Drug delivery strategies for the treatment of malignant gliomas

International Journal of Pharmaceutics 436 (2012) 299–310

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Review

Drug delivery strategies for the treatment of malignant gliomas Daniela Allhenn a,∗ , Maryam Alsadat Shetab Boushehri a , Alf Lamprecht a,b a b

Department of Pharm. Technology, Institute of Pharmacy, University of Bonn, Germany Laborartory of Pharmaceutical Engineering, University of Franche-Comté, Besanc¸on, France

a r t i c l e

i n f o

Article history: Received 16 January 2012 Received in revised form 31 May 2012 Accepted 2 June 2012 Available online 19 June 2012 Keywords: Gliomas Localized drug delivery Systemic drug delivery Polymeric implants Endogenous transport systems

a b s t r a c t As primary brain tumors, malignant gliomas are known to be one of the most insidious types of brain cancer afflicting the humans. The current standard strategy for the treatment of malignant gliomas includes the surgical resection of the tumor when possible, followed by a combination of radiotherapy and/or a certain chemotherapeutic protocol. However, due to the short mean survival, frequent recurrences, and poor prognosis associated with the tumors, new therapeutic strategies are investigated consecutively. These novel drug delivery approaches can be subdivided as systemic and local drug administration. This review focuses on localized drug delivery strategies for the treatment of malignant gliomas, including the injections, infusions, trans-nasal delivery systems, convection enhanced delivery (CED) systems, and various types of polymeric implants. Furthermore, systemic strategies to increase the drug penetration into the brain, such as temporary disruption of the blood brain barrier (BBB), chemical modification of the available therapeutic substances, and utilization of endogenous transport systems will be briefly discussed. © 2012 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Localized drug delivery strategies for the treatment of gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Infusions and convection enhanced delivery (CED) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Trans-nasal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Polymeric implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic drug delivery strategies for gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Temporary disruption of the BBB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Chemical modification of the available chemotherapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Endogenous transport systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Carrier-mediated transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Receptor-mediated transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Adsorptive-mediated transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction According to the World Health Organization (WHO) classification of the central nervous system (CNS) tumors in 2007, malignant

∗ Corresponding author at: Department of Pharm. Technology, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Str. 3, 53121 Bonn, Germany. Tel.: +49 228 736430; fax: +49 228 735268. E-mail address: [email protected] (D. Allhenn). 0378-5173/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2012.06.025

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gliomas are classified as neuroepithelial tumors (Louis et al., 2007). Based on this classification, these tumors can be subdivided as astrocytic, oligodendroglial, oligoastrocytic, and ependymal, on the basis of their resemblance to the glial cells (Louis et al., 2007; Westphal and Lamszus, 2011). Gliomas are primary CNS tumors with the ability to infiltrate in the healthy brain tissue and form satellite tumors. Such a migration characteristic makes them exceedingly hard to treat and invariably fatal (Sawyer et al., 2006). According to the statistics, 5–6 out of each 100,000 people are annually diagnosed with brain tumors (Brown et al., 2010;

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Chandana et al., 2008; Stupp et al., 2010; Wick, 2008), of which around 80% suffer from gliomas (Cbrtus, 2011; Schwartzbaum et al., 2006). Based on certain features such as proliferative potential, possibility of cure, nuclear atypia, mitotic activity, vascular proliferation, necrosis, and so forth, it is possible to assign malignant gliomas a WHO-grade (Kleihues, 2007; Kleihues et al., 1995, 2002). In 1978, it was asserted that surgical resection of the tumor followed by the best conventional care available at the time led to a median survival of approximately 3 months (Walker et al., 1978). Additional radiotherapy proved to prolong the median survival of the patients with high-grade gliomas up to 8–12 months. Although it was believed that the systemic administration of the chemotherapeutic agents such as carmustine (BCNU) following the surgical resection and radiotherapy could lead to the further prolongation of the patients’ survival, the increase of the median survival was not practically significant (van den Bent et al., 2006; Walker et al., 1978). Of course, the systemic administration of temozolomide (TMZ) as a chemotherapeutic agent in combination with surgical resection and radiotherapy could successfully prolong the patients’ median survival to 15 months (Clarke et al., 2010; Stupp et al., 2005; van den Bent et al., 2006). However, all efforts for the further increase of the median survival of the patients suffering from malignant gliomas through the systemic administration of the chemotherapeutics have been in vain. The main problem associated with the treatment of gliomas is the exposure of the tumor cells to sufficient doses of the chemotherapeutics, which cannot be easily accomplished, since many forms of systemic chemotherapy are excluded from the CNS by the blood–brain barrier (BBB) (Sawyer et al., 2006). Therefore, new therapeutic strategies are constantly developed and explored to circumvent this barrier. These novel therapeutic strategies can be broadly classified into localized and systemic drug delivery approaches.

2. Localized drug delivery strategies for the treatment of gliomas One of the most significant advantages offered by the localized delivery strategies is the automatic bypass of the BBB, which results in the delivery of the therapeutic agents to the target site with high bioavailability and almost no drug loss. Various localized drug delivery approaches such as the injection and infusion of the therapeutic agents as well as the convection enhanced drug delivery (CED), and administration of implants have been introduced so far (reviewed by Walter et al., 1995). The injection of the chemotherapeutic agents can be performed intraneoplasticly (Hassenbusch et al., 2003; Reddy et al., 1998), or into the resection cavity after the surgery (Garfield, 1976). Further strategies include the infusion of the chemotherapeutic agents using a catheter, which can be fulfilled with or without pumps (AyubK, 1963; Bakhshi and North, 1995; Chandler et al., 1988; Johnston et al., 1988; Lord et al., 1988), as well as the CED (Allard et al., 2009). Moreover, application of implants containing polymeric systems (Brem and Langer, 1996; Menei et al., 1996), gels (Akbar et al., 2009; Elstad and Fowers, 2009), and microchips (Santini et al., 2000a) are other promising approaches investigated for the treatment of malignant gliomas. However, for some reasons, the number of the investigations made on the application of the implants for the delivery of the chemotherapeutics is limited. For instance, amongst more than 700 clinical trials dealing with the treatment of glioblastoma multiforme, only few have used implants as localized drug delivery systems (Table 1) (US National Institute of Health, 2011). Different approaches for the localized drug delivery of the anti-glioma therapeutics will be further discussed in the upcoming sections.

2.1. Injections The general injection approach for the treatment of gliomas is to inject the chemotherapeutics into the remaining cavity after the resection of the tumor, or intraneoplasticly in case the tumor is inoperable (Tomita, 1991). Tator et al. (1977) compared the results of the intraperitoneal injection of various nitrosoureas with their intraneoplastic injection in a mouse brain tumor model. The findings suggested that the intraneoplastic injection of these nitrosoureas were less toxic and more effective than their intraperitoneal injection. Consecutively, intracerebral injection of various chemotherapeutics such as vinchristine (Oliver et al., 1985), gamma leinolic acid (Reddy et al., 1998), and BCNU in 100% EtOH (Hassenbusch et al., 2003) was tested on different glioma models. In another study, local injection into the resection cavity and the solid tumor was applied to carry out a local radiotherapy with the radiolabelled peptidic vector 90 Y-DOTATOC, which serves as a means for the management of somatostatin receptorexpressing low-grade and anaplastic gliomas (Schumacher et al., 2002). However, neither this, nor other injection approaches tested became a breakthrough in the treatment of the brain tumor, for despite the undeniable benefits offered by injection approaches, they are generally associated with a high risk of side effects such as infections, edema, and backflow of the solution along the catheter. 2.2. Infusions and convection enhanced delivery (CED) When dissolved in a proper fluid, chemotherapeutics can be administered using various techniques. In 1963, Ommaya reservoir was invented, which transferred the therapeutic solutions to the tumor cells (AyubK, 1963). The Ommaya reservoir is a system consisting of a catheter and a capsule facilitating the transfer of the therapeutic agents to the cerebrospinal fluid (CSF), while circumventing the BBB. The capsule is implanted under the scalp, and the catheter is placed within the target side. The Ommaya reservoir can be refilled through the injection into the capsule, while the chemotherapeutic solution is advanced by the manual compression of the subcutaneous capsule (AyubK, 1963; Walter et al., 1995). Although the Ommaya reservoir reduces the risk of infection and edema in comparison with a simple catheter, it is still associated with another weak point. In fact, the Ommaya reservoir can deliver the chemotherapeutic solutions for only an ascertained period, i.e. until the time of the next refill. This inconvenience limits the clinical application of the system. Over the time, various therapeutics or combinations of them (Asano et al., 1990; Boiardi et al., 1996, 1999; Nakagawa et al., 2001; Yoshida et al., 1988) were administered through the infusion approach for the treatment of malignant gliomas. Nevertheless, none of the obtained results were budding enough to establish the method as a standard therapy. However, another improvement was definitely the development of the implantable pumps, which further reduced the risk of infections during the therapy (reviewed by Walter et al., 1995). Compared to the Ommaya reservoir, implantable pumps are able to provide a more constant flow of the therapeutic agent. Examples of these systems are the MiniMed® (Bakhshi and North, 1995; Lord et al., 1988), Infusaid® (Bakhshi and North, 1995; Chandler et al., 1988; Johnston et al., 1988), and Medtronic® pump systems (Bakhshi and North, 1995; Heruth, 1988). The MiniMed® system is convenient for the intravenous, intraarterial, intrathecal, and intraperitoneal administration of the therapeutic solutions. The Shiley Infusaid® pump, which was developed at the University of Minnesota in 1969 and implanted in human brain in 1975 (Bakhshi and North, 1995), is able to transfer the therapeutic solutions through the intraarterial, intraventricular, and intratumoral administration. The Medtronic® SynchroMed

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Table 1 Studies, that deals with implants as wafers, gels, microspheres, microparticles, nanospheres, nanoparticles, nanocapsules, liposomes, microchips (US National Institute of Health, 2011). Title

Conditions

Phase

Identifier

O6-Benzylguanine and Carmustine implants in treating patients with recurrent malignant glioma Internal radiation therapy plus carmustine implants in treating patients with recurrent or refractory malignant glioma Carmustine Implants and O(6)-Benzylguanine in treating children with recurrent malignant glioma Phase IIa safety and light dose-escalation study in patients with primary or recurrent/high-grade glioma using the LitxTM system to confirm the zone of tumor destruction during the intraoperative treatment of glioma Carmustine wafers plus Irinotecan in treating patients with Study of NPC-08 is to treat for newly-diagnosed malignant glioma and recurrent glioblastoma multiforme Radiation with concominant and then sequential Temozolomide in malignant glioma Examination of changes on Magnetic Resonance Imaging (MRI) in patients who receive Gliadel wafers during initial surgery for glioblastoma multiforme. Response or failure to Gliadel wafers for subjects with glioblastoma multiforme. Gliadel wafer, Temozolomide and radiation therapy for newly diagnosed GBM The PRECISE trial: Study of IL13-PE38QQR compared to Gliadel wafer in patients with recurrent glioblastoma multiforme Phase IIb clinical trial with TGF-␤2 antisense compound AP12009 for recurrent or refractory high-grade glioma Lymphokine-activated killer cells or Gliadel wafer in treating patients with newly diagnosed glioblastoma multiforme that can be removed by surgery Surgery with implantable biodegradable Carmustine (BCNU) wafer followed by Chemo for patients with recurrent glioblastoma multiforme Dose-escaltion study of Carboplatin administration into the brain for glioblastoma multiforme Gliadel wafer and O6-benzylguanine in treating patients with recurrent glioblastoma multiforme Gliadel wafer and fluorescence-guided surgery with Aminolevulinic acid followed by radiation therapy and Temozolomide in treating patients with primary glioblastoma Temozolomide during and after radiation therapy in treating patients who have undergone previous surgery and placement of gliadel wafers for newly diagnosed glioblastoma multiforme Gliadel, XRT, Temodar, Avastin followed by Avastin, Temodar for newly diagnosed glioblastoma multiforme (GBM) 6-TG, Capecitabine and celecoxib plus TMZ or CCNU for anaplastic glioma patients Gliadel wafers and Temodar in the treatment of glioblastoma multiforme A study of intraventricular liposomal encapsulated Ara-C (DepoCyt) in patients with recurrent glioblastoma

Brain and central nervous system tumors

Completed

NCT00004892

Brain and central nervous system tumors

Completed

NCT00003876

Brain and central nervous system tumors

Terminated

NCT00045721

Glioma, glioblastoma multiforme, anaplastic astrocytoma

Completed

NCT00409214

Brain and central nervous system tumors Malignant glioma

Completed Active, not recruiting

NCT00003463 NCT00919737

Newly diagnosed supratentorial malignant glioma

Unknown

NCT00283543

Glioblastoma multiforme, anaplastic astrocytoma, anaplastic Oligodendroglioma

Terminated

NCT00645385

Glioblastoma multiforme, high-grade glioma

Terminated

NCT00548938

Glioblastoma multiforme

Completed

NCT00076986

Glioblastoma, anaplastic astrocytoma

Completed

NCT00431561

Brain and central nervous system tumors

Recruiting

NCT00814593

Glioblastoma multiforme

Terminated

NCT00984438

Glioblastoma multiforme

Not yet recruiting

NCT01317212

Brain and central nervous system tumors

Unknown

NCT00362921

Brain and central nervous system tumors

Recruiting

NCT01310868

Brain and central nervous system tumors

Terminated

NCT00238277

Glioblastoma multiforme, gliosarcoma, grade iV malignant glioma Anaplastic glioma of brain, glioblastoma multiforme, brain cancer Primary glioblastoma multiforme

Recruiting

NCT01186406

Completed

NCT00504660

Terminated

NCT00574964

Glioblastoma multiforme, glioma, astrocytoma, brain tumor

Recruiting

NCT01044966

system can be completely implanted, and is equipped with several catheters and an external programming unit (Heruth, 1988). All these systems have been undoubtedly to a certain extent successful for the treatment of gliomas; still none was established as standard therapy due to their limited efficiency. A real progress in the field of infusions, however, was the development of the CED method, already studied by Bobo et al. (Bobo et al., 1994; Krauze et al., 2008). CED is a delivery technique employing a catheter as well as a pump as the necessary tools. Normally, catheters are introduced stereotactically, while the direct delivery of small amounts of therapeutic solutions to the target site under pressure leads to a convective flow independent of the drug solution diffusivity. Due to the convective flow while using CED, therapeutic solutions can cover longer distances in the brain compared to the conventional infusion techniques (Fig. 1) which are merely diffusion based (Allard et al., 2009; Bobo et al., 1994). In another study in this respect, it was found that the design and placement of the cannula as well as the infusion rate are important to obtain a good distribution of the delivered therapeutic agent, and to avoid the

backflow of the solution (Yin et al., 2010). They also reported that acceptable results were obtained by means of a 1 mm stepped cannula with 1 mm tip. CED has been tested for the delivery of a broad spectrum of therapeutic agents, such as small molecules (Mardor et al., 2001; Yin et al., 2010) as well as macromolecules (Astary et al., 2010; Krauze et al., 2008; Kunwar et al., 2006; Patel et al., 2005; Weaver and Laske, 2003), and nanocarriers such as nanospheres, liposomes, micelles and dendrimers (Allard et al., 2009; Cirpanli et al., 2010; Grahn et al., 2009; Yang et al., 2009; Yokosawa et al., 2010). The application of the CED for the delivery of the nanocarriers to the tumor is of utmost important, given the fact that some like liposomes offer advantages such as larger distribution within the target site, sustained drug release, and less systemic side effects compared to the conventional drug solutions. However, CED also associates with inconveniences such as unpredictable drug distribution along with the common drawbacks of the infusion approach. To monitor the delivery and distribution of liposomes through CED, an investigation was devoted to establish a real-time imaging magnetic resonance method, which

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Diffusion-controlled Drug Delivery

Convection-controlled Drug Delivery

Conventional Injections & Infusions

Convection enhanced drug delivery

Fig. 1. Diffusion- and convection-controlled drug delivery modified from Benoit et al. (Allard et al., 2009).

was fulfilled through the encapsulation of gadoteridol, a magnetic resonance contrast agent, within the liposomes (Krauze et al., 2008). It is believed that CED is a promising approach for the treatment of malignant gliomas. Nevertheless, inconveniences such as invasiveness as well as the imposition of the same side effects associated with the conventional infusion methods, such as infection and edema, have hindered the system from developing into a standard therapeutic system for the treatment of the disease.

2.3. Trans-nasal drug delivery Another way to deliver drugs to the brain is the trans-nasal administration approach which involves the delivery of the therapeutic agents through the nasal route. The introduced drug has to cross the nasal olfactory epithelium and the arachnoid membrane to reach the CSF (Illum, 2000; Pardridge, 2007). Different paths for the chemotherapeutic molecules to cross the nasal olfactory epithelium including the intracellular, paracellular, and transcellular paths have been identified so far (Illum, 2000; Lochhead and Thorne, 2011). The intracellular transport involves the endocytosis or pinocytosis of the drug molecules which are then transferred to the olfactory bulb by the olfactory or the trigeminal ganglion nerves. In case the therapeutic agents take the extra- or paracellular pathway to the lamina propria, they can be removed by blood or lymphatic vessels (Lochhead and Thorne, 2011). Another possibility seems to be the extracellular diffusion or convection of therapeutics through the areas adjacent to the olfactory nerves across the arachnoid membrane into the olfactory CSF, from where the therapeutic agents can reach the general CSF. Pardridge various factors such as the molecular weight and the lipophilicity of the drug as well as the involvement of certain receptors can influence its delivery across the nasal mucosal barrier to the CSF (Illum, 2000; Pardridge, 2007). Furthermore, Pardridge assumed that a breakdown of the nasal mucosal barrier following the administration of a large volume of the drug solution instilled intranasally can result in the penetration of several agents to the SCF, which due to their special physicochemical properties, could not normally reach this spot (Pardridge, 2007). Hence it can be concluded that further research has to be done to thoroughly understand the mechanism of the nasal drug delivery to the brain.

2.4. Implants 2.4.1. Polymeric implants Polymeric implants may contain biodegradable or nonbiodegradable polymers. Delivery systems with non-degradable polymers are taken advantage of, when a removable system is required, although the persistence of the polymer after delivery limits their clinical use. Controlled release systems using biodegradable polymers are, however, more common, mostly due to the complete erosion and clearance of the carrier during the delivery (Wang et al., 2002). Drug release from the biodegradable systems can be influenced by a combination of degradation, diffusion, and erosion processes, while release from the nonbiodegradable implants is mostly diffusion-controlled (Liechty et al., 2010). A typical example of non-biodegradable systems frequently used for drug delivery purposes is the copolymer of ethylene vinyl acetate (Tamargo et al., 1993; Wang et al., 2002). Nevertheless, since non-biodegradable systems are associated with various disadvantages such as the persistence of the polymer after delivery and purely diffusion-controlled release kinetics, biodegradable polymeric drug delivery systems such as the polylactide-co-glycolide copolymer (PLGA) were developed and investigated. As reviewed by Siepmann and Göpferich, drug release from PLGA implants are affected by a variety of processes such as diffusion, dissolution, degradation, water-invasion, crystallization, formation of pores, and changes in the pH (Siepmann and Gopferich, 2001). In general, there are two different types of erosion. One is the bulk erosion in which the polymer is degraded from the inside toward the outside, while in the second type, the surface erosion, the degradation direction of the polymer is from the outside inwards (Brem and Langer, 1996; Siepmann and Gopferich, 2001). It is believed that the degradation of PLGA is mainly a bulk erosion process (Siepmann and Gopferich, 2001). Therefore, since unlike the bulk erosion, surface erosion results in a release mechanism closer to the zero order controlled release kinetics (Siepmann and Gopferich, 2001), other biodegradable polymers such as polyanhydride-poly[bis (p-carboxyphenoxy)] propane-sebacic acid or the fatty acid dimer–sebacic acid were developed (Brem and Langer, 1996; Leong et al., 1985), which were mainly degradated through the surface erosion. During the last two decades, a broad range of polymeric delivery systems such as wafers, microspheres, nanospheres, gels, and microchips have been designed and explored, and will be further discussed in the upcoming sections.

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2.4.1.1. Wafers. Polymeric wafers are delivery systems loaded with the therapeutic agents, which almost look like a coin in geometrical shape and size. They can be implanted after the surgical resection of a tumor into the remaining cavity. Polymeric wafers provide sustained release drug reservoirs with defined and tunable release kinetics based on the composition of the polymers. Nevertheless, the major drawback restricting the success of wafers as standard delivery systems is the limited penetration depth of the incorporated therapeutics into the brain tissue and the tumor site. Especially the combination of low diffusion coefficients with high elimination rates can limit the drug distance from the delivery site to few millimeters (Sawyer et al., 2006). Furthermore, several side effects such as “intracranial abscesses, meningitis, impaired wound healing, wound dehiscence, CSF leak, and tumor cyst formation” (Engelhard, 2000) are associated with these systems. In one study, Brem et al. tested BCNU, the most effective agent for the treatment of gliomas at the time, in a I–II clinical trial investigating the localized delivery of chemotherapeutics by wafers (Brem et al., 1991). The results demonstrated that the localized therapy with BCNUloaded polymeric wafer, currently available in the market under the name Gliadel® (Fig. 2), was safe and well tolerated. In addition, localized chemotherapy with Gliadel® followed by radiation therapy in the treatment of recurrent and newly diagnosed malignant gliomas proved to be secure and effective (Brem et al., 1995). The use of Gliadel® for the treatment of recurrent and newly diagnosed glioma was approved by FDA in 1996 and 2003, respectively (Brem and Langer, 1996; Gallia et al., 2005; Wang et al., 2002). In another study, La Rocca and Mehdorn demonstrated the feasibility and efficiency of a combined therapy with Gliadel® , radiation and systemic administration of TMZ in a prospective phase III clinical trial (La Rocca and Mehdorn, 2009). In addition to Gliadel® , several other polymeric wafers were designed and tested. For instance, polyanhydride-poly[bis (pcarboxyphenoxy)]propane-sebacic acid polymer discs containing 20–40% taxol were tested in an in vivo 9L intracranial rat model, though the delivery system was not further pursued due to the observed toxicity resulted from the system (Walter et al., 1994). Furthermore, fatty acid dimer–sebacic acid wafers containing cyclophosphamid were tested in rat glioma models, which proved to be effective and safe for the local treatment of 9L rat glioma (Judy et al., 1995). In 2001, 4-hydroxyperoxycyclophosphamid was encapsulated alone and in combination with l-buthionine sulfoximine in wafers made of fatty acid dimer–sebacic acid. The investigation of the wafers in 9L glioma rat models demonstrated that drug combination resulted in better therapeutic effects compared to the wafers containing 4-hydroxyperoxycyclophosphamid alone (Sipos et al., 2001). In other studies, fatty acid dimer–sebacic acid copolymer and polyanhydride-poly[bis (p-carboxyphenoxy)] propane-sebacic acid copolymer were employed for the local delivery of carboplatin, camptothecin, and mitoxantrone in rat glioma models

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(DiMeco et al., 2002; Olivi et al., 1996; Storm et al., 2002). Although various chemotherapeutics were incorporated into a variety of polymeric systems as ethylene vinyl acetate extrudates, polylactide-co-glycolide copolymer matrices, polymethylmetacrylate devices, and polylactide rods, and were tested in various trials in different animal models, none but Gliadel® was legally approved for the treatment of malignant gliomas (DiMeco et al., 2002; Judy et al., 1995; Lin et al., 1989; Olivi et al., 1996; Rama et al., 1987; Sipos et al., 2001; Storm et al., 2002; Walter et al., 1994). 2.4.1.2. Gels. To fulfill the localized delivery of the anti-tumor drugs, it is also possible to incorporate them in gel formulations. A controlled release delivery system for paclitaxel known as OncoGel® was developed in this respect (Elstad and Fowers, 2009). The base gel formulation of the system named ReGel® is a triblock copolymeric system consisting of polylactideco-glycolide-polyethylene glycol-polylactide-co-glycolide entities, which is normally a water soluble, low viscous solution at 2–15 ◦ C (sol-state), and which changes to a viscous, water insoluble biodegradable controlled-release gel at the body temperature (gel state). ReGel® is a non-ionic surfactant spontaneously able to form micelles with a hydrophobic core. These micelles are capable of dissolving poor soluble active agents. Therefore, it is applicable for the delivery of various agents such as chemotherapeutics, peptides, and proteins. OncoGel®, a controlled release formulation of paclitaxel in ReGel® , has been evaluated in various nonclinical studies, in which it proved to be safe and effective (Elstad and Fowers, 2009). However, whether OncoGel® can be an innovative treatment option for malignant gliomas has to be further investigated. Akbar et al. developed another type of gel delivery system which was then assessed in terms of safety and efficiency (Akbar et al., 2009). The gel matrix-TMZ formulation was well tolerated in subcutaneous as well as intracranial resection models. Significant reduction in tumor size was observed in a group treated with a 30% TMZ formulation, compared to a control group treated with the blank formulation (Akbar et al., 2009). The gel matrix-TMZ system seems to be safe and effective in vivo, though further research has to be done before it can be inserted to adjuvant therapy. It should be noted, however, that gel formulations also share the main drawback associated with the wafers, i.e. small penetration depth of the chemotherapeutic agent into the tumor tissue (Akbar et al., 2009; Elstad and Fowers, 2009). Until resolved, this drawback limits their application for the treatment of malignant gliomas. 2.4.1.3. Microcarrier and nanocarrier systems. In general, there are various techniques for the preparation of the microparticles. The most common preparation techniques include the emulsion methods in which the solvent can be removed through evaporation or extraction. Due to their convenient size, the implantation of microcarriers is technically much easier than wafers or large implants, decreasing the possibility of huge tissue damage (Engelhard, 2000;

Fig. 2. Wafers are inserted into the tumor resection cavity. Reprint with the kind permission of Science and Medicine of figure, p57 top – placement of polymer wafers Sci & Med Jul/Aug 1996:3(4):52–61 (Brem and Langer, 1996).

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Menei et al., 1993). Various drug loaded microspheres have been explored for the treatment of malignant gliomas. As an effective chemotherapeutic agent against malignant gliomas in rat and human cell culture models (Cahan et al., 1994), paclitaxel was selected to be delivered by various microparticulate systems for the treatment of glioma. Brem et al. developed biodegradable microspheres known as Paclimer, which were shown to extend median survival in 9L gliosarcoma bearing rat models (Li et al., 2003). Almost six years later, Wang et al. developed paclitaxel-loaded PLGA microspheres embedded in an alginate gel matrix (Ranganath et al., 2009). Microspheres were produced by a specific electrospray process. Advantageous were their sustained drug release and low initial burst effect in vivo. In another trial, paclitaxel and suramin-loaded core/shell microspheres were developed for the treatment of brain tumors. Core and shell were made of different polymer types, whereby release of paclitaxel and suramin could be controlled. The previously described drug delivery system exhibited acceptable activity both in vitro and in vivo (Nie et al., 2010). Furthermore, submicron/nanoscale PLGA implants with the aim to supply high amounts of paclitaxel at the implant surface were developed for the treatment of glioblastoma. In this experiment, paclitaxel-loaded PLGA nanofiber discs, paclitaxel-loaded PLGA submicron-fiber discs, and paclitaxel-loaded PLGA microspheres embedded in various hydrogel matrices were compared in terms of distribution in mouse brain, and efficacy in the treatment of glioma. Improvement of paclitaxel penetration was only shown to be up to a distance of 5 mm around nanoscale-fiber discs and PLGA-microspheres in H80-hydrogel matrices. These formulations exhibited promising pharmacokinetics as well as significant tumor inhibiting ability in glioblastoma xenografts mice models (Ranganath et al., 2010). Still, clinical studies have to be carried out to ascertain the efficiency and safety of paclitaxel loaded microsphere systems in the treatment of gliomas. In another investigation, Benoit et al. implanted 5-fluorouracilloaded PLGA microspheres stereotactically in healthy and C6bearing rats, to study them in terms of fate and toxicity (Menei et al., 1996). Based on this study, they discovered that 5-FU loaded microspheres led to a decreased mortality rate in the group of tumor-bearing animals. Therefore, they devoted another research project to the localized and sustained delivery of 5-FU from PLGA microspheres in eight patients after surgical resection of the tumor (Menei et al., 1999). External beam radiation was carried out as in conventional therapy. This pilot study demonstrated certain efficacy of the drug delivery system for the treatment of brain tumors due to an improved median survival of 98 weeks (Menei et al., 1999). Later, Benoit et al. studied the drug diffusion from the [3 H] (6)-5-FU microspheres in the implantation site. They figured out, however, that the drug diffusion was most unfortunately limited (Roullin et al., 2002). Thereafter, a phase I clinical trial was carried out with 10 patients diagnosed with inoperable malignant gliomas, in which 5-FU microspheres were implanted stereotactically, followed by external beam radiation therapy. Median survival was only 40 weeks, insignificantly different from the control group (Menei et al., 2004), which was apparently due to the poor drug diffusion into the tumor tissue (Clarke et al., 2010; Stupp et al., 2005). Recently, it was found that locally implanted doxorubicinloaded beads could improve median survival in 9L glioma bearing rat models when compared to the blank beads. However, median survival of the group treated with drug loaded beads did not improve compared to the group subjected to radiation therapy (Vinchon-Petit et al., 2010). In another investigation, TMZ-PLGA microspheres were developed, for the systemic use of TMZ in combination with radiotherapy was found to increase the median survival (Clarke et al., 2010; Stupp et al., 2005). Furthermore, a combination of TMZ and the anti-angiogenic agent vatalanib was

also tested in a rat orthotopic glioma model. It was found that TMZ microspheres led to an improved tumor inhibition compared to the non-encapsulated TMZ. TMZ-vatalanib microspheres were found to improve the tumor inhibition even further (Zhang et al., 2010). Another strategy for the treatment of gliomas is the activation of the host’s immune system against glioma cells through the localized delivery of immunotherapeutics. Based on this theory, microspheres containing interleukin 2 (IL-2) were developed and tested alone and in combination with BCNU wafers in 9L glioma rat models. A synergistic effect of immunotherapy and chemotherapy was shown, in which the combination of IL-2-loaded microspheres and BCNU-loaded wafer (10%) could significantly improve the mean survival of rats in comparison with the monotherapy (Rhines et al., 2003). The combination of local immunotherapy and chemotherapy is investigated continuously, and further results are expected. It should be noted, however, that the main drawback of all microcarrier devices is the small penetration depth of incorporated drug into the surrounding tumor tissue, which has to be overcome as well. Another approach for the localized treatment of malignant gliomas includes the application of nanocarriers such as liposomes, polymeric nanocapsules, and solid lipid nanocapsules, which are all particles ranging from 10 to 1000 nm in size (Kreuter, 2001), and which can be injected into the tumor for localized therapy. One reason for the development of nanocarrier implants was to overcome the multi-drug resistance (MDR) mechanism at the tissue as well as the cellular levels. Moreover, these systems are believed to increase the drug stability and improve the drug distribution. In one study, lipid nanocapsules containing paclitaxel prepared by an emulsion inversion method were tested in vitro and in vivo for the treatment of F98 glioma (Garcion et al., 2006). In vivo F98 cells were implanted subcutaneously into the left thigh, followed by the treatment with lipid nanocapsules after five days. It was found that lipid nanocapsules containing paclitaxel were superior alternatives compared to the commercially available paclitaxel formulation (Garcion et al., 2006). In another study, lipid nanocapsules containing an organometallic tamoxifen derivative (Fc-diOH) were tested for the treatment of malignant gliomas in rats. F344 rats received 9L cells subcutaneously into the right thigh. Six days after the injection of the tumor cells, the rats received various intratumoral treatments. Fc-diOH lipid nanocapsules were shown to cause a significant reduction of the tumor mass and volume (Allard et al., 2008). However, despite the relative effectiveness of the nanocarrier systems, further research should be devoted to explore the safety and efficacy of the system as well as the diffusivity of the drug into surrounding tumor tissue. 2.4.1.4. Microchips. Microchips are other controlled release drug delivery systems employed for the treatment of malignant gliomas, which can be implanted in the remaining cavity after the surgical debulking of a brain tumor. They are capable of delivering single or combinations of various chemotherapeutics to the tumor site. Classical microchips consist of silicon which guarantees the controlled release of drug from a variety of small reservoirs. Normally, these reservoirs are covered by a membrane which serves as the anode. The drug will be released in case the device is placed in an electrolyte solution, while an electric potential is applied to the anode membrane (Santini et al., 2000a). Depending on the composition of the membrane, the chemotherapeutics trapped in these reservoirs can be released autonomously. Langer et al. investigated the principle of microchips using gold and saline solution as the model system (Santini et al., 1999). Microchip reservoirs can be accommodated in accordance with their size. For instance, more than 1000 reservoirs can exist on a microchip with a size around 17 mm. Along with microchips made of non-biodegradable materials, biodegradable microchips have

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been also explored. Biodegradable microchips do not contain any electronics, power sources, or microprocessors. Their reservoirs can be left uncovered, or can be covered by either biodegradable or nonbiodegradable materials with known permeability for the drug. Release kinetics is actuated by the degradation rate of the cover material or the diffusion rate through the matrix. Degradation and diffusion rates can be in turn controlled by the thickness and formulation of matrix material as well as drug properties (Santini et al., 1999, 2000a,b). In 2005, a drug delivery microelectromechanical system (MEMS) was employed to treat experimental tumors in rats (Li et al., 2005). This system consisted of a silicone substrate in which various reservoirs were etched. BCNU was also incorporated, while the release of the drug was fulfilled by electrochemical dissolution of gold membranes which built the covers of the reservoirs. However, MEMS exhibited the same anti-tumor growth efficacy as equipotent injections of BCNU. Therefore, resorbable polymer microchips releasing BCNU to inhibit tumor growth were developed and tested in rat 9L flank models (Kim et al., 2007). The efficacy of microchips containing BCNU was compared to impregnated wafers. It was found that BCNU was more stable within microchips compared to wafers at 37 ◦ C. Furthermore, a dose dependent decrease in tumor size was found for BCNU microchips. Microchips loaded with 1.24 mg BCNU demonstrated a significant decrease in tumor growth in comparison with the empty microchips (Kim et al., 2007). Nevertheless, treatment with biodegradable wafers and biodegradable microchips at the same dose range showed similar efficacy. 3. Systemic drug delivery strategies for gliomas In contrast with the localized delivery, systemic drug delivery to the brain and especially to a brain tumor is much more challenging, given the fact that most of the chemotherapeutics are excluded from the CNS by the BBB (Sawyer et al., 2006). Consequently, various strategies such as temporary disruption of the BBB, chemical modification of available chemotherapeutic agents as well as utilization of endogenous transport systems were explored to overcome the mentioned problem (Gabathuler, 2010; Pardridge, 2005, 2007; Scherrmann, 2002). These approaches will be further discussed under the upcoming sections. 3.1. Temporary disruption of the BBB One option to increase the drug concentration in the brain is the transient disruption of the BBB. A temporary disruption of the BBB can be achieved by the administration of various substances, or application of special techniques (reviewed by Lesniak and Brem, 2004; Pardridge, 2005, 2007). Examples of these include the administration of a hyperosmolar mannitol solution (Fortin et al., 2005), bradykinin analogs such as RMP-7 (Bartus et al., 2000; Prados et al., 2003), surfactants such as SDS or Tween 80 (Saija et al., 1997; Sakane et al., 1989), and several cytokines (Barichello et al., 2011; Kebir et al., 2007) as well as the application of a special ultrasound technique (Hynynen et al., 2001, 2006). This transient disruption results in the increment of the BBB permeability, which in turn leads to the achievement of a higher drug concentration in the brain, and in the tumor site. 3.2. Chemical modification of the available chemotherapeutics As a general rule, only active agents with high hydrophobicity (able to form less than 8 hydrogen bonds) and small molecular weight (less than 400–600 Da) are able to cross the BBB by passive diffusion (Pardridge, 2007; Scherrmann, 2002). Therefore, some researchers have endeavored to increase the lipophilicity of the available drugs to enhance their ability to cross the BBB. For

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instance, the lipophilicity of various molecules was increased by the introduction of certain lipophilic groups such as methyl- or chlorine-, to obtain more BBB-traversable molecules (Hansen et al., 1992; Weber et al., 1991). The lipophilicity of a drug can also be improved through the introduction of hydrophobic entities such as special chemical delivery systems (Bodor and Buchwald, 1997; Bodor et al., 2002), adamantane (Tsuzuki et al., 1994) or fatty acyl entities (Shashoua and Hesse, 1996). However, it should be noted that an enhanced lipophilicity does not automatically bring about a higher drug uptake by the brain, or a higher efficiency of the chemotherapeutic agent, since an increased lipophilicity can also account for higher uptake of the drug by other tissues, which can in turn result in higher risks of toxicity (Scherrmann, 2002). 3.3. Endogenous transport systems Endogenous transport mechanisms across the BBB include the carrier-mediated, receptor-mediated, and adsorptive-mediated transports (reviewed by Beduneau et al., 2007; Gabathuler, 2010; Pardridge, 2005, 2007). “Active drug targeting” is a term applied to refer to the use of these transport systems for drug delivery. 3.3.1. Carrier-mediated transport Among the carrier-mediated transport systems are the glucose, large amino acid, cationic amino acid, concentrative nucleoside, choline, and nucleobase transporters (Pardridge, 2005, 2007). These systems are responsible for the delivery of substances such as glucose (Pardridge and Oldendorf, 1975), neutral amino acids or drugs with a similar structure e.g. l-DOPA (Wade and Katzman, 1975) and melphalan (Cornford et al., 1992), basic amino acids, molecules with a ketone structure or several monocarboxylic acid drugs, purin bases, nucleobases, and choline across the BBB (Ganapathy et al., 2009; Pardridge, 2007; Tsuji, 2005; Tsuji and Tamai, 1999). The aforementioned carriers could only be used for drug delivery in case the molecular structure of the drug has been adapted to the endogenous substrate, or the endogenous substrate is linked to the active agent. For every individual case, the effectiveness of the adapted active agent for a particular therapy, i.e. whether the active agent can be effectively transported, should be verified. However, none of these carrier-mediated transport systems could be successfully established for the treatment of malignant gliomas so far. 3.3.2. Receptor-mediated transport Receptor-mediated transport across the BBB by transferrin, insulin receptors, and low-density lipoprotein receptor as well as the related proteins has been investigated for the transport of large molecules (Pardridge, 2007, 2008; Wagner et al., 1994) as well as drug loaded colloidal carriers such as nanoparticles (Kreuter et al., 2002; Ulbrich et al., 2009; Wagner et al., 2012; Wohlfart et al., 2011b) and liposomes (Boado and Pardridge, 2011; Pardridge, 2007), through their binding to specific endogenous receptor ligands or monoclonal antibodies (mAb). These compounds are then able to cross the BBB like “molecular Trojan horses” (Gabathuler, 2010; Pardridge, 2007). The therapeutic approach of receptor-mediated transport has been tested in various studies for the treatment of gliomas. For instance, Pardridge et al. could increase the survival of glioma bearing mice for about 88% through the liposomal delivery of a gene therapeutic agent causing RNA interference of EGFR gene expression (Zhang et al., 2004). In another study, the receptor-mediated transport approach was used successfully for the treatment of glioblastoma bearing rats with surface modified doxorubicin nanoparticles (Wohlfart et al., 2011a). Furthermore, a phase I, open-label, dose escalation study with a peptide-paclitaxel conjugate which crossed the BBB through the receptor-mediated transport via the low-density

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lipoprotein receptor related protein was conducted in patients with malignant glioma (Angiochem Inc, 2012). This study demonstrated that the peptide-paclitaxel conjugate was well tolerated, and seemed to be promising for the treatment of recurrent gliomas (Drappatz et al., 2010; Wen, 2010). Nevertheless, although the results of the conducted experiments refer to the promising nature of the receptor-mediated transport for the treatment of gliomas (Drappatz et al., 2010; Wohlfart et al., 2011a; Zhang et al., 2004), the efficiency and selectiveness of the approach for the delivery of the drugs into the brain should be verified, for these receptors do not specifically exist at the BBB tissue, but also in other tissues of the body (Belfiore et al., 2009; Lillis et al., 2008; Wagner et al., 1994). 3.3.3. Adsorptive-mediated transport In the adsorptive-mediated transport, electrostatic interactions between the positively charged ligands and the negatively charged BBB determine the transport across the BBB (Abbott et al., 2010; Beduneau et al., 2007; Bickel et al., 2001; Gabathuler, 2010; Pardridge et al., 1993). In case of the adsorptive-mediated endocytosis, polycationic substances directly bind to the negatively charged luminal plasma membrane to initiate the process (Abbott et al., 2010; Bickel et al., 2001; Pardridge et al., 1993). As reviewed earlier by Gabathuler, several systems such as positively charged peptides as well as positively charged protein transduction domains conjugated with active agents or nanoparticles have been explored in this respect (Gabathuler, 2010). However, none of these systems have been so far able to open their ways to the market as a standard treatment for gliomas. To ensure a safe and efficient transport across the BBB, it is essential to completely understand the transport mechanism. In this case, the selectiveness of the adsorptive-mediated transport across the BBB should be thoroughly verified. Moreover, since the cationic nanoparticles are suspected to provoke toxicity at the BBB, the toxicity of the therapeutic agents along with the conjugates has to be investigated as well (Lockman et al., 2004). 4. General discussion Malignant gliomas are amongst the most insidious and destructive brain cancers associated with disproportionally high mortality rates. Despite intensive research for more effective treatments, these tumors remain refractory to the primary treatment strategies, including cytoreductive surgery, external-beam radiation, and systemic chemotherapy (Williams et al., 1997). This might be due to the limitations such as tumor invasion into functional brain tissue, lack of chemosensitivity, and shortcomings of the systemic delivery (Mamelak, 2005). Unfortunately, the prognosis of the disease is dismal. Even after surgical resection, the median survival rate is no more than 6 months, which could be extended up to 9 months by additional radiation therapy (Wang et al., 2002). Recurrences are common as well, particularly at the same locus, or within centimeters of the pre-surgical tumor margin (Williams et al., 1997). Malignant gliomas are also especially refractory to systemic chemotherapy. Many forms of systemic chemotherapy are excluded from the CNS by the BBB. In case of the few compounds partially able to cross the BBB- such as the class of antiproliferative agents known as nitrosoureas (including BCNU and lomustine), and some other alkylating agents (TMZ)- clinical studies suggest that the systemic delivery only offers modest benefit as a supplement to radiotherapy (Sawyer et al., 2006). Furthermore, in order to achieve therapeutic doses of the chemotherapeutic agents within the CNS, the exposure of the body to intolerably high systemic drug levels is inevitable (Wang et al., 2002). Thus, there is a constant search for new therapeutic approaches for the treatment of gliomas.

Since the BBB is still the major factor limiting the efficacy of systemically delivered drugs, various therapeutic strategies have been developed to circumvent this barrier. Injection into the tumor or into the resection cavity is the easiest way to circumvent the BBB. These localized injections can indeed lead to an increased concentration of the drug in the tumor as well as lower systemic toxicity (Tomita, 1991). However, intracerebral injections are believed to be associated with a high risk of side effects. The therapeutic agent itself, especially when administered in high doses or volumes might cause toxicity during the intracerebral delivery (Hassenbusch et al., 2003). Furthermore, given the clearance of the drug from the brain as well as its metabolism by the cells, it is not possible to cure the lesions with a single injection, i.e. the injection might need to be repeated several times, which in turn corresponds with a higher risk of infection (Walter et al., 1995). All these inconveniences lead to a less frequent application of the intracerebral injection approach in the treatment of gliomas. To decrease the risk of infection, the Ommaya reservoir which is a specific catheter system transferring the therapeutics as solutions to the SCF was developed (AyubK, 1963). Although the system is able to decrease the risk of infection in comparison with the conventional catheter systems, the complete elimination of the infection risk with the system is not possible. Furthermore, the system is not able to fulfill the continuous delivery of the drug. In general, the main drawback of infusions in the treatment of malignant gliomas is the resulted small diffusion and distribution ranges of the delivered therapeutic agents (Bobo et al., 1994; Sawyer et al., 2006). The diffusion of a therapeutic agent in the tumor tissue depends upon its physicochemical properties, biological structure of the surrounding tumor tissue, and free concentration gradient of that particular drug (Di Paolo and Bocci, 2007; Jain, 1987). High molecular weight drugs have smaller diffusivity in the brain tumor tissue compared to low molecular weight agents, whereas clearance and metabolism often restrict the efficacy of low molecular weight agents (Jain, 1987, 1989; Morrison and Dedrick, 1986; Sendelbeck and Urquhart, 1985). A further development in the treatment of malignant gliomas has been minipumps, which could indeed deliver the therapeutic agents more constantly to the target site. However, active agents delivered by such pumps could only reach a small area of the surrounding tissue, and their use is limited due to mechanical failures (Chandler et al., 1988; Giussani et al., 2003). Therefore, Bobo et al. (1994) developed CED as a novel localized delivery method. In this process, a solution of the therapeutic agent is transferred intracerebrally by a stereotactically implanted catheter and under a certain pressure which leads to the maintenance of a convective flow, and which in turn results in the delivery of the drug to a wider area in the brain compared to that covered by the conventional infusion techniques (Allard et al., 2009; Bobo et al., 1994). The trans-nasal drug delivery to the brain is another approach to be further explored, in order to verify the possibility to transfer sufficient amounts of the therapeutic agents across the BBB. Furthermore, it is necessary to thoroughly understand the transport mechanism from the nose to the brain, before it is clinically established as a standard method for the treatment of malignant gliomas. The development of biodegradable polymers was a breakthrough, which allowed the design of various drug delivery systems such as polymeric wafers, and micro- and nanocarriers. However, these drug delivery systems comprise several drawbacks. The main drawback limiting the success of the polymeric delivery systems seems to be limited penetration depth of the drug from the system into the tumor site. Several studies showed that therapeutic concentrations of drugs are only available in a several millimeter range from the implantation site (Fung et al., 1996; Grossman et al., 1992; Roullin et al., 2002; Walter et al., 1994). This implies that the

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tumor cells which are not located in this distance range from the system cannot be exposed to sufficient concentrations of the drugs, a weak point which might have led to the limitation of the survival extension to a few months (Brem et al., 1995; Valtonen et al., 1997; Westphal et al., 2003, 2006). Another approach for the localized delivery of the therapeutics includes their incorporation in special gel systems. However, these formulations are also not able to overcome the limited penetration depth of the therapeutic agents into the tumor tissue (Akbar et al., 2009; Elstad and Fowers, 2009). Therefore, they are not considered as a real breakthrough in localized drug delivery for the treatment of malignant gliomas. Biodegradable microchips were also developed as a novel approach for the drug delivery to malignant glioma cells. According to an investigation made in regard with the BCNU-loaded microchips, they were shown to provide similar drug release kinetics as the BCNU-loaded polymeric wafers, which is as effective as the release from FDA approved Gliadel® wafer (Kim et al., 2007). Nevertheless, the results suggested that BCNU is more stable when formulated in microchips than when incorporated in wafers. In general, biodegradable microchips share advantages offered by polymeric systems such as controlled drug release, defined drug release kinetics, tunable release properties, biocompatibility, and possibility of the localized delivery. However, they also share the inconveniences of the polymeric systems including poor drug penetration, limitation of the drug dosage by the size of the system, and high risk of infection. A relative inconvenience of the microchips in comparison with the microspheres is that unlike micro- and nanoparticulate systems, the implantation of the microchips requires open surgery. In addition, a relative superiority of the polymeric micro- and nanoparticulate systems is their ability to release various therapeutic agents time dependently. Therefore, microchips are not considered to be superior therapeutic alternatives to the polymeric delivery systems. Other systemic, non-localized approaches for the circumvention of the BBB have been also explored, amongst which carrier-mediated transport, receptor-mediated transport, and absorptive-mediated transport are the most important. It should be noted, however, that all these approaches should be examined in terms of the selectiveness of the transport system as well as the sufficiency of the resulted drug concentration in the tumor site, to guarantee a successful therapy with as few side effects as possible. Moreover, these systems should be further investigated for the complete understanding of the transport mechanism. The conduction of long term toxicological investigations to ensure the safety of the transport systems for the delivery of the therapeutic agents is also of vital importance.

5. Conclusions Further research is still needed to improve the available therapeutic systems, and to develop novel approaches for the successful management and treatment of malignant gliomas. Nevertheless, the fact that some of the recently introduced systems are considerably more promising compared to the conventional therapeutic systems cannot be denied. This raises hope that the application of right combinations of strategies, delivery systems, and therapeutic agents might lead to a successful treatment of malignant gliomas. It seems that the main problem to be solved in future perspective for localized strategies will be the limited diffusiveness of the drugs into the tumor tissue. None of the various systems have offered a breakthrough in this aspect. The resolution of this problem, therefore, will probably be the key to the treatment of malignant gliomas.

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