drug Discovery Today, 1996

Research into the delivery of potentially useful peptide therapeutic agents to the CNS has lagged behind the exponential growth in their discovery. There remain many problems in developing effective and safe delivery strategies, but there has been some progress in overcoming this major obstacle. The author provides an overview of those properties of the blood-brain barrier that are specific for peptides and outlines current methods addressing peptide drug delivery to the CNS.

Peptides: Important tools for the treatment of central nervous system disorders

Neuropeptides, 2011

This review shows some classical applications of peptides and suggests there is great promise for the treatment of various central nervous system diseases. Actually, peptides are considered the new generation of biologically active tools because they are key regulators in cellular and intercellular physiological responses, which possess enormous potential for the treatment of various diseases. In spite of their clinical potential, native peptides have seen limited use due to their poor bioavailability and low stability in physiological conditions. Moreover, most peptide or protein pharmaceuticals currently in use are delivered by invasive routes such as via subcutaneous injection. Considerable efforts have been made to design new drugs based on peptides and recent developments in technology and science have provided the means and opportunity to produce a stable as well as controlled-release form of peptide and protein drugs to combat poorly controlled diseases and to increase patients' quality of life. A major challenge in this regard, however, is the delivery of peptides over the blood-brain barrier. This review gives an overview of some strategies used to improve both bioavailability and uptake of peptide drugs for delivery into the brain. Indeed, recent findings suggest that the use of peptides by conjugation to a polymer such as nanoparticles can offer tremendous hope in the treatment of brain disorders. The polymer conjugation improves pharmacokinetics by increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes. These new strategies will create new opportunities for the future development of neurotherapeutic drugs. In the present review we have focused our attention on the peptide controlled delivery, summarizing literature reports on the use of peptides and nanotechnology for the treatment and diagnosis of brain disorders.

Peptide delivery into the central nervous system: invasive, physiological and chemical approaches

Expert Opinion on Therapeutic Patents, 1997

The capillary endothelium of the brain and spinal cord possesses tight junctions and, thus, behaves as a continuous lipid bilayer that prevents the passage of highly polar and lipid-insoluble substances. Highly active enzymes expressed in the brain endothelial cells and cerebral pericytes also represent a metabolic component that contributes to the homeostatic balance of the central nervous system (CNS). Peptides cannot enter the brain and spinal cord from the circulating blood because they are highly polar and lipid insoluble, metabolically unstable, and generally do not have active transport systems in this membranous barrier. Hence, the blood-brain barrier (BBB) is the major obstacle to peptide-based therapeutics that are potentially useful for combating diseases affecting the central nervous system. The article discusses invasive, physiologicalbased and chemical-enzymatic approaches to overcome the BBB by reviewing both primary and patent literature.

Peptide transport and delivery into the central nervous system

Hypo- or hypersecretion, alteration in storage, release, catabolism, and post-translational processing of neuropeptides are associated with the etiology of many diseases affecting the central nervous system (CNS). Various peptides native to the brain and the spinal cord, as well as various synthetic peptides, peptide analogues and peptidomimetics developed as their agonists or antagonists could be useful in the treatment of these CNS maladies. However, peptides face a formidable obstacle in reaching the intended site of action due to the existence of the blood-brain barrier (BBB), a vital element in the regulation of the internal environment of the brain and the spinal cord. After reviews on the role and neuropharmaceutical potential of peptides, properties of the BBB in the context of peptide transport in the CNS and potential transport mechanisms to cross the BBB, this volume discusses the development, present state-of-the-art and future trends of various strategies to overcome th...

Identification and Design of Peptides as a New Drug Delivery System for the Brain

Journal of Pharmacology and Experimental Therapeutics, 2007

By controlling access to the brain, the blood-brain barrier (BBB) restricts the entry of proteins and potential drugs to cerebral tissues. We demonstrate here the transcytosis ability of aprotinin and peptides derived from Kunitz domains using an in vitro model of the BBB and in situ brain perfusion. Aprotinin transcytosis across bovine brain capillary endothelial cell (BBCEC) monolayers is at least 10-fold greater than that of holo-transferrin. Sucrose permeability was unaffected by high concentrations of aprotinin, indicating that transcytosis of aprotinin was unrelated to changes in the BBCEC monolayer integrity. Alignment of the amino acid sequence of aprotinin with the Kunitz domains of human proteins allowed the identification and design of a family of peptides, named Angiopeps. These peptides, and in particular Angiopep-2, exhibit higher transcytosis capacity and parenchyma accumulation than aprotinin. Overall, these results suggest that these Kunitz-derived peptides could be advantageously used as a new brain delivery system for pharmacological agents that do not readily enter the brain. Fig. 8. Effect of excess Angiopep-2 on its brain V d . A, V d in the brain was measured for 0.025 M 125 I-Angiopep with and without 0.5 and 10 M unlabeled Angiopep-2. Data represent the means Ϯ S.D. obtained from the perfusion of at least five mice. ‫,ء‬ p Ͻ 0.01 and ‫,ءء‬ p Ͻ 0.001, significant difference compared with 0.025 M 125 I-Angiopep-2 using one-way analysis of variance). B, V d in the brain was also measured for 0.025 M 125 I-Angiopep in the absence (control) or in the presence of 10 M aprotinin. Data represent the means Ϯ S.D. obtained from the perfusion of 10 mice for the control and three for aprotinin. ‫,ء‬ p Ͻ 0.02. 1072 Demeule et al. at ASPET Journals on September 4, 2016 jpet.aspetjournals.org Downloaded from

Delivery of peptides and proteins through the blood–brain barrier

Advanced Drug Delivery Reviews, 2001

Peptide and protein therapeutics are generally excluded from transport from blood to brain, owing to the negligible permeability of these drugs to the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo. However, peptides or protein therapeutics may be delivered to the brain with the use of the chimeric peptide strategy for peptide drug delivery. Chimeric peptides are formed when a non-transportable peptide therapeutic is coupled to a BBB drug transport vector. Transport vectors are proteins such as cationized albumin, or the OX26 monoclonal antibody to the transferrin receptor; these proteins undergo absorptive-mediated and receptor-mediated transcytosis through the BBB, respectively. In addition to vector development, another important element of the chimeric peptide strategy is the design of strategies for coupling drugs to the vector that give high efficiency coupling and result in the liberation of biologically active peptides following cleavage of the bond linking the therapeutic and the transport vector. The avidin / biotin system has been recently shown to be advantageous in fulfilling these criteria for successful linker strategies. The use of the OX26 monoclonal antibody, the use of the avidin / biotin system as a linker strategy, and the design of a vasoactive intestinal peptide (VIP) analogue that is suitable for monobiotinylation and retention of biologic activity following cleavage, allowed for the recent demonstration of in vivo pharmacologic effects in brain following the systemic administration of relatively low doses (12 mg / kg) of neuropeptide.

Delivery of peptide and protein drugs over the blood–brain barrier

Progress in Neurobiology, 2009

A B S T R A C T Peptide and protein (P/P) drugs have been identified as showing great promises for the treatment of various neurodegenerative diseases. A major challenge in this regard, however, is the delivery of P/P drugs over the blood-brain barrier (BBB). Intense research over the last 25 years has enabled a better understanding of the cellular and molecular transport mechanisms at the BBB, and several strategies for enhanced P/P drug delivery over the BBB have been developed and tested in preclinical and clinicalexperimental research. Among them, technology-based approaches (comprising functionalized nanocarriers and liposomes) and pharmacological strategies (such as the use of carrier systems and chimeric peptide technology) appear to be the most promising ones. This review combines a comprehensive overview on the current understanding of the transport mechanisms at the BBB with promising selected strategies published so far that can be applied to facilitate enhanced P/P drug delivery over the BBB. ß

Cell Permeable Peptides: A Promising Tool to Deliver Neuroprotective Agents in the Brain

Pharmaceuticals, 2010

The inability of most drugs to cross the blood-brain barrier and/or plasma membrane limits their use for biomedical applications in the brain. Cell Permeable Peptides (CPPs) overcome this problem and are effective in vivo, crossing the plasma membrane and the blood-brain barrier. CPPs deliver a wide variety of compounds intracellularly in an active form. In fact, many bioactive cargoes have neuroprotective properties, and due to their ability to block protein-protein interactions, offer exciting perspectives in the clinical setting. In this review we give an overview of the Cell Permeable Peptides strategy to deliver neuroprotectants against neurodegeneration in the CNS.

Peptide drug modifications to enhance bioavailability and blood-brain barrier permeability

Peptides, 2001

Peptides have the potential to be potent pharmaceutical agents for the treatment of many central nervous system derived maladies. Unfortunately peptides are generally water-soluble compounds that will not enter the central nervous system, via passive diffusion, due to the existence of the blood-brain barrier. Peptides can also undergo metabolic deactivation by peptidases, thus further reducing their therapeutic benefits. In targeting peptides to the central nervous system consideration must be focused both on increasing bioavailability and enhancing brain uptake. To date multiple strategies have been examined with this focus. However, each strategy comes with its own complications and considerations. In this review we assess the strengths and weaknesses of many of the methods currently being examined to enhance peptide entry into the central nervous system.