Cancer Issue: New Methods for Direct Delivery of = Chemotherapy for Treating Brain Tumors

Journal=20 List > Yale=20 J Biol Med > v.7= 9(3-4);=20 Dec 2006

PubMed=20 articles by:

Sawyer, A.

Piepmeier, J.

Saltzman, = W.

Yale J Biol Med. = 2006 December; 79(3-4): 141=E2=80=93152.=20

Published online 2007 October.=20

Cancer Issue

New Methods for Direct Delivery of = Chemotherapy for=20 Treating Brain Tumors

Andrew J. Sawyer, Joseph M. = Piepmeier, and W. Mark Saltzman^*

Department of Biomedical Engineering, Yale = University=20 School of Medicine, New Haven, Connecticut

^*To whom all = correspondence=20 should be addressed: W. Mark Saltzman, Department of Biomedical=20 Engineering, Yale University School of Medicine, Malone = Engineering=20 Center, Room 414, P.O. Box 208284, New Haven, CT 06520. Tel: = 203-432-4262;=20 E-mail: mark.saltzman/at/yale.edu .

This is an Open Access article distributed under the terms of = the=20 Creative Commons Attribution Non-Commercial No Derivatives = License, which=20 permits for noncommercial use, distribution, and reproduction in = any=20 digital medium, provided the original work is properly cited and = is not=20 altered in any way.

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"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Abstract

Introduction

Polymeric-controlled release

Convection-enhanced delivery

Conclusions

Outlook

References

Abstract

Despite advances in diagnostic = imaging and drug=20 discovery, primary malignant brain tumors remain fatal. Median = survival=20 for patients with the most severe forms is rarely past eight = months. The=20 severity of the disease and the lack of substantial improvement in = patient=20 survival demand that new approaches be explored in drug delivery = to brain=20 tumors. Recently, local delivery of chemotherapy to brain tumors = has=20 provided a way to circumvent the blood-brain barrier, allowing = delivery of=20 chemotherapy drugs directly to malignant cells in the brain. Two = methods=20 of local delivery have been developed: polymeric-controlled = release and=20 convection-enhanced delivery. Controlled release utilizes = degradable or=20 non-degradable polymers as carriers of chemotherapy; polymer = implants or=20 microparticles are implanted locally to introduce a sustained = source of=20 drug for periods of days or months. Convection-enhanced delivery = employs=20 the bulk flow of drugs dissolved in fluid, which is introduced=20 intracranially using a catheter and pump. The convective fluid = flow is=20 capable of delivering drugs great distances within the brain, = potentially=20 treating invasive cells at a distance from the catheter infusion = site.=20 These two new delivery strategies are capable of delivering both = standard=20 chemotherapeutic drugs and new methods of anti-cancer therapy. = Taken=20 individually, or used in tandem, they represent a potential = revolution in=20 brain cancer treatment.

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Abstract

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Introduction

Polymeric-controlled release

Convection-enhanced delivery

Conclusions

Outlook

References

Introduction

Each year, approximately 14,000 people are stricken with brain = cancer.=20 The disease occurs across both social and economic lines, with = incidence=20 rates peaking both in childhood and later in old age. Despite = advances in=20 imaging technology =E2=80=94 which has led to earlier diagnosis of = many tumors =E2=80=94=20 the ability to treat the most aggressive form of brain cancer,=20 glioblastoma multiforme (GBM), has not improved since 1980. The = one-year=20 survival rate for invasive central nervous system (CNS) cancer was = 57.9=20 percent in 2002, and survival for GBM in particular is even lower = [1].

Gliomas are primary CNS tumors arising from the glial cells. = Malignant=20 gliomas have a characteristic ability to infiltrate healthy brain = tissue=20 and form satellite tumors. This capacity for migration makes them=20 exceedingly difficult to treat and invariably fatal. Even after = resection,=20 invasive cells can give rise to tumors within centimeters of the = resection=20 site [2].=20 Untreated malignant tumors can eventually spread to the = contralateral=20 hemisphere [3].=20 Many forms of systemic chemotherapy are excluded from the CNS by = the=20 blood-brain barrier (BBB) [4].=20 A few compounds =E2=80=94 such as the class of antiproliferative = drugs called=20 nitrosoureas (including carmustine and lomustine) or other = alkylating=20 agents (temozolomide) =E2=80=94 have some ability to cross the BBB = and have been=20 used clinically [5].=20 Unfortunately, systemic delivery of these agents appears to offer = modest=20 benefit as a supplement to radiotherapy [6,7].

Over the past two decades, a variety of approaches to enhance = the=20 activity of systemically delivered chemotherapy drugs have been = tested.=20 Hyperosmolar BBB disruption has been used to enhance BBB transfer = of=20 chemotherapy agents, with mixed results. One study, using PET = imaging to=20 evaluate a combination of methotrexate and hyperosmolar BBB = disruption,=20 indicated a negligible effect in brain tumors, which is echoed by = the=20 marginal findings in clinical trials [8,9].=20 A variety of approaches have been tested for enhancing BBB = permeability of=20 systemically administered drugs =E2=80=94 by modification with = hydrophobic side=20 groups, conjugation to ligands with known BBB carriers, such as=20 transferrin, or encapsulation in liposomes or nanoparticles = =E2=80=94 but none of=20 these approaches have impacted clinical treatment of glioma [10].

The failure of conventional systemic drug delivery for glioma = has=20 motivated more direct approaches to drug delivery. Direct = intracranial=20 drug delivery would eliminate the need for a chemotherapeutic = agent to=20 cross the BBB. The ability to bypass the BBB would enable a wider = range of=20 agents =E2=80=94 such as paclitaxel, doxorubicin, immunotoxins, = and even gene=20 therapy vectors =E2=80=94 to be evaluated for brain cancer = treatment. This review=20 describes two of the most promising approaches for direct delivery = of=20 agents to intracranial tumors: polymeric-controlled release and=20 convection-enhanced delivery.

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Abstract

Introduction

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Polymeric-controlled release

Convection-enhanced delivery

Conclusions

Outlook

References

Polymeric-controlled = release

Polymeric-controlled release has long been used for drug = delivery. Some=20 early systems =E2=80=94 the five-year subcutaneous Norplant=C2=AE = contraceptive and the=20 conjuctival Ocusert=C2=AE system for glaucoma =E2=80=94 have = proven the effectiveness=20 of this approach for both systemic and local therapy [11].=20 The controlled release of drug also protects it from elimination = [12].

Controlled release systems can be designed from both degradable = and=20 nondegradable polymers. When constructed from nondegradable = polymers, drug=20 release is usually governed by diffusion of the drug through the = matrix.=20 In contrast, release from degradable polymers is governed by a = combination=20 of drug diffusion through the polymer and erosion of the polymer = matrix.=20 Polymers can be combined into copolymers to tune degradation and = release=20 characteristics. Correctly designed, polymer and drug systems can = provide=20 reliable sustained release for periods of days or many years (see = review=20 in [12]).

Non-degradable polymer=20 systems

Delivery systems constructed from nondegradable = polymers can=20 be employed when a removable system is required. The most common=20 nondegradable polymer system is a copolymer of ethylene and vinyl = acetate.=20 Polyethylene-co-vinyl acetate (EVAc) materials exhibit excellent=20 biocompatibility and are typically implanted chronically. EVAc = have been=20 developed for the controlled release of DNA, antibodies, as well = as=20 chemotherapeutics [13,14].=20 Two studies that examined the delivery of amsacrine and = mitoxantrone in=20 rat glioma models observed potent anti-tumor effects [15,16].=20 While the engineering of these systems is highly developed = =E2=80=94 so that=20 delivery systems of virtually any size, shape, rate, and duration = of=20 release can be produced =E2=80=94 the persistence of the polymer = after delivery=20 limits their clinical use.

Degradable polymer=20 systems

Controlled release systems using biodegradable = polymers are=20 more common than non-degradable systems. The biodegradable systems = offer=20 the same advantages as the persistent wafers, but they completely = erode=20 during delivery and are cleared from the body. This disappearance=20 attenuates the response to the implant and makes it clinically = attractive.=20 Most systems are diffusion regulated and the kinetics are=20 well-characterized [17].=20 Many degradable systems are designed to erode via hydrolysis, = taking=20 advantage of the prevalence of water in the human body. For = example, a=20 variety of controlled release systems have been designed around = the=20 hydrolysable anhydride bond. Copolymers are typically coupled with = anhydride bonds to control the rate of hydrolysis [12].=20 The addition of a copolymer affects the degradation of the polymer = device.=20 The correct copolymer system can achieve ordered erosion, which = provides a=20 consistent release of drug. The most common copolymer systems used = intracranially is polybis(p-carboxyphenoxy)propane-sebacic acid=20 (p(CPP-SA).

p(CPP-SA)-based delivery systems have been characterized for a = variety=20 of drugs and already are used clinically. Many controlled release = systems=20 are based on an implantable wafer, which has been studied with the = drugs=20 mitoxantrone, carmustine (BCNU), 4-hydroperoxycyclophosphamide = (4-HC),=20 paclitaxel, carboplatin, and adriamycin [18-21].=20 The characteristics of drug release from wafers depend on the = polymer and=20 drug used. A typical controlled release curve for BCNU is shown in = [Figure=20 1] [22].=20 The linear region in Figure 1b indicates that the drug release is=20 diffusion controlled [12].=20 In drug-polymer systems with a high degree of surface associated = drug, a=20 burst release phase is observed. p(CPP-SA) wafers of BCNU and 4-HC = have=20 demonstrated release for 50 days. The release of paclitaxel = proceeded at a=20 much lower rate, less than 0.01 mg/day, and for a much longer = period of=20 time (160 days). The slower release rate can be attributed to the=20 hydrophobicity of the drug that causes a strong affinity for the = polymer.=20 The controlled release of drugs from these wafers has demonstrated = performance in many in vitro and in vivo glioma = models.=20 Studies have demonstrated improved performance of these wafers = when=20 compared to free drug administration in a rat model challenged = with an=20 intracranial 9L tumor [23].=20 Small cylindrical wafers have been studied in the same way [18].

Figure=20 1

The=20 cumulative release of BCNU into a well-stirred reservoir as = a=20 function of time (a) and the square root of time = (b). The=20 linear portion indicated in b is indicative of diffusion = controlled=20 release from a planar geometry. Reprinted with permission=20 from=20 (more ...)

The p(CPP-SA) wafer loaded with BCNU has undergone further=20 characterization and is available clinically as Gliadel=C2=AE [24].=20 The Gliadel=C2=AE wafer is 14 mm in diameter and 1 mm thick. It is = loaded with=20 7.7 mg of the drug carmustine and is implanted intracranially = after=20 surgical debulking of the tumor [Figure=20 2]. Gliadel=C2=AE has been studied for clinical use in initial = treatment,=20 treatment of recurrences, and in conjunction with radiotherapy for = malignant gliomas [25-27].=20 In all cases, therapy with Gliadel=C2=AE was well tolerated with = no significant=20 increase in toxicity, infection, or inflammation. The majority of = studies=20 indicated a modest improvement in survival for patients with = malignant=20 gliomas that received Gliadel=C2=AE [28,29].=20 Further research is directed at improving the Gliadel=C2=AE wafer = by examining=20 dosing and combination therapy [30].

Figure=20 2 Intracranial=20 placement of Gliadel=C2=AE wafer. The wafer is = implanted in the=20 cavity left after surgical resection of the tumor. Wafers = are=20 dime-sized and impregnated with carmustine. Reprinted with=20 permission from Fleming. Pharmacokinetics of the = carmustine=20 (more ...)

Fatty acid dimer copolymers use the same polyanhydride = linkages, but=20 they offer a distinct advantage over carboxyphenoxy propane = polymer=20 systems. FAD-SA is typically formed into a disk shape and then = implanted=20 intracranially. The primary use of FAD-SA is the controlled = delivery of=20 the drug 4-hydroperoxycyclophosphamide (4HC) [31].=20 FAD-SA is used for delivery of this drug because 4-HC is = hydrolytically=20 unstable in the p(CPP-SA) wafer [32].=20 The ability to tailor the chemical and physical properties of the = vehicle=20 to the drug is one of the advantages of polymeric delivery.

Other degradable polymers are also useful for drug delivery.=20 Biodegradable polymer matrices based on polymers of lactide and = glycolide=20 are perhaps the most popular platform for local drug delivery. = Polylactic=20 acid (PLA), polyglycolic acid (PGA), and their copolymer=20 polylactic-co-glycolic acid (PLGA) have a long history of use as=20 biomaterials, beginning in the 1970s with biodegradable sutures. = Matrices=20 made from these polymers are biocompatible, hydrophobic, and = degrade to=20 the naturally occurring monomers via ester hydrolysis. Polymer=20 nanospheres, microspheres, and wafers of varying sizes are made = via=20 emulsion/solvent evaporation, salt leaching, and other methods [33].=20 When making spherical particles using the emulsion process, the = solvent,=20 surfactant, and polymer properties can be modified to tune size = and=20 release characteristics [34,35].

Implantable PLGA matrices loaded with chemotherapeutics are = currently=20 under development. The implants can be in the form of electrospun=20 scaffolds, thin films, or even wafers. The process of = electrospinning uses=20 a voltage differential to produce a non-woven mesh. Paclitaxel has = been=20 mixed with the polymer solution before electrospinning to create a = mesh=20 with drug-delivery capability [36].=20 The drug-loaded mesh has controlled release properties and was = effective=20 in vitro against C6 glioma cells. A mesh delivery system = might=20 have advantages over a wafer, because the mesh can potentially = conform to=20 the shape of the resection cavity. The C6 glioma line was also = used to=20 evaluate the controlled release of radioiododeoxyuridine from a = thin film=20 of PLGA [37].=20 Biodegradable PLGA wafers containing BCNU can be used in an = analogous=20 method to Gliadel=C2=AE. The release profile of BCNU from the PLGA = wafer shows=20 a similar profile and duration when compared to the p(CPP-SA) = wafer [38].=20 A reformulated wafer made of compressed BCNU containing = microparticles=20 yielded a longer in vitro release profile, 70 days = compared to=20 seven [39].

PLGA nanoparticles and microparticles can be fabricated using = the=20 single emulsion method to encapsulate hydrophobic compounds and = the double=20 emulsion method to encapsulate hydrophilic compounds [Figure=20 3] [41,41].=20 The advantages of polymer particles lie in the route of = administration.=20 Polymer nanoparticles may be administered using a burr hold and = catheter,=20 which is significantly less invasive than the implantation of = polymer=20 wafers.

Figure=20 3

SEM image=20 of PLGA microparticles loaded with BCNU. The = particles were=20 formed using the solvent extraction/evaporation method. = Average=20 sphere diameter is 30 mm. Reprinted with permission from = Elsevier.=20 Painbeni T, et al., Internal morphology of=20 poly(D,L-lactide-co-glycolide)=20 (more ...)

Polymeric-controlled release is able to administer drugs=20 intracranially, which would be excluded for systemic use or as a = new route=20 of administration. This is the case with doxorubicin (adriamycin), = which=20 exhibits dose-limiting cardiotoxicity [42].=20 The drug temozolomide (TM) has demonstrated clinical efficacy when = given=20 systemically [5].=20 A controlled release form of TM using PLGA microparticles gave the = characteristic biphasic release profile, burst release followed by = a=20 linear period, with a 35-day release period [43].=20 The TM microparticles demonstrated cytotoxicity in culture with C6 = cells=20 and could be administered intracranially as part of the same = regimens=20 currently evaluating systemic TM.

Polymeric-controlled release systems can be engineered for = drugs, such=20 as paclitaxel, that are difficult to administer with conventional = methods.=20 Two drug properties that can limit traditional use are = hydrophobicity and=20 toxicity. Paclitaxel is hydrophobic and sparingly soluble in = water; this=20 restricts its use in injection buffers. Intravenous chemotherapy = with=20 paclitaxel utilizes an adjuvant called Cremophor EL to disperse = the drug,=20 which can cause serious side effects. PLGA is naturally = hydrophobic and=20 encapsulates hydrophobic drugs efficiently. The hydrophobicity of = a drug=20 also affects its release profile. Paclitaxel preferentially = partitions=20 inside PLGA and exhibits a lengthy release curve. A study with = PLGA=20 microparticles showed a sustained release of paclitaxel for more = than 60=20 days without a burst release period [44].=20 The controlled release of paclitaxel also limits the systemic = toxicity.=20 The release is so slow that a variety of coencapsulants have been=20 evaluated to quicken the release of paclitaxel from PLGA matrices. = Two=20 examples are isopropyl myristate and vitamin E TPGS [45,46].=20 Both emulsifiers produced a burst release period. The formulation = using=20 vitamin E TPGS decreased the release time compared to particles = made with=20 the surfactant poly(vinyl alcohol) (PVA) [47].

Controlled release systems may be particularly useful for = agents=20 produced by biotechnology, such as the proteins and nucleic acids = that are=20 needed for immunotherapy or gene therapy. The rare instances of = complete=20 recovery from malignant gliomas typically have been attributed to = an=20 immune response. This observation triggered the search for = compounds that=20 could cause immune cell-mediated cytotoxicity. Type 1 interferons = show=20 antitiumor activity but have a short half-life and high dose = toxicity [48].=20 The short half-life necessitates a continuous delivery for the = molecule to=20 be active, but the continuous delivery will pose the risk of side = effects.=20 Encapsulating these agents protects them from elimination and = provides a=20 means to control the amount released. Interleukin-18, which can be = used in=20 this manner, can be encapsulated in PLGA microspheres and is = active upon=20 release [49].=20 PLGA can also encapsulate and release viable adenovirus [50].=20 The controlled release approach improved in vivo = efficacy.

Polymeric-controlled release provides a biocompatible, tunable = platform=20 in which drug loading, release rate, longevity, and form can be = altered=20 via polymer combination and processing. The method of delivery, as = witnessed by Gliadel=C2=AE, adds minimal complexity, requires no = additional=20 surgical procedures, and minimizes solubility limitations. = Furthermore,=20 the controlled release of the drug slows elimination and increases = duration of exposure. This increases the amount of drug = administered=20 without exposing the tissue to high concentrations that could = cause tissue=20 damage. Most importantly, polymeric-controlled release has a = clinical=20 history of beneficial use.

While controlled release systems can deliver drugs for long = periods of=20 time locally in the brain, local penetration of the drug is = frequently=20 limited by diffusion [21].=20 When low diffusion coefficients are coupled with a high rate of=20 elimination, drug distance from the delivery locus can be limited = to=20 millimeters [51].=20 The extracellular matrix (ECM) of the brain also imposes its own = limits on=20 diffusive transport. The ECM of the brain is a hydrated = environment with a=20 low volume fraction, a high degree of tortuosity, and small pore = size [52-55].=20 The local environment of a tumor limits diffusion even further [56].=20 These factors conspire to confine a high drug concentration to = within 3 mm=20 of the delivery site [24].=20 This distance is exceeded by invasive glioma. Controlled release = also is=20 limited by size. The polymer delivery system must be large enough = or be=20 used in enough amount to deliver clinically relevant drug = dosage.

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Abstract

Introduction

Polymeric-controlled release

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Convection-enhanced delivery

Conclusions

Outlook

References

Convection-enhanced=20 delivery

Convection-enhanced delivery (CED) was developed to deliver = compounds=20 throughout the brain to overcome the diffusion barrier seen with=20 polymeric-controlled release [57].=20 CED utilizes an applied external pressure gradient to induce fluid = convection in the brain. Fluid is typically administered via a = small=20 catheter using a pump [58].=20 Because moderately high pressures (up to 70 mmHg) must be used to = drive=20 convective flows, such procedures are plagued by backflow along = the=20 catheter and often subject the tissue to high pressures. The = increase in=20 pressure is due to occlusions that may block the catheter from = delivering=20 an adequate flow rate. The use of microfabricated silicon probes = reduces=20 those concerns and improves on the general delivery method [59].=20 The outlet of the silicon probes is along an axis perpendicular to = the=20 insertion direction; this geometry prevents tissue from plugging = the=20 orifice. A controlled pressure source in stream with a fluid = reservoir=20 ensures operation at constant pressure. This prevents the pressure = spikes=20 that accompany constant volume delivery. An added advantage to = constant=20 pressure delivery is the ease with which fluid properties can be=20 determined using simple mathematical models.

CED and drug delivery

The = main=20 benefit to administering drug via CED is the greater distribution = volume.=20 Studies that have compared a bolus injection to CED have noted a = larger=20 distribution and a greater efficacy [60,61].=20 The benefits are derived from the greater distribution and a = continued=20 exposure due to the long infusion time. The technique is = inherently=20 flexible and can be used in chemotherapy, gene therapy, and immune = therapy. Methods of drug delivery using free drug have been = studied in=20 animals and clinically. The drugs administered run the gamut from=20 nontraditional compounds to typical chemotheraputic drugs. Typical = clinical use of CED is for salvage therapy after a recurrence of = glioma=20 and follows one of two protocols. Patients are either given local=20 infusions after surgical resection or given infusions directly = into the=20 tumor. Drugs used clinically include both targeted toxins and = traditional=20 chemotherapeutics (Table 1). Studies using the drug paclitaxel = have=20 observed the highest response rates, which are around 75 percent. = Typical=20 response rates for targeted toxin treatment were lower [62].=20 Response rate and the occurrence of adverse events have been = observed to=20 be dose dependent [63].=20 Ongoing clinical trials include the CED of IL13-PE38QQ, and the = CED of=20 topotecan.

The drugs listed in Table 1 reflect only a small sample of the=20 therapeutic agents that have been evaluated in animal models = =E2=80=94 which=20 include the traditional chemotherapy drugs BCNU and topotecan [64,65].=20 However, the drugs available for delivery via CED are still = limited by=20 solubility. A way to avoid solubility issues and protect = antineoplastic=20 agents from elimination is to encapsulate them. Recent research = studied=20 nanoliposomal encapsulated CPT-11 in a rat glioma model [66].=20 The study showed that CPT-11 benefited from the increased = distribution via=20 CED and a longer residence time.

Large particles, with severely restricted diffusion, stand to = benefit=20 most from CED. Accordingly, several research groups are = determining and=20 improving the penetration of particles within the brain delivered = via CED=20 [Figure=20 4]. Studies looking at the size of particle infusate concluded = that=20 smaller particles, around 20 nm, distributed further than larger = particles=20 [67].=20 The same behavior was observed using liposomes [68].=20 Interestingly, particles 40nm and larger had similarly restricted=20 distributions. The surface properties of the small particles play = a=20 significant role in their volume distribution. Surfaces that were = neutral,=20 negatively charged, or coated with poly(ethylene glycol) (PEG) or = bovine=20 serum albumin (BSA) maximized distribution volume [69].=20 Coatings that were positively charged severely restricted particle = distribution. Adjuvants have been used to improve distribution = regardless=20 of particle properties. A hyperosmolar infusion of mannitol = significantly=20 increased volume distribution [68].=20 When the infusate experiences specific cell binding, an infusion = of excess=20 unencapsulated ligands can increase the distribution [70].

Figure=20 4

20 nm=20 Polystyrene beads delivered via CED into the caudate of a=20 rat. Image shows local nanoparticle penetration = after a 5=20 =C2=B5L infusion (Sawyer AJ, Neeves KB, Foley CP, Olbricht = WL, and=20 Saltzman WM, unpublished=20 data).

One objective of the previous particle infusion studies was to = model=20 the delivery of either viral vectors that could be used for gene = therapy=20 or drug loaded particles. CED has the potential to improve gene = therapy by=20 increasing the available concentration of vectors. Two studies = looked at=20 the distribution of adeno-associated vectors (AAVs) administered = via CED=20 [71,72].=20 Each realized a greater and more homogeneous distribution of = transduction=20 by combining AAVs with CED, which was further improved with = adjuvant=20 heparin.

CED and imaging

CED has = the ability=20 to improve both the imaging and treatment of brain tumors. This = allows for=20 a combination approach that can monitor the distribution of drugs = as they=20 are being delivered [73].=20 To observe the distribution via CED, liposomes were labeled with = the MRI=20 contrast agent gadolinium. The gadolinium liposomes can then be = infused=20 with particles of similar size and monitored using MRI. This = approach was=20 validated in a primate model [74].=20 The distributions observed via MRI completely coincided with = distributions=20 determined using fluorescence. Administering contrast agent along = with=20 chemotherapeutic drugs allows for the initial volume distribution = to be=20 observed and for tissue necrosis to be monitored within that = distribution=20 area [75].

CED is limited by its invasiveness and by the anatomical = influences on=20 drug distribution. CED requires the insertion of a catheter = several=20 centimeters deep into the brain, which can cause tissue damage and = may=20 induce air bubbles [76].=20 The anatomy of the brain affects the distribution of drugs. White = matter=20 tracks provide areas of comparatively high fluid conductivity. If = the=20 catheter is inserted through white matter, for example the corpus=20 callosum, the high conductivity combined with reflux up the = catheter=20 siphons drug away from parenchyma. The perivascular spaces have = also been=20 observed to collect infusate during CED [77].=20 The unpredictable flow can lead to collection of drug either in = the=20 perivascular spaces, wound track, or under the scalp. This has = caused=20 incidences of edema and wound dehiscence. The localized high dose = area=20 caused the same symptoms during the delivery of viral vectors [78].

Clinical trials

A Phase = III=20 randomized clinical trial (PRECISE TRIAL) comparing the outcome = between=20 Gliadel and CED of IL13-PE38QQR has been completed (unpublished = data).=20 This study randomized patients with GBM for treatment after they = had=20 failed conventional therapy (surgery, radiotherapy, +/- = chemotherapy).=20 This study revealed no significant difference in outcome. Median = survival=20 following tumor recurrence was 35.3 weeks for the Gliadel and 36.4 = weeks=20 for IL13-PE38QQR. It is anticipated that inaccurate catheter = placement and=20 unresolved problems with adequate drug distribution may have = contributed=20 to the absence of benefit for the CED arm. These data support the = need for=20 continued research in improving drug distribution and better = delivery=20 methods.

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Abstract

Introduction

Polymeric-controlled release

Convection-enhanced delivery

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Conclusions

Outlook

References

Conclusions

Local delivery to brain tumors can be accomplished using the = two=20 strategies of polymeric-controlled release and convection-enhanced = delivery. Each technique strives to address the need for = controllable=20 intracranial drug delivery. The two technologies offer unique = benefits and=20 suffer distinctive limitations, which are listed in Table 2. The = principle=20 disadvantage to controlled release is the restricted drug = distribution.=20 The limitations imposed by diffusion within the brain limit drug=20 penetration to a region smaller than the typical invasive area of=20 malignant gliomas.

CED=E2=80=99s strength lies in the potential for large = distribution volume of=20 infused drugs. The long infusion times and unpredictable = distribution have=20 also caused an abundance of side effects in recent clinical = trials. Trials=20 using paclitaxel have noticed a high rate of drug related adverse = events=20 that include wound dehiscence, inflammation, and edema [79,80].=20 These side effects are attributed to drug backflow along the = catheter, and=20 drug localization in the perivascular and subarachnoid spaces. = Infusing an=20 encapsulated drug may decrease the incidence of these adverse=20 events.

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Abstract

Introduction

Polymeric-controlled release

Convection-enhanced delivery

Conclusions

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Outlook

References

Outlook

CED was developed as a method to address the shortcomings of=20 polymeric-controlled release. Coincidentally, many of the flaws in = CED are=20 the strengths of a polymeric-controlled release approach. = Encapsulation of=20 drug would limit the reflux and promote better wound healing after = delivery. Delivering encapsulated drug could shorten the infusion = time. A=20 shorter infusion time would deliver a lower maximum drug = concentration=20 which could address the instances of edema and inflammation. = Moreover, a=20 combined treatment strategy could truly localize the delivery by=20 restricting it to a prescribed area. Nanoparticle technology has = advanced=20 such that high levels of targeting ligand can be expressed on the = surface=20 of the degradable particles [81].=20 These particles could then be targeted to a subpopulation of = cells.

A combined approach is not without its potential pitfalls. The = polymer=20 particles would have to be large enough to deliver a clinically = relevant=20 dose. The increase in size could restrict the distribution of = particles in=20 the parenchyma. While the adjuvants could improve the = distribution, a=20 multi-focal delivery strategy may be necessary to circumvent the = transport=20 limitations.

Local delivery to brain tumors has already provided a modest = increase=20 in survival when used in addition to surgery and radiotherapy. = Despite the=20 advances, GBM remains fatal regardless of the mode of treatment. = There is=20 untapped potential in both of the local delivery strategies = discussed=20 here. Polymeric-controlled release and CED can be used as = techniques to=20 administer the standard agents, combinations of drugs, as well as = new=20 methods of anti-tumor therapy.

=E2=80=8B=20

Table=20 1

Therapeutic agents=20 evaluated in clinical trials for glioma=20 treatment

Table=20 2

Advantages and=20 disadvantages of polymeric-controlled release and=20 convection-enhanced drug=20 delivery

Abbreviations

GBM	Glioblastoma multiforme
CNS	Central nervous system
EVAc	Polyethylene-co-vinyl acetate
BBB	Blood-brain barrier
p(CPP-SA)	Polybis(p-carboxyphenoxy)propane-sebacic acid
BCNU	Carmustine
4-HC	4-hydroperoxycyclophosph amide
PLA	Polylactic acid
PGA	Polyglycolic acid
PLGA	Polylactic-co-glycolic acid
TM	Temozolomide
PVA	Polyvinyl alcohol
CED	Convection-enhanced delivery
PEG	Polyethylene glycol
AAVs	Adeno-associated vectors

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Abstract

Introduction

Polymeric-controlled release

Convection-enhanced delivery

Conclusions

Outlook

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<= /TD>

References

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Articles=20 from The Yale Journal = of Biology=20 and Medicine are provided here courtesy of
Yale = Journal of=20 Biology and Medicine

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oThis.iScaleIndex < = oMetadata.aView.length - 1; oThis.iScaleIndex++) {=0A= var s =3D oMetadata.aView[oThis.iScaleIndex].W / W;=0A= if (s <=3D 0.5 || s < 1.36) break;=0A= }=0A= } else =0A= oThis.iScaleIndex =3D 0;=0A= =0A= =0A= =0A= // var W =3D oThis.oPanorama.img.width;=0A= // var H =3D oThis.oPanorama.img.height;=0A= // console.info(W, H);=0A= // Set array scale data=0A= for (var i =3D 0; i < oMetadata.aView.length; i++) {=0A= // if (oMetadata.aView[i].W > oThis.oViewport.w || = oMetadata.aView[i].H > oThis.oViewport.h) {=0A= var v =3D oMetadata.aView[i].W / W;=0A= oThis.oScales[i] =3D {n:oMetadata.aView[i].sName, v:v};=0A= // } else =0A= // oThis.oScales[i] =3D null;=0A= =0A= if (oMetadata.aView[i].W =3D=3D oMetadata.aView[i].w =0A= && oMetadata.aView[i].H =3D=3D oMetadata.aView[i].h) {=0A= var v =3D oMetadata.aView[i].W / W;=0A= oThis.oScales[i] =3D {n:oMetadata.aView[i].sName, v:v};=0A= break;=0A= }=0A= }=0A= =0A= x_Update(oMetadata, oThis.iScaleIndex);=0A= }, null);=0A= =0A= =0A= this.oNotifier.setListener(this, "scale", function(oListener, = oComment) {=0A= // save previous scale index=0A= // skip unneccessary scales (if tiled picture less viewport)=0A= oThis.iScaleIndexPrevious =3D oThis.iScaleIndex;=0A= switch (oComment) {=0A= case "up":=0A= if (oThis.iScaleIndex < 1) return;=0A= oThis.iScaleIndex--;=0A= while (!oThis.oScales[oThis.iScaleIndex]) {=0A= oThis.iScaleIndex--;=0A= if (oThis.iScaleIndex < 1) break;=0A= }=0A= break;=0A= case "down":=0A= if (oThis.oScales.length - 1 <=3D oThis.iScaleIndex) return;=0A= oThis.iScaleIndex++;=0A= while (oThis.oScales[oThis.iScaleIndex] =3D=3D null) {=0A= oThis.iScaleIndex++;=0A= if (oThis.oScales.length - 1 <=3D oThis.iScaleIndex) = break;=0A= }=0A= break;=0A= default:=0A= oThis.iScaleIndex =3D oComment;=0A= break;=0A= }=0A= x_Update(oThis.oMetadata, oThis.iScaleIndex);=0A= }, null);=0A= =0A= =0A= setTimeout(function() {=0A= oDataProvider.Request();=0A= }, 5);=0A= }=0A= =0A= TileDataDb.prototype =3D new TileData();=0A= =0A= TileDataDb.prototype.Parse =3D function(arr) {=0A= var tmp;=0A= if (arr.indexOf("p=3D") =3D=3D 0) {=0A= tmp =3D arr.split("=3D");=0A= this.sProjectId =3D tmp[1];=0A= =0A= } else if (arr.indexOf("id=3D") =3D=3D 0) {=0A= tmp =3D arr.split("=3D");=0A= this.sPictureId =3D tmp[1];=0A= =0A= }=0A= }=0A= =0A= =0A= TileDataDb.prototype.GetTileUrl =3D function(row, col) {=0A= return this.sUrl + "?p=3D" + this.sProjectId =0A= + "&id=3D" + this.sTileDbId + "&s=3D" + this.sSat=0A= + "&r=3D" + (row + 1) + "&c=3D" + (col + 1);=0A= }=0A= =0A= =0A= TileDataDb.prototype.GetFitUrl =3D function() {=0A= return this.sUrl + "?p=3D" + this.sProjectId =0A= + "&id=3D" + this.oMetadata.aView[this.oMetadata.aView.length - = 1].sId =0A= + "&s=3D" + this.sSat + "&r=3D1&c=3D1";=0A= }=0A= ------=_NextPart_000_0000_01C814F7.39FBCCA0--