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.
Superior delivery of anticancer drug gemcitabine has been achieved with mesoporous silica nanoparticles (MSN), by addressing three challenges in MSN synthesis: (i) MSN was synthesized with particle diameter between 42 to 64 nm, to utilize enhanced permeability and retention effect of small particles, (ii) MSN of larger internal pore diameter (2.5–5.2 nm) was made as a tunable morphological parameter to optimize both drug loading and its release rate, in a controlled, differential manner and (iii) higher drug release at extracellular cancer-cell pH (5.5) was achieved, compared to physiological pH (7.4) of healthy cells. MSN with above features was made by the sol–gel route, with trimethylmethoxysilane as a size-quencher and hexane or decane as a pore expander. Highest gemcitabine loading of 14.92% and a cumulative release of 58% at pH 5.5 could be obtained with the optimum sample having pore diameter of 5.2 nm, in comparison to the desirably low 22% release at pH 7.4. Consequently, we obtained 60% cell growth-inhibition of pancreatic cancer cell-line (MIA Paca-2), via gemcitabine loaded MSN. This was possible because of increased gemcitabine release from MSN with larger pore diameter of 5.2 nm, simultaneously demonstrating good target-selectivity of MSN as a drug-carrier, due to engineering of its pore-size.
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