NANO: Brief Reports and Reviews Vol. 9, No. 1 (2014) 1430001 (16 pages) © World Scienti¯c Publishing Company DOI: 10.1142/S1793292014300011
THE APPLICATION OF NANOMATERIALS IN DIAGNOSIS AND TREATMENT FOR MALIGNANT PRIMARY BRAIN TUMORS RUICHAO LIANG* and FANG FANG† Department of Neurosurgery, West China Hospital Sichuan University, Chengdu, Sichuan, P. R. China
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
*
[email protected] †
[email protected]
Received 2 May 2013 Accepted 7 September 2013 Published 21 October 2013
Malignant primary brain tumors have a very high morbidity and mortality. Even though enormous advances have been made in primary brain tumor management, in the case of malignant primary brain tumors, current diagnostic strategies cannot identify exact in¯ltrating margins, surgery alone cannot achieve total mass resection, and adjuvant therapies cannot improve survivals. Therefore, there is an urgent need to explore novel strategies to diagnose and treat such in¯ltrating brain tumors. Nanomaterials, particularly zero-dimensional and one-dimensional platforms, can carry various compounds such as contrast agents, anticancer drugs and genes into brain tumor cells speci¯cally. Thus, contrast agent-based nanomaterials can selectively present in¯ltrating tumor outlines, while anticancer agent-based nanomaterials can speci¯cally kill malignant tumor cells. In addition, dual-targeting nanomaterials, multifunctional nanocarriers, theranostic nanovehicles as well as convection-enhanced delivery technology hold promise to increase drug accumulation in tumor tissues, which could largely improve anticancer e±cacy. In this review, we will mainly focus on the application of nanomaterials in preoperative diagnosis, intraoperative diagnosis and adjuvant treatment for malignant primary brain tumors. Keywords: Nanomaterials; nanoparticles; carbon nanotubes; dual targeting; diagnosis; treatment; multifunctional; malignant primary brain tumors.
1. Introduction Malignant primary brain tumors are in¯ltrating intracranial mass lesions that primarily originate from brain parenchyma, meninges, hypophysis, etc. Malignant primary brain tumors have a very high morbidity and mortality. In the US, the annual incidence of malignant primary brain tumors is about 7.30 per 100 000, while the data in China is †Corresponding
about 7.65 per 100 000.1,2 Like other primary brain tumors, malignant primary brain tumors can also cause focal neural de¯cits, epilepsy and signs of raised intracranial pressure (i.e., headache, vomiting and papilloedema) in patients,3 but with a faster pace and heavier symptom. The representative neuroimaging techniques for primary brain tumor diagnosis include computed X-ray tomography (CT),
author. 1430001-1
R. Liang & F. Fang
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT).4 Contrastenhanced MRI is the main method for localization of primary brain tumors preoperatively. But conventional gadolinium-based MRI contrast agents (shown in Fig. 1), which solely enhance tumor areas with disrupted blood brain barrier (BBB), often fail to enhance the in¯ltrating tumor margins.5,6 Surgery is the standard treatment for primary brain tumors,7 and there have been substantial advances in this ¯eld. For instance, total mass resection of benign and low-grade malignant primary brain tumors can help patients obtain a longer survival time and better life quality. To date, however, patients with high-grade malignant primary brain tumors, especially glioblastoma multiforme (GBMs)
(a)
(b)
(c)
(d)
Fig. 1. MRI scan of the brain of a 37-year old woman with a GBM. (a) A T1-weighted image of tumor foci. (b) A T2weighted image of tumor foci. (c) A °uid attenuated inversion recovery (FLAIR)-weighted image of a peripheral edema. (d) A T1-weighted image with contrast MRI of irregular enhancing tumor foci. (MRI pictures were obtained from Department of Neurosurgery, West China Hospital, Sichuan University)
and medulloblastoma, still have a poor prognosis.7 This is because there are few methods to accurately locate intraoperative tumor margin and guide exact resection of in¯ltrating primary brain tumors, which often lead to high recurrence rates. Therefore, postoperative radiotherapy and chemotherapy are needed to avoid recurrences in patients with malignant primary brain tumors.8 Even combined with intensive radiotherapy, the patient outcome remains disappointing, not to mention the numerous adverse e®ects caused by radiotherapy.9 On the other side, the existing BBB and blood tumor barrier (BTB) restrict the delivery of chemotherapeutic agents into brain tumors, which result in little e±cacy of chemotherapy.10,11 Furthermore, circulation agents may cause some signi¯cant side e®ects, such as myelosuppression, liver and kidney toxicity.12 There is an urgent need to explore e®ective strategies to deliver contrast agents and anticancer drugs to malignant primary brain tumor cells, that is, across the BBB and BTB. The BBB mainly refers to continuous, nonfenestrated capillaries in normal brain tissue that have tight junctions between endothelia11 [BBB structure was shown in Figs. 2(a) and 2(c)]. Substrates that are essential for normal brain functions can permeate the BBB through several ways includeing passive di®usion, carrier-mediated/active transport systems, transcytosis and receptor-mediated endocytosis systems. As for drugs, there are special transporters within BBB to mediate in°ux and e®lux of various bioactive agents in the brain.10 Importantly, diverse antineoplastic agents are extruded out of brain by the P-glycoprotein (P-gp) and multidrug resistance protein family (MRP) in the BBB and brain parenchyma.10,13,14 Furthermore, various drug-metabolizing enzymes within brain capillary endothelia and brain parenchyma cells (i.e., astrocytes and microglia) provide an additional enzymatic barrier for potentially harmful xenobiotics and drugs.10 All these together maintain an optimal homeostasis of the brain microenvironment and also restrict the accumulation of anticancer/contrast agents in brain parenchyma. The BTB refers to brain tumor capillaries that are highly variable in permeability among di®erent tumors and/or among di®erent regions within a single tumor.11,15 The capillary population of malignant primary brain tumors is likely to have interendothelial gaps in the more central parts of tumor interstitium [shown in Figs. 2(b) and 2(d)]. Thus, it is
1430001-2
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
Diagnosis and Treatment for Malignant Primary Brain Tumors
(a)
(b)
(c)
(d)
Fig. 2. Light and electron microscopical aspects of human normal (a), (c) and human glioblastoma vessels (b), (d). Cap: capillary, E: endothelial cell, G: glioma cell, NP: neuropil, P: pericyte. The arrows in (d) point to the glial limiting membrane (color online). (Reprinted from Ref. 15, with permission from Elsevier.)
easier to deliver diagnostic contrast agents and/or anticancer drugs into the main center of a malignant primary brain tumor than that of normal brain.16 Nevertheless, radiologically, contrast MRI of glioblastoma shows irregular signals with enhanced contours and nonenhanced tumor extending areas.17 The latter MRI feature indicates glioblastoma in¯ltration zone where BBB is not or less altered.15,16 Therefore, tumor foci may be divided into three di®erent parts, that is, the main bulk of tumor with leaky capillaries, the tumor in¯ltration zone with less altered BBB and the peritumoral brain parenchyma with almost normal BBB where the malignant cells may in¯ltrate in but can not be detected by current neuroimaging techniques.15,16,18 The BTB of malignant primary brain tumors contains all capillary systems within the three areas. Additionally, like the normal BBB, the BTB also express the P-gp, MRP and other drug transporters to form the multidrug resistance (MDR) of malignant primary brain tumors.15,19,20 Thanks to the complexity of BBB and BTB, brain agent delivery is a formidable challenge in malignant
primary brain tumor diagnosis and treatment. For decades, various researchers in various ¯elds have been trying every e®orts to conquer this problem.21 These e®orts comprise invasive approaches, pharmacological approach and physiological approaches. Invasive approaches such as intracerebral/intraventricular infusion, convection-enhanced delivery (CED), exploitation of implants and focused ultrasound (FUS)/osmotic/bioactivator can breach the BBB or just help open BBB transiently to improve drug transportation into the brain.21–24 However, all these approaches seem to have dimmed prospects because of little e±cacy and some unwanted brain complications.21,22 Pharmacological approach consists of chemical modi¯cation of anticancer drugs to improve their lipid solubility so that they may imitate endogenous small lipophilic molecules to passively di®use across the BBB. Whereas, due to complex molecular mechanisms of the BBB and BTB, this approach also present with little e±cacy.25 Physiological approaches have been based on the physiological properties of the BBB, such as the transporters, receptors, and even surface charge of the BBB endothelia.10 Brain drugs can mimic the endogenous transporter substrates and/or conjugate to ligand/antibody of the various receptors to cross the BBB and bypass enzyme systems.21 The sustainable development of physiological approaches has made several promising achievements in the delivery of anticancer drugs across the BBB, some of these drugs have entered into clinical research stage.21,26 In recent years, the nanomaterials have been exploited as drug delivery systems across the BBB and BTB and have shown broad prospects in this ¯eld when combined with the above physiological approaches. Nanomaterials are microstructural materials with a length scale less than 100 nm. These nanostructural materials can be divided into four categories: nanoparticles nano¯bers, nano¯lms and bulk nanomaterials.27 Since their ¯rst advent in the 1970s, nanomaterials have been dramatically developed and applied to several ¯elds,28 including biomedicine, information technology, physical and chemical industry, environmental protection, etc. The application of nanomaterials in biomedical ¯elds has been experiencing a revolution, including nano¯ber-based controlled delivery devices in tissue regeneration,29,30 nano¯ber-based biosensor in diagnosis,31 NP-based targeted delivery system,32 nanomaterialbased gene therapy,33,34 nanomaterial-based
1430001-3
R. Liang & F. Fang
antibiotics,35,36 nanomaterials in arti¯cial organ,37 etc., Among which, agent delivery is the most attractive application of nanomaterials in biomedicine. In the present review, we will mainly discuss nanomaterial-based delivery systems in the selective diagnosis and treatment of malignant primary brain tumors as well as the targeted mechanisms and toxicology concerns of nanomaterials.
2. Nanomaterial-Based Delivery System
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
2.1. General concepts Nanomaterials have been making every e®orts to collaborate with biomedicine in drug delivery since their advent.38 This is predicated on the fact that monodisperse nanomaterials are small enough to get into many substructures of organs like tissues, cells and even subcellular organelles which is the dawn of many unstable active molecules to cross the cell membrane.39,40 The dawn also belongs to brain agent delivery to treat the malignant primary brain tumors.41 Over the years, nanomaterials synthesized for malignant primary brain tumors have undergone several generations, from \naked" carriers to surfacemodi¯ed vectors and from monofunctional vehicles to multifunctional transporters.42–44 Multifunctional transporters refer to nanomaterials with dual or more surfactants and that can load various compounds simultaneously to guide multimodal functions.45 Speci¯cally, nanomaterials that deliver drugs and diagnostic agents simultaneously to combine treatment and diagnosis together are called theranostic nanomaterials.46
2.2. The categories 2.2.1. NP-based platforms NPs, also called zero-dimensional nanomaterials, consist of organic and inorganic delivery systems. Organic NPs such as liposomes and micelles have long been exploited as agent delivery platforms for primary malignant brain tumors and have made great progress.42,44 Some liposomal agents are even now in clinical trials.44 In recent years, nanogels, dendrimers, and solid lipid NPs (SLNs) have also been popular in this ¯eld.47–50 Inorganic NPs like magnetic NPs (MNPs), noble metallic NPs, silica NPs and quantum dots (QDs) have become popular research topic for brain agent delivery with the in-depth collaboration between nanomaterial science and biomedicine.43,51
The synthetic approaches for each organic NPs vary. In general, there are two main methods, i.e., noncovalent and covalent interactions. Under speci¯c circumstances, some reversible NPs like liposomes, micelles and nanogels can self-assemble spontaneously via noncovalent forces, i.e., Van der Waals forces or lipophilic interactions.42 Liposomes are phospholipid bilayer microspheres which can encapsulate both hydrophilic and hydrophobic compounds in the aqueous core.52–54 Micelles, such as poly (lactic-co-glycolic acid) (PLGA),55 poly (butyl cyanoacrylate) (PBCA),56 and poly ("-caprolactone), (PCL),57–60 are hydrophobic core compositions coated with surface-active agents such as polyethylene glycol (PEG) and dextran. These polymeric micelles self-assemble to form a lipophilic core for hydrophobic drug delivery. Nanogels are novel polymeric micelles with cross-linked cores which can encapsulate hydrophobic agents.61,62 The physical self-assembly and/or chemical cross-linking of polymer networks which form nanogels have made them highly stable and °exible agent delivery systems.62 Dendrimers63–67 are highly-branched, polymer-based NPs with small diameters. Such repetitively branched organic NPs can encapsulate drugs and diagnostic agents in the whole sca®old via physical absorbing and/or covalent bonding. The exterior end group of dendrimers are often conjugated to PEG. SLNs are typical core–shell NPs synthesized from physiologic lipids via high-pressure homogenization or microemulsion.50 The relatively rigid core (compared to reversible NPs) makes SLNs the stable transport platforms for hydrophobic drugs.50 In general, chemical cross-linked nanogels and covalently formed dendrimers and SLNs are more stable in biological systems than reversible NPs. Unlike organic NPs, inorganic NPs consist of a similar framework, a rigid solid core decorated with various hydrophilic ligands like PEG.68–71 Hydrophobic agents are mainly stored on the surface of solid core via adsorption and protected by the polymer layer. Besides these generalities, each inorganic NPs have unique properties. MNPs such as nanoparticulate gadolinium and iron oxide NPs have been well known for the characteristic of paramagnetism and can be applied to tumor detection, thermotherapy and drug delivery.69,72–74 Noble metallic NPs such as AuNPs have excellent optical properties due to the surface plasmon resonance (SPR), which has made these NPs useful for applications such as optical imaging and photothermal
1430001-4
Diagnosis and Treatment for Malignant Primary Brain Tumors
therapy in tumors.68,75–77 The large internal volume of mesoporous silica NPs (SiNPs), along with their good chemical stability, has made them promising therapeutic delivery platforms and intracellular controlled drug release systems on tumor chemotherapy.78 QDs can serve as diagnostic means for malignant primary brain tumors, owing to their sizedependent °uorescent emission spectra properties.71
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
2.2.2. Other nanomaterials Carbon nanotubes (CNTs), which belong to onedimensional nanomaterials, also have a role in tumor diagnosis and treatment.79 CNTs are allotropes of carbon formed by rolling sheets of a single or multiple graphene layers with hollow tubes.79 CNTs can be divided as single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs) based on the number of carbon layers assembled.80,81 Chemical vapor deposition (CVD) systems are the most popular method to synthesize CNTs. Like inorganic NPs mentioned above, CNTs also need post-synthetic process to obtain puri¯ed and biocompatible agent carriers. The relatively large surface area and hollow core of CNTs have made them ideal candidates as multimodal transporters for various compounds to diagnose and treat malignant primary brain tumors.79
2.3. Nanomaterials and BBB/BTB Over the years, the direct and principal aim to treat malignant primary brain tumors lies on searching for e®ect methods to increase the fraction of drug that reaches the tumors.11 Similarly, in the case of nanomaterials, we need enough drug-loaded nanocarriers to encircle the tumor site and then cross the BBB and BTB. Thus, stable dispersed, biocompatible and targeted nanomaterials are mainly discussed here. Reticuloendothelial system (RES), mainly refers to macrophages and monocytes from liver and spleen, to guide natural defense of the organism by phagocytosing various exogenous elements that include nanomaterials that are intruding into the blood stream and/or tissues.38 Surface properties of nanocarriers may impact the phagocytosis. When administrated intravenously, surface charge of liposomes and micelles and hydrophobic surfaces of various inorganic NPs as well as CNTs are high risk factors for opsonization, a process prior to phagocytosis,
leading to high uptake of these nanomaterials in liver and spleen.38 Surface coating of some hydrophilic polymers like PEG and dextran can form nanocarriers with stable dispersed and biocompatible features in circulation and reduce RES uptake.82,83 As a result, nanomaterials have prolonged circulation half-life to act on BBB and BTB. Two important reasons to introduce nanomaterials in anticancer drug transport are that they can speci¯cally target to the responsible foci and hardly reduce the side e®ects of free drugs to normal tissues.43,47,51 Thus, in the case of treating malignant primary brain tumors, the newly synthesized drug delivery nanovehicles tend to be more targeted to the BTB and tumor cells as well as to protect the loaded drugs from unmatured release. Generally, there are two main targeting pathways in nanomaterial-based drug delivery to malignant primary brain tumors, the active targeting and passive targeting.84 The latter takes advantage of the enhanced permeability and retention e®ect (EPR) of tumor vasculature, that is, the disrupted BBB in the main center of malignant primary brain tumors. The tumor microenvironment (such as lower pH) and poor lymphatic drainage in these tumor tissues also induce EPR.85–88 As for tumor margins and/or peritumoral brain parenchyma where the BBB is intact or less altered, EPR mechanism is not appropriate for drug transport, it should rely on active targeting. One similar characteristic of various nanomaterials is that they can be decorated with ligands or antibodies to actively target to the corresponding receptors on BBB and/or tumor cells.43,47,51,84 Antibody/ligandcoated nanovehicles such as angiopep-2,59,60,64,66,67,81 chlorotoxin (CTX),63,69,89 transferrin (Tf),54,90,91 EGF/EGFRvIIIAb,68,92 folacin,54 IL-13,93,94 F3,49,95 and RGD53,67,96 conjugated nanomaterials can cross BBB selectively and then speci¯cally bind to malignant primary brain tumor cells. The interaction between ligands/antibodies and receptors will trigger endocytosis and transcytosis of these nanomaterials on BBB endothelia.38 Additionally, surface charge of nanomaterials and some cell-penetrating peptides (i.e., TAT53) generally display better internalization rates, which mediate the well-known adsorptive endocytosis.97
2.4. Safety issues Wide applications of nanomaterials have raised toxicology concerns. Many years of study in
1430001-5
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
R. Liang & F. Fang
nanomaterial-based brain tumor drug delivery has moved rare results into clinical application (except for liposomal agents).44 One formidable challenge is the toxic issues of these neuro-nanomaterials, both in brain and the rest organs of the body.98–100 The brain tumor targeted nanomaterials may have less toxicity to other extracranial organs except for liver, spleen and kidney, the main RES and excretory system. Inorganic NPs are less biodegradable in vivo as compared to organic NPs, and have raised more toxic problems in organism. Generally, the compositions, sizes and surface properties of these nanomaterials are main factors causing toxicity.101–103 Cadmiumbased QDs are considered toxic due to their heavy metal content, the intracellular released Cd 2þ can cause oxidative stress response.104,105 Oxidative stress and the consequent free radical activity may damage cell components such as lipids, proteins and nucleic acids, and the brain is more vulnerable due to high content of lipids and proteins.106 Other inorganic nanomaterials involved in this review have been demonstrated to trigger oxidative stress both in vitro and in vivo. For example, iron oxide MNPs have been observed in vitro to induce cell death of cultured neuronal phenotype PC12 cells with increasing concentration.107 Another study has shown signs of oxidative stress in rat spleen, liver and kidney after intravenous administration of iron oxide MNPs, but the e®ect only sustained for three days.108 Similarly, Au NPs, SiNPs and CNTs have also shown oxidative stress injuries in animal studies.109–111 SiNPs and CNTs have uncertain acute and/or longterm chronic tissue damages, while Au NPs have controversial study conclusions.102,111–113 All these results call for further researches to ensure systemic toxicity of inorganic nanomaterials. In the case of neurotoxicity, there are only a few in vivo investigations.100 It has been reported that intranasal administration of iron oxide MNPs and Au NPs can induce slight oxidative stress response, nerve cell damage and/or activation of microglia.114,115 Similarly, intranasal instillation of SiNPs also induced oxidative and in°ammatory response in rat striatum, yet with no apparent changes in the histological analysis of brain tissue.116 Intranasal and/or intracerebral administration of QDs and CNTs have only caused microglia activation without showing major signs of neurotoxicity.100 Nevertheless, lipid peroxidation of brain are highly associated with various neurodegeneration (i.e., Parkinson's disease and
Alzheimer's disease),117 thus, further researches are required to assess the certain impact of these nanomaterials on brain. Organic NPs are generally accepted to be biocompatible and biodegradable drug delivery systems, and hydrophilic polymer surfactants like PEG can protect nanomaterials from being hijacked by RES. Nonetheless, several studies have observed immunogenicity of PEG and high rate of plasma clearance for PEGylated liposomes.82 Altogether, further studies are needed to carry out conclusive statement of such concerns.
3. Application of Nanomaterials in Diagnosis for Malignant Primary Brain Tumors 3.1. Preoperative diagnosis With relatively high sensitivity and speci¯city, MRI has become the main method for brain tumor diagnosis. And the continuous improvement in multimodal MRI technology has largely increased the diagnostic rate of brain tumors. Conventional contrast-enhanced MRI can image tumor sites. However, as discussed above, gadolinium-based contrast agents can solely enhance the main bulk of malignant primary brain tumor tissues, failing to seek out in¯ltrating area tumor cells. Thus, speci¯cal malignant primary brain tumor cell-targeted MRI contrast agents may hold potential to solve such problems. Iron oxide NPs and gadolinium NPs have raised great interest in malignant primary brain tumor image due to their paramagnetic features.74,118 Early studies have shown that such MNPs can reside in tumor bed much longer than non-nanoparticulate gadolinium-based agents.119,120 Single intravenous administration of MNPs can be imaged over a period of 24 h to 72 h post-administration, while nonnanoparticulate gadolinium-based agents need to be readministrated.120 Iron oxide-based MNPs are better visualized in T2-weighted images as hypointense signals, while gadolinium-based MNPs mainly cause contrast enhancement as hyperintense signals in T1-weighted images.72,121 Recently, investigators have explored targeted MNPs with surface-coated ligands/peptides.69,122 Xie and coworkers122 have reported lactoferrin-conjugated superparamagnetic iron oxide nanoparticles (Lf-SPIONs) to detect glioma in vivo, such targeted NPs speci¯cally seek
1430001-6
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
Diagnosis and Treatment for Malignant Primary Brain Tumors
for glioma cells overexpressed with Tf receptors to selectively improve the delineation of tumor site in MRI (T2-weighted negative contrast enhancement). Furthermore, the contrast enhanced image of tumor site caused by Lf-SPIONs was persistent up to 48 h post-injection, thus providing a time-dependent MRI.122 Therefore, such MNPs are promising for accurate surgical plan as well as postoperative check with their high speci¯city and sensitivity on whole delineation of malignant primary brain tumors. In addition to MNPs, other nanomaterials like dendrimers and liposomes have also been introduced in preoperative diagnosis of malignant primary brain tumors.52,63 Huang et al. have synthesized a dendrimer-based polymer, D3-PEG-CTX, to speci¯cally deliver Gd-DTPA for glioma imaging in intracranial tumor-bearing nude mice.63 Such new dendrimerbased MRI contrast agents conjugated with CTX can selectively cause T1-weighted contrast enhanced imaging of malignant glioma for a period of 24 h.63 Thus, it has demonstrated that contrast agent-loaded nanomaterials may also promise for targeted and accurate malignant primary brain tumor diagnosis. Recently, Oku et al.52 have explored a liposome coated with an angiogenic homing peptide to transport positron emitter into gliomas, their results have shown that such liposomal PET imaging agent can diagnose glioma more selectively and sensitively compared with the common positron emitter, [218 F]-2-deoxy°uoro-d-glucose (FDG), and may be promising for early diagnosis of malignant primary brain tumors. AuNPs, owing to their SPR properties, are able to absorb and scatter visible light, which makes them suitable for tumor optical imaging.123,124 However, the optical signals emitted from AuNPs possess restricted tissue penetration ability, limiting the application of optical imaging merely to tissues close to the skin surface.124 Thus, AuNPs have not yet been applied to preoperative diagnosis of brain tumors. Nevertheless, due to their high atomic weight, AuNPs have been reported as contrast agents for CT imaging of malignant gliomas.75
3.2. Intraoperative diagnosis It is a major challenge to achieve complete resection of malignant primary brain tumor mass without causing any damage to peritumoral essential neural structures. Nevertheless, maximal possible surgery
is still recommended to help improve e±cacy of adjuvant therapies.125 Intraoperative auxiliary diagnosis technologies, such as stereotaxy neuronavigation, ultrasonography and MRI, can help locate exact tumor site, which have shown a positive in°uence in the extent of tumor resection.126,127 However, above-mentioned intraoperative diagnostic methods have not been widely used because of limited devices and contamination. In addition, as discussed above, the conventional imaging tests cannot accurately locate tumor in¯ltrating margins even at the time of surgery. Therefore, there is an urgent need to apply novel technology to intraoperative diagnosis. Recently, °uorescence-guided surgery with 5aminolevunilic acid (ALA) for malignant primary brain tumor resection has been reported.128,129 ALA is a non°uorescent prodrug that leads to intracellular accumulation of °uorescent porphyrins in malignant gliomas, which emit red luminescence under °uorescent microscope.129 In the third stage clinical test of ALA, it has beenshown that °uorescence-guided surgery can achieve signi¯cant improvement in patient outcome. At the same time, however, circulation half-lifeand side e®ects should also be taken into account. To this point, nanocarriers have been explored to load imaging dyes such as Cy5.5 (a nearIR °uorophore), Coomassie Brilliant Blue (a blue dye) and Raman imaging agents to facilitate the intraoperative tumor mass resection as well as to overcome the drawbacks of free agents.48,49,66,67,76,89 Iron oxide NPs have been investigated to carry Cy5.5 for real-time monitoring of medulloblastoma mass in a transgenic mouse model, surface-conjugated PEG and CTX are to prolong circulation half-life of the nanoprobes and target them to tumor cells, respectively.89 The magneto°ouroscent NPs have been shown to be able to speci¯cally target medulloblastoma cells and highly discriminate tumor from healthy tissue in both MRI and °uorescent image.89 Therefore, such multifunctional NPs will potentially combine preoperative diagnosis and intraoperative real-time tumor margin delineation to facilitate tumor resection. Similarly, multifunctional nanoprobes based on AuNPs have been synthesized to further facilitate malignant primary brain tumor resection.76 Recently, Kircher et al. have reported a triple-modality MRI–photoacoustic imaging–Raman imaging NP that can accurately guide intraoperative tumor resection relying on an EPR passive targeting mechanism.76 This NP
1430001-7
R. Liang & F. Fang
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
Fig. 3. Illustration of Cy5.5-Lf-MPNA nanogels, which included magnetic contrast agents, °uorescent imaging agents, activetargeting moiety as well as pH/temperature sensitivity structure. Lf: lactoferrin, LRP 1: low density lipoprotein receptor-related protein 1 (color online). (Reprinted from Ref. 48, with permission from Elsevier.)
comprises a gold core which exerts intensive photoacoustic e®ect and surface-enhanced Raman scattering e®ect, a Raman imaging agent layer to present high-resolution surface imaging of tumor margins, a silica shell to protect the Raman-active layer and a Gd coating to acquire T1-weighted enhanced MRI. The researchers have concluded that photoacoustic imaging could guide main gross resection and Raman imaging could guide completely microscopic tumor deposits removing.76 SiNPs are not separately reported to load imaging agents for intraoperative delineation of malignant primary brain tumors, while they have been designed as silica shell in multifunctional AuNPs.76 QDs and CNTs have not yet been applied to experimental orthotopic malignant primary brain tumors as diagnostic agents.130,131 Apart from these inorganic NPs, some organic nanovehicles, i.e., dendrimers and nanogels, have also found roles in intraoperative brain tumor delineation.48,49,65–67 Yan et al. have developed a multimodal optical/paramagnetic dendrimer to load gadolinium and Cy5.5 across the BBB and image glioma with high-sensitivity in vivo.66 The researchers have modi¯ed the dendrimer surface with angiopep-2 peptide to target the BBB and brain tumors.66 Follow-up work of the same group has demonstrated a dual-targeting dendrimer with surface-labeled angiopep-2 and RGD peptide to improve BBB transcytosis e±cacy and sensitivity of tumor delineation.67 Recently, Jiang et al. have explored an interesting multimodal nanocarrier, pH/temperature-sensitive magnetic nanogel48 (the illustration was shown in Fig. 3). Fe3O4 NPs-loaded stimuli-responsive nanogel was coated with Cy5.5labeled lactoferrin (Cy5.5-Lf).48 Interestingly, such
novel nanogel will undergo hydrophilic-hydrophobic transition at lower critical solution temperature (LCST), which could be adjusted by pH change within tumor environment.48 In low pH circumstance of tumor parenchyma, these nanogels would become hydrophobic. As a result, the multimodal imaging agents would stay longer in tumor tissue. The researchers have demonstrated that the stimuli-responsive nanogel has long blood circulation time as well as speci¯c accumulation in tumor tissue, which achieve a precisely dual imaging of glioma.48 Unlike these special optical imaging approaches which largely rely on special device or particular visualizing condition, Nie et al. have reported an in vivo tumor-speci¯c visible color staining, using Coomassie Brilliant Blue-loaded hydrogel NPs.49 The transportation of this blue dye into brain tumor cells makes tumor visible under normal lighting conditions in operating room and can be used to guide mass resection during operation.49 Multifunctional nanomaterials loading two or more imaging agents simultaneously have dual advantages in malignant primary brain tumor diagnosis. On one hand, the multimodal nanocarriers can be used for imaging exact tumor margins preoperatively, which helps neurosurgeons better assess patient conditions and make a surgical plan. On the other hand, they allow a better contrast of tumor and peritumoral tissues intraoperatively, which can provide a better guidance for the tumor resection. Additionally, dual tumor targeting moieties modi¯ed nanovehicles may have high tumor distribution. Therefore, these multifunctional nanomaterials are quite promising for diagnosing malignant primary brain tumors.
1430001-8
Diagnosis and Treatment for Malignant Primary Brain Tumors
4. Application of Nanomaterials in Treatment for Malignant Primary Brain Tumors 4.1. Nanomaterials in intravenous administration
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
As discussed above, current clinical improvements in surgery and adjuvant therapies for malignant primary brain tumors have not led to meaningful improvements in patient outcome.7 Apart from low complete resection rate, decreased chemotherapy e±cacy by BBB and BTB also need to be taken into account. For example, doxorubicin and paclitaxel have been shown to have high cytotoxicity to glioma cell lines, but their clinical use is limited because these drugs alone are incapable of crossing the BBB and BTB.132
4.1.1. Nanomaterial-based chemotherapy Nanomaterials, as demonstrated above, can e®ectively traverse BBB and BTB via passive/active targeting mechanisms. Various chemotherapeutic drugs, i.e., doxorubicin, gemcitabine and docetaxel, have been successfully loaded onto targeted nanomaterials to increase the uptake of drugs into malignant primary brain tumors and improve e±cacy of chemotherapy.55,56,58,93,133 Nevertheless, the percentage of injected drug dose accumulated in brain is still less than 1%, large amounts of targeted drug-loaded nanomaterials are localized in the liver.44 Low drug accumulation in brain leads to less overall e®ective treatment of malignant primary brain tumors, and high localization in liver may cause some unwanted side e®ects. The current aim of nanovehicle-based drug delivery is to increase drug accumulation in tumors as well as to largely improve treatment e±cacy. Dual-targeting moieties modi¯ed nanocarriers, as discussed, may have higher BBB and BTB traversing ability and more precise tumor localization. Liposomes and micelles are the most well-known anticancer drug delivery systems, and have been deeply explored as dual active-targeting platforms.54,57,59,60,90,91,134 These NPs are surface-modi¯ed with one or two ligands and/or antibodies that will enable them to target BBB/BTB ¯rst and then target malignant primary brain tumors, forming a two-stage targeting.59,134 Such NPs have been demonstrated with a high BBB penetration and speci¯c tumor-targeting abilities. For instance, Gao et al.
have utilized a TGN peptide to facilitate BBB traversing and an AS1411 aptamer to speci¯cally target the BBB and glioma cells, PEG-PCL micelles modi¯ed with TGN and AS1411 have been shown to highly accumulate paclitaxel in glioma and present the best anti-glioma e®ect.57 CNTs have also found a role in dual-targeting chemotherapy for malignant primary brain tumors. Recently, Ren et al. have explored angiopep-2 modi¯ed PEGylated oxidized multi-walled carbon nanotubes (O-MWNTs-PEGANG) with high drug-loading e±ciency and an obvious pH-dependent drug release ability (the detail illustration is shown in Fig. 4) the multifunctional nanocarriers have been demonstrated to increase doxorubicin accumulation at glioma sites.81 Therefore, dual-targeting nanomaterials are valuable for improving drug accumulation in malignant primary brain tumors as well as the anticancer e±cacy. Recently, magnetic targeting mechanism has raised interest in anticancer drug delivery for malignant primary brain tumors, which has been considered as alternative targeted routes. MNPs are optimizing magnetic targeting nanovehicles that responded to an external local magnetic ¯eld.135–137 Hua et al. have utilized an external magnetic ¯eld to actively target carmustine-loaded MNPs to glioma as well as e±ciently enhance drug concentrations.138 Since magnetic targeting mechanism relies mainly on the localized BBB disruptures, the use of FUS to increase the EPR e®ect has been explored.24 FUS can form microbubbles in the capillary lumen which, in turn, increases permeability of the BBB transiently. FUS combined with an external magnetic ¯eld can increase the retention of doxorubicin-MNPs in glioma, achieving improvement in chemotherapy.139
4.1.2. Nanomaterial-based gene therapy Similarly, nanomaterial-based gene therapy is also believed to hold a promise for improving the treatment outcome of malignant primary brain tumors.34 It has been shown that DNA/siRNA-loaded nanomaterials such as micelles, polymer NPs, QDs and SLNs can guide gene therapy in glioblastomabearing mice, which mainly focus on cell function block, gene silence as well as cell apoptosis of glioma.71,96,140,141 Again, dual-targeting mechanism utilized in gene therapy could enhance anticancer e±cacy of such gene agents.64,96 Recently, attempts have been made in co-loading of drug and gene for enhancing therapeutic e®ects of glioma, this
1430001-9
R. Liang & F. Fang
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
(a)
(b)
(c) Fig. 4. Illustration of the work from Ren et al.81 which are promising for drug accumulation in glioma foci.(a) The TEM image of oxidized MWNTs. (b) The Raman spectra of raw MWNTs (a) and oxidized MWNTs (b). (c) Synthetic scheme to DOX-O-MWNTsPEG -ANG. MWNTs: multiwalled carbon nanotubes, ANG: angiopep-2 peptide, DOX: doxorubicin (color online). (Reprinted from Ref. 81, with permission from Elsevier)
multimodal anticancer agents may act as an alternative method for conventional chemotherapy, since drug accumulation in brain tumor tissues are still a large challenge even with targeted nano-based drug delivery.53
4.2. Nanomaterials-based local therapy Even the most malignant brain tumors have shown a rare systemic metastasis behavior.142 Therefore, systemic chemotherapy may not be the best choice due to its severe side e®ects. There is a demand to explore in situ cancer therapies to help improve patient outcome.
4.2.1. Local thermotherapy technology Thermotherapy is a therapeutic technology that can increase tissue temperature locally, which disrupts
the functionality of tumor tissue cells and then kills them.143 This technique has been shown to have good results in clinic. However,conventional methods cannot achieve a heat homogenous distribution inside tumor tissue. And peritumoral tissue damage must be taken into account. The magnetic hyperthermia technique (MTH) relies on selective distribution of magnetic NPs inside the tumor tissue. External application of an alternating magnetic ¯eld (AMF) can heat up the MNPs, which will cause thermal damage to tumor cells speci¯cally. An excellent review of MTH has been presented by Silva et al.73 Clinical trials have successfully demonstrated the safety and e±cacy of MTH, and it can largely improve the outcome in patients with recurrent GBMs when combined with external radiotherapy.144,145 AuNPs and CNTs have also shown good results in thermotherapy under infrared or radiofrequency
1430001-10
Diagnosis and Treatment for Malignant Primary Brain Tumors
pulses, due to their inherent SPR properties.77,80,146,147 However, to date, they have not yet been applied to brain tumors. Recently, Wang et al.94 have explored a super multifunctional theranostic nanomaterial for visualized glioma therapy. The 200 nm super jumbo has been based on biocompatible mesoporous silica containing graphene oxide nanosheets for photothermal therapy, Fe3O4 NPs for magnetic targeting and MRI detection, doxorubicin for chemotherapy and surface-modi¯ed targeting peptide IL-13. This targeting system has been demonstrated successfully as visualized glioma medicine with pH-sensitive and sustained release features.
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
4.2.2. Nanomaterial-based photodynamic therapy Photodynamic therapy (PDT) is a photosensitizerdependent light-activated anticancer treatment, which can produce reactive oxygen species (ROS) to cause oxidative damage and subsequent death of cells. Due to this inherent feature of photosensitizers, nanocarriers have been explored to target such photodynamic agents for malignant primary brain tumor therapy.68,148,149 Reddy et al.148,149 have explored nanogels to encapsulate Photofrin as well as iron oxide for extracellular and intracellular PDT of i.e., gliomas, using RGD peptide and F3 peptide as surface-modi¯ed targeting moieties, respectively. Activation of such photodynamic nanomaterials via laser treatment using a ¯ber optic probe into tumor sites have signi¯cantly increased the survival time of rats. Furthermore, MRI agents in nanogels and inherent °uorescent characteristic of Photofrin can guide detection of gliomas as well as track drug's distribution in vivo. Cheng et al. have reported EGF peptide-modi¯ed AuNPs to deliver phthalocyanine 4 (Pc 4), a photosensitizer, for glioma PDT. Similarly, the °uorescent Pc 4 combines therapy with optical imaging.68 Theranostic nanomaterials like MNPs, and the above-mentioned nanocarriers combine glioma treatment and diagnosis simultaneously.68,94,138,148,149 They can track real-time drug uptake as well as the fate of anticancer drugs before and after crossing the BBB and BTB, which is a potential avenue for future research to improve drug accumulation in tumor sites.
4.2.3. Nanomaterials in local administration While systemic administration of nanomaterialbased diagnostic/anticancer agents will face two
obstacles (i.e., the RES and BBB/BTB) before making any anticancer e®ects, researchers have made e®orts on local administration. In situ administration of drug-loaded nanocarriers can bypass the BBB/BTB as well as increase drug accumulation in tumor sites. For instance, gene/drug–NPloaded micro¯bers and MNPs-loaded thermosensitive hydrogels implanted in tumor beds have been demonstrated to achieve a sustained release of each agent, resulting in e®ective therapy and diagnosis.150,151 Nevertheless, the complex anticancer agent di®usion is less than a few millimeters from the injection/implantation site. What is more, the di®usion technologies is hard to standardize and control.152 The use and development of CED technology has been considered as a promising method to extend drug di®usion diameter as well as distribution volume within tumor parenchyma.152,153 Relying on pressure gradient and bulk °ow in brain parenchyma, CED can expand drug di®usion diameter up to 3 cm.153 Several CED nanomaterials have been applied for preclinical studies and clinical trials in brain tumor diagnosis and therapy.154 Surface modi¯ed with targeting moieties has been introduced to enhance tumor a±nity of such CED nanocarriers.154 Whereas, CED does have its drawbacks, besides bleeding and contamination from catheter implantation, CED can produce uneven and unpredictable distribution and leakage of drug into the subarachnoid space, resulting in unwanted widespread neurotoxicity.153 Thus, the future development of such technology will focus on new instrumentations and methods to improve drug distribution in tumor tissues as well as to reduce unwanted side e®ects. The theranostic nanomaterials mentioned in this review may hold promise for creating real-time visualization of CED technology in malignant primary brain tumor therapy, which could largely reduce side e®ects of CED.92
5. Prospects Nanotechnology has been developing rapidly in the ¯eld of biomedicine and provides more choices in malignant primary brain tumor diagnosis and treatment. Nanomaterial-based contrast agents for MRI, CT and PET have held promise for neuroimaging of malignant primary brain tumors. Anticancer agent-based nanovehicles have been widely used in malignant primary brain tumor treatment, which can largely reduce drug side e®ects. Although
1430001-11
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
R. Liang & F. Fang
application of surface-modi¯ed targeting moieties can improve anticancer e±cacy of drug-loaded nanomaterials, drug accumulation in tumor tissue is still a challenge. The use of hydrophilic surfactants like PEG could prolong drug circulation half-life. Dual-targeted nanocarriers may highly increase drug accumulation in tumor tissues. In addition, multimodal nanomaterials that combine di®erent anticancer agents simultaneously may create synergistic therapy e®ects, which could improve anticancer e±cacy even with less chemotherapeutic accumulation. Theranostic nanomaterials provide a visualization therapy in vivo, which hold promise for future researches to increase drug accumulation in tumor tissues. In spite of some unwanted drawbacks, CED technology is indeed a prospective approach to improve e±cacy of drug delivery to malignant primary brain tumors. Toxicology concerns should be clari¯ed before nanomaterials can be applied to clinic, and there are plenty to solve. Altogether, nanomaterials have been shown as potential platforms in malignant primary brain tumor diagnosis and treatment. We believe that more novel nanotechnologies will be applied to clinicin the near future.
Acknowledgments The authors would like to acknowledge the ¯nancial supports by the projects of National Natural Science Foundation of China (contract/Grant number: 81100925).
References 1. T. A. Dolecek, J. M. Propp, N. E. Stroup and C. Kruchko, Neuro Oncol. 14, v1 (2012). 2. T. Jiang, G. Tang, Y. Lin, X. Peng, X. Zhang, X. Zhai, X. Peng, J. Yang, H. Huang and N. Wu, Chin. Med. J. 124, 2578 (2011). 3. E. A. Knopp and W. Montanera. Brain tumors in Diseases of the Brain, Head & Neck, Spine 2012– 2015, Vol. 3 (Springer, 2012). 4. T. F. Massoud and S. S. Gambhir, Genes Dev. 17, 545 (2003). 5. S. P. Manninger, L. L. Muldoon, G. Nesbit, T. Murillo, P. M. Jacobs and E. A. Neuwelt, Am. J. Neuroradiol. 26, 2290 (2005). 6. E. Neuwelt, P. Varallyay, A. Bago, L. Muldoon, G. Nesbit and R. Nixon, Neuropathol. Appl. Neurobiol. 30, 456 (2004).
7. D. Ricard, A. Idbaih, F. Ducray, M. Lahutte, K. Hoang-Xuan and J. Y. Delattre, Lancet 379, 1984 (2012). 8. M. A. Castello, A. Clerico, G. Deb, C. Dominici, P. Fidani and A. Donfrancesco, J. Pediatr. Hematol. Oncol. 12, 297 (1990). 9. Y. R. Lawrence, X. A. Li, I. El Naqa, C. A. Hahn, L. B. Marks, T. E. Merchant and A. P. Dicker, Int. J. Radia. Oncol. Biol. Phys. 76, S20 (2010). 10. G. Lee, S. Dallas, M. Hong and R. Bendayan, Pharmacol. Rev. 53, 569 (2001). 11. D. R. Groothuis, Neuro Oncol. 2, 45 (2000). 12. C. Carr, J. Ng and T. Wigmore, Curr. Anaesth. Crit. Care 19, 70 (2008). 13. N. J. Abbott, A. A. Patabendige, D. E. Dolman, S. R. Yusof and D. J. Begley, Neurobiol. Dis. 37, 13 (2010). 14. D. S. Miller, Trends Pharmacol. Sci. 31, 246 (2010). 15. H. Wolburg, S. Noell, P. Fallier-Becker, A. F. Mack and K. Wolburg-Buchholz, Mol. Aspects Med. 33, 579 (2012). 16. S. Noell, D. Mayer, W. S. Strauss, M. S. Tatagiba and R. Ritz, Int. J. Oncol. 38, 1343 (2011). 17. E. G. Van Meir, C. G. Hadjipanayis, A. D. Norden, H. K. Shu, P. Y. Wen and J. J. Olson, CA Cancer J. Clin. 60, 166 (2010). 18. N. A. de Vries, J. H. Beijnen, W. Boogerd and O. van Tellingen, Expert Rev. Neurother. 6, 1199 (2006). 19. A. Regina, M. Demeule, A. Laplante, J. Jodoin, C. Dagenais, F. Berthelet, A. Moghrabi and R. Beliveau, Cancer Metastasis Rev. 20, 13 (2001). 20. H. Bronger, J. Konig, K. Kopplow, H. H. Steiner, R. Ahmadi, C. Herold-Mende, D. Keppler and A. T. Nies, Cancer Res. 65, 11419 (2005). 21. R. Gabathuler, Neurobiol. Dis. 37, 48 (2010). 22. W. M. Pardridge, Pharm. Res. 24, 1733 (2007). 23. W. A. Vandergrift and S. J. Patel, Neurosurg. Focus 20, E13 (2006). 24. K. Hynynen, N. McDannold, N. Vykhodtseva, S. Raymond, R. Weissleder, F. A. Jolesz and N. Sheikov, J. Neurosurg. 105, 445 (2006). 25. L. Juillerat-Jeanneret, Drug Discov. Today 13, 1099 (2008). 26. A. Regina, M. Demeule, C. Che, I. Lavallee, J. Poirier, R. Gabathuler, R. Beliveau and J. P. Castaigne, Br. J. Pharmacol. 155, 185 (2008). 27. H. Gleiter, Acta Mater. 48, 1 (2000). 28. G. Adlakha-Hutcheon, R. Khaydarov, R. Korenstein, R. Varma, A. Vaseashta, H. Stamm and M. Abdel-Mottaleb. Nanomaterials, Nanotechnology in Nanomaterials: Risks and Bene¯ts, Vol. 3 (Springer, 2009), p. 195.
1430001-12
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
Diagnosis and Treatment for Malignant Primary Brain Tumors
29. M. E. Padin-Iruegas, Y. Misao, M. E. Davis, V. F. M. Segers, G. Esposito, T. Tokunou, K. Urbanek, T. Hosoda, M. Rota and P. Anversa, Circulation 120, 876 (2009). 30. E. Luong-Van, L. Grøndahl, K. N. Chua, K. W. Leong, V. Nurcombe and S. M. Cool, Biomaterials 27, 2042 (2006). 31. V. Vamvakaki, K. Tsagaraki and N. Chaniotakis, Anal. Chem. 78, 5538 (2006). 32. A. Brioschi, F. Zenga, G. P. Zara, M. R. Gasco, A. Ducati and A. Mauro, Neurol. Res. 29, 324 (2007). 33. I. Liao, S. Chen, J. B. Liu and K. W. Leong, J. Control. Release 139, 48 (2009). 34. W. Lu, Q. Sun, J. Wan, Z. She and X. G. Jiang, Cancer Res. 66, 11878 (2006). 35. R. Konaka, E. Kasahara, W. C. Dunlap, Y. Yamamoto, K. C. Chien and M. Inoue, Redox Rep. 6, 319 (2001). 36. S. K. Choi, M. Mammen and G. M. Whitesides, Chem. Biol. 3, 97 (1996). 37. L. Yubao, J. Wijn, C. Klein, S. Meer and K. Groot, J. Mater. Sci. Mater. Med. 5, 252 (1994). 38. H. Hillaireau and P. Couvreur, Cell. Mol. Life Sci. 66, 2873 (2009). 39. C. D. Black and G. Gregoriadis, Intracellular Fate and E®ect of Liposome-entrapped Actinomycin D Injected into Rats (Portland, 1974). 40. P. Couvreur, P. Tulkens, M. Roland, A. Trouet and P. Speiser, FEBS Lett. 84, 323 (1977). 41. S. Shibata, A. Ochi and K. Mori, Neurol. Med. Chir. (Tokyo) 30, 242 (1990). 42. P. Ramos-Cabrer and F. Campos, Int. J. Nanomed. 8, 951 (2013). 43. J. D. Meyers, T. Doane, C. Burda and J. P. Basilion, Nanomedicine 8, 123 (2013). 44. L. Costantino and D. Boraschi, Drug Discov. Today 17, 367 (2012). 45. D. E. Lee, H. Koo, I. C. Sun, J. H. Ryu, K. Kim and I. C. Kwon, Chem. Soc. Rev. 41, 2656 (2012). 46. S. S. Kelkar and T. M. Reineke, Bioconjug. Chem. 22, 1879 (2011). 47. N. Y. Hernandez-Pedro, E. Rangel-Lopez, R. Magana-Maldonado, V. P. de la Cruz, A. S. del Angel, B. Pineda and J. Sotelo, Biomed. Res. Int. 2013, 351031 (2013). 48. L. Jiang, Q. Zhou, K. Mu, H. Xie, Y. Zhu, W. Zhu, Y. Zhao, H. Xu and X. Yang, Biomaterials 34, 7418 (2013). 49. G. Nie, H. J. Hah, G. Kim, Y. E. K. Lee, M. Qin, T. S. Ratani, P. Fotiadis, A. Miller, A. Kochi and D. Gao, Small 8, 884 (2012). 50. J. Jin, K. H. Bae, H. Yang, S. J. Lee, H. Kim, Y. Kim, K. M. Joo, S. W. Seo, T. G. Park and D. H. Nam, Bioconjug. Chem. 22, 2568 (2011).
51. D. A. Orringer, Y. Koo, T. Chen, R. Kopelman, O. Sagher and M. Philbert, Clin. Pharmacol. Ther. 85, 531 (2009). 52. N. Oku, M. Yamashita, Y. Katayama, T. Urakami, K. Hatanaka, K. Shimizu, T. Asai, H. Tsukada, S. Akai and H. Kanazawa, Int. J. Pharm. 403, 170 (2011). 53. H. Wang, W. Su, S. Wang, X. Wang, Z. Liao, C. Kang, L. Han, J. Chang, G. Wang and P. Pu, Nanoscale 4, 6501 (2012). 54. J. Q. Gao, Q. Lv, L. M. Li, X. J. Tang, F. Z. Li, Y. L. Hu and M. Han, Biomaterials 34, 5628 (2013). 55. S. Wohlfart, A. S. Khalansky, S. Gelperina, O. Maksimenko, C. Bernreuther, M. Glatzel and J. Kreuter, PLoS One 6, e19121 (2011). 56. C.-X. Wang, L.-S. Huang, L.-B. Hou, L. Jiang, Z.-T. Yan, Y.-L. Wang and Z.-L. Chen, Brain Res. 1261, 91 (2009). 57. H. Gao, J. Qian, S. Cao, Z. Yang, Z. Pang, S. Pan, L. Fan, Z. Xi, X. Jiang and Q. Zhang, Biomaterials 33, 5115 (2012). 58. H. Gao, J. Qian, Z. Yang, Z. Pang, Z. Xi, S. Cao, Y. Wang, S. Pan, S. Zhang, W. Wang, X. Jiang and Q. Zhang, Biomaterials 33, 6264 (2012). 59. H. Xin, X. Jiang, J. Gu, X. Sha, L. Chen, K. Law, Y. Chen, X. Wang, Y. Jiang and X. Fang, Biomaterials 32, 4293 (2011). 60. H. Xin, X. Sha, X. Jiang, W. Zhang, L. Chen and X. Fang, Biomaterials 33, 8167 (2012). 61. A. V. Kabanov and S. V. Vinogradov, Angew. Chem. Int. Ed. Engl. 48, 5418 (2009). 62. L. Zha, B. Banik and F. Alexis, Soft Matter 7, 5908 (2011). 63. R. Huang, L. Han, J. Li, S. Liu, K. Shao, Y. Kuang, X. Hu, X. Wang, H. Lei and C. Jiang, Biomaterials 32, 5177 (2011). 64. S. Huang, J. Li, L. Han, S. Liu, H. Ma, R. Huang and C. Jiang, Biomaterials 32, 6832 (2011). 65. H. Sarin, A. S. Kanevsky, H. Wu, K. R. Brimacombe, S. H. Fung, A. A. Sousa, S. Auh, C. M. Wilson, K. Sharma, M. A. Aronova, R. D. Leapman, G. L. Gri±ths and M. D. Hall, J. Transl. Med. 6, 80 (2008). 66. H. Yan, J. Wang, P. Yi, H. Lei, C. Zhan, C. Xie, L. Feng, J. Qian, J. Zhu, W. Lu and C. Li, Chem. Commun. (Camb.) 47, 8130 (2011). 67. H. Yan, L. Wang, J. Wang, X. Weng, H. Lei, X. Wang, L. Jiang, J. Zhu, W. Lu and X. Wei, ACS Nano 6, 410 (2011). 68. Y. Cheng, J. D. Meyers, R. S. Agnes, T. L. Doane, M. E. Kenney, A. M. Broome, C. Burda and J. P. Basilion, Small 7, 2301 (2011). 69. C. Sun, O. Veiseh, J. Gunn, C. Fang, S. Hansen, D. Lee, R. Sze, R. G. Ellenbogen, J. Olson and M. Zhang, Small 4, 372 (2008).
1430001-13
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
R. Liang & F. Fang
70. F. Barandeh, P. L. Nguyen, R. Kumar, G. J. Iacobucci, M. L. Kuznicki, A. Kosterman, E. J. Bergey, P. N. Prasad and S. Gunawardena, PLoS One 7, e29424 (2012). 71. J. Jung, A. Solanki, K. A. Memoli, K. I. Kamei, H. Kim, M. A. Drahl, L. J. Williams, H. R. Tseng and K. Lee, Angew. Chem. 122, 107 (2009). 72. J. Y. Park, M. J. Baek, E. S. Choi, S. Woo, J. H. Kim, T. J. Kim, J. C. Jung, K. S. Chae, Y. Chang and G. H. Lee, ACS Nano 3, 3663 (2009). 73. A. C. Silva, T. R. Oliveira, J. B. Mamani, S. M. F. Malheiros, L. Malavolta, L. F. Pavon, T. T. Sibov, E. Amaro Jr, A. Tannús and E. L. G. Vidoto, Int. j. Nanomedicine 6, 591 (2011). 74. M. Wankhede, A. Bouras, M. Kaluzova and C. G. Hadjipanayis, Expert Rev. Clin. Pharmacol. 5, 173 (2012). 75. J. F. Hainfeld, H. M. Smilowitz, M. J. O'Connor, F. A. Dilmanian and D. N. Slatkin, Nanomedicine (Lond) 8, 1601 (2012). 76. M. F. Kircher, A. de la Zerda, J. V. Jokerst, C. L. Zavaleta, P. J. Kempen, E. Mittra, K. Pitter, R. Huang, C. Campos and F. Habte, Nat. Med. 18, 829 (2012). 77. R. R. Letfullin, C. B. Iversen and T. F. George, Nanomed. Nanotechnol. Biol. Med. 7, 137 (2011). 78. D. P. Ferris, J. Lu, C. Gothard, R. Yanes, C. R. Thomas, J. C. Olsen, J. F. Stoddart, F. Tamanoi and J. I. Zink, Small 7, 1816 (2011). 79. R. G. Mendes, A. Bachmatiuk, B. B€ uchner, G. Cuniberti and M. H. R€ ummeli, J. Mater. Chem. B 1, 401 (2013). 80. P. Chakravarty, R. Marches, N. S. Zimmerman, A. D.-E. Swa®ord, P. Bajaj, I. H. Musselman, P. Pantano, R. K. Draper and E. S. Vitetta, Proc. Nat. Acad. Sci. 105, 8697 (2008). 81. J. Ren, S. Shen, D. Wang, Z. Xi, L. Guo, Z. Pang, Y. Qian, X. Sun and X. Jiang, Biomaterials 33, 3324 (2012). 82. K. Knop, R. Hoogenboom, D. Fischer and U. S. Schubert, Angew. Chem. Int. Ed. Engl. 49, 6288 (2010). 83. J. V. Jokerst, T. Lobovkina, R. N. Zare and S. S. Gambhir, Nanomedicine 6, 715 (2011). 84. G. Orive, O. A. Ali, E. Anitua, J. L. Pedraz and D. F. Emerich, Biochim. Biophys. Acta 1806, 96 (2010). 85. H. A. Edens, B. P. Levi, D. L. Jaye, S. Walsh, T. A. Reaves, J. R. Turner, A. Nusrat and C. A. Parkos, J. Immunol. 169, 476 (2002). 86. G. Sledge and K. Miller, Eur. J. Cancer 39, 1668 (2003). 87. L. Brannon-Peppas and J. O. Blanchette, Adv. Drug Deliv. Rev. 56, 1649 (2004). 88. R. K. Jain, Cancer Metastasis Rev. 6, 559 (1987).
89. O. Veiseh, C. Sun, C. Fang, N. Bhattarai, J. Gunn, F. Kievit, K. Du, B. Pullar, D. Lee, R. G. Ellenbogen, J. Olson and M. Zhang, Cancer Res. 69, 6200 (2009). 90. W. Tian, X. Ying, J. Du, J. Guo, Y. Men, Y. Zhang, R. J. Li, H. J. Yao, J. N. Lou, L. R. Zhang and W. L. Lu, Eur. J. Pharm. Sci. 41, 232 (2010). 91. X. Ying, H. Wen, W. L. Lu, J. Du, J. Guo, W. Tian, Y. Men, Y. Zhang, R. J. Li, T. Y. Yang, D. W. Shang, J. N. Lou, L. R. Zhang and Q. Zhang, J. Control. Release 141, 183 (2010). 92. C. G. Hadjipanayis, R. Machaidze, M. Kaluzova, L. Wang, A. J. Schuette, H. Chen, X. Wu and H. Mao, Cancer Res. 70, 6303 (2010). 93. A. B. Madhankumar, B. Slagle-Webb, X. Wang, Q. X. Yang, D. A. Antonetti, P. A. Miller, J. M. Sheehan and J. R. Connor, Mol. Cancer Ther. 8, 648 (2009). 94. Y. Wang, R. Huang, G. Liang, Z. Zhang, P. Zhang, S. Yu and J. Kong, Small (2013), doi: 10.1002/ smll.2013012197. 95. G. R. Reddy, M. S. Bhojani, P. McConville, J. Moody, B. A. Mo®at, D. E. Hall, G. Kim, Y. E. L. Koo, M. J. Woolliscroft and J. V. Sugai, Clin. Cancer. Res. 12, 6677 (2006). 96. C. Zhan, Q. Meng, Q. Li, L. Feng, J. Zhu and W. Lu, Chem. Asian. J 7, 91 (2012). 97. Z. H. Wang, Z. Y. Wang, C. S. Sun, C. Y. Wang, T. Y. Jiang and S. L. Wang, Biomaterials 31, 908 (2010). 98. Y. L. Hu and J. Q. Gao, Int. J. Pharm. 394, 115 (2010). 99. V. I. Shubayev, T. R. Pisanic, 2nd and S. Jin, Adv. Drug Deliv. Rev. 61, 467 (2009). 100. A. Nunes, K. T. Al-Jamal and K. Kostarelos, J. Control. Release 161, 290 (2012). 101. N. Chen, Y. He, Y. Su, X. Li, Q. Huang, H. Wang, X. Zhang, R. Tai and C. Fan, Biomaterials 33, 1238 (2012). 102. X. D. Zhang, D. Wu, X. Shen, P. X. Liu, N. Yang, B. Zhao, H. Zhang, Y. M. Sun, L. A. Zhang and F. Y. Fan, Int. J. Nanomedicine 6, 2071 (2011). 103. C. J. Rivet, Y. Yuan, D. A. Borca-Tasciuc and R. J. Gilbert, Chem. Res. Toxicol. 25, 153 (2012). 104. G. Gobe and D. Crane, Toxicol. Lett. 198, 49 (2010). 105. A. Cuypers, M. Plusquin, T. Remans, M. Jozefczak, E. Keunen, H. Gielen, K. Opdenakker, A. R. Nair, E. Munters, T. J. Artois, T. Nawrot, J. Vangronsveld and K. Smeets, BioMetals 23, 927 (2010). 106. T. T. Win-Shwe and H. Fujimaki, Int. J. Mol. Sci. 12, 6267 (2011). 107. T. R. Pisanic 2nd, J. D. Blackwell, V. I. Shubayev, R. R. Finones and S. Jin, Biomaterials 28, 2572 (2007).
1430001-14
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
Diagnosis and Treatment for Malignant Primary Brain Tumors
108. T. K. Jain, M. K. Reddy, M. A. Morales, D. L. Leslie-Pelecky and V. Labhasetwar, Mol. Pharm. 5, 316 (2008). 109. J. J. Li, D. Hartono, C. N. Ong, B. H. Bay and L. Y. Yung, Biomaterials 31, 5996 (2010). 110. E. J. Park and K. Park, Toxicol. Lett. 184, 18 (2009). 111. C. P. Firme 3rd and P. R. Bandaru, Nanomedicine 6, 245 (2010). 112. T. Liu, L. Li, X. Teng, X. Huang, H. Liu, D. Chen, J. Ren, J. He and F. Tang, Biomaterials 32, 1657 (2011). 113. C. Lasagna-Reeves, D. Gonzalez-Romero, M. A. Barria, I. Olmedo, A. Clos, V. M. Sadagopa Ramanujam, A. Urayama, L. Vergara, M. J. Kogan and C. Soto, Biochem. Biophys. Res. Commun. 393, 649 (2010). 114. B. Wang, W. Feng, M. Zhu, Y. Wang, M. Wang, Y. Gu, H. Ouyang, H. Wang, M. Li, Y. Zhao, Z. Chai and H. Wang, J. Nanopart. Res. 11, 41 (2008). 115. E. Hutter, S. Boridy, S. Labrecque, M. LalancetteHebert, J. Kriz, F. M. Winnik and D. Maysinger, ACS Nano 4, 2595 (2010). 116. J. Wu, C. Wang, J. Sun and Y. Xue, ACS Nano 5, 4476 (2011). 117. J. M. MatÉs, C. Perez-Gómez and I. N. De Castro, Clin. Biochem. 32, 595 (1999). 118. I. Miladi, G. Le Duc, D. Kryza, A. Berniard, P. Mowat, S. Roux, J. Taleb, P. Bonazza, P. Perriat, F. Lux, O. Tillement, C. Billotey and M. Janier, J. Biomater. Appl. 28, 385 (2012). 119. P. Varallyay, G. Nesbit, L. L. Muldoon, R. R. Nixon, J. Delashaw, J. I. Cohen, A. Petrillo, D. Rink and E. A. Neuwelt, Am. J. Neuroradiol. 23, 510 (2002). 120. E. A. Neuwelt, C. G. V arallyay, S. Manninger, D. Solymosi, M. Haluska, M. A. Hunt, G. Nesbit, A. Stevens, M. Jerosch-Herold and P. M. Jacobs, Neurosurgery 60, 601 (2007). 121. M. Kumar, Z. Medarova, P. Pantazopoulos, G. Dai and A. Moore, Magn. Reson. Med. 63, 617 (2010). 122. H. Xie, Y. Zhu, W. Jiang, Q. Zhou, H. Yang, N. Gu, Y. Zhang, H. Xu, H. Xu and X. Yang, Biomaterials 32, 495 (2011). 123. P. Ghosh, G. Han, M. De, C. K. Kim and V. M. Rotello, Adv. Drug Deliv. Rev. 60, 1307 (2008). 124. Z. Z. J. Lim, J. E. J. Li, C. T. Ng, L. Y. L. Yung and B. H. Bay, Acta Pharmacol. Sin. 32, 983 (2011). 125. W. Stummer, M. J. van den Bent and M. Westphal, Acta Neurochir. (Wien.) 153, 1211 (2011). 126. C. Senft, K. Franz, S. Blasel, A. Oszvald, J. Rathert, V. Seifert and T. Gasser, Technol. Cancer Res. Treat. 9, 339 (2010). 127. H. M. Mehdorn, F. Schwartz, S. Dawirs, J. Hedderich, L. D€ orner and A. Nabavi, Intraoperative Imaging, Acta Neurochir Suppl 109, 103 (2011).
128. E. G. Van Meir, C. G. Hadjipanayis, A. D. Norden, H. K. Shu, P. Y. Wen and J. J. Olson, CA Cancer J. Clin. 60, 166 (2010). 129. W. Stummer, U. Pichlmeier, T. Meinel, O. D. Wiestler, F. Zanella and H. J. Reulen, Lancet Oncol. 7, 392 (2006). 130. D. J. Arndt-Jovin, S. R. Kantelhardt, W. Caarls, A. H. de Vries, A. Giese and T. M. Jovin, IEEE Trans. Nanobioscience 8, 65 (2009). 131. A. de la Zerda, Z. Liu, S. Bodapati, R. Teed, S. Vaithilingam, B. T. Khuri-Yakub, X. Chen, H. Dai and S. S. Gambhir, Nano Lett. 10, 2168 (2010). 132. X. Dong, C. A. Mattingly, M. T. Tseng, M. J. Cho, Y. Liu, V. R. Adams and R. J. Mumper, Cancer Res. 69, 3918 (2009). 133. B. Gupta and V. P. Torchilin, Cancer Immunol. Immunother. 56, 1215 (2007). 134. J. Du, W.-L. Lu, X. Ying, Y. Liu, P. Du, W. Tian, Y. Men, J. Guo, Y. Zhang and R.-J. Li, Mol. Pharm. 6, 905 (2009). 135. B. Chertok, A. E. David, B. A. Mo®at and V. C. Yang, Biomaterials 30, 6780 (2009). 136. B. Chertok, A. E. David and V. C. Yang, Biomaterials 31, 6317 (2010). 137. B. Chertok, A. E. David and V. C. Yang, J. Control. Release 155, 393 (2011). 138. M. Y. Hua, H. L. Liu, H. W. Yang, P. Y. Chen, R. Y. Tsai, C. Y. Huang, I. C. Tseng, L. A. Lyu, C. C. Ma, H. J. Tang, T. C. Yen and K. C. Wei, Biomaterials 32, 516 (2011). 139. C. H. Fan, C. Y. Ting, H. J. Lin, C. H. Wang, H. L. Liu, T. C. Yen and C. K. Yeh, Biomaterials 34, 3706 (2013). 140. J. Li, B. Gu, Q. Meng, Z. Yan, H. Gao, X. Chen, X. Yang and W. Lu, Nanotechnology 22, 435101 (2011). 141. J. Jin, K. H. Bae, H. Yang, S. J. Lee, H. Kim, Y. Kim, K. M. Joo, S. W. Seo, T. G. Park and D.-H. Nam, Bioconjug. Chem. 22, 2568 (2011). 142. P. D. Mourad, L. Farrell, L. D. Stamps, M. R. Chicoine and D. L. Silbergeld, Surg. Neurol. 63, 511 (2005). 143. R. Coss and W. Linnemans, Int. J. Hyperthermia 12, 173 (1996). 144. K. Maier-Hau®, F. Ulrich, D. Nestler, H. Nieho®, P. Wust, B. Thiesen, H. Orawa, V. Budach and A. Jordan, J. Neurooncol. 103, 317 (2011). 145. K. Maier-Hau®, R. Rothe, R. Scholz, U. Gneveckow, P. Wust, B. Thiesen, A. Feussner, A. von Deimling, N. Waldoefner and R. Felix, J. Neurooncol. 81, 53 (2007). 146. N. W. S. Kam, M. O'Connell, J. A. Wisdom and H. Dai, Proc. Natl. Acad. Sci. USA 102, 11600 (2005).
1430001-15
R. Liang & F. Fang
150. C. Lei, Y. Cui, L. Zheng, P. Kah-Hoe Chow and C. H. Wang, Biomaterials 34, 7483 (2013). 151. J. I. Kim, C. Chun, B. Kim, J. M. Hong, J. K. Cho, S. H. Lee and S. C. Song, Biomaterials 33, 218 (2012). 152. M. S. Fiandaca, M. S. Berger and K. S. Bankiewicz, Toxins 3, 369 (2011). 153. D. S. Bidros, J. K. Liu and M. A. Vogelbaum, Future Oncol. 6, 117 (2010). 154. E. Allard, C. Passirani and J. P. Benoit, Biomaterials 30, 2302 (2009).
NANO 2014.09. Downloaded from www.worldscientific.com by 37.44.207.7 on 01/24/17. For personal use only.
147. L. R. Hirsch, R. Sta®ord, J. Bankson, S. Sershen, B. Rivera, R. Price, J. Hazle, N. Halas and J. West, Proc. Natl. Acad. Sci. 100, 13549 (2003). 148. R. Kopelman, Y.-E. Lee Koo, M. Philbert, B. A. Mo®at, G. R. Reddy, P. McConville, D. E. Hall, T. L. Chenevert, M. S. Bhojani, S. M. Buck, A. Rehemtulla and B. D. Ross, J. Magn. Magn. Mater. 293, 404 (2005). 149. G. R. Reddy, M. S. Bhojani, P. McConville, J. Moody, B. A. Mo®at, D. E. Hall, G. Kim, Y. E. Koo, M. J. Woolliscroft, J. V. Sugai, T. D. Johnson, M. A. Philbert, R. Kopelman, A. Rehemtulla and B. D. Ross, Clin. Cancer. Res. 12, 6677 (2006).
1430001-16
