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Advanced Drug Delivery Reviews (v.64, #7)

Editorial Board (pp. ii).

Delivery of therapeutics to the central nervous system by James J. Chambers (Guest Editor) (pp. 589-589).

Challenges in drug delivery to tumors of the central nervous system: An overview of pharmacological and surgical considerations by Laura P. Serwer; C. David James (pp. 590-597).

The majority of newly diagnosed brain tumors are treated with surgery, radiation, and the chemotherapeutic temozolomide. Development of additional therapeutics to improve treatment outcomes is complicated by the blood–brain barrier (BBB), which acts to protect healthy tissue from chemical insults. The high pressure found within brain tumors adds a challenge to local delivery of therapy by limiting the distribution of bolus injections. Here we discuss various drug delivery strategies, including convection-enhanced delivery, intranasal delivery, and intrathecal delivery, as well as pharmacological strategies for improving therapeutic efficacy, such as blood–brain barrier disruption.Display Omitted

Keywords: Convection-enhanced delivery; CED; Intrathecal; Intranasal; Glioma; Glioblastoma; Liposome; Chemotherapy

Guided delivery of adeno-associated viral vectors into the primate brain by Ernesto A. Salegio; Lluis Samaranch; Adrian P. Kells; John Forsayeth; Krystof Bankiewicz (pp. 598-604).

In this review, we discuss recent developments in the delivery of adeno-associated virus-based vectors (AAV), particularly with respect to the role of axonal transport in vector distribution in the brain. The use of MRI-guidance and new stereotactic aiming devices have now established a strong foundation for neurological gene therapy to become an accepted procedure in interventional neurology.Display Omitted

Keywords: Gene delivery; AAV; Non-human primate; MRI-guided delivery; Thalamus; Basal ganglia

Nanomaterial-mediated CNS delivery of diagnostic and therapeutic agents by Laura Biddlestone-Thorpe; Nicola Marchi; Kathy Guo; Chaitali Ghosh; Damir Janigro; Kristoffer Valerie; Hu Yang (pp. 605-613).

Research into the diagnosis and treatment of central nervous system (CNS) diseases has been enhanced by rapid advances in nanotechnology and an expansion in the library of nanostructured carriers. This review discusses the latest applications of nanomaterials in the CNS with an emphasis on brain tumors. Novel administration routes and transport mechanisms for nanomaterial-mediated CNS delivery of diagnostic and therapeutic agents to bypass or cross the blood brain barrier (BBB) are also discussed. These include temporary disruption of the BBB, use of impregnated polymers (polymer wafers), convection-enhanced delivery (CED), and intranasal delivery. Moreover, an in vitro BBB model capable of mimicking geometrical, cellular and rheological features of the human cerebrovasculature has been developed. This is a useful tool that can be used for screening CNS nanoparticles or therapeutics prior to in vivo and clinical investigation. A discussion of this novel model is included.Display Omitted

Keywords: Blood–brain barrier (BBB); Brain cancer; Central nervous system (CNS); Convection enhanced delivery (CED); Flow-based; in vitro; BBB model; Nanoparticle

Intranasal delivery of biologics to the central nervous system by Jeffrey J. Lochhead; Robert G. Thorne (pp. 614-628).

Treatment of central nervous system (CNS) diseases is very difficult due to the blood–brain barrier's (BBB) ability to severely restrict entry of all but small, non-polar compounds. Intranasal administration is a non-invasive method of drug delivery which may bypass the BBB to allow therapeutic substances direct access to the CNS. Intranasal delivery of large molecular weight biologics such as proteins, gene vectors, and stem cells is a potentially useful strategy to treat a variety of diseases/disorders of the CNS including stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease, epilepsy, and psychiatric disorders. Here we give an overview of relevant nasal anatomy and physiology and discuss the pathways and mechanisms likely involved in drug transport from the nasal epithelium to the CNS. Finally we review both pre-clinical and clinical studies involving intranasal delivery of biologics to the CNS.Display Omitted

Keywords: Abbreviations; Aβ; beta amyloid; ANG II; angiotensin II; AVP; arginine vasopressin; BBB; blood–brain barrier; ChAT; choline acetyltransferase; CNS; central nervous system; CSF; cerebrospinal fluid; EPO; erythropoietin; Ex; exendin; GALP; galanin-like peptide; GBC; globose basal cell; HBC; horizontal basal cell; HRP; horseradish peroxidase; IGF-1; insulin-like growth factor-1; INF-β1b; interferon β1b; IN; intranasal; IV; intravenous; MCAO; middle cerebral artery occlusion; MOG; myelin oligodendrocyte protein; MSC; mesenchymal stem cells; MW; molecular weight; NGF; nerve growth factor; OEC; olfactory ensheathing cell; OSN; olfactory sensory neuron; PACAP; pituitary adenylate cyclase-activating polypeptide; siRNA; small interfering RNA; TGF-β1; transforming growth factor β1; TJ; tight junctions; VEGF; vascular endothelial growth factor; V; ₁; ophthalmic division of trigeminal nerve; V; ₂; maxillary division of trigeminal nerve; V; ₃; mandibular division of trigeminal nerve; WGA-HRP; wheat germ agglutinin-horseradish peroxidase; ZO; zonula occludensDrug delivery; Nasal passage; Olfactory; Trigeminal; Proteins; Gene vectors; Stem cells

Drug delivery to the brain in Alzheimer's disease: Consideration of the blood–brain barrier by William A. Banks (pp. 629-639).

The successful treatment of Alzheimer's disease (AD) will require drugs that can negotiate the blood–brain barrier (BBB). However, the BBB is not simply a physical barrier, but a complex interface that is in intimate communication with the rest of the central nervous system (CNS) and influenced by peripheral tissues. This review examines three aspects of the BBB in AD. First, it considers how the BBB may be contributing to the onset and progression of AD. In this regard, the BBB itself is a therapeutic target in the treatment of AD. Second, it examines how the BBB restricts drugs that might otherwise be useful in the treatment of AD and examines strategies being developed to deliver drugs to the CNS for the treatment of AD. Third, it considers how drug penetration across the AD BBB may differ from the BBB of normal aging. In this case, those differences can complicate the treatment of CNS diseases such as depression, delirium, psychoses, and pain control in the AD population.Display Omitted

Keywords: Blood–brain barrier; Alzheimer's disease; Drug delivery; Cerebrospinal fluid; Biologicals; Peptides; Regulatory proteins; Transport; Transmembrane diffusion; P-glycoprotein

Modern methods for delivery of drugs across the blood–brain barrier by Yan Chen; Lihong Liu (pp. 640-665).

The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are essential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable, highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better understood, particularly under different pathological conditions. 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. Modern methods which can take advantage of these opportunities will be reviewed. Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, and finally cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective therapy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take into account BBB biology as well as the unique features associated with the pathological condition to be treated.Display Omitted

Keywords: Abbreviations; a; ₂; M; alpha-2 macroglobulin; Aβ; amyloid β; ABC; ATP binding cassette; AD; Alzheimer's disease; AIDS; autoimmunodeficiency syndrome; AJ; adherens junction; AMT; adsorptive-mediated transport; AMP; adenosine monophosphate; ANG1005; angiopep 2 conjugated with 3 molecules of paclitaxel; Antp; Antennapedia; APP; amyloid beta precursor protein; ApoE; Apolipoprotein E; ATP; adenosine triphosphate; AUC; area under curve; BBB; blood–brain barrier; BCSFB; blood–cerebrospinal fluid barrier; BSA-NP; bovine serum albumin conjugated nanoparticles; cAMP; cyclic AMP; CBSA; cationic bovine serum albumin; CBSA-NP; CBSA conjugated PEG-PLA nanoparticles; CED; convection enhanced diffusion; CHP; hydrophobic cholesterol groups; CMC; critical micelle concentration; CMT; carrier-mediated transport; CNS; central nervous system; CPP; cell penetrating peptide; CRM; cross reacting material; CSF; cerebrospinal fluid; DT; diphtheria toxin; DT; _R; diphtheria toxin receptor; EAE; experimental autoimmune encephalomyelitis; EO; ethylene oxide; EC; endothelial cell; EMF; electromagnetic fields; FBP; fusion sequence-based peptide; g7; similopioid peptide; GMP; guanosine monophosphate; HB-EGF; heparin binding epidermal growth factor; HIRMAb; human insulin receptor monoclonal antibody; HIV; human immunodeficiency virus; HLB; hydrophobic–hydrophilic balance; HSA; human serum albumin; HSP-96; heat shock protein 96; HUVEC; human umbilical vein endothelial cells; ICH; intercerebral haemorrhage; ICV; intracerebroventricular; IgG; immunoglobulin G; IL; interleukin; INF; interferon; JAM; junction adhesion molecules; LDL; low density lipoprotein; LDLR; low density lipoprotein receptor; Lf; lactoferrin; LMV; large multilamellar vesicles; LPA; lysophosphatidic acid; LRP; lipoprotein receptor protein; LUV; large unilamellar vesicles; MAP; model amphipathic peptide; MAPK; mitogen activated protein kinase; MCP; monocyte chemotactic protein; MHC; major histocompatibility complex; MLCK; myosin light chain kinase; MP; mononuclear phagocytes; MRP; multidrug resistant protein; MS; multiple sclerosis; NOS; nitric oxide syntheses; NP; nanoparticles; NVU; neurovascular unit; P97; melanotransferrin; PAI-1; plasminogen activator inhibitor 1; PHDCA; poly(hexadecylcyanoacrylate); PBCA; poly(butylcyanoacrylate); PEG; polyethylene glycol; PEG-PCL; PEG-polycaprolactone; PEG-G-CSF; PEGylated-recombinant methionyl human granulocyted colony stimulating factor; PEG-PLA; polyethylene glycol-polylactic acid; P-gp; P-glycoprotein; PKA; protein kinase A; PKC; protein kinase C; PKG; protein kinase G; PLGA; poly(; d,l; -lactide-co-glycolide); PO; propylene oxide; PTD; protein transduction domain; PTK; protein tyrosine kinase; Qdots; quantum dots; RAP; receptor associated protein; RES; reticuloendothelial system; REV; reverse phase evaporation vesicles; RMT; receptor-mediated transport; R123; rhodamine 123; SA; sialic acid residue; SBP; sequence signal-based peptide; SUV; small unilamellar vesicles; TAT; HIV-1 trans-activating transcriptor; TEM; transmission electron microscopy; TER; transendothelial electrical resistance; TfR; transferrin receptor; TJ; tight junction; TNF; tumour necrosis factors; tPA; tissue plasminogen activator; VE; vascular endothelial; VEGF; vascular endothelial growth factor; ZO; zonula occludensBlood–brain barrier; Drug delivery; Receptor-mediated transport; Cell-mediated transport; Nanoparticles; Liposomes; Pathological conditions

Prodrug approaches to reduce hyperexcitation in the CNS by Devaiah Vytla; Rosamund E. Combs-Bachmann; Amanda M. Hussey; Stephen T. McCarron; Devon S. McCarthy; James J. Chambers (pp. 666-685).

Hyperexcitation in the central nervous system is the root cause of a number of disorders of the brain ranging from acute injury to chronic and progressive diseases. The major limitation to treatment of these ailments is the miniscule, yet formidable blood–brain barrier. To deliver therapeutic agents to the site of desired action, a number of biomedical engineering strategies have been developed including prodrug formulations that allow for either passive diffusion or active transport across this barrier. In the case of prodrugs, once in the brain compartment, the active therapeutic agent is released. In this review, we discuss in some detail a number of factors related to treatment of central nervous system hyperexcitation including molecular targets, disorders, prodrug strategies, and focused case studies of a number of therapeutics that are at a variety of stages of clinical development.Display Omitted

Keywords: CNS prodrug; Hyperexcitation prodrug; Receptors; Targeting; Stroke; Alzheimer's disease

Nanotechnological advances for the delivery of CNS therapeutics by Ho Lun Wong; Xiao Yu Wu; Reina Bendayan (pp. 686-700).

Effective non-invasive treatment of neurological diseases is often limited by the poor access of therapeutic agents into the central nervous system (CNS). The majority of drugs and biotechnological agents do not readily permeate into brain parenchyma due to the presence of two anatomical and biochemical dynamic barriers: the blood–brain barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB). Therefore, one of the most significant challenges facing CNS drug development is the availability of effective brain targeting technology. Recent advances in nanotechnology have provided promising solutions to this challenge. Several nanocarriers ranging from the more established systems, e.g. polymeric nanoparticles, solid lipid nanoparticles, liposomes, micelles to the newer systems, e.g. dendrimers, nanogels, nanoemulsions and nanosuspensions have been studied for the delivery of CNS therapeutics. Many of these nanomedicines can be effectively transported across various in vitro and in vivo BBB models by endocytosis and/or transcytosis, and demonstrated early preclinical success for the management of CNS conditions such as brain tumors, HIV encephalopathy, Alzheimer's disease and acute ischemic stroke. Future development of CNS nanomedicines need to focus on increasing their drug-trafficking performance and specificity for brain tissue using novel targeting moieties, improving their BBB permeability and reducing their neurotoxicity.Display Omitted

Keywords: Abbreviations; ABC transporter; ATP-binding cassette membrane transporter; AD; Alzheimer's disease; ApoE; apolipoprotein E; BBB; blood–brain barrier; BCNU; 1,3-bis(2-chloroethyl)-1-nitrosourea; BCSFB; blood–cerebro spinal fluid barrier; BCRP; Breast Cancer Resistance Protein; CNS; central nervous system; CSF; cerebrospinal fluid; CT; computed X-ray tomography; EGF; epidermal growth factor; HIV; human immunodeficiency virus; LDL; low-density lipoprotein; MRI; magnetic resonance imaging; MRP; multidrug resistance-associated proteins; OAT; organic anion transporter; OATP; organic anion transporting polypeptide; PBCA; poly(butyl cyanoacryalate); PD; Parkinson's disease; PEG; polyethylene glycol; PET; positron emission tomography; P-gp; P-glycoprotein; PLA; polylactide; PLGA; poly(; d; ,; l; -lactide-co-glycolide); RES; reticuloendothelial system; ROS; reactive oxidative species; siRNA; small-interfering RNA; SLN; solid lipid nanoparticles; SOD; superoxide dismutase; SPECT; single-photon emission computed tomography; TAT; transcriptional activator; tPA; tissue plasminogen activatorCentral nervous system; Nanomedicine; Nanotechnology; Drug delivery; Blood–brain barrier; Brain targeting

Polymeric nanoparticles for drug delivery to the central nervous system by Toral Patel; Jiangbing Zhou; Joseph M. Piepmeier; W. Mark Saltzman (pp. 701-705).

The central nervous system (CNS) poses a unique challenge for drug delivery. The blood–brain barrier significantly hinders the passage of systemically delivered therapeutics and the brain extracellular matrix limits the distribution and longevity of locally delivered agents. Polymeric nanoparticles represent a promising solution to these problems. Over the past 40years, substantial research efforts have demonstrated that polymeric nanoparticles can be engineered for effective systemic and local delivery of therapeutics to the CNS. Moreover, many of the polymers used in nanoparticle fabrication are both biodegradable and biocompatible, thereby increasing the clinical utility of this strategy. Here, we review the major advances in the development of polymeric nanoparticles for drug delivery to the CNS.

Keywords: Nanoparticle; Polymer; Brain; Blood-brain barrier; Convection-enhanced delivery

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Advanced Drug Delivery Reviews (v.64, #7)