Customizing intracranial nanoparticle distribution during convection-enhanced delivery: Application in the treatment of an intracranial tumor model with camptothecin-loaded PLGA nanoparticles

Despite advances in medical imaging, the survival rate for patients with Glioblastoma Multiforme (GBM), the most prevalent variety of primary brain tumor, remains unchanged for the past two decades. GBM is difficult to treat because of its aggressive invasion into the surrounding tissue. Traditional chemotherapy is largely ineffective against GBM due to the blood-brain-barrier, which excludes many chemotherapy agents. Local polymeric drug delivery has had clinical success, but the efficacy is limited by low drug penetration via diffusional transport. Convection-enhanced delivery (CED) is a new clinical technology to increase intracranial drug distribution by inducing convective flow; it is hampered however, by unpredictable distribution of the infused drug.;The goal of this project was to design and evaluate a drug delivery strategy utilizing both controlled release technology via polymer nanoparticles and CED. Nanoparticle surface coatings and infusate solution properties were selected to improve intracranial distribution volume. Infusate solutions were selected to either dilate the extracellular matrix (ECM) of the brain, or to degrade selected components of the ECM. Each infusion strategy was designed to increase the extracellular volume fraction available for particle movement. The ECM dilation strategies, a saline pretreatment or a co-infusion with mannitol, increased distribution volume by 123% and 51%. Degrading the ECM with hyaluronidase increased nanoparticle distribution by 64%.;Nanoparticle surfaces were selected to either extend or restrict their distribution by taking advantage of ECM properties. A range of nanoparticle surfaces were evaluated in an intracranial model. Distribution could be extended as far as 2.2 mm3 by coating with bovine serum albumin (BSA), or restricted to 0.2 mm3 with the adhesion protein fibronectin (FN).;Biodegradable poly(lactic-co-glycolic acid) nanoparticles loaded with camptothecin and surface modified with either BSA or FN were used against an orthotopic glioma model using CED. The drug-loaded nanoparticles were effective against an experimental tumor; they increased median survival, and in 30% of the cases the animals survived until the end of the study and exhibited no residual tumor. The success in our intracranial model illustrates the utility of the combined approach to brain cancer chemotherapy, and invites the use of this easily translatable therapy.