Diagnoza raka mózgu i terapia z nanoplatforms.pdf

Advanced Drug Delivery Reviews 58 (2006) 1556

–

1577

www.elsevier.com/locate/addr

Brain cancer diagnosis and therapy with nanoplatforms ☆

Yong-Eun Lee Koo a , G. Ramachandra Reddy b , Mahaveer Bhojani c ,

Randy Schneider d , Martin A. Philbert d , Alnawaz Rehemtulla c ,

Brian D. Ross e , Raoul Kopelman a,

⁎

a Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA

b Molecular Therapeutics, Inc., Ann Arbor, MI 48109, USA

c Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA

d Department of Environmental Sciences, University of Michigan, Ann Arbor, MI 48109, USA

e Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA

Received 9 August 2006; accepted 13 September 2006

Available online 28 September 2006

Abstract

Treatment of brain cancer remains a challenge despite recent improvements in surgery and multimodal adjuvant therapy.

Drug therapies of brain cancer have been particularly inefficient, due to the blood – brain barrier and the non-specificity of the

potentially toxic drugs. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the problems of

current strategies. Moreover, multi-functionality can be engineered into a single nanoplatform so that it can provide tumor-

specific detection, treatment, and follow-up monitoring. Such multitasking is not possible with conventional technologies. This

review describes recent advances in nanoparticle-based detection and therapy of brain cancer. The advantages of nanoparticle-

based delivery and the types of nanoparticle systems under investigation are described, as well as their applications.

Keywords: Nanoparticles; Blood – brain barrier; Drug delivery; MRI; Chemotherapy; Photodynamic therapy; Targeting

Contents

1. Introduction .................................................... 1557

2. Drug delivery methods for the brain ....................................... 1559

2.1. Chemical modification of a drug and prodrugs .............................. 1559

2.2. Temporary disruption of the BBB ..................................... 1559

2.3. Local delivery into brain.......................................... 1559

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “ Particulate Nanomedicines ” Vol. 58/14, 2006.

⁎ Corresponding author. Tel.: +1 734 764 7541; fax: +1 734 936 2778.

E-mail address: kopelman@umich.edu (R. Kopelman).

doi: 10.1016/j.addr.2006.09.012

Y.-E.L. Koo et al. / Advanced Drug Delivery Reviews 58 (2006) 1556 – 1577

1557

2.4. Convection-enhanced delivery (CED) ................................... 1560

2.5. Carrier/receptor-mediated delivery..................................... 1560

3. Nanoparticle delivery system ........................................... 1560

3.1. Nanoparticle platform ........................................... 1561

3.2. Nanoparticle synthesis and characterization ................................ 1562

4. Magnetic nanoparticles for MRI ......................................... 1563

4.1. Iron oxide core surface-coated with polymer ............................... 1563

4.2. Nanoparticles with incorporated iron oxide ................................ 1564

5. Dual imaging nanoparticles (MRI and optical imaging) ............................. 1565

6. Nanoparticles for chemotherapy ......................................... 1565

6.1. Solid lipid nanoparticles (SLNs)...................................... 1565

6.2. Poly(butylcyanoacrylate) (PBCA) nanoparticles.............................. 1566

7. Targeted multi-functional PAA nanoparticles for PDT and MRI ......................... 1567

7.1. In vitro targeting.............................................. 1568

7.2. MRI .................................................... 1569

7.3. PDT .................................................... 1569

7.4. Bioelimination study ........................................... 1570

8. Conclusions.................................................... 1571

Acknowledgements .................................................. 1572

References ....................................................... 1572

1. Introduction

brain tumors, however, do not readily allow quantita-

tion of the actual tumor volume since a lot of extra-

cellular water (edema) can build up around the tumor

site, making exact discrimination of tumor margins

difficult. Moreover, the delivery of contrast agents is

inefficient, due to the blood

Brain tumors constitute a profound and unsolved

clinical problem although significant strides have been

made in the treatment of many other cancer types. The

incidence of primary brain tumors in the United States

has been estimated at approximately 43,800 per year

brain barrier (BBB). The

BBB is a very specialized system of endothelial cells

that separates the blood from the underlying brain

cells, providing protection to brain cells and preserving

brain homeostasis. The use of contrast agents often

allows estimates of tumor domains from the largest

cross-sectional area of contrast enhancement, indicat-

ing a compromised BBB. However, the contrast agents

tend to diffuse away from the vessel, making precise

measurements of the location of the disrupted BBB

somewhat displaced. Finally, even in a tumor

surrounded by an extensive zone of edema, there are

most likely regions of infiltrating tumor cells which are

not apparent. Therefore imaging is typically used to

locate and stage neoplasm and visualize a tumor before

biopsy or at the time of surgery [4] .

The current practice of waiting for altered neuro-

logical function, neurological exam and pathological/

microscopic evaluation/confirmation of the malignan-

cy usually requires that the tumor (benign or malig-

nant) develops either a significant mass or potential

for migration in the neuraxis before invasive surgical

–

3] and 18,500 of these are expected to be ma-

lignant. Currently brain tumors account for at least

12,690 deaths in the United States yearly and are the

most common cause of cancer-related death for chil-

dren 0

3] .

The earliest stages of intracranial cancer remain

difficult to detect and treat. This problem is confound-

ed by the location of several brain tumors that lie

adjacent to or within anatomical structures critical for

basic motor, cognitive, reflexive and other functions.

As with most other tumors, early detection and reme-

diation correlates with a positive prognosis. Currently

an invasive biopsy is the preferred method to confirm

the diagnosis of cancer as it can provide information

about histological type, classification, grade, potential

aggressiveness and other information that may help

determine the best treatment. Modern imaging techni-

ques such as CT, PET, ultrasound and MRI are rapidly

emerging as standards in the detection of tumors and

cancers. These imaging scans of malignant human

14 years of age [1

–

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Y.-E.L. Koo et al. / Advanced Drug Delivery Reviews 58 (2006) 1556 – 1577

or non-invasive neuroradiological therapies are

invoked.

Treatment of brain tumors, therefore, has histori-

cally consisted of surgery followed by adjuvant

therapy such as radiation therapy, chemotherapy and

photodynamic therapy (PDT). Despite recent improve-

ments in surgical and adjuvant therapy for brain

tumors, the multimodality approach currently used in

the treatment of malignant brain tumors does not

produce a meaningful improvement in patient outcome

[5] . Each treatment modality has limiting factors, as

stated below.

Surgery is invasive but currently the primary mode

of treatment for the vast majority of brain tumors due

to difficulties in finding a tumor at early stages [6] .

One of the greatest challenges in brain tumor surgery is

achieving a complete resection without damaging cru-

cial structures near the tumor bed. Unfortunately, neo-

plastic tissue that is easily detected radiographically, is

virtually indistinguishable from normal brain. While

surgery is the recommended initial treatment for brain

tumors, it is rarely capable of eradicating all tumor

cells [7] . Furthermore, surgery is not an option when

eloquent structures are likely to be damaged during a

resection. To address the inability of current surgical

techniques to reliably eradicate residual or unresect-

able tumor, adjuvant radiation and chemotherapy regi-

mens have been developed.

Radiation therapy, chemotherapy and PDT are non-

invasive and often used as adjuvant therapy after sur-

gery but may also be effective for curing early-stage

tumors. Radiation therapy usually results in a delayed,

but well-documented, decline in cognitive function

in adults, in addition to posing the risk of secondary

malignancy in the irradiated area [8] . In children, ra-

diation therapy is known to interfere with brain de-

velopment [9] . The efficiency of radiation therapy is

often hindered by diffusely invasive characteristics of

brain tumors as well as the emergence of radiation-

resistant populations.

Most chemotherapeutic agents have a low thera-

peutic index. They are toxic and can affect not only

cancer cells but also healthy cells, which leads to severe

systemic side effects, generally resulting in morbidity

or mortality in the patient. The chemotherapeutic treat-

ment of brain cancer is further restricted due to the

ability of the BBB to exclude a wide range of anti-

cancer agents. Another limiting factor is the develop-

ment of multi-drug resistance (MDR) by the cancer

cells. A combinational chemotherapy, i.e. the use of

more than one drug, is a common practice in clinical

oncology. However, cancer cells often develop resis-

tance against a wide variety of chemotherapeutic drugs,

due to the very effective drug efflux system P-glyco-

protein or multi-drug resistance-associated protein

(MDRP) [10,11] . The P-glycoprotein is an ATP-de-

pendent transporter responsible for the cellular extrusion

of a number of drugs. It is expressed in many tis-

sues, including the luminal membrane of the cerebral

endothelium.

The combination of chemotherapy and radiation

therapy has been implemented with variable success in

adult brain tumors [12] but also carries significant

treatment-related morbidity. Moreover, the improve-

ments in outcome demonstrated with the use of

combination therapy are minimal: a prospective ran-

domized controlled study on temozolomide, the most

effective and best tolerated agent for treating gliomas,

demonstrated an increase in the median two-year

survival of only 2.5 months in patients with newly

diagnosed glioblastoma receiving radiation and temo-

zolomide, compared to those receiving radiation thera-

py alone [13] .

PDT involves the delivery of photosensitizers (PS)

such as Photofrin ® to tumors, combined with local

excitation by the appropriate wavelength of light,

resulting in the production of singlet oxygen and other

reactive oxygen species which initiate apoptosis and

cytotoxicity in many types of tumors, with minimal

systemic toxicity. PDT has emerged as a promising

method for overcoming some of the problems inherent

in classical cancer therapies [14

–

25] . Recently it was reported that

PDT of primary and recurrent gliomas resulted in an

increase in patient median survival [26] . The efficacy

of PDT for brain cancer is also limited by the BBB

and MDR, just like chemotherapy, as it requires the

delivery of the PS to the brain.

17] . It is more selec-

tive and less toxic than chemotherapy because the drug

is not activated until the light is delivered. PDT was

initially applied clinically to cutaneous and bladder

malignancies that can easily be exposed to light. How-

ever, PDT is also an interesting approach for the treat-

ment of malignant gliomas, as it offers a localized

treatment approach. Several investigations have been

made on the application of PDT for the treatment of

brain tumors [18

–

Y.-E.L. Koo et al. / Advanced Drug Delivery Reviews 58 (2006) 1556 – 1577

1559

The therapeutic efficacy of chemotherapy and PDT

can be greatly improved by efficient delivery of the

drugs to the specific tumor location. The recent mo-

lecularly-targeting approach allows the medical inter-

vention to affect only cancer cells but not the normal

cells, based on molecular recognition processes

(ligand

category. Therefore, delivery of drugs to the brain

needs a special strategy to bypass the BBB and thus to

achieve high intratumoricidal drug concentrations

within the central nervous system (CNS). Various

strategies have been explored for manipulating the

BBB, as summarized below.

–

receptor or antibody

–

antigene interaction)

31] . This innovative approach is inherently

different from classical modalities. It has the potential

to improve the therapeutic efficacy or imaging contrast

enhancement, by increasing the amount of therapeutic

or contrast agents delivered to the specific site, and to

minimize toxicity, or imaging background signal, by

reducing systemic exposure. The promise of the

molecularly targeted approach in imaging is that one

may be able to obtain dramatic contrast enhancement

so as to detect the tumor at an earlier stage than

possible by current methods, with sensitivity good

enough to avoid an invasive biopsy. Since the specific

molecular signature of one brain tumor may be dif-

ferent from that of another, and can not be differ-

entiated based upon traditional anatomical imaging,

the ability to diagnose brain tumors based on their

genetic presentation, in a targeted manner, would be of

great value. By the same notion, the approach of

delivering a therapeutic agent in a targeted manner

should give clinicians the ability to treat cancer or to

manage it as a chronic disease, thus preventing it from

progressing to its later, more virulent stages. Towards

more efficient chemotherapeutic treatment of brain

cancer, there have been continuous efforts to develop

special delivery methods designed to overcome the

BBB. Proper combination of these methods and the

molecular-targeting approach should be a key factor

for achieving an improved therapeutic efficacy.

–

2.1. Chemical modification of a drug and prodrugs

Lipid solubility is a key factor in enhancing passive

diffusion into the BBB. Chemical modification of the

drug itself into a more lipophilic and neutral form as

well as a prodrug approach have been investigated.

The prodrug approach involves the administration of the

drug in a form that is inactive or weakly active, but

readily able to penetrate the BBB and then to be con-

verted into the active form within the brain. Both

approaches have pharmacokinetic difficulties, as lipidi-

zation may bring in undesirable pharmacokinetic ef-

fects, such as increased uptake by the reticuloendothelial

system and increasing non-specific plasma protein

binding when administered intravenously [32] .For

example, several lipophilic variants of BCNU were

clinically tried but have not shown improved clinical

efficacy over BCNU [33] .

2.2. Temporary disruption of the BBB

The BBB can be permeabilized using either osmotic

disruption by certain hyperosmolar agents, such as

mannitol, or biochemical opening by bradykinin ana-

logs such as RMP-7. This leads to a reversible opening

of the tight junction, but is not specific enough to

disallow CNS entry of toxins and unwanted molecules,

thus potentially resulting in significant damage. The

experimental studies have clearly shown an increased

penetration of the drug into the brain parenchyma, but

the clinical studies did not show improvement in the

efficacy of the drug with concurrent use of these agents.

Therefore, this has not translated into clinical efficacy

[34] .

2. Drug delivery methods for the brain

In contrast to the open endothelium of the peripheral

circulation, the tightly fused junctions of the cerebral

capillary endothelium, the anatomic basis for the BBB,

essentially form a continuous lipid layer that effectively

restricts free diffusional movement of molecules into

and out of the brain. Only small, electrically neutral,

lipid-soluble molecules (molecular weight up to

500 Da) can penetrate the BBB by passive diffusion

and most chemotherapeutic agents do not fall into this

2.3. Local delivery into brain

This method has been achieved by direct infusion

of a drug via a catheter or implantation of a gel wafer, a

polymer matrix containing a drug. It is, however, a

highly invasive procedure that requires neurosurgery

[27

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Y.-E.L. Koo et al. / Advanced Drug Delivery Reviews 58 (2006) 1556 – 1577

3 weeks. Clinical trials have

shown that Gliadel wafers can lengthen survival time

and help control symptoms of high grade gliomas for

longer times than surgery and radiotherapy alone [35] .

To date this is the most efficient method of delivery of

drugs into the brain.

–

key factor for the efficacy of cancer detection and

therapy. The utilization of the nanoparticle as a po-

tential vector for brain or other site-specific delivery

has the following advantages, due to its excellent

engineerability and non-toxicity:

1. The loading/releasing of active agents (drugs/con-

trast agents) can be controlled. The drugs are loaded

into nanoparticles by encapsulation, adsorption or

covalent linkage. The loaded amount is controllable

by changing the size of the nanoparticles or the

number of linkers inside and on the surface of the

nanoparticles. Each nanoparticle can carry a large

amount of molecular therapeutic and/or contrast

agents. Release of the agents may occur by desorp-

tion, diffusion through the NP matrix, or polymer

wall, and/or NP erosion, which can all be controlled

by the type of the nanoparticle's polymer matrix,

i.e., having it become swollen or degradable in the

tumor environment.

2. Specific molecular-targeting factors can be attached

for localized binding to and/or uptake by the tumor

cells, as well as for passage through the blood

2.4. Convection-enhanced delivery (CED)

While invasive it is currently an area of active in-

vestigation for drug delivery to the CNS. This method

utilizes convection so as to supplement diffusion for the

distribution of certain compounds and thus treat much

larger volumes of brain than can be achieved by dif-

fusion alone. The convection results from a simple

pressure gradient and is independent of molecular

weight, resulting in greater pharmacokinetic advan-

tages over systemic administration [34] . The CED

delivery system is currently used in two clinical treat-

ment trials for high grade gliomas [36,37] .

–

brain barrier when appropriate. It should be noted

that the selective delivery of nanoparticles to tumor

is sometimes achieved due to the

2.5. Carrier/receptor-mediated delivery

tumor

vasculature, which is known as the enhanced per-

meability and retention (EPR) effect [39

“

leaky

”

The CNS (or brain) has transport routes that

overcome the BBB by other than passive diffusion,

such as carrier/receptor-mediated influx or transcytosis

[38] , in order to receive essential polar metabolites

such as glucose, amino acids and lipoprotein. These

carriers/receptors can be used to deliver drugs to the

CNS. It requires the discovery and development of

receptor specific ligands, which can be attached directly

to the drug of interest or the drug delivery system, such

as nanoparticle and liposome. This methodology has

been receiving significant attention with the remarkable

development of nanotechnology and non-invasiveness,

compared to the other delivery methods listed above.

The combination of nanoparticles and delivery methods

is especially promising, as shown below.

42] . This

and tumor-specific targeting moieties on the surface

turn the nanoparticles into very efficient delivery

vectors for tumors. Moreover, the use of targeted

nanoparticles can achieve the delivery of large

amounts of therapeutic or imaging agents per tar-

geting biorecognition event, which is a major clini-

cal advantage over simple immunotargeted drugs.

3. A hydrophilic coating can be given to the nano-

particle to provide reduced uptake by the RES,

resulting in both increased delivery of the nano-

particles to tumor sites and reduced toxicity to other

body tissues.

4. The nanoparticle matrix provides protection, for the

active agents, from enzymatic or environmental

degradation.

5. The nanoparticles can alleviate the problem posed by

theMDR of cancer cells against many drugs; done by

masking the drugs entrapped within the nanoparti-

cles. This feature may enhance the delivery of drugs

that are normally excluded from tumors.

–

3. Nanoparticle delivery system

The ability to deliver effective concentrations of

contrast or therapeutic agents selectively to tumors is a

and special equipment. To date, Gliadel ® Wafer

(BCNU-loaded biodegradable polymer) is the only

wafer approved for clinical use in the US; it releases

the chemotherapy drug directly into the brain as the

polymer degrades over 2

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