Magnetic nanoparticles for drug delivery

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22. Magnetic nanoparticles for drug delivery. Controlled release of drugs from nanostructured functional materials, especially nanoparticles (NPs), is attracting ...

Magnetic nanoparticles for drug delivery Controlled release of drugs from nanostructured functional materials, especially nanoparticles (NPs), is attracting increasing attention because of the opportunities in cancer therapy and the treatment of other ailments. The potential of magnetic NPs stems from the intrinsic properties of their magnetic cores combined with their drug loading capability and the biochemical properties that can be bestowed on them by means of a suitable coating. Here we review the problems and recent advances in the development of magnetic NPs for drug delivery, focusing particularly on the materials involved. Manuel Arruebo, Rodrigo Fernández-Pacheco, M. Ricardo Ibarra, and Jesús Santamaría* Nanoscience Institute of Aragon (INA), Pedro Cerbuna 12, University of Zaragoza, 50009 Zaragoza, Spain *E-mail: [email protected]

NPs are submicron moieties (between 1 nm and 100 nm according

coating that renders the particles biocompatible, stable, and may serve

to the usual definition, although there are examples of NPs

as a support for biomolecules. Their magnetic properties enable these

several hundreds of nanometers in size) made of inorganic or

particles to be used in numerous applications, belonging to one or

organic (e.g. polymeric) materials, which may or may not be

more of the following groups:

biodegradable. Their importance relates to the fact that the

(i) Magnetic contrast agents in magnetic resonance imaging (MRI)2;

characteristics of NPs are different from those of bulk materials of

(ii) Hyperthermia agents, where the magnetic particles are heated

the same composition, which is mainly because of size effects, the

selectively by application of an high frequency magnetic field.

magnetic and electronic properties, and the role played by surface

(e.g. in thermal ablation/hyperthermia of tumors3); and

phenomena as the size is reduced. Preparation methods for NPs generally fall into the category of socalled ‘bottom-up’ methods, where nanomaterials are fabricated from

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(iii) Magnetic vectors that can be directed by means of a magnetic field gradient towards a certain location, such as in the case of the targeted drug delivery4.

atoms or molecules in a controlled manner that is thermodynamically

The scientific community is seeking to exploit the intrinsic properties

regulated by means such as self-assembly1. Some biomedical

of magnetic NPs to obtain medical breakthroughs in diagnosis, and

applications require core-shell magnetic NPs. They consist of a metal

drug delivery. Perhaps the most promising applications relate to the

or metallic oxide core, encapsulated in an inorganic or a polymeric

diagnosis and treatment of cancer.

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Even though, according to the American Cancer Society, cancer deaths in the US have dropped for a second straight year, which is attributed to the decrease in smoking rates and to earlier detection and more effective treatment of tumors5, cancer is still one of the leading causes of death in developed countries. Conventional treatments, including surgery, radiation, chemotherapy, and biologic therapies (immunotherapy) are limited by the accessibility to the tumor, the risk of operating on a vital organ, the spread of cancer cells throughout the body, and the lack of selectivity toward tumor cells. Immunotherapy is still relatively recent, and is most likely to be applied to small tumors, since its effectiveness seems to decrease for more advanced stages of cancer. Multimodal therapy that uses radiotherapy, chemotherapy, immunotherapy, and other forms of treatment in combination with surgery provides a better chance of survival6. The potential of drug delivery systems based on the use of nanoand microparticles stems from significant advantages such as: (i) the ability to target specific locations in the body; (ii) the reduction of the quantity of drug needed to attain a particular concentration in the vicinity of the target; and (iii) the reduction of the concentration of the drug at nontarget sites7 minimizing severe side effects. All these benefits justify the exponential growth in the number of publications

Fig. 1 Temporal evolution in the number of scientific papers published involving drug delivery using NPs. (Source: ISI Web of Knowledge © The Thomson Corporation. Search terms: ‘drug delivery’ and ‘nanoparticles’. Date of search: December 2006.)

dealing with NPs for drug delivery applications (Fig. 1). NPs can act at the tissular or cellular level. The latter implies that

pore cut-off size between 380 nm and 780 nm, although vasculature

they can be endocytosed or phagocytosed (i.e. by dendritic cells,

organization may differ depending on the tumor type, its growth rate,

macrophages) resulting in internalization of the NP. In this process, the

and microenvironment9. Apart from tumors, size-dependent removal

NP can reach beyond the cytoplasmatic membrane and, in some cases,

of NPs is a common occurrence in healthy capillaries. Table 110 shows

also beyond the nuclear membrane (i.e. transfection applications).

the morphological pore sizes contributing to diffusive permeability

Tumor targeting with magnetic NPs may use passive or active

in the capillaries of the human vascular system. It can be seen that,

strategies. Passive targeting occurs as a result of extravasation of

from the delivery point of view, there is practically no limitation as

the NPs at the diseased site (tumor) where the microvasculature is

the diameters of typical NPs are well below that of the narrowest

hyperpermeable and leaky, a process aided by tumor-limited lymphatic

capillaries. Instead, the main limitation concerns the residence time

drainage. Combined, these factors lead to the selective accumulation

of NPs in the bloodstream. Thus, the use of conventional NPs for

of NPs in tumor tissue, a phenomenon known as enhanced permeation

drug delivery by passive targeting would be limited to tumors in

and retention (EPR)8. The majority of solid tumors exhibit a vascular

mononuclear phagocyte system (MPS) organs (liver, spleen, and bone

Table 1 Relevant sizes regarding particle distribution through and removal from the capillaries of the human vascular system. Size

System/Organ

Particle removal*

Tight-junction capillaries Continuous capillaries Fenestrated capillaries Sinusoidal capillaries

< 1 nm ~ 6 nm ~ 50-60 nm ~ 100-1000 nm

Central nervous system, blood-brain barrier Tissues such as muscle, skin, and lung Kidney, intestine, and some endocrine and exocrine glands Liver, spleen, and bone marrow

Particle delivery

Arteriole radius Artery radius Venule radius

0.005-0.07 mm 0.08-7.5 mm 8-100 µm

Circulatory system. Particles supplied by intravenous administration. Elimination involves opsonization and removal by monocytes in blood

*It is noted that this table expresses only the morphological pores contributing to diffusive permeability. Actual transcapillary exchanges are modified by vesicular transports, which are able to internalize particles with sizes up to 20-30 nm. (Adapted with permission from10. © 1999 Elsevier.)

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Magnetic nanoparticles for drug delivery

marrow). Addressing other tumoral tissues does not seem feasible

factor affecting the fate of NPs in passive targeting processes using the

without active targeting strategies because of the short circulation

permeability of the capillary vessels, as discussed above.

times involved and the low concentration of NPs that is achieved in

Here we shall concentrate on the therapeutic applications of

the tumor area (despite the EPR effect), leading to drug concentrations

magnetic drug targeting using NPs. Hyperthermia/thermal ablation

below the therapeutic level11.

will not be addressed, although the general implications between

Active targeting is based on the over or exclusive expression

both therapies based on magnetism can be inferred. Applications in

of different epitopes or receptors in tumoral cells, and on specific

diagnosis, where magnetic NPs are widely used as contrast agents, will

physical characteristics. Thus, vectors sensitive to physical stimuli (e.g.

not be addressed here either.

temperature, pH, electric charge, light, sound, magnetism) have been developed and conjugated to drugs. Alternatively, active targeting

Magnetic drug delivery

may be based on over-expressed species such as low molecular weight

The development of magnetic drug delivery

ligands (folic acid, thiamine, sugars), peptides (RGD, LHRD), proteins

Any overview on drug delivery should start with the deserved

(transferrin, antibodies, lectins), polysaccharides (hyaluronic acid),

recognition of Paul Ehrlich (1854-1915), who proposed that if an agent

polyunsaturated fatty acids, peptides, DNA, etc.

could selectively target a disease-causing organism, then a toxin for

Different moieties including dendrimers, micelles, emulsions, nanoparticulated drugs, and liposomes are used to target specific areas in the body (Fig.

2)12,13.

The NPs must be endowed with the

that organism could be delivered along with the agent of selectivity. Hence, a ‘magic bullet’ would be created able to kill the targeted organism exclusively. Ehrlich received the 1908 Nobel Prize in Medicine

specific characteristics needed to reach a given target, which means

for his work in the field of immunity, and the magic bullet idea was

attaining a suitable combination of nature, size, way of conjugating

even used as a script for the 1940 movie Dr. Ehrlich’s Magic Bullet.

the drug to the NP (attached, adsorbed, encapsulated), surface

Since then, various strategies have been proposed to deliver a drug

chemistry, hydrophilicity/hydrophobicity, surface functionalization,

to the vicinity of a tumor including, as mentioned above, the use of

biodegradability, and physical response properties (temperature, pH,

vectors sensitive to physical stimuli and tumor-recognition moieties

electric charge, light, sound, magnetism). Among these, size is the main

conjugated to a drug.

Fig. 2 NP systems for drug delivery applications. (Adapted with permission from119 © 2005 Elsevier; and from120 © 2005 PharmaVentures Ltd.)

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Prior to their use for drug delivery, magnetic microparticles were

the drug or give rise to a local effect (irradiation from radioactive

proposed as contrast agents for localized radiation therapy14 and to

microspheres or hyperthermia with magnetic NPs)33. Drug release

induce vascular occlusion of the tumors (antiangiogenic

therapy)15,16.

can proceed by simple diffusion or take place through mechanisms

Freeman et al.17 proposed in 1960 that magnetic NPs could be

requiring enzymatic activity or changes in physiological conditions

transported through the vascular system and concentrated in a specific

such as pH, osmolality, or temperature34; drug release can also be

part of the body with the aid of a magnetic field.

magnetically triggered from the drug-conjugated magnetic NPs.

The use of magnetic micro- and NPs for the delivery of chemotherapeutics has evolved since the 1970s. Zimmermann and

Drug delivery with magnetic NPs

Pilwat18

Different organic materials (polymeric NPs, liposomes, micelles) have

in 1976 used magnetic erythrocytes for the delivery of

cytotoxic drugs. Widder et al.19 described the targeting of magnetic

been investigated as drug delivery nanovectors using passive targeting,

albumin microspheres encapsulating an anticancer drug (doxorubicin)

active targeting with a recognition moiety (e.g. antibody), or active

in animal models. In the 1980s, several authors developed this

targeting by a physical stimulus (e.g. magnetism in magnetoliposomes).

strategy to deliver different drugs using magnetic microcapsules and

However, these organic systems still present limited chemical and

microspheres20-23. In 1994, Häfeli et al.24 prepared biodegradable

mechanic stability, swelling, susceptibility to microbiological attack,

poly(lactic acid) microspheres that incorporated magnetite and the

inadequate control over the drug release rate35, and high cost.

beta-emitter 90Y for targeted radiotherapy, and successfully applied them to subcutaneous

tumors25.

Polymer NPs also suffer from the problem of high polydispersity. Synthesis produces particles with a broad size distribution and irregular

However, all these initial approaches were microsized. Magnetic

branching, which could lead to heterogeneous pharmacological

NPs were used for the first time in animal models by Lübbe et al.26. In

properties. One alternative is to use dendrimers, which have a

1996, the first Phase I clinical trial was carried out by the same group

monodisperse character and globular architecture resulting from

in patients with advanced and unsuccessfully pretreated cancers using

their stepwise synthesis and can be purified at each step of growth36.

magnetic NPs loaded with

epirubicin27.

However, in that first trial,

more than 50% of the NPs ended up in the liver. Since then, a number of groups around the world have synthesized

Visualization of dendrimers requires tagging with a specific moiety (i.e. a fluorophore or metal). A major drawback of dendrimers and dendritic polymers, however, is their high cost. The preparation

magnetic vectors and shown potential applications. Different start-ups

of dendritic polymers that circulate in the blood long enough to

now manufacture magnetic micro- and NPs, which are used in MRI,

accumulate at target sites but that can also be removed from the body

magnetic fluid hyperthermia, cell sorting and targeting, bioseparation,

at a reasonable rate to avoid long-term accumulation also remains a

sensing, enzyme immobilization, immunoassays, and gene transfection

challenge.

and detection systems. FeRx, Inc. (founded in 1997) produced doxorubicin-loaded

Passive targeting using drug-conjugated dendrimers and dendritic polymers has been widely studied, mainly using the EPR effect.

magnetic NPs consisting of metallic Fe ground together with activated

Therapies based on active targeting, such as antibody-conjugated

carbon28,29. A Phase II clinical study in patients with primary liver

dendrimers, constitute a promising alternative in view of the potential

cancer was conducted using these NPs, although the trial was not

of antibodies for selective targeting37. Because of the disadvantages

successful. Chemicell GmbH currently commercializes TargetMAG-

of organic NPs for drug delivery, inorganic vectors constitute an

doxorubicin NPs involving a multidomain magnetite core and a

interesting option and are the subject of intense research. Some

cross-linked starch matrix with terminal cations that can be reversibly

examples of inorganic magnetic NPs will be given below.

exchanged by the positively charged doxorubicin. The particles have

The main advantages of magnetic (organic or inorganic) NPs are

a hydrodynamic diameter of 50 nm and are coated with 3 mg/ml

that they can be: (i) visualized (superparamagnetic NPs are used in

doxorubicin30. These NPs loaded with mitoxantrone have already

MRI); (ii) guided or held in place by means of a magnetic field; and

been used in animal models with successful results31. Chemicell also commercializes FluidMAG® for drug delivery applications. Magnetic

(iii) heated in a magnetic field to trigger drug release or to produce

NP hydro-gel (MagNaGel®) from Alnis Biosciences, Inc. is a material

latter capability is not restricted to magnetic NPs, but also to other

comprising chemotherapeutic agents, Fe oxide colloids, and targeting

particles capable of absorbing near-infrared, microwave, and ultrasound

ligands32.

radiation.

In summary, for magnetic targeting, a drug or therapeutic

hyperthermia/ablation of tissue. It is important to point out that the

Depending on the synthesis procedure, magnetic NPs or

radionuclide is bound to a magnetic compound, introduced in the body,

nanocapsules can be obtained. We refer to NPs when the drug is

and then concentrated in the target area by means of a magnetic field

covalently attached to the surface or entrapped or adsorbed within

(using an internally implanted permanent magnet or an externally

the pores of the magnetic carrier (polymer, mesoporous silica, etc.).

applied field). Depending on the application, the particles then release

Nanocapsules (‘reservoirs’) designate magnetic vesicular systems where

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Magnetic nanoparticles for drug delivery

Magnetic nanoparticles Therapy

Diagnosis Hyperthermia/ thermal ablation

Drug delivery Radiotherapy combined with MRI

In vivo

In vitro

MRI

Sensing

Musculoskeletal system associated diseases

Cell sorting Bioseparation

Anemic chronic * kidney disease

Enzyme immobilization Immunoassays Transfection Purification

Fig. 3 Biomedical applications of magnetic NPs. *Ferumoxytol® (Advanced Magnetics, Inc.) is in Phase III multicenter clinical studies for use as an intravenous Fe replacement therapeutic for patients with anemic chronic kidney disease.

the drug is confined to an aqueous or oily cavity, usually prepared by

area or which triggers the drug desorption. Permanent Nd-Fe-B

the reverse micelle procedure, and surrounded by an organic membrane

magnets in combination with SPION, which have excellent magnetic

(magnetoliposomes) or encapsulated within a hollow inorganic

properties, can reach effective magnetic field depths up to 10-15 cm

capsule35.

in the body39. However, it must be noted that the magnetic carriers

The key parameters in the behavior of magnetic NPs are related to

accumulate not only at the desired site but also throughout the cross-

surface chemistry, size (magnetic core, hydrodynamic volume, and size

section from the external source to the depth marking the effective

distribution), and magnetic properties (magnetic moment, remanence,

field limit. Obviously, the geometry of the magnetic field is extremely

coercivity). The surface chemistry is especially important to avoid the

important and must be taken into account when designing a magnetic

action of the reticuloendothelial system (RES), which is part of the

targeting process.

immune system, and increase the half-life in the blood stream. Coating

As a means to elude the limitations of using external magnetic

the NPs with a neutral and hydrophilic compound (i.e. polyethylene

fields, internal magnets can be located in the vicinity of the target by

glycol (PEG), polysaccharides, dysopsonins (HSA), etc.) increases the

using minimally invasive surgery40. Several studies have simulated the

circulatory half-life from minutes to hours or days. Another possibility

interaction between a magnetic implant and magnetic NPs, enabling

is to reduce the particle size; however, despite all efforts, complete

drug delivery6,41,42. In addition, work in several laboratories40,43,44 is

evasion of the RES does not seem

feasible38

and unwanted migration

to other areas in the body could cause toxicological problems. In addition to cancer treatment, magnetic NPs can also be used

addressing targeted drug delivery with magnetic implants. Another limitation relates to the small size of NPs, a requisite for superparamagnetism, which is in turn needed to avoid magnetic

in anemic chronic kidney disease and disorders associated with

agglomeration once the magnetic field is removed (see below). A small

the musculoskeletal system (i.e. local inflammatory processes, side

size implies a magnetic response of reduced strength, making it difficult

effects) (Fig. 3). For those disorders, superparamagnetic Fe oxide NPs

to direct particles and keep them in the proximity of the target while

(SPION), in conjunction with external magnetic fields, seem a suitable

withstanding the drag of blood flow45. Targeting is likely to be more

alternative for drug delivery to inflammatory sites by maintaining

effective in regions of slower blood velocity, and particularly when the

appropriate local concentrations while reducing overall dosage and side

magnetic field source is close to the target site.

effects39.

As for all biomedical applications, limitations also arise in extrapolating from animal models to humans. There are many

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Limitations of magnetic drug delivery

physiological parameters to consider, ranging from differences in

Since the magnetic gradient decreases with the distance to the target,

weight, blood volume, cardiac output, and circulation time to tumor

the main limitation of magnetic drug delivery relates to the strength

volume/location/blood flow, complicating the extrapolation of data

of the external field that can be applied to obtain the necessary

obtained in animal models46,47. Related to this point is the fact

magnetic gradient to control the residence time of NPs in the desired

that studies on toxicity (not only direct toxicity, but also toxicity

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of the degradation products and induced responses48) and the fate

magnetic field, the magnetic moment of entire crystallites aligns with

of magnetic carriers are insufficient and, in many cases, there is

the magnetic field (Fig. 4).

insufficient characterization. Finally, state-of-the-art magnetic drug delivery seems mainly

In large NPs, energetic considerations favor the formation of domain walls. However, when the particle size decreases below a

applicable to well-defined tumors, as treatment of metastatic

certain value, the formation of domain walls becomes unfavorable

neoplasms and small tumors in the early stages of their growth

and each particle comprises a single domain. This is the case for

still remains a challenge. Treating emerging tumors will involve

superparamagnetic NPs. Superparamagnetism in drug delivery is

the development of a new generation of seek-and-destroy NPs,

necessary because once the external magnetic field is removed,

which specifically recognize small clusters of cancer cells and carry

magnetization disappears (negligible remanence and coercivity, see

the necessary elements (drugs or hyperthermia agents) for their

Fig. 4), and thus agglomeration (and the possible embolization of

destruction. A strong interest continues in this field given the capability

capillary vessels) is avoided.

of NPs to access tumors in regions where conventional surgery cannot be applied.

Another key requirement is the biodegradability or intact excretion of the magnetic core. Thus, SPION are considered to be biodegradable with Fe being reused/recycled by cells using normal biochemical

Tailoring magnetic NPs

pathways for Fe metabolism50,51. For nonbiodegradable cores, a specific

Essential requisites

coating is needed to avoid exposure (and possible leaching) of the

Magnetic NPs for biomedical applications must be endowed with

magnetic core and to facilitate intact excretion through the kidneys,

the specific characteristics required. As mentioned above, the first

so that the half-life of the agent in the blood is determined by the

requirement is often superparamagnetism.

glomerular filtration rate (e.g. contrast agents based on gadolinium)51.

Superparamagnetism occurs in magnetic materials composed of

Coatings on magnetic NPs

very small crystallites (threshold size depends on the nature of the

The coatings on magnetic NPs often serve multiple purposes. Their

material, for instance, Fe-based NPs become superparamagnetic at

role in reducing leaching of the cores has already been mentioned. The

sizes

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