Glioblastoma multiforme is a devastating disease with a median survival of approximately 15 months from the time of diagnosis. The difficulty in treating the disease is highlighted by the relatively small improvements made in survival over the past two decades (Deorah et al. 2006
; Brandsma and van den Bent 2007
). The presence of the blood–brain barrier (BBB), which prevents systemically administered compounds from crossing into the brain, confounds treatment (Groothuis 2000
). The current standard of care for malignant gliomas combines surgical resection with radiation and an oral DNA alkylating agent, temozolomide (Stupp et al. 2007
). While temozolomide reduces the side effects observed with other nitrosourea-based chemotherapies, headaches, fatigue, nausea, and myelosuppression are still observed (Parney and Chang 2003
) and overall survival is still limited.
Biomaterials are potentially useful in treating malignant gliomas because they can provide sustained, local drug delivery and bypass the BBB. The only clinically approved method for local delivery of chemotherapeutic agents to malignant gliomas is Gliadel®, a poly(carboxyphenoxypropane/sebacic acid) (PCPP:SA) anhydride wafer containing 3.85% carmustine (biodegradable carmustine (BCNU)). After maximal tumor resection, these wafers are placed along the surface of the resection cavity, where they subsequently release BCNU over a period of ~3 weeks (Fung et al. 1996
; Attenello et al. 2008
). Randomized placebo-controlled trials demonstrated that treatment with Gliadel® wafers results in improvements (~2 months) in median survival for patients with primary malignant gliomas (Westphal et al. 2003
). Despite this success, it is clear that diffusional penetration of drug from the wafer, which is limited to ~1.5 mm from the polymer-tissue interface (Fung et al. 1996
), limits effectiveness. Direct delivery methods that provide controlled release, precise deployment, and penetration into the brain should improve patient survival.
In addition to improvements in survival, any new method should address concerns about feasibility and safety, which have limited the use of Gliadel®. Gliadel® wafers can only be used in patients that are candidates for surgery. In addition, they are not recommended if gross-total tumor resection cannot be achieved, because of the potential for significant post-operative mass effect. Indeed, even with a gross-total resection, patients treated with Gliadel® must be placed on high-dose corticosteroids for several weeks post-operatively to minimize cerebral edema (Lawson et al. 2007
); this post-operative edema can be life-threatening, with some patients requiring repeat operations for decompression (Brem et al. 1991
; Weber and Goebel 2005
). Increased rates of noninfectious wound-healing abnormalities, as well as surgical-site infections, are reported in patients receiving Gliadel® wafers as compared to patients receiving placebo wafers or no wafers at all (Attenello et al. 2008
). Patients receiving Gliadel® were also noted to have increased rates of cerebrospinal fluid leak, which can impair wound healing and is a known risk factor for infection (Attenello et al. 2008
). Additionally, the high-dose corticosteroid therapy required with Gliadel® can also impair wound healing and increase infectious complications. A further limitation of Gliadel is that it cannot be implanted into patients with large ventricular openings due to the potential for dislodgement and subsequent obstructive hydrocephalus (Lawson et al. 2007
)—this is significant since it is not uncommon for large malignant gliomas to abut the ventricular surface. As experience with the Gliadel wafer increases, complication rates appear to be decreasing (Attenello et al. 2008
). Nonetheless, improved modalities for local delivery are needed.
Convection-enhanced delivery (CED) techniques were developed to address the diffusion-limited penetration of agents directly delivered to the brain (Bobo et al. 1994
). This strategy has been used to deliver proteins (Lieberman et al. 1995
; Laske et al. 1997
) and small particles, including liposomes (Mamot et al. 2004
; Saito et al. 2004
; Noble et al. 2006
) and polymeric nanoparticles (Chen et al. 2005
; Neeves et al. 2007
), into the brain. CED allows stereotactic placement of drug and provides penetration through a large volume of brain tissue, when compared to diffusion-mediated delivery methods, but it is limited by unpredictable drug distribution and potentially high intracranial pressures (Sawyer et al. 2006
). In addition, CED methods do not naturally provide sustained release of agent, which is a significant limitation. Liposomes have been delivered by CED and are effective at treating intracranial tumors in animal models, presumably because the drug within the liposome remains at the tumor site for many days (Noble et al. 2006
; Saito et al. 2006
). While liposomes are sometimes assumed to have a controlled release effect, release usually depends on factors that are not easily controlled, such as degradation or disruption of the lipid bilayer. Polymer nanoparticles, on the other hand, are well-known to provide versatile, reliable controlled release, but drug-loaded polymer nanoparticles have not previously been delivered by CED.
Combining polymeric controlled release with CED could improve the drug distribution limitations of implantable wafers while also offering spatiotemporal distribution control that is lacking from CED. Poly(lactic-co-glycolic acid) (PLGA) is an FDA-approved polymer that can be formed into nanoparticles of controlled size. These nanoparticles are capable of encapsulating and releasing a variety of agents, including chemotherapy drugs, for long periods of time (Blum and Saltzman 2008
; Park et al. 2009
). Furthermore, they can be modified by placement of proteins, polymers, and other ligands on their surface (Fahmy et al. 2005
Here, we evaluate the efficacy of CED of surface-modified, drug-loaded, PLGA nanoparticles to treat intracranial glioma using the topoisomerase I inhibitor camptothecin (CPT). CPT is an attractive drug for delivery by controlled release because it has known anticancer activity, but is limited by low solubility and serious systemic toxicity (O'Leary and Muggia 1998
). In addition to its limited solubility in water, CPT must remain in its lactone form to maintain biological activity. Encapsulation in PLGA allows for the delivery of the hydrophobic drug, while stabilizing and protecting it (Ertl et al. 1999
). We fabricated PLGA nanoparticles encapsulating CPT and characterized them for size, drug loading, and dose-response for in vitro cytotoxicity. CED of the nanoparticles was accomplished in animals with intracranial tumors using a step-down catheter. We demonstrate that drug-loaded nanoparticles, when delivered by CED, provide enhancements in survival at much lower dose than any other controlled release systems.