Nanoparticulate systems for brain delivery of drugs

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Abstract

The blood–brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics, antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, especially neuropeptides. One of the possibilities to overcome this barrier is a drug delivery to the brain using nanoparticles. Drugs that have successfully been transported into the brain using this carrier include the hexapeptide dalargin, the dipeptide Kyotorphin, loperamide, tubocurarine, the NMDA receptor antagonist MRZ 2/576, and doxorubicin. The nanoparticles may be especially helpful for the treatment of the disseminated and very aggressive brain tumors. Intravenously injected doxorubicin-loaded polysorbate 80-coated nanoparticles were able to lead to a 40% cure in rats with intracranially transplanted glioblastomas 101/8. The mechanism of the nanoparticle-mediated transport of the drugs across the blood–brain barrier at present is not fully elucidated. The most likely mechanism is endocytosis by the endothelial cells lining the brain blood capillaries. Nanoparticle-mediated drug transport to the brain depends on the overcoating of the particles with polysorbates, especially polysorbate 80. Overcoating with these materials seems to lead to the adsorption of apolipoprotein E from blood plasma onto the nanoparticle surface. The particles then seem to mimic low density lipoprotein (LDL) particles and could interact with the LDL receptor leading to their uptake by the endothelial cells. After this the drug may be released in these cells and diffuse into the brain interior or the particles may be transcytosed. Other processes such as tight junction modulation or P-glycoprotein (Pgp) inhibition also may occur. Moreover, these mechanisms may run in parallel or may be cooperative thus enabling a drug delivery to the brain.

Introduction

The blood–brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics, antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, especially neuropeptides. This barrier is formed at the level of the endothelial cells of the cerebral capillaries and essentially comprises the major interface between the blood and the brain. A barrier function also occurs at the arachnoid membrane and in the ependymal cells surrounding the circumventricular organs of the brain [1], [2]. It is a vital element in the regulation of the constancy of the internal environment of the brain. The composition of the extracellular fluid of the brain is controlled within precise limits, largely independently of the composition of the circulating blood, to provide a stable environment in which the integrative neuronal functions of the brain can optimally take place [3]. The brain blood vessel endothelial cells are characterized by having tight continuous circumferential junctions between them thus abolishing any aqueous paracellular pathways between these cells [4]. The presence of the tight junctions and the lack of aqueous pathways between cells greatly restricts the movement of polar solutes across the cerebral endothelium [3].

Passive diffusion of substances across the brain endothelial cells may occur and is dependent on lipophilicity and molecular weight. However, a large number of drugs that possess a favourable lipophilicity that normally should enable an easy transport across these cells are rapidly pumped back into the blood stream by extremely effective efflux pumps [3]. These pump systems include multiple organic anion transporter (MOAT) and especially P-glycoprotein (Pgp) sometimes referred to as multidrug resistance protein (mdr).

A number of attempts have been made to overcome the above barrier including osmotic opening of the tight junctions [5], use of prodrugs or carrier systems such as antibodies [6], liposomes [7], [8], [9], and nanoparticles. The opening of the tight junctions by osmotic pressure, however, is a very invasive procedure that also enables the entry of unwanted substances into the brain. Prodrugs take advantage of a higher lipophilicity enabling a better penetration and transport into and across the lipophilic endothelial barrier and/or of a circumvention of the efflux-pump systems, but often the prodrug approach is not possible. The colloidal carriers, on the other hand, may take advantage of the biochemical transport systems that are also present in the BBB: The brain is dependent on the blood to deliver substrates as well as to remove metabolic waste. For this reason, carrier-mediated transport systems exist that enable the entry or the elimination of a variety of compounds including hydrophilic substances such as hexoses, amino acids, purine compounds, and mono-carbonic substances as well as lipoproteins including low density lipoprotein (LDL) [10], [11]. Among these systems, for instance, the LDL-receptor and the transferrin transcytosis systems may be employed in the delivery of drugs by the above particulate colloidal drug delivery systems.

Section snippets

In vivo brain drug delivery with nanoparticles

One of the possibilities to deliver drugs to the brain is the employment of nanoparticles. Nanoparticles are polymeric particles made of natural or artificial polymers ranging in size between about 10 and 1000 nm (1 μm) [12]. Drugs may be bound in form of a solid solution or dispersion or be adsorbed to the surface or chemically attached. Poly(butyl cyanoacrylate) nanoparticles represent the only nanoparticles that were so far successfully used for the in vivo delivery of drugs to the brain.

In vitro experiments with brain blood vessel endothelial cells

In vitro experiments using brain blood vessel endothelial cells were conducted to gain insight in the quantitation and possible mechanism of the nanoparticle-mediated transport of drugs into the brain. The first in vitro experiments employed poly(methyl-[2-14C]-methacrylate) nanoparticles [38]. These particles were overcoated with several surfactants and their uptake by bovine brain microvessel endothelial cells (BMEC) was measured. The BMECs were isolated from the grey matter of the cerebral

Mechanism of nanoparticle-mediated drug transport to the brain

A number of possibilities exist that could explain the mechanism of the delivery of the above mentioned substances across the BBB:

  • 1.

    An increased retention of the nanoparticles in the brain blood capillaries combined with an adsorption to the capillary walls. This could create a higher concentration gradient that would enhance the transport across the endothelial cell layer and as a result the delivery to the brain.

  • 2.

    A general surfactant effect characterized by a solubilization of the endothelial

Conclusions

Nanoparticles represent a tool to transport essential drugs across the BBB that normally are unable to cross this barrier. Drugs that have successfully been transported into the brain using this carrier include the hexapeptide dalargin, the dipeptide kytorphin, loperamide, tubocurarine, the NMDA receptor antagonist MRZ 2/576, and doxorubicin. The nanoparticles may be especially helpful for the treatment of the disseminated and very aggressive brain tumors. First promising results in this

Acknowledgements

The author wishes to thank Dr. Gelperina, Institute for Medical Ecology, Moscow, Russia, for carefully reading the manuscript and for valuable suggestions.

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    PII of original article: S0169-409X(00)00122-8. The article was originally published in Advanced Drug Delivery Reviews 47 (2001) 65–81.

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