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  • Author: Richard A. Gemeinhart x
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Karol Sokolowski, Jason S. Buhrman and Richard A. Gemeinhart

Background: Cancer therapy has made incredible leaps in extending patient lifespans. Unfortunately, most therapy is delivered via a systemic route and often suffers from dose-limiting systemic toxicities, resulting in cessation of therapy or decline in quality of life. Nanotechnology efforts to improve tolerability of systemic agents have suffered limited market viability due to problems such as rapid clearance, circulation instability, and low tumor site accumulation. While local delivery allows for overcoming the aforementioned hurdles, pre-set formulations and nonspecific release pose alternate issues. To approach these challenges, we aimed to investigate our previously developed solid nanoparticles for delivery of protein-based therapy capable of addressing a tumor-specific profile and with selective release within the tumor environment due to elevated thrombin levels. Methods: Poly(ethylene glycol) diacrylate microspheres [PEGDAmS] were prepared using previously described polymerization within a reverse phase emulsion. Compounding patient-specific therapy was evaluated using fluorophore labeled glutathione-S-transferase (GST) and GST-green fluorescent protein (GFP) fusion proteins. Protein loading was analyzed using fluorescence reading and concurrent gel densitometry. Loaded PEGDAmS were delivered into the frontal lobes of Sprague-Dawley rats through a syringe and analyzed using fluorescence microscopy after sacrifice at 48 hours. Results: The addition of 0.2% tween20 surfactant to polymerization reduced PEGDAmS diameter (38.3±30.7 μm to 8.6±6.5 μm) and allowed for minimally invasive delivery to the cranial cavity through a 26S gauge needle. Compounding a tumor-specific regimen is achievable as premixed protein solutions exhibited solution-representative loading on PEGDAmS. Additionally, preloaded vehicles did not demonstrate appreciable cross contamination over 7 days when incubated in close proximity, demonstrating the feasibility of concurrent delivery of various preloaded formulations. Loaded PEGDAmS exhibited environment specific delivery with extensive release of thrombin cleavable GST-GFP in plasma but greatly reduced in anticoagulated plasma. Conclusion: We have shown the ability to locally administer a delivery system with modular therapy-loading and responsiveness to the tumor microenvironment. Further investigation is warranted to explore local delivery of GST-tagged oncology-relevant biologic agents in the presence of a tumor in vivo.