Brain cancer diagnosis and therapy with nanoplatforms

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

d

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 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 tumorspecific 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 nanoparticlebased delivery and the types of nanoparticle systems under investigation are described, as well as their applications. © 2006 Elsevier B.V. All rights reserved. Keywords: Nanoparticles; Blood–brain barrier; Drug delivery; MRI; Chemotherapy; Photodynamic therapy; Targeting

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . Drug delivery methods for the brain . . . . . . . . . 2.1. Chemical modification of a drug and prodrugs 2.2. Temporary disruption of the BBB . . . . . . . 2.3. Local delivery into brain . . . . . . . . . . . .

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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: [email protected] (R. Kopelman).

0169-409X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2006.09.012

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2.4. Convection-enhanced delivery (CED) . . . . . . . . . . 2.5. Carrier/receptor-mediated delivery. . . . . . . . . . . . 3. Nanoparticle delivery system . . . . . . . . . . . . . . . . . . 3.1. Nanoparticle platform . . . . . . . . . . . . . . . . . . 3.2. Nanoparticle synthesis and characterization . . . . . . . 4. Magnetic nanoparticles for MRI . . . . . . . . . . . . . . . . 4.1. Iron oxide core surface-coated with polymer . . . . . . 4.2. Nanoparticles with incorporated iron oxide . . . . . . . 5. Dual imaging nanoparticles (MRI and optical imaging) . . . . 6. Nanoparticles for chemotherapy . . . . . . . . . . . . . . . . 6.1. Solid lipid nanoparticles (SLNs). . . . . . . . . . . . . 6.2. Poly(butylcyanoacrylate) (PBCA) nanoparticles . . . . . 7. Targeted multi-functional PAA nanoparticles for PDT and MRI 7.1. In vitro targeting. . . . . . . . . . . . . . . . . . . . . 7.2. MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. PDT . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Bioelimination study . . . . . . . . . . . . . . . . . . 8. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction 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 [1–3] and 18,500 of these are expected to be malignant. 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 children 0–14 years of age [1–3]. The earliest stages of intracranial cancer remain difficult to detect and treat. This problem is confounded 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 remediation 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 techniques 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

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brain tumors, however, do not readily allow quantitation of the actual tumor volume since a lot of extracellular 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 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, indicating 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 neurological function, neurological exam and pathological/ microscopic evaluation/confirmation of the malignancy usually requires that the tumor (benign or malignant) develops either a significant mass or potential for migration in the neuraxis before invasive surgical

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or non-invasive neuroradiological therapies are invoked. Treatment of brain tumors, therefore, has historically consisted of surgery followed by adjuvant therapy such as radiation therapy, chemotherapy and photodynamic therapy (PDT). Despite recent improvements 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 crucial structures near the tumor bed. Unfortunately, neoplastic 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 unresectable tumor, adjuvant radiation and chemotherapy regimens have been developed. Radiation therapy, chemotherapy and PDT are noninvasive and often used as adjuvant therapy after surgery 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, radiation therapy is known to interfere with brain development [9]. The efficiency of radiation therapy is often hindered by diffusely invasive characteristics of brain tumors as well as the emergence of radiationresistant populations. Most chemotherapeutic agents have a low therapeutic 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 treatment of brain cancer is further restricted due to the ability of the BBB to exclude a wide range of anticancer 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 resistance against a wide variety of chemotherapeutic drugs, due to the very effective drug efflux system P-glycoprotein or multi-drug resistance-associated protein (MDRP) [10,11]. The P-glycoprotein is an ATP-dependent transporter responsible for the cellular extrusion of a number of drugs. It is expressed in many tissues, 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 improvements in outcome demonstrated with the use of combination therapy are minimal: a prospective randomized 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 temozolomide, compared to those receiving radiation therapy 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 [14–17]. It is more selective 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. However, PDT is also an interesting approach for the treatment 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 [18–25]. 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.

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The therapeutic efficacy of chemotherapy and PDT can be greatly improved by efficient delivery of the drugs to the specific tumor location. The recent molecularly-targeting approach allows the medical intervention to affect only cancer cells but not the normal cells, based on molecular recognition processes (ligand–receptor or antibody–antigene interaction) [27–31]. 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 different from that of another, and can not be differentiated 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. 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

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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. 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 converted into the active form within the brain. Both approaches have pharmacokinetic difficulties, as lipidization may bring in undesirable pharmacokinetic effects, 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 analogs 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]. 2.3. 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

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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 2–3 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. 2.4. Convection-enhanced delivery (CED) While invasive it is currently an area of active investigation 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 diffusion alone. The convection results from a simple pressure gradient and is independent of molecular weight, resulting in greater pharmacokinetic advantages over systemic administration [34]. The CED delivery system is currently used in two clinical treatment trials for high grade gliomas [36,37]. 2.5. Carrier/receptor-mediated delivery 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.

3. Nanoparticle delivery system The ability to deliver effective concentrations of contrast or therapeutic agents selectively to tumors is a

key factor for the efficacy of cancer detection and therapy. The utilization of the nanoparticle as a potential 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/contrast 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 desorption, 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– brain barrier when appropriate. It should be noted that the selective delivery of nanoparticles to tumor is sometimes achieved due to the “leaky” tumor vasculature, which is known as the enhanced permeability and retention (EPR) effect [39–42]. 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 targeting biorecognition event, which is a major clinical advantage over simple immunotargeted drugs. 3. A hydrophilic coating can be given to the nanoparticle to provide reduced uptake by the RES, resulting in both increased delivery of the nanoparticles 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 the MDR of cancer cells against many drugs; done by masking the drugs entrapped within the nanoparticles. This feature may enhance the delivery of drugs that are normally excluded from tumors.

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Table 1 Examples of nanoparticles investigated for brain cancer Function

Nanoparticle matrix

Key components

Size (nm)

Refs.

Imaging (MRI)

Dextran-coated iron oxide Polyacrylamide Stearic acid Dextran- or PEG-coated iron oxide Polysorbate-coated poly(butylcyanoacrylate) Stearic acid or stearic acid–PEG 2000 Emulsifying wax Polyacrylamide

Iron oxide Iron oxide PEG Iron oxide Iron oxide Cy5.5 Chlorotoxin-peptide Doxorubicin Doxorubicin Paclitaxel Photofrin® iron oxide F3-peptide

20–30 30–70 160–230 15, 32 250–270 60–100 b100 30–70

[75–79] [60] [80] [65,81] [44,45,82,83] [84,85] [86] [55–58]

Imaging (MRI + optical) Therapy (chemotherapy)

Therapy (PDT) + imaging (MRI)

6. The nanoparticles can reduce immunogenicity and side effects. The maximum tolerated dose of the drug or contrast agents can be increased as the nontoxic (biocompatible) polymer reduces the exposure to toxicity. The nanoparticles with enhanced surface properties (targeting and/or hydrophilic coating) may be able to deliver a high amount of drugs/contrast agents selectively to tumor sites and improve the efficacy of existing imaging and treatment of cancer in general. Success of the nanoparticle delivery systems for brain cancer, however, depends on the ability of the nanoparticles to get across the BBB and enter the brain. Some nanoparticles have been found to successfully cross the BBB. They are often nanoparticles coated with surfactant (for example, polysorbate) or covalently linked to peptides. The exact mechanism of nanoparticle transport into the brain is not fully understood, but most likely relies on receptor-mediated endocytosis, phagocytosis and/or passive leakage of nanoparticles across defects in the blood–brain barrier [38,43]. For example, polysorbate-coated nanoparticles are thought to mimic low-density lipoproteins (LDL), allowing them to be transported into the brain by the same endocytotic process as LDL undergoes at the BBB [44,45]. Nanoparticles conjugated with synthetic peptides may be transported across the BBB presumably by a mechanism similar to that of the opioid peptides [46]. The opioid peptides bind to specific receptors on the capillary walls, which help carry the nanoparticles into the brain [47]. However, the BBB may be partially disrupted and altered by the brain cancer and thus allow the nanoparticles to penetrate into the brain [48]. The brain cancer may enhance

the BBB permeability by increased pinocytosis [49]. Furthermore, the brain concentration of the BBB permeable drug (by passive diffusion) can be significantly enhanced due to a large concentration gradient at the BBB resulting from the enhanced plasma concentration of the drug and its long plasma half-life [50]. These considerations suggest that nanoparticles are the ideal candidates for delivering drug/contrast agents for the purpose of recognizing and treating brain cancer. Furthermore, nanoparticles can be designed as multi-functional nanoplatforms that carry multiple components, for example, (1) imaging agents and (2) drugs, as well as (3) targeting ligands and (4) “cloaking” agents that avoid interference with the immune system. The multi-functional nanoparticle concept provides a new paradigm for cancer diagnosis and treatment, which integrates the efforts for detection, treatment and follow-up monitoring of the tumor response, leading to decisions about the need for further treatment [51,52]. This concept has drawn much interest from the cancer research community and there have been investigations to develop and translate this innovative nanoparticle-based strategy into clinical practice for various kinds of cancer, including brain cancer [53–60]. 3.1. Nanoparticle platform A broad spectrum of biocompatible nanoparticles, either synthesized or purified from the living body, has been investigated so far [53,61–71]. The types of nanoparticles include polymeric, ceramic and metallic matrixes, polymeric micelles, liposomes and dendrimers [72].

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For cancer imaging, various types of nanoparticles have been investigated for MRI, optical imaging and ultrasound imaging [73]. Several nanoparticle formulations have been clinically approved for MRI [61]. For cancer therapy, liposome-encapsulated formulations of doxorubicin were approved 10 years ago. Recently, a polymeric nanoparticle-based drug, albumin–paclitaxel was approved for breast cancer [74]. Nanoparticle-based therapeutic or imaging agents have not yet been approved specifically for brain cancer. However, various types of nanoparticles have been investigated for brain cancer, as exemplified in Table 1. In order to make a successful delivery across the BBB, the nanoparticles may need to have several properties such as avoidance of the reticuloendothelial system (RES), long circulation time, being stable in plasma, etc. [87]. Initially, delivering nanoparticles to reach the brain in appreciable quantity was unsuccessful. Failure of the nanoparticles to reach the CNS was due to the nanoparticle uptake by the RES. A primary strategy to overcome the RES uptake and prolong plasma circulation time is the coating of the nanoparticles with hydrophilic polymers or surfactants and the use of hydrophilic nanoparticles. It should be noted that the nanoparticles in Table 1 are either coated with dextran, polysorbate or polyethylene glycol (PEG) or made of a hydrophilic matrix or hydrogel (polyacrylamide) which has a long plasma circulation time even without additional surface coating. The size of the particles is an important factor determining the efficacy of cancer detection and therapy. For several reasons, “the bigger the particle, the better”: The contrast enhancement and therapeutic action all improve with the cube of the radius, due to the increased loaded amount of the agents. Also, the target recognition improves with the particle's surface area, i.e. with the square of the radius. However, the RES uptake of the nanoparticles may also increase with size. Although the efficiency and kinetics of particle delivery varies from one model to another, nanoparticles of 10–100 nm are believed to provide the best option because they are too large to undergo renal elimination and too small to be recognized by phagocytes [41,88,89]. The use of the nanoparticles for imaging of brain cancer has been mostly limited to MRI, which is the current gold standard imaging method for brain cancer.

MRI is useful in both basic research and clinical settings, due to its inherent depth of imaging, low toxicity/discomfort, relatively high resolution and its permitting good contrast between healthy and abnormal tissues. Two different nanoparticle-based therapeutic modalities have been investigated for brain cancer: Chemotherapy and PDT. Multi-functionality is a key advantage of the nanoparticle-based approach for the cancer-specific delivery of therapeutic or imaging agents. Targeted dual imagings (MRI and Near IR optical imaging) [65,81] and targeted multifunctional nanoparticles for imaging (MRI) and therapy (PDT) [55–58] have been investigated. 3.2. Nanoparticle synthesis and characterization The nanoparticles of different matrices and sizes are prepared by various methods and drug loading can be accomplished by absorption, adsorption, encapsulation and covalent linkage [90]. Covalent linkage of hydrophilic polymer or targeting ligands to the nanoparticles is typically made by a simple coupling reaction between amine-functionalized nanoparticles and succinimidyl ester derivatives. The physicochemical properties of the nanoparticles affect their functional efficiency and therefore should be well-characterized to produce quality controlled nanoparticles for the functional tests. The size, surface charge, surface morphology, hydrophobicity and the amount of drug/contrast agents and targeting peptides may be important parts of the nanoparticle characterization. The size and morphology of the dried nanoparticles are commonly determined by SEM (Scanning Electron Microscopy) while the size and extent of aggregation of nanoparticles in aqueous solution are determined by light scattering (LS). The encapsulated amount of drug or imaging agents is determined by elemental, spectrophotometric or chromatographic analysis. For example, the superparamagnetic iron oxide content can be obtained from the % of iron present in the sample. The amount of drug such as Photofrin® or doxorubicin can be obtained by measuring the absorbance of the prepared nanoparticle sample solution and comparing it with the calibration curve constructed from the mixture of free drug and blank nanoparticles of known concentrations. The surface charge is determined by measuring the zeta potential.

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4. Magnetic nanoparticles for MRI MRI of the CNS is usually performed with shortlived gadolinium-based contrast agents, which gives rapid and transient imaging of brain and spinal permeability. Iron oxide nanoparticle-based MRI contrast agents also show excellent potential for imaging in the CNS. The iron oxide contrast agents are termed superparamagnetic iron oxide (SPIO) or ultrasmall superparamagnetic iron oxide (USPIO), depending on the size distribution of the nanoparticles. Two generic types of magnetic nanoparticles have been used: iron oxide core with a polymer coating and polymeric nanoparticles with incorporated iron oxide crystals (Fig. 1). Some of the SPIO and USPIO are already clinically approved or on preclinical trial. For example, Endorem® is approved for liver and spleen disease detection and Sinerem® (or Combidex®), an USPIO, is in Phase III stage for the detection of metastatic disease in lymph nodes. There have been continuous efforts to improve the efficiency of the agents and extend their applications to the CNS. 4.1. Iron oxide core surface-coated with polymer Dextran-coated USPIO have been investigated by in vitro cellular studies and in vivo animal studies as well as human studies in order to evaluate their efficacy as MRI contrast agents in the brain. The USPIO typically consist of a 5–6 nm iron oxide core surrounded by a dextran coating to give a hydrodynamic

Fig. 1. Schematic diagram of magnetic nanoparticles. Left: Iron oxide core surface-coated with polymer; right: nanoparticle with incorporated iron oxide.

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diameter of 20–30 nm with light scattering [75,78]. The in vitro cellular uptake studies were done in various tumor cells and primary isolates of different organs with 125 I-labeled or fluorescently labeled dextran-coated iron oxide nanoparticles [75,78]. The cellular uptake was found to be varying but ubiquitous in different tumor cells and was not saturable, suggesting that it is based on fluid-phase endocytosis rather than receptor-mediated endocytosis. The in vivo animal studies were performed on rats bearing implanted 9L gliosarcoma or C6 glioma cells [75,78]. MR imaging was performed 14 days after tumor implantation. All animals were imaged before and 24 h after injection of dextran-coated iron oxide nanoparticles (19 mg/kg iron). All the images were obtained with a 1.5-T superconducting magnet. The total amount of the nanoparticles taken up by the glioma was sufficient to alter the MR signal intensity at tumors, compared to that at adjacent brain tissues, in both T1-weighted and T2-weighted images. An in vivo biodistribution study with 125I-labeled dextran-coated iron oxide nanoparticles showed that 24 h after intravenous administration, the majority of the agents was localized in the liver, spleen and lymph nodes, with 1.9%, 9.8% and 25.9% of injected dose per gram of each tissue, respectively. Accumulation in brain tumor was low (0.11% of injected dose per gram of tumoral tissue) but was 10-fold higher than brain tissue adjacent to the tumor. The pattern of intratumoral distribution of the iron oxide nanoparticles was also studied by ex vivo studies using fluorescent microscopy and immunohistochemistry. The nanoparticles accumulated preferentially in the tumor periphery and heterogeneously throughout the remainder of the tumor. The heterogeneity was correlated with the presence of vessels within individual histologic sections. The feasibility study to extend the use of the dextran-coated USPIO to human brain tumors has been done with Sinerem® [77,78,91]. All tested brains, including both primary and metastatic brain tumors, showed readily detectable T1 signal enhancement. Unlike the pattern of enhancement with Gd chelate, which occurs immediately and decreases within hours, the contrast enhancement with the USPIO occurred gradually, with a peak at 24–48 h after iron administration. The margin with the USPIO remained sharp with time while that with the Gd chelate blurred with time due to diffusion. The studies showed that

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iron oxide agents would not replace conventional gadolinium-enhanced MR imaging but could add additional information especially in identifying the inflammatory component and compromised blood– brain barrier involved in infiltrating malignant brain tumors [91]. These agents could also be used in intraoperative and post-operative imaging of residual tumor due to a long plasma half-life (24–30 h). The mechanism of MR enhancement from USPIO appears to be leakage across the breached BBB, followed by intracellular trapping by reactive cells (astrocytes, macrophages) in and around the tumor, rather than by tumor cells [77]. 4.2. Nanoparticles with incorporated iron oxide A different type of nanoparticle having magnetic properties has been developed as an MRI contrast agent. The nanoparticles were prepared by incorporating iron oxide crystals into polymer matrices, instead of coating the iron oxide with hydrophilic polymer [60,80,92]. These nanoparticles are bigger than the conventional monocrystalline iron oxide ones and they may reveal a higher relaxivity per individual particle. The polyacrylamide (PAA) nanoparticles with encapsulated superparamagnetic iron oxide crystals were used for in vivo MRI of brain tumor in a rat 9L gliosarcoma model [60]. The nanoparticles with or without surface-linked PEG of different sizes (0.6, 2 and 10 kDa) were prepared by a w/o microemulsion polymerization. The relaxivities in solution were measured using a 12-cm bore, 7-T Varian animal imaging system. Measured R2 and R2⁎ relaxivities of nanoparticle preparations were in the range of 620– 1140 s− 1 mM− 1, which is approximately five-fold greater than that measured in other superparamagnetic iron oxides (SPIOs) [93]. R1 values were in the range of 1.7 to 2.4 s− 1 mM− 1, which is significantly lower than R1 values of other SPIO preparations. The results indicate that each of these nanoparticles encapsulated many iron oxide crystals into the PAA matrix and resulted in a stable nanoparticle. It should be noted that the addition of PEG moieties did not significantly alter the overall values. The in vivo pharmacokinetic studies were performed with four different nanoparticle preparations (one non-PEGylated and three PEGylated iron oxide-encapsulated PAA nanoparticles) on rats bearing implanted 9L gliosarcoma. The nanoparticle

preparations were administered by tail vein injection into a rat bearing an intracerebral 9L tumor (60– 100 μl) at a dose of about 200 mg/kg of body weight as a suspension (approx. 40 mg/ml) in normal saline solution. To determine the distribution and preliminary pharmacokinetic behavior, MR images, before and after the nanoparticle injection, were obtained using dynamic T2⁎-weighted gradient echo MRI. Images were analyzed by measuring signal intensity time courses within manually drawn regions of interest (ROIs) in the vein, normal brain, tumor periphery, and tumor core. The magnitudes of MR signal decrease for normal brain, tumor core and tumor periphery were approximately 20, 30 and 40–50%, respectively. These results reveal significant MR contrast in the tumor mass as compared to the normal brain for all nanoparticle preparations. The higher degree of contrast enhancement that was found in the tumor periphery, compared with the tumor core, is consistent with the higher vascular density characteristic of the periphery. There was no PEG weight-dependence of signal reduction in the 0.6, 2 and 10 kDa PEGylated particles. The recovery of the MR signal over time was shown to be PEG weight-dependent, with a greater PEG weight corresponding to a greater relative particle concentration half-life. Changes in vasculature MR signal intensities clearly showed that the plasma halflife increased with the size (N 0.6 kDa) of the PEG subunits. This indicates that PEGylation can be used to control the in vivo clearance of particles. The mechanism of the accumulation of these nanoparticles in the brain tumor may need further study but presumably includes diffusion/convection through the altered/ disrupted blood–brain barrier and possibly interaction of PEG with the brain endothelial cells, as suggested for other PEGylated nanoparticles [94]. The 9L glioma tumor is known to have a disrupted blood–brain barrier, allowing entry of contrast agents such as GdDTPA and monocrystalline iron oxide nanoparticles into the extravascular space [25]. Solid lipid nanoparticles (SLNs) were also utilized for preparing this type of magnetic nanoparticles [80]. The stearic acid-based SLNs with incorporated iron oxides (Endorem®) were prepared by a microemulsion method. In vivo MRI of the brain of healthy rats, after i.v. injection of these nanoparticles and Endorem®, showed that these nanoparticles have slower blood clearance and longer lasting brain uptake than

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Endorem®, indicating the ability of SLNs to overcome the BBB. These results indicate that the nanoparticles with incorporated iron oxide can be potent MRI contrast agents with enhanced relaxivity and brain uptake, as compared to polymer-coated SPIOs for brain cancer.

5. Dual imaging nanoparticles (MRI and optical imaging) Following earlier design [51,52], two groups made a multi-functional nanoprobe detectable by both magnetic resonance imaging and fluorescence microscopy [65,81]. This dual imaging nanoprobe could potentially be used for the determination of brain tumor margins both during the pre-surgical planning phase (MRI) and during surgical resection (optical imaging). Surgery has been limited in its effectiveness because it is difficult to distinguish visually between cancerous and normal brain tissue, and any cancer cells left behind are likely to proliferate and form new tumors. Surgical outcomes could be improved by this dual probe that accurately marks the location of a tumor in preoperative MRI scans and guides the surgeon to those same locations in the exposed brain as well. The dual imaging nanoparticle from both groups was an iron-based nanoparticle tagged with the near-infrared fluorescent (NIRF) molecule Cy5.5. The fluorescent molecule was either conjugated to the amine-functionalized dextran coat on the surface [65] or to the amineterminated PEG that is linked to the iron oxide core [81]. The Cy5.5 linked to dextran-coated iron oxide (Cy5.5– CLIO) nanoparticles were i.v. injected to rats with implanted 9L glioma for pre-operative in vivo MRI and intra-operative NIRF imaging [65]. The 9L glioma cells used here were specially engineered to express green fluorescence protein (GFP). The T2-weighted MR images show hypointense tumor relative to the surrounding tissue, demonstrating the ability of the nanoparticles as MRI contrast agents. After surgical exposure of the tumor and surrounding tissue, NIRF imaging was performed and compared with the GFP fluorescence of true tumor. There was a good correlation between NIRF of Cy5.5 and GFP fluorescence. The results showed the feasibility of the multimodal magneto/optical nanoparticle as a pre-operative and intra-operative imaging probe. The Cy5.5–PEG–iron oxide nanoparticles were

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modified with clorotoxin, a glioma tumor-targeting peptide made of 36-amino acids in order to improve tumor-specific binding of multimodal imaging probe [81]. Cellular uptake study was performed with two cells: 9L glioma cells (positive control) and rat cardiomyocyte (rCM) cells (negative control). The confocal imaging and MRI of the cells incubated with the nanoparticles showed tumor-specific binding and internalization of the targeted nanoparticles by glioma cells.

6. Nanoparticles for chemotherapy Chemotherapy has shown a poor outcome due to the low permeability of most anti-cancer agents through the blood–brain barrier. The nanoparticle delivery system has emerged as a promising tool for chemotherapy of brain cancer due to the nanoparticle advantages and the evidence for their ability to cross the BBB (Section 3). Several types of nanoparticles have been adopted so far as anti-cancer drug delivery systems to the brain, as given below. 6.1. Solid lipid nanoparticles (SLNs) The SLNs loaded with two different anti-tumor drugs have been investigated as potential drug carriers to the brain. The SLNs loaded with paclitaxel were investigated in vitro and in vivo [86]. Paclitaxel has been demonstrated to be an active chemotherapeutic agent against malignant gliomas and brain metastases but is also known to have a very low therapeutic index as it is a substrate for MDRP, p-glycoprotein. The SLNs were prepared by a warm o/w microemulsion technique using emulsifying wax (cetyl alcohol/polysorbate 60 in a 4:1 w/w ratio) as the oil phase, water, and Brij 78 as the surfactant at 50–55 °C. The loading of paclitaxel was made by dissolving the drugs in the melted emulsifying wax. The SLNs were smaller than 100 nm and the incorporation of paclitaxel in the NPs has no effect on particle size. In vitro cytotoxicity tests with the paclitaxel-loaded SLNs as well as with a commercially available Taxol® formulation containing paclitaxel were performed using two different cell lines, U-118 (a human glioblastoma cell that does not express p-glycoprotein) and HCT-15 (a human colorectal aenocarcinoma that does express p-glycoprotein

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and is resistant to paclitaxel). While the viability of U118 was similar in the presence of paclitaxel-loaded SLNs and Taxol, that of HCT-15 cells was markedly decreased in the presence of paclitaxel nanoparticles when compared to free paclitaxel. This demonstrates that the paclitaxel delivery by the SLNs was efficient to overcome drug efflux at the BBB. The brain uptake studies in an in situ rat brain perfusion model were performed with radiolabeled paclitaxel-loaded SLNs and Taxol® . The results suggest that the paclitaxel brain uptake was significantly increased by the use of the nanoparticle delivery system. Another type of SLNs loaded with doxorubicin was investigated as a potential drug carrier to the brain [84,85]. Doxorubicin is a chemotherapeutic agent that inhibits DNA and RNA synthesis as well as cleaves DNA. Doxorubicin is a polar molecule and not known to be able to cross the BBB by normal i.v. injection. Non-stealth and stealth solid lipid nanoparticles (SLNs) were prepared from a warm oil-in-water (o/w) microemulsion technique containing stearic acid (for non-stealth SLNs) or mixture of stearic acid and stearic acid–PEG 2000 (for stealth SLNs), water and surfactants at 70 °C. The doxorubicin was loaded in the SLNs as an ion pair complex by adding doxorubicin hydrochloride and a counter ion (hexadecylphosphate). The average size of SLNs was 60–100 nm in diameter. The pharmacokinetics and tissue distribution of doxorubicin were studied after i.v. administration of equivalent doses (6 mg kg− 1) of commercial doxorubicin solution and doxorubicin incorporated SLNs to conscious (healthy) rats [84]. Several blood samples and tissue samples of liver, spleen, heart, lung, kidney, and brain were collected. The mean peak plasma concentrations of doxorubicin with non-stealth and stealth SLNs were higher than that with the doxorubicin solution by a factor of 5 and 7, respectively. In all rat tissues, except the brain, the amount of doxorubicin was always lower after the injection of the two types of SLNs than after the injection of the commercial solution. In the brain, however, SLNs, especially stealth SLNs, increased the doxorubicin concentration significantly. The same study was repeated after i.v. injection into rabbits of four different types of SLNs (non-stealth SLNs and three stealth SLNs with varying amount of stearic acid–PEG 2000) and doxorubicin solution [85]. A pharmacokinetic behavior and tissue distribution characteristics similar to those in the study

with rats were observed. It is noticeable that relatively small increases in the amount of stealth agents not only improved the circulation time but also the amount of doxorubicin in the brain. These results show the possibility of the SLN being an efficient carrier to the brain of the BBB impermeable drugs. However, the therapeutic potential of the SLN-based chemotherapy has not yet been investigated in tumor model. 6.2. Poly(butylcyanoacrylate) (PBCA) nanoparticles The PBCA nanoparticles have been reported to achieve successful delivery of various drugs to the brain with the help of surface-coated surfactant. Polysorbate 80 (Tween® 80) was found to be the most efficient surfactant among a number of surfactants tested [95,96]. The favored transport of the nanoparticles coated with polysorbate 80 has been suggested to be a receptor-mediated endocytosis by the brain endothelial cells: Tween 80 preferentially absorbs apolipoprotein E (Apo-E) in plasma and then the nanoparticles coated with the Apo-E are recognized as LDL and internalized by the LDL uptake system [44,45]. The polysorbate 80-coated PBCA nanoparticles loaded with the anti-cancer drug doxorubicin have been investigated intensively for delivery efficiency, therapeutic efficacy as well as biodistribution by in vivo animal study [82,83]. The PBCA nanoparticles were synthesized by an anion emulsion polymerization method. Doxorubicin was added to the reaction mixture during the polymerization process. The size of PBCA nanoparticles is typically 250–270 nm in diameter. For surfactant coating, the nanoparticle suspension is incubated with 1% polysorbate 80 for 30 min–1 h under stirring prior to administration. The pharmacokinetic behaviors of four different formulations of doxorubicin were studied after intravenous injection into healthy rats [82]. The results showed that the polysorbate 80-coated PBCA nanoparticles produced very high (6 μg/g) doxorubicin concentrations in the brain whereas three other control preparations (doxorubicin, doxorubicin in 1% polysorbate 80 solution and doxorubicin-loaded uncoated PBCA nanoparticles) were below the detection limit of 0.1 μg/g. The results from this study suggested that the polysorbate 80-coated PBCA nanoparticles could be an efficient delivery system for chemotherapy of brain cancer.

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The therapeutic efficacy of doxorubicin-loaded PBCA nanoparticles for treating brain cancer was studied in an experimental system based on intracranially implanted 101/8 glioblastoma in rat brains [83]. Groups of 5–8 tumor-bearing rats (total n = 151) were subjected to 3 cycles of 1.5 or 2.5 mg/kg body weight of doxorubicin in one of following formulations: 1. untreated control; 2. blank nanoparticles coated with polysorbate 80 (NP/PS); 3. doxorubicin; 4. doxorubicin in 1% polysorbate solution (DOX/PS); 5. doxorubicin-loaded uncoated PBCA nanoparticles (DOXNP); 6. doxorubicin-loaded polysorbate 80-coated PBCA nanoparticles (DOX-NP/PS). The rats treated with DOX-NP/PS (Group 6) showed the most significant increase in survival times compared to the controls (Group 1) and the doxorubicin (Group 3). More than 20% of the rats (5 out of 23) in this group survived more than 180 days after tumor implantation while none of the rats in other groups survived more than 180 days. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. The rats treated with DOX/PS (Group 4) also showed an increase in the survival time but not as significant as Group 6. The rats treated with polysorbate-containing formulations (Groups 4 and 6) also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. The biodistribution of the PBCA nanoparticles was investigated after i.v. injection of three different 14C radiolabeled nanoparticle preparations into glioblastoma 101/8-bearing rats [97]: uncoated PBCA nanoparticles; polysorbate 80-coated PBCA nanoparticles (NP/PS); and doxorubicin-loaded polysorbate 80-coated PBCA nanoparticles (DOX-NP/PS). The polysorbate 80 coating decreased their concentrations in the organs of the RES (liver, spleen and lung) but the loading with doxorubicin counteracted the effects of the surfactant coating, which results in similar or even higher RES organ concentrations of DOX-NP/PS as compared to the uncoated particles. However, the highest nanoparticle concentration in the brain was also obtained by the DOX-NP/PS. The concentrations of the nanoparticles in the contralateral hemisphere and tumor sites in tumorbearing rats at 10 days post-tumor implantation were significantly higher than those in healthy rats and those in tumor-bearing rats at 5 and 8 days post-implantation. This demonstrates the efficacy of the EPR effect on the nanoparticle delivery into the brain.

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The results indicate that the doxorubicin-loaded polysorbate 80-coated PBCA nanoparticles have a therapeutic potential for the treatment of human glioblastoma.

7. Targeted multi-functional PAA nanoparticles for PDT and MRI Nanoparticles of various matrices have also been investigated for PDT, demonstrating that the nanoparticle-based PDT is a promising approach for killing tumor cells [55–58,98–101]. The nanoparticle-based PDT of cancer shares the general advantages of the nanoparticle delivery system with the nanoparticlebased chemotherapy (Section 3). Moreover, it has additional advantages: 1) Unlike chemotherapy, the PDT efficacy does not depend on the drugs' release from the nanoparticles, as singlet oxygen, the primary cytotoxic agent of PDT, can be released not only from free photosensitizers but also from the photosensitizers entrapped in the nanoparticles; 2) Toxicity is even lower than that in nanoparticle-based chemotherapy because the cytotoxic agents are produced only locally by the illuminating light. Nanoparticle-based PDT for brain cancer has been investigated using polyacrylamide (PAA) nanoparticles [55–58]. Specifically, a targeted multi-functional nanoplatform combining PDT and MRI with optional hydrophilic coating has been designed for synergistic cancer detection, diagnosis and treatment (Fig. 2). The developed multi-functional nanoparticle has a PAA nanoparticle core and carries the following components: 1) PDT agent (Photofrin® ); 2) MRI-detectable contrast agent (iron oxide); 3) vascular-targeting ligand (F3 peptide or RGD peptide); 4) polyethylene glycol (PEG) (optional). The PAA nanoparticle is a small hydrogel (b100 nm in diameter) and has been proven to have good loading ability for various chemicals and biological molecules, via encapsulation or covalent attachment [102–107]. The PAA matrix has been demonstrated to produce little or no toxicity below the maximum tolerated dose [108–110]. Toxicity studies of PAA nanoparticles showed no evidence of alterations in histopathology or clinical chemistry values at doses of 10 mg/kg to 1 g/kg in an in vivo animal study [111]. The application of PAA nanoparticles appears to be advantageous due to its size, hydrophilicity and the

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[28,115–117]. The F3 peptide is a 31-amino acid fragment of human high mobility group protein 2 (HMGN2), which targets to and gets internalized into tumor endothelial cells and certain cancer cells through the nucleolin receptor [29,118–120]. The PAA nanoparticles were synthesized by a microemulsion polymerization technique. The Photofrin® and iron oxide were encapsulated into the PAA nanoparticles by adding these components into the reaction mixture at the beginning of the reaction. The F3 peptide, PEG or fluorescent dye was covalently linked to the amine group on the surfaces of the nanoparticles. The introduction of amine groups was accomplished by partial exchange of acrylamide monomers with 3(aminopropyl)methacrylamide. The typical size of the PAA nanoparticles was in the range of 30–70 nm. 7.1. In vitro targeting Fig. 2. Schematic diagram of multi-functional nanoplatform with photodynamic dye, MRI contrast enhancement agent, polyethylene glycol (PEG) cloaking and molecular targeting.

non-toxicity of the PAA. Moreover, the PAA nanoparticles were made to be slowly biodegradable by introducing biodegradable cross-linkers so as to improve their in vivo bioelimination. The PAA degradation is not into toxic monomers but into nontoxic polymeric chains that were biodegradably linked. The bioelimination property is one of the most important factors for clinical use of the nanoparticles. Although the biodegradability is not a requirement for the nanoparticle used for PDT, the biodegradation may enhance the bioelimination rate of the nanopaticles. The PDT agent, Photofrin® is the photosensitizer that is currently approved for clinical use in the USA. The iron oxide was selected as MRI component as the iron oxideencapsulated PAA nanoparticles had already shown good in vitro and in vivo MRI efficacy (see Section 4.2). The vascular-targeting ligand was selected as a targeting moiety by the following reason: Systemic PDT has been reported to be effective only when it leads to complete ischemia of solid tumors through localization in the intravascular space. Vascular targeting of a photosensitizing agent is therefore required to produce irreversible damage of the tumor vascular system leading to ischemia resulting in tumor necrosis [112– 114]. The RGD peptide specifically binds to the αVβ3 integrin that is overexpressed in the tumor vasculature

Cellular uptake of the nanoparticles was monitored using targeted fluorescently labeled PAA nanoparticles [55,56,58]. Targeted fluorescently labeled PAA nanoparticles were prepared by treating amine-functionalized PAA nanoparticles with carboxy succinimidyl ester of AlexaFluor 594 followed by conjugating the fluorescently labeled amine-functionalized PAA nanoparticles with RGD or F3 peptide. MDA-MB-435 cells, human breast cancer cells expressing αVβ3 and nucleolin, were utilized as positive controls. The cells were incubated with the nanoparticles for 4 h, washed three times and monitored under a fluorescent microscope. Analysis of subcellular localization of these nanoparticles revealed that RGD-targeted nanoparticles were distinctly bound to the cell surface and the F3-targeted nanoparticles were internalized into the cell. No specific signal from the cells incubated with non-targeted nanoparticles was observed, thus confirming the specificity of these peptides. A noticeable fact from this experiment is that the affinity of the peptides is strong enough so that the “bulky” nanoparticle is retained at the cell surface, or internalized into the cell, despite the shear forces that were imposed on the particles during the washing step, after incubation. The PAA nanoparticles that were taken up by the cells, with the peptides, are 6–20 times larger than the previously reported F3-linked Qdots [121] or the clorotoxin-linked Cy5.5–iron oxide nanoparticles discussed above (Section 5) [81].

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7.2. MRI The MR images were obtained after i.v. administration of targeted (n = 4) and non-targeted (n = 9) iron oxide-encapsulated nanoparticles to rats bearing 9L glioma (60–100 μl) at a dose of 200 mg/kg body weight. Dynamic scanning MRI, performed using a 7T imaging system, revealed that targeting with F3 peptides resulted in a significant increase of the contrast enhancement, both in magnitude and duration. There was a 3-fold increase (from 39 min to 123 min, with p b 0.001) in the half-life of the tumor and a 2-fold increase (2.4 to 5.3 with p b 0.008) in the tumor-tobrain contrast-to-noise ratios (for the CNR) at 2 h postadministration. These results reveal that the nanoparticles can be delivered intravascularly to the tumor site and that the presence of the F3-targeting moiety results in a significantly greater amount of nanoparticle accumulation and a longer duration time within the tumor. 7.3. PDT F3-targeted and non-targeted PAA nanoparticles with encapsulated Photofrin® and iron oxide were investigated in test-tube, in vitro and in vivo experiments for the PDT efficacy of the nanoparticles. The production of singlet oxygen from Photofrin®-encapsulated nanoparticles was determined chemically using 1,3-diphenylisobenzofuran (DPIBF) as a singlet oxygen detection probe [121,122]. The quantitative analysis was made based on a kinetic model analogous to the one developed for anthracene-9,10-dipropionic acid, disodium salt [100]. The fluorescent decay of the DPIBF in light-activated Photofrin ® nanoparticle solutions demonstrated that the singlet oxygen is produced from this polymeric nanoparticle formulation and is able to exit the particles into the surrounding medium. In vitro evaluation of the Photofrin®-encapsulated nanoparticles for photodynamic therapy was done using two cell lines [55,56,58]: 9L rat gliosarcoma cell and MDA-MB-435 cell (nucleolin expressing cell). The PDT was performed with Diomed 630 PDT Class IV diode laser (630 ± 3 nm) for 5 min at various intensities (or no light as a control). The treated or control samples were stained using a vital stain (Calcein acetoxymethylester (AM) and propidium iodide at a final concentration of 1 μM and 1 μg/ml,

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respectively) to monitor dead and live cells, respectively, with a fluorescent microscope. The 9L gliosarcoma cells were treated with various concentrations of non-targeted Photofrin®-encapsulated nanoparticle solutions in PBS (or no particles as a control). No detectable cytotoxicity was observed from the nanoparticle treatment alone or the irradiation with laser light alone. However, the combination of laser light and the Photofrin®-encapsulated nanoparticles produced significant amounts of singlet oxygen species in a concentration-dependent manner. The MDA-MB-435 cells were used to test the PDT efficacy as well as the targeting efficiency. The cells were incubated with the nanoparticles for 4 h and gently washed three times before PDT. The F3 tagged nanoparticles, together with laser light, were lethal, i.e. killing nearly 90% of the cells, but the untargeted nanoparticles, with laser light, did not induce cell death. The cell death induced by the nanoparticles with encapsulated Photofrin® was also found to be dosedependent when monitored in the range of 2–10 mg/ ml. The results show that the targeting peptides on the surface did not interrupt the PDT efficiency, demonstrating the validity of the multi-functional design. The in vivo therapeutic activity of the targeted and untargeted nanoparticles containing Photofrin® was evaluated by diffusion MRI as well as by Kaplan– Meier survival statistics [58]. Rats bearing intracerebral 9L gliosarcoma tumors of approximately 50 μl in size were used. Rats were divided into the following five groups: (1) untreated control (n = 5), (2) laser exposure only (n = 9), (3) i.v. Photofrin ® (dye) administration (7 mg/kg) followed by 24 h delay prior to light activation (n = 6), (4) i.v. administration of non-targeted Photofrin® /iron oxide-encapsulated nanoparticles with light activation 1 h later (n = 9), and (5) i.v. administration of F3-targeted Photofrin®/ iron oxide-encapsulated nanoparticles with light activation 1 h later (n = 5). Laser exposure was administered with a Diomed 630 PDT Class IV diode laser (630 ± 3 nm) at a setting of 750 mW for 7.5 min. This was accomplished through the same 1 mm diameter burr hole which was initially made to inject 9L tumor cells to initiate tumor growth. Diffusion MRI relies upon the ability of MRI to quantify the Brownian motion (diffusion) of water within tissues and examines the changes in the apparent diffusion coefficients (ADC) within the tumor tissue [123]. The increase in

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tumor diffusion values corresponds to a loss of tumor cellularity within the region under study. Administration of Photofrin® either by itself or within a nontargeted nanoparticle matrix, each followed by laser activation, resulted in similar and significant increased tumor ADC values (25% at 8 days post-treatment). However, administration of F3-targeted Photofrin® encapsulated nanoparticles resulted in the most significant increase in mean tumor ADC values (40% at 8 days post-treatment). The animal survival evaluation resulted in a good correlation with diffusion MRI results. There was a statistically very significant difference in median survival time between the nontargeted versus F3-targeted ( p = 0.02), as well as between the Photofrin® versus the F3-targeted nanoparticle group (p = 0.01). However, there was no significant difference in animal survival between the control versus laser-only groups nor between the Photofrin® versus the non-targeted nanoparticle groups. The animals from the Photofrin® group had a median survival time of only 13 days whereas animals treated with the F3-targeted Photofrin® nanoparticles had a median survival time of 33 days with 3 out of 5 animals surviving past 60 days. Two of these three animals were found to be disease free 6 months following treatment and while one recurred ectopically from tumor spread subcutaneously on the surface of the head at the injection site it had no intracerebral involvement. These results showed that the nanoparticles with encapsulated photosensitizer and MRI contrast agents, as well as surface-linked vascular-targeting ligands, produced a significantly improved treatment outcome in rat 9L glioma models. This demonstrates that a multi-functional nanoparticle technology can be adapted for future diagnostic and therapeutic purposes. The mechanism for the improved PDT efficacy here appears to result from efficient targeting of the nanoparticles to the tumor vascular cells. Traditional PDT studies using Photofrin® have reported that Photofrin® accumulates in tumor vessel endothelial cells and upon exposure to light, activation of Photofrin® produces damage to the tumor vessels themselves, resulting in vascular collapse followed by tumor cell death. In this vascular targeted nanoparticle PDT approach, Photofrin® was encapsulated within the matrix of the nanoparticles which were targeted to the vascular cells, resulting in a clear initial vascular collapse which leads to more effective killing of the tumor cells as demonstrated by diffusion MRI and

preliminary histological analysis of tumor samples. Future studies will be required to provide further insights into these distinct processes. There is an interesting finding to be noted from this study: Traditionally, a 24 h delay between Photofrin ® administration and light exposure (24 h), needed to allow for enough clearance from normal adjacent tissue to occur, along with prolonged cutaneous photosensitization, are well known disadvantages of PDT. However, these disadvantages were not observed in the application in this study involving targeted nanoparticle-encapsulated Photofrin®. 7.4. Bioelimination study A series of radiolabeled pharmacokinetic studies in rats were performed for both non-degradable and degradable PAA nanoparticles [111]. The studies with non-degradable PAA nanoparticles have shown tissue distributions of the PAA nanoparticles in the reticular endothelial systems that are consistent with other nanoparticle studies [124]. A comprehensive 42-day study with three formulations of degradable PAA nanoparticles with different percentages of biodegradable cross-linker (BC) was performed: 1) 10% BC– PAA 2) 15% BC–PAA 3) 20% BC–PAA. The plasma level and excretion in urine and feces were monitored after a single i.v. injection each of 14C labeled nanoparticles into healthy nulliparous male rats (15 rats per each formulation). The overall decay kinetics of the nanoparticle concentration in the plasma of injected rats was apparently biphasic. The plasma half-life times of the three matrices in this study did not differ, suggesting that the percentage of cross-linker used in the synthesis of the nanoparticles does not significantly affect plasma clearance in the time period evaluated. The first phase of clearance was approximately 25 h, followed by a second phase of clearance that was significantly longer, 300 h. Such long plasma half-life values could be attributed to the hydrophilic nature of the material or prolonged avoidance of opsonization by plasma proteins and subsequent RES uptake. Total body elimination profiles of the three biodegradable PAA nanoparticles showed that the lower percentage of cross-linker used in the synthesis results in a greater fraction of the recovered dose by 42 days. It is noticeable that the PAA platforms, 10%, 15% and 20% BC–PAA, show equal or better clearance than the

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estimated clearance of 100 nm PLGA–PEG platforms given in the literature [125]. The elimination rates of the three formulations (Fig. 3) show that the long term bioelimination rates are essentially the same by 42 days and that there is no significant difference attributable to the % cross-linking (except day 1 and day 2). It is also important to notice the dramatic multiphasic trend seen in the clearance from urine and feces: The initial rate of urinary and fecal clearance declines markedly after 24 h but then begins to increase again at 2 weeks. The multi-phasic nature of this clearance profile suggests that the material has the capacity to clear the body following a significant contribution from cellular degradation of the polymer into smaller molecular components. A similar degradation profile has been reported for the PLGA polymer (FDA approved class) [126,127]. An additional 90-day elimination study performed on a group of 4 rats followed the same profile as that of the 42-day study, suggesting that the material will sufficiently clear over time but at a slow rate. Elimination of 20% of the administered dose was achieved by approximately two weeks and that of ∼ 33% of the dose at 90 days postadministration. The cumulative trends indicate that the material is clearing at different rates over the 90-day sampling interval, through a complex process of degradation and elimination of the nanoparticle constituents, involving, inter alia, the Kupffer cells. In addition, the increased rate of excretion observed approximately 2 weeks after administration might be indicative of a delayed action occurring inside the Kupffer cells, followed by an increased rate of degradation and sub-

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sequent rate of excretion. These pharmacokinetic and bioelimination studies indicate that PAA nanoparticles with biodegradable cross-linkers will undergo metabolic and/or physiologic pathways to facilitate the elimination of these nanoparticles after i.v. administration. MRI and histopathological data indicate that the nanoparticles do not efficiently escape the tumor and so collateral spread is minimized. Moreover, polyacrylamide is not toxic although the monomer is neurotoxic at doses that are orders of magnitude larger than those delivered to the brain [109]. These data taken together provide compelling evidence that the breakdown of nanoparticles should pose little or no threat to the healthy brain. This idea is further supported by a lack of histopathological change that was observed in the brains of animals after receiving a single intravenous dose of 500 mg/kg nanoparticle. The study results showed a significantly improved PDT efficacy in a rat model by using vascular targeted multi-functional nanoparticles, compared to nontargeted nanoparticles or Photofrin. In clinical application, total eradication of brain cancer by nanoparticle-based PDT may be possible at an early or intermediate stage and the detection could be made by the same multi-functional nanoparticle. The laser light illumination could be either directly from outside the skull, if the tumor is located close enough, or through a surgically made hole. The direct illumination from outside the skull may need a photosensitizer with a longer absorption wavelength than Photofrin®, for deeper photon penetration. Making a hole for light passage is a clinically used [24] but a somewhat invasive procedure. A more easily applicable clinical practice would be post-operative PDT, i.e., after surgical debulking of brain cancers. Multi-functional nanoparticles with optical and MRI imaging agents together with PDT agents, may be useful for pre- and intra-operative imaging and also for post-surgical treatment.

8. Conclusions

Fig. 3. Bioelimination rate of three PAA nanoparticle formulations.

Brain cancer is a life-threatening disease in which a minority of patients are likely to survive (only 5% for glioma after five years). Late diagnosis and the limitations of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast

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agents to brain tumors, due to the BBB and nonspecificity of the agents, are major reasons for this unsolved clinical problem. There have been numerous investigations on special delivery strategies to overcome the BBB and achieve an efficient level of drugs. The nanoparticle-based delivery has emerged as a potential method to improve the efficacy of the existing detection and treatment armamentarium due to the nontoxicity and “engineerability” of nanoparticles. The desirable properties such as high payload, controlled drug release profile, tumor-specific targeting, long blood circulation time, as well as the ability of getting across the BBB, can be achieved by the nanoparticle delivery systems. Multi-functionality is another advantage that the use of nanoparticles could achieve, which could integrate detection, treatment and tracking of tumor response, leading to informed decisions about further treatment. Several types of nanoparticles have been investigated for imaging and treating brain cancer. The magnetic nanoparticles based on iron oxide have shown excellent potential as MRI contrast agents in the brain, based on in vitro cellular studies, in vivo animal studies as well as human studies. Multi-modal imaging nanoparticles were designed for MRI and NIRF. In vivo animal studies demonstrated the ability of the nanoparticles as pre-operative MRI contrast agents as well as intra-operative delineating agents based on NIRF. The surface-modified multi-modal imaging nanoparticles with targeting peptide showed an improvement in tumor-specific binding. For nanoparticle-based chemotherapy, two types of nanoparticles were investigated. The SLNs were found to be promising drug carriers to the brain, by enhancing the brain uptake of anti-cancer drugs in in vivo studies done with healthy rats. More encouraging results were reported with the PBCA nanoparticles. In a comprehensive animal study done with rats bearing 101/ 8 glioblastoma, the rats treated with doxorubicinloaded PBCA nanoparticles had significantly higher survival times compared to free drugs. A targeted multi-functional nanoplatform was designed using a PAA nanoparticle core for MRI and PDT. Photosensitizers (Photofrin®) and iron oxide were encapsulated within a nanoparticle core and vascular-targeting peptides were linked to the nanoparticle surface. In vivo studies using rats with implanted 9L glioma showed significantly higher and

longer MRI enhancement at tumor than at normal brain tissues as well as a significantly improved PDT efficacy (high animal survival rate and cellular water diffusion rate) by the targeted nanoparticles. Bioelimination studies with radiolabeled PAA nanoparticles indicate that the PAA nanoplatform is a good candidate for further clinical development due to its lack of toxicity and favorable kinetics of bioelimination. These results demonstrated the feasibility of nanoparticles as imaging agents, therapeutic agents as well as multi-functional agents (therapy + imaging) for brain cancer. Further improvement of the detection and treatment of brain cancer can be made with higher targeting efficiency and therapeutic index per nanoparticle. The achievement of higher targeting efficiency per nanoparticle will need: 1) finding more efficient biomarkers for cancer and corresponding targeting moieties, and 2) development of proper engineering techniques to avoid the BBB or to have optimal amounts of single- or multiple-targeting moieties. Higher therapeutic index per nanoparticle will need: 1) better engineering for higher loading and better controlled releasing of the drugs at the tumor site, and 2) the development of drugs with a higher therapeutic index. The improved imaging and therapeutic agents with more specific tumor-targeting and a higher therapeutic index may allow the early detection and efficient treatment of cancer. The contribution of the nanoparticle-based approach to this area is expected to grow. Acknowledgements We thank Rodney Agayan for preparing Figures 1 and 2. This work was supported, in part, by NCI Contract N01-CO-37123, by NIH/NCI Grants R01ES08854, P50CA93990, P01CA85878, and by NIH Grant R24CA83099. References [1] Cancer Facts and Figures 2004, American Cancer Society, 2004. [2] Statistical Report: Primary Brain Tumors in the United States, 1998–2002, Central Brain Tumor Registry of the United States, 2005. [3] http://www.cdc.gov/cancer/natlcancerdata.htm. [4] C. Nimsky, O. Ganslandt, H. Kober, M. Buchfelder, R. Fahlbusch, Intraoperative magnetic resonance imaging

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