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.
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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