Transferrin-Conjugated Polymer-Coated Mesoporous Silica Nanoparticles Loaded with Gemcitabine for Killing Pancreatic Cancer Cells

In order to achieve superior delivery of the anticancer drug gemcitabine to Mia PaCa-2 pancreatic cancer cell lines, we have synthesized transferrin (Tf)-conjugated, polymer-coated, mesoporous silica nanoparticles (MSNs), with optimization of multiple parameters. The following challenges were thereby addressed to improve the efficacy of gemcitabine delivery: (i) optimization of internal pore diameter (within the range 2.5-5.2 nm) and amine functionalization of MSN (NH2-MSN) to improve drug loading and its controlled release, (ii) coating of MSN with pH-sensitive polymers such as either chitosan or poly(D,L-lactide-co-glycolide) (PLGA), so as to prevent premature release of the drug at physiological pH 7.4 and to also achieve its controlled release at a lower pH 5.5 (extracellular cancer cell pH), and finally, (iii) conjugation of Tf ligand on this optimized, polymer-coated MSN, for better uptake of MSN by the MIA PaCa-2 cells, through ligand-receptor interactions. Consequently, the highest drug loading of 27.2% could be achieved for the sample having amine-functionalized MSN with larger pore diameter of 5.2 nm, compared to only 13.1% for small pore diameter of 2.5 nm, demonstrating better drug loading with larger pores. Furthermore, with coating of PLGA on MSN, a more controlled and desirable constant release rate of gemcitabine with time was achieved at pH 5.5, compared to a miniscule 3% of undesirable drug release at physiological pH 7.4. Finally, for Tf-conjugated, polymer-coated MSN, 70-75% of MIA PaCa-2 cells killing was achieved, as compared to 60% without Tf conjugation. This was due to improved uptake of nanoparticles by cancer cells, via ligand-receptor interactions. Thus, the above-optimized MSN-based gemcitabine delivery system can be a superior formulation to contain pancreatic cancer cell growth.