Nanotechnological advances for the delivery of CNS therapeutics

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Abstract

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.

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.

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