Drug delivery to the central nervous system by polymeric nanoparticles: What do we know?

doi:10.1016/j.addr.2013.08.008

Advanced Drug Delivery Reviews

Volume 71, May 2014, Pages 2-14

https://doi.org/10.1016/j.addr.2013.08.008 Get rights and content

Abstract

Nanoparticles enable the delivery of a great variety of drugs including anticancer drugs, analgesics, anti-Alzheimer's drugs, cardiovascular drugs, protease inhibitors, and several macromolecules into the brain after intravenous injection of animals. The mechanism of the nanoparticle-mediated drug transport across the BBB appears to be receptor-mediated endocytosis followed by transcytosis into the brain or by drug release within the endothelial cells. Modification of the nanoparticle surface with covalently attached targeting ligands or by coating with certain surfactants that lead to the adsorption of specific plasma proteins after injection is necessary for this receptor-mediated uptake. A very critical and important requirement for nanoparticulate brain delivery is that the employed nanoparticles are biocompatible and, moreover, rapidly biodegradable, i.e. over a time frame of a few days. In addition to enabling drug delivery to the brain, nanoparticles, as with doxorubicin, may importantly reduce the drug's toxicity and adverse effects due to an alteration of the body distribution. Because of the possibility to treat severe CNS diseases such as brain tumours and to even transport proteins and other macromolecules across the blood–brain barrier, this technology holds great promise for a non-invasive therapy of these diseases.

Graphical abstract

Introduction

The blood–brain barrier (BBB) represents an insurmountable obstacle for most drugs, including neurological drugs, cytostatics, antibiotics, etc. One efficient possibility to deliver drugs including peptides [1], [2], [3] and even macromolecules [4] across this barrier is the employment of polymeric nanoparticles. This possibility was recently summarised in a short review in this journal [5]. Unfortunately, previous reviews frequently cite similar references and highlight similar points, often for studies that are repetitive or incremental over time. Focus on increasingly important pharmacological effects achieved with nanoparticle-based delivery as well as studies regarding mechanisms of nanoparticle-mediated drug transport are not often analysed. This review seeks to achieve this goal.

The above mentioned reports [1], [2], [3] demonstrate that overcoating of drug-loaded biodegradable poly(butyl cyanoacrylate) nanoparticles with certain surfactants such as polysorbate 80 (Tween® 80) or poloxamer 188 (Pluronic® F68) yields significant dose- and time-dependent [6] pharmacological effects in the CNS after intravenous injection into mice and also rats, whereas all the controls, including drug solution, empty nanoparticles, polysorbate 80 solution, simple mixtures of the components, i.e. nanoparticles, drug, and polysorbate 80, or uncoated drug-loaded nanoparticles did not achieve such effects [7]. These results clearly showed that the drugs indeed were transported across the BBB by the polysorbate-coated particles [1], [8]. Similar results were obtained by overcoating of the poly(butyl cyanoacrylate) nanoparticles with polysorbate 20, 40, or 60 whereas a large number of other surfactants were not able to achieve a delivery across the BBB [9]. Alternative to poly(butyl cyanoacrylate), polylactic acid and polylactic acid-polyglycolic acid copolymers [10], [11] as well as albumin [12] and chitosan [13], [14] also can be used as nanoparticle materials.

Given these in vivo results demonstrating efficiency with particle-based penetration of the BBB using translatable drug delivery methods, new important questions remain to be addressed. These include: 1) the mechanism of nanoparticle-mediated drug transport across the BBB, and, 2) closely related to this, the influence of the surface properties and of targeting ligands, 3) the amount of drug that can be transported by this pathway in order to achieve a pharmacological effect, and 4) the aspect of toxicity. This review attempts to critically evaluate past in vivo results with a deliberate effort to identify mechanisms that might lead to new delivery breakthroughs, as well as to highlight key features of particle-based systems and approaches that seem to penetrate the BBB.

Section snippets

Definition of nanoparticles and particle size influence

This review follows the classical definition of nanoparticles in the Encyclopedia of Pharmaceutical Technology [15] and in the Encyclopedia of Nanoscience and Nanotechnology [16] which was formulated already 40 years ago [17]:

Nanoparticles for pharmaceutical purposes are solid colloidal particles ranging in size from 1 to 1000 nm (1 μm) consisting of macromolecular materials in which the active principle (drug or biologically active material) is dissolved, entrapped, or encapsulated, or to which

Mechanism of nanoparticle-mediated uptake of drugs into the brain

About eight possibilities exist for the mechanism of uptake of nanoparticles and of bound drugs into the brain that were proposed in an earlier review in this journal [2], [21]:

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 increase the transport across the endothelial cell layer and as a result enhance the delivery to the brain.
2.
The polysorbate 80 used as

Types of nanoparticle polymers

As stated in a recent review by Wohlfart et al. [3], an important major requirement for nanoparticulate brain delivery systems is that they are rapidly biodegradable, i.e. over a time frame of not more than a few days. Non-degradable particles such as fullerenes, metal particles, toxic systems such as quantum dots, or potentially risky needle-shaped delivery systems such as carbon nanotubes, which may have hazardous effects similar to asbestos, therefore, are not useful. Likewise, silica

Influence of the surface properties

As discussed in Section 3, the surface properties of the nanoparticles play the paramount role for the ability of the particles to deliver drugs to the brain. Apart from polysorbate 80, also polysorbate 20, 40, and 60 [9], [28] and poloxamer 188 [10], [11] were able to achieve antinociceptive effects in mice after binding of dalargin following intravenous injection, whereas other surfactants such as poloxamers 184, 338, 407, poloxamine 908, Cremophor® EZ, Cremophor® RH 40, and

Targeting ligands

In Section 3 the importance of apolipoprotein A-I, B, or E adsorptive binding or covalent attachment for the nanoparticle-mediated drug delivery to the brain was described. These ligands interact either with the scavenger receptor class B type I (SR-BI) (apo A-I) [42], [43] or with the LDL receptor (LRP1) (apo E and B) [44]. However, there exist a lot of other receptors that transport peptides and large molecules across the BBB [74], [75], [76]. One possibility is to use the transferrin

Quantification of the in vivo uptake into the brain

Several in vivo techniques have been developed to study and measure the uptake of CNS compounds into the brain which were discussed in detail by van Roy et al. [89]. With these techniques, various parameters can be determined after drug administration, including the blood-to-brain influx constant (Kin), the permeability-surface area (PS) product, and the brain uptake index (BUI). For nanoparticles the best methods appear to be capillary depletion [90] and microdialysis: The latter two

In vitro–in vivo correlation, route of administration

In vitro no fundamental difference appeared in the ability of brain endothelial cells to take up polysorbate 80-coated nanoparticles between cells of mammalian origin including human [33], bovine [33], porcine [34], rat [33], and mice endothelial cells [26], [44]. However, some important differences can be observed between in vitro and in vivo: In vivo only single particles were observed in the brain capillary endothelial cells whereas in vitro in the mouse cell line b.End3 cells [26] as well

Drugs that were transported across the BBB

A considerable number of drugs so-far have been transported into the brain across the blood–brain barrier using nanoparticles. These drugs include anticancer drugs, analgesics, cardiovascular drugs, protease inhibitors, several macromolecules, and others. The majority of these drugs are listed in Table 1 which is an extended and updated version of a table in a recent review by Wohlfart et al. [3]. In principle nanoparticles seem to enable the brain drug delivery of all sorts of compounds if a

Toxicity

The toxicity of empty as well as doxorubicin-loaded poly(butyl cyanoacrylate) nanoparticles and of doxorubicin control solutions was investigated in a number of studies in normal and also in glioma 101/8-bearing rats [7], [140], [141], [142]. Doses up to 400 mg/kg of empty nanoparticles did not cause any mortality within the period of observation (30 days) nor did they affect body weight or weight of internal organs after intravenous injection. Higher doses cannot be administered intravenously by

Conclusions

Nanoparticles were shown to enable the delivery of a great variety of drugs into the brain after intravenous injection in animals. These drugs include analgesics, anti-Alzheimer's drugs, cardiovascular drugs, protease inhibitors, and most importantly, anticancer drugs and several macromolecules. At the moment, it appears that any drug or larger biologically active compound or complex can be transported across the BBB if it can be efficiently bound to the BBB-transcytosable nanoparticles and is

Acknowledgements

The author wishes to thank Dr. Gelperina, Nanosytem Ltd., Moscow, Russia, for carefully reading the manuscript and for valuable suggestions.

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Drug delivery to the central nervous system by polymeric nanoparticles: What do we know?☆

Abstract

Graphical abstract

Introduction

Section snippets

Definition of nanoparticles and particle size influence

Mechanism of nanoparticle-mediated uptake of drugs into the brain

Types of nanoparticle polymers

Influence of the surface properties

Targeting ligands

Quantification of the in vivo uptake into the brain

In vitro–in vivo correlation, route of administration

Drugs that were transported across the BBB

Toxicity

Conclusions

Acknowledgements

Brain Res.

Adv. Drug Deliv. Rev.

J. Control. Release

Adv. Drug Deliv. Rev.

J. Control. Release

Eur. J. Pharm. Biopharm.

Int. J. Pharm.

Adv. Drug Deliv. Rev. Suppl.

J. Control. Release

Int. J. Pharm.

J. Biol. Chem.

J. Control. Release

J. Control. Release

J. Biol. Chem.

Eur. J. Pharm. Biopharm.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

Biomaterials

J. Pharm. Sci.

Life Sci.

Int. J. Pharm.

J. Control. Release

Pharmacol. Ther.

Adv. Drug Deliv. Rev.

Methods Enzymol.

Eur. J. Pharm. Biopharm.

Neurobiol. Dis.

J. Control. Release

Biomaterials

J. Control. Release

Biomaterials

J. Control. Release

Int. J. Pharm.

Biomaterials

Biomaterials

Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles

J. Drug Target

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Chronobiol. Int.

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Pharm. Res.

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PLoS One

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Nanoparticles as drug delivery systems

Nanoparticles and nanocapsules — new dosage forms in the nanometer size range

Pharm. Acta Helv.

Phagocytosis and degradation of human serum albumin microspheres and nanoparticles in human macrophages

J. Microencapsul.

Specific delivery of mitomycin C to the liver, spleen and lung: nano- and microsperical carriers of gelatin

Int. J. Pharm.