Polymeric Nanoparticles for Nonviral Gene Therapy Extend Brain Tumor Survival in Vivo

Abstract

Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(β-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival (p = 0.0012 vs control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.

Cell encapsulation: technical and clinical advances

“…This is accomplished with the added benefits of reducing the burden of cell sourcing, obviating the need for complex repeated surgical procedures, and providing targeted drug delivery with more beneficial safety profiles. While other approaches that are currently under investigation (including direct tissue infusions [7], various gene therapy approaches [8], cell therapies [9,10], and biomaterial-based drug-delivery systems [11,12]), cell encapsulation is the only approach that, in principle, meets all of the essential prerequisites for a truly transformative medicine. This technology overcomes many of the fundamental obstacles encountered by other approaches by providing a targeted, continuous, de novo synthesized source of molecules that can be distributed over significant portions of the body or within tightly regulated compartments, such as the brain [13].…”

Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery

“…Currently, no ongoing or completed clinical trials have used polymeric NPs for NDDs. It must be noted that polymeric NPs are being used in cancer drug delivery studies and can soon be expected to transition into clinical trials for gene delivery based on the translational data available in literature (Jensen et al, 2013; Guerrero-Cázares et al., 2014; Mangraviti et al, 2015). All gene delivery systems require careful and comprehensive analyses for route, dose, and frequency of administration, in addition to immunological profiling of the animal models to improve the transition from in vitro to in vivo and further into clinical trials.…”

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies

“…Indeed, they can be engineered to exhibit cell-type specificity and to selectively transfect tumor tissue while avoiding surrounding healthy tissue. PBAE polymers can also increase tumor biodistribution when delivered via CED, rather than via direct bolus injection, and can provide significant benefit in survival when loaded with herpes simplex virus type I thymidine kinase (HSVtk) [67]. Finally another category of nanoparticle, dendrimers, has shown to be a promising carrier for brain tumor-targeted therapy.…”