Local And Sustained Delivery Of GM-CSF And IL-2 Microspheres To Tumor For Cancer Therapy

Objective: A potent tumor-specific immune response depends on the concentrations of cytokines local to the tumor cells. In this circumstances, developing a sustained-release cytokine delivery system as artificial cytokine depot at tumor site would be a theoretically feasible scheme for cancer therapy. However, it was difficult for protein drug to be long-acting sustained-release. This paper aimed to develop GM-CSF/IL-2 microspheres which could maintain therapeutic concentration of GM-CSF/IL-2 at tumor site to result in the ultimate destruction of surrounding tumor cells.Methods: The presented microspheres were prepared in two steps: GM-CSF/IL-2 was firstly loaded into dextran glassy particles by a unique method of stabilizing aqueous-aqueous “emulsion”; subsequently, the particles were encapsulated into PLGA/PLA to form core-shell microspheres. Then the intro and vivo release GM-CSF/IL-2 microspheres was investigated by ELISA. Finally, we explored pharmacodynamics of GM-CSF/IL-2 microspheres in BALB/c mice bearing colon carcinoma by observing tumor size, tumor weight and inhibition ratio, NTABW, serum IFN-γ concentration and histological sections.Results: GM-CSF/IL-2 microspheres processed smooth surface and uniform size distributions. The vitro release curve showed that both GM-CSF microspheres and IL-2 microspheres were released in a steady and gradual way which both lasted nearly 30 days. At the same time, the vivo release in the SD mouse demonstrated a steady and 21-day release period. Finally, the pharmacodynamics experiments showed that the best tumor inhibitory could be achieved when both GM-CSF microspheres and IL-2 microspheres were locally administrated together.Conclusion: Comparing the same dose of GM-CSF or IL-2 solution or their combination, local injection of both GM-CSF microspheres and IL-2 microspheres at tumor site could achieve a better tumor inhibitory result.