(510f) Targeted Pegylated Mesoporous Silica Nanoparticles for the Delivery of Curcumin in a Pancreatic Cancer Animal Model: Inhibition of Both Tumor Growth and Metastasis

Background: Pancreatic cancer is one of the most difficult to detect and treat among all types of cancer. In fact, the five-year survival rate is less than 5% and is the only cancer, for which, the survival rate has not improved over the last 40 years. This is because nearly 80% of the pancreatic cancer cases are diagnosed when it spreads to nearby organs, a stage where surgery is not possible. So, there is a need to develop an effective way to deliver the anticancer drug to pancreatic cancer patients.

Method: Gemcitabine is the first-line chemotherapeutic drug for treatment of pancreatic cancer. Recent studies have shown that curcumin can potentiate the anticancer effect of gemcitabine in an animal model of human pancreatic cancer. The problem with curcumin is that, it is poorly water soluble, so one is not able to achieve its real potency. To counter this issue, mesoporous silica nanoparticles (MSN) were prepared by the sol-gel method, then loaded with curcumin (CUR) and coated with polyethylene glycol (PEG), with final conjugation via the targeting moiety transferrin (Tf) to synthesize MSN-NH₂-CUR-PEG-Tf, in order to target pancreatic cancer cells. Ability to load the drug in 2.5 nm pore diameter of MSN, bypasses the problem of poor solubility of curcumin, and in turn, potentially facilitate the controlled release of the drug, when it reaches the targeted cancer-site. In addition, the controllable and tunable pore diameter of MSN, over a range of approximately 2-6 nm pore diameter, helps in optimizing the relative balance between higher loading of drug and its controlled release rate from MSN and on to the target-site.

Results: TEM images reveal that, uniform spherical MSN were formed with an average particle diameter of 100 nm, which increased to 120 nm after coating of PEG over the external surface of MSN. This implies a 10 nm PEG coating thickness. BET analysis of gas-adsorption confirmed that, the drug was encapsulated in the pores of MSN, since surface area reduced from 669 to 80 m²/g, and pore volume from 0.59 to 0.38 cm³/g, for MSN and MSN-NH₂-CUR-PEG-Tf samples, respectively. From TGA we obtain the presence of 11.5% by wt. of curcumin in MSN.

Subsequently, in vitro cytotoxicity study on Mia Paca-2 pancreatic cancer cells proved that MSN-NH₂-CUR-PEG-Tf exhibited 2-folds higher cytotoxicity than free curcumin, proving that, nanoparticle mediated drug has higher cancer-cell killing capability. Confocal microscopy proved that the reason behind it is the 7 times higher curcumin uptake for MSN-NH₂-CUR-PEG-Tf, compared to free curcumin. The in vivo antitumor efficacy study in subcutaneous MIA Paca-2 mice model showed that MSN-NH₂-CUR-PEG and MSN-NH₂-CUR-PEG-Tf inhibit the tumor growth to a significant level and prevents its metastasis in different organs, like spleen, lung, liver, kidney etc. Furthermore, by using these curcumin nanoformulations, in combination with the standard chemotherapy regimen (gemcitabine), the cytotoxic efficacy increases many folds, in comparison to gemcitabine alone.

Conclusion: Hence, we propose that, targeted PEGylated mesoporous silica nanoparticles can be used as a carrier to deliver curcumin, in addition to gemcitabine, as an adjuvant therapy, in order to possibly improve the outcome of pancreatic cancer patients.