Nanotechnological advances for the delivery of CNS therapeutics☆
Graphical abstract
Introduction
Nanotechnology, in the context of nanomedicine, can be defined as the technologies for making nanocarriers of therapeutics and imaging agents, nanoelectronic biosensors, nanodevices, and microdevices with nanostructures. Unlike the definition in core nanotechnology field, which restricts the “nano” to at least 1–100 nm in one dimension, nanocarriers in the biomedical field are often referred to as particles with a dimension a few nanometers to 1000 nm. In fact, researchers in the biomedical field design nanocarriers for useful clinical applications and best therapeutic outcomes rather than fitting the particle dimension to the strict definition of nanotechnology. In other words, nanotechnology, when applied to biomedical and clinical applications, has a broader definition. Nevertheless, nanomedicine and nanotechnology share a common ground of basic science and technologies. The methods applied for characterization of nanostructured materials, particle size and surface properties of nanoparticles can also be employed to characterize nanocarriers. Many techniques for making nanomaterials, especially those bottom-up techniques such as chemical synthesis, self-assembly, and positional assembly methods [1], are used to prepare nanocarriers for delivering therapeutics and imaging agents.
Nanomedicine is generally defined as the application of nanotechnology in the clinical field. Unlike nanotechnology products intended for industrial applications, selection of starting materials for nanomedicine is stringent with the biosafety on the top list of considerations. There are two major medical applications of nanotechnology: i) medical imaging/diagnosis and ii) therapeutic delivery. The latter faces more challenges, in particular for delivery of therapeutics to the central nervous system (CNS), due to the strict requirements for therapeutic purpose. To achieve maximal therapeutic benefits, the carriers must be designed so that the drugs can be delivered to the target sites at the right time with an optimal level (available dose) and appropriate release kinetics. As discussed in this article, multiple physiological, pathological and cellular barriers must be overcome before an adequate drug dose can reach the site of action. The primary objective of this manuscript is to review the field of nanotechnology for CNS therapeutic applications.
Section snippets
Biological aspects in CNS drug delivery
The brain is a unique organ highly protected from the periphery by two major barriers, the blood–brain barrier (BBB) which displays the largest surface area (approximately 20 m2) and the blood–cerebrospinal fluid barrier (BCSFB). The BBB presents a wide permeability range, highly regulates intracellular and intercellular signaling pathways and overall maintains CNS homeostasis [2]. Several neuropathological conditions such as stroke, trauma, bacterial or viral infection, multiple sclerosis,
In vitro and ex vivo models
Various in vitro and ex vivo models established for the investigation of drug transport across the BBB [41], [42] can also be employed to study nanoparticle systems [43]. For details please see Ribeiro et al.'s review and references therein [44]. Fig. 3 summarizes the different types of in vitro BBB models that can be applied for nanocarrier evaluation. In general, three types of in vitro BBB models have been established: i) isolated brain capillaries (ex vivo model), ii) in vitro cell-based
Rationale for the use of CNS nanomedicine
Recent advances in nanotechnology have created exciting opportunities for the management of CNS diseases [see reviews [58], [59], [60]]. At present, a drug poorly distributed to the brain can be loaded on a nanocarrier system which interacts well with the endothelial microvessel cells at the BBB and produces higher drug concentrations in brain parenchyma. This nanocarrier can be further modified with targeting moieties to preferentially bind to putative receptors or transporters expressed at
Human immunodeficiency virus (HIV)
Upon primary infection, HIV can permeate into the CNS and actively replicate in brain macrophages and microglia. Since the majority of antiretroviral compounds are unable to achieve effective brain drug concentrations, HIV can eventually form an independent viral reservoir [123], [124] which leads to a high prevalence of neuropathologic abnormalities such as HIV-encephalitis and neurocognitive disorders. HIV in CNS reservoirs which is “protected” by the BBB from exposure to high antiretroviral
Active targeting strategies
Nanocarriers can cross the BBB via receptor-mediated transcytosis, but this process is often inefficient. By modifying these systems with “targeting molecules” such as monoclonal antibodies, cell-penetrating peptides and/or receptor substrates, their CNS delivery can be significantly improved. Table 2 lists some examples of nanocarriers and major findings of active CNS targeting strategies. Overall, significant improvement in CNS specificity and transcytosis efficiency has generally been
Major challenge: potential neurotoxicity of nanocarriers
The CNS is an organ highly protected from xenobiotic's exposure by the barrier structures. The ability of nanocarriers to cross these structures can therefore be viewed as a double-edged sword. While it enables efficient passage of therapeutic agents into the CNS compartment, it can also increase the risks of over-exposure to drugs and nanomaterials which can result in CNS toxicity.
Both in vitro and in vivo neurotoxic effects have been reported in studies examining nanocarriers. Table 4
Future perspectives and conclusions
Overall, nanotechnology can provide exciting opportunities for improved therapeutic management of CNS diseases. This is particularly important considering that the pharmaceutical industry is moving toward the development of high molecular weight biotechnology products, which normally cannot cross the BBB and could substantially benefit from the use of nanocarriers. However, this field is still in at the infant stage. Several issues should be resolved before CNS nanomedicine becomes useful in
Acknowledgements
Dr. Reina Bendayan is a recipient of a Career Scientist Award from the Ontario HIV treatment Network (OHTN), Ministry of Health of Ontario. This work is supported by operating grants from the Canadian Institutes of Health Research (MOP-56976) and OHTN, awarded to Dr. Bendayan.
References (211)
The blood–brain barrier in health and chronic neurodegenerative disorders
Neuron
(2008)The blood–brain barrier: bottleneck in brain drug development
NeuroRx
(2005)- et al.
Efflux transport systems for drugs at the blood–brain barrier and blood–cerebrospinal fluid barrier (Part 1)
Drug Discov. Today
(2001) - et al.
Efflux transport systems for drugs at the blood–brain barrier and blood–cerebrospinal fluid barrier (Part 2)
Drug Discov. Today
(2001) Potential role of ABC transporters as a detoxification system at the blood–CSF barrier
Adv. Drug Deliv. Rev.
(2004)- et al.
Two types of chloride channel in the apical membrane of rat choroid plexus epithelial cells
Brain Res.
(1992) - et al.
Active efflux across the blood–brain barrier: role of the solute carrier family
NeuroRx
(2005) - et al.
The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters
Trends Pharmacol. Sci.
(2010) - et al.
Binding and uptake of transferrin-bound liposomes targeted to transferrin receptors of endothelial cells
Vascul. Pharmacol.
(2002) - et al.
Combinational treatment with doxorubicin and GG918 (Elacridar) using polymer-lipid hybrid nanoparticles (PLN) and evaluation of strategies for multidrug-resistance reversal in human breast cancer cells
J. Control. Release
(2006)
Electron microscopic analysis of nanoparticles delivering thioflavin-T after intrahippocampal injection in mouse: implications for targeting β-amyloid in Alzheimer's disease
Neurosci. Lett.
Nanotechnology applications for improved delivery of antiretrovirals (ARVs) to the brain in HIV Infection
Adv. Drug Deliv. Rev.
Chemotherapy with anticancer drugs encapsulated in solid lipid nanoparticles
Adv. Drug Deliv. Rev.
Sustained release of dexamethasone from hydrophilic matrices using PLGA nanoparticles for neural drug delivery
Biomaterials
Transport of Poly(n-butylcyano-acrylate) nanoparticles across the blood–brain barrier in vitro and their influence on barrier integrity
Biochem. Biophys. Res. Commun.
Influence of particle size on transport of methotrexate across blood–brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles
Int. J. Pharm.
Double-coated poly(butylcynanoacrylate) nanoparticulate delivery systems for brain targeting of dalargin via oral administration
J. Pharm. Sci.
Effect of nanoparticulate polybutylcyanoacrylate and methylmethacrylate-sulfopropylmethacrylate on the permeability of zidovudine and lamivudine across the in vitro blood–brain barrier
Int. J. Pharm.
Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration
J. Control. Release
Lipid nanocapsules: a new platform for nanomedicine
Int. J. Pharm.
Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways
J. Pharm. Sci.
Pharmacokinetics of doxorubicin incorporated in solid lipid nanospheres (SLN)
Pharm. Res.
Baclofen-loaded solid lipid nanoparticles: preparation, electrophysiological assessment of efficacy, pharmacokinetic and tissue distribution in rats after intraperitoneal administration
Eur. J. Pharm. Biopharm.
Tailoring nanostructured solid-lipid carriers for time-controlled intracellular siRNA kinetics to sustain RNAi-mediated chemosensitization
Biomaterials
Solid lipid nanoparticles for brain tumors therapy: State of the art and novel challenges
Colloidal systems for CNS drug delivery
Liposome entrapped phenytoin locally suppresses amygdaloid epileptogenic focus created by db-cAMP/EDTA in rats
Brain Res.
The Royal Society & The Royal Academy of Engineering, Chapter 4. Nanomanufacturing and the industrial application of nanotechnologies
Engaging neuroscience to advance translational research in brain barrier biology
Nat. Rev. Neurosci.
Blood–brain barrier-specific properties of a human adult brain endothelial cell line
FASEB J.
Astrocyte-endothelial interactions and blood–brain barrier permeability
J. Anat.
Astrocyte-endothelial interactions at the blood–brain barrier
Nat. Rev. Neurosci.
The blood–brain barrier/neurovascular unit in health and disease
Pharmacol. Rev.
Functional expression and localization of p-glycoprotein at the blood brain barrier
Microsc. Res. Tech.
In situ localization of p-glycoprotein (ABCB1) in human and rat brain
J. Histochem. Cytochem.
The blood–brain barrier and cancer: transporters, treatment, and Trojan horses
Clin. Cancer Res.
Drug resistance in brain diseases and the role of drug efflux transporters
Nat. Rev. Neurosci.
Regulation of ABC membrane transporters in glial cells: relevance to the pharmacotherapy of brain HIV-1 Infection
Glia
Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development
Pharm. Res.
Multidrug Resistance Protein (MRP) 4- and MRP 5-mediated efflux of 9-(2-phosphonylmethoxyethyl)adenine by microglia
J. Pharmacol. Exp. Ther.
HIV-1 viral envelope glycoprotein Gp120 produces oxidative stress and regulates the functional expression of multidrug resistance protein-1 (MRP1) in glial cells
J. Neurochem.
Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line
J. Neurosci. Res.
Multidrug resistance-associated proteins: expression and function in the central nervous system
Pharmacol. Rev.
The mammalian choroid plexus
Sci. Am.
The entry of antiviral and antiretroviral drugs into the central nervous system
J. Neurovirol.
The choroid plexuses and the barriers between the blood and the cerebrospinal fluid
Cell. Mol. Neurobiol.
Antiretroviral drugs and the central nervous system
AIDS
The mechanism of drainage of the cerebrospinal fluid
Brain
Barrier mechanisms in the brain, I. adult brain
Clin. Exp. Pharmacol. Physiol.
The rat blood–brain barrier transcriptome
J. Cereb. Blood Flow Metab.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of therapeutics to the central nervous system”.