Noninvasive Preclinical Evaluation of Targeted Nanoparticles for the Delivery of Curcumin in Treating Pancreatic Cancer.

ABSTRACT

Conventional therapy regimens for pancreatic cancer (PC) are surgical resection and systemic gemcitabine based chemotherapy. Recent studies showed that curcumin could potentiate the anticancer effect of gemcitabine in PC. However, due to its poor water solubility, effective bioavailability of curcumin is insufficient, resulting in poor efficacy. To address this issue, mesoporous silica nanoparticles (MSN) were prepared by the sol-gel method, then loaded with curcumin (Cur), coated with polyethylene glycol (PEG), and finally conjugated with the targeting moiety transferrin (Tf) to target human PC cells. TEM analysis revealed that uniform sized spherical MSN formed with an average size of 100 nm, which increased to 120 nm after PEG coating on MSN surface. Confocal microscopy proved that curcumin uptake being seven-times higher for MSN-NH2-Cur-PEG-Tf, when compared to free curcumin. The in vitro cytotoxicity study on MIA PaCa-2 cells showed that MSN-NH2-Cur-PEG-Tf exhibited three-fold higher cytotoxicity than free curcumin. On the basis of the encouraging in vitro cytotoxicity results obtained, preclinical assessment of antitumor efficacy in MIA PaCa-2 subcutaneous xenograft model proves that both MSN-NH2-Cur-PEG and MSN-NH2-Cur-PEG-Tf inhibit tumor growth and minimize distant metastasis to major organ sites. The in vitro studies also proved that nanoparticles can enhance the sensitization effect, caused by curcumin on cancer cells, which help the gemcitabine to kill a higher percentage of cancer cells. Hence, we propose that transferrin targeted, PEGylated, mesoporous silica nanoparticles can be used as a carrier to deliver curcumin, and used in addition to gemcitabine to reduce disease burden significantly for pancreatic cancer patients.