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.

Improving Curcumin Bioavailability: Current Strategies and Future Perspectives

“…Curcumin-loaded mesoporous silica nanoparticles were prepared and coated with polyethylene glycol (PEG) and ultimately conjugated with the targeting moiety transferrin (Tf) for targeting pancreatic cancer cells. Data showed enhanced uptake and, consequently, higher cell killing in vitro, while in vivo results on animal models clearly demonstrated inhibition of tumor growth and prevention from distant metastasis spreading [164].…”

Mesoporous Silica Nanoparticle-Based Drug Delivery Systems for the Treatment of Pancreatic Cancer: A Systematic Literature Overview

“…Pioneering studies showed that surface modification by conjugation with polyethyleneimine (PEI) [37], folic acid [82], or monoclonal antibodies targeting anti-claudin4 and anti-mesothelin [83] indeed improved nanoparticle uptake by PDAC cells, whereas modification with polyethylene glycol (PEG) was shown to enhance biodistribution and circulation time in experimental animal models [40,42]. More recent studies use alternative surface modifications to target chemotherapeutics to PDAC tumors, and MSNs have been conjugated with transferrin [46,47,83], urokinase plasminogen activator [54], anti-GPC1, anti-tMUC1 [48], or V7 [84] peptides for this purpose. As envisioned, cellular uptake was increased using tumortargeting moieties compared to controls lacking a modification both in vitro [46,47,83] and in vivo [48,54,84].…”

“…More recent studies use alternative surface modifications to target chemotherapeutics to PDAC tumors, and MSNs have been conjugated with transferrin [46,47,83], urokinase plasminogen activator [54], anti-GPC1, anti-tMUC1 [48], or V7 [84] peptides for this purpose. As envisioned, cellular uptake was increased using tumortargeting moieties compared to controls lacking a modification both in vitro [46,47,83] and in vivo [48,54,84]. A recent study confirmed the importance of tumor-targeting surface modifications [84].…”

“…Utilizing V7 peptide-conjugated MSNs in an orthotopic PDAC model, MacCuaig and colleagues showed that active targeting of MSNs (i.e., including surface modifications to increase tumor cell uptake) outperforms passive targeting (i.e., no tumor targeting modifications on the MSNs) irrespective of nanoparticle size [84]. However, it is important to note that improved uptake and cytotoxicity in vitro does not always translate to similar findings in vivo, as PEGylated MSNs showed higher tumor uptake compared to PEG-transferrin-modified MSNs in one study [47]. More importantly, drug-loaded anti-tMUC1-conjugated MSNs outperformed MSNs lacking the anti-tMUC1 moiety in reducing tumor volume and weight in a syngeneic mouse model in which human tMUC expressing PDAC cells were implanted [48].…”

“…The clinical efficacy of curcumin, a candidate anticancer drug [88] that potentiates the effect of gemcitabine [89,90], is limited by its poor solubility. Loading curcumin into MSNs was found to inhibit tumor growth and minimize distant metastasis in a subcutaneous xenograft model [47]. Of note, subsequent administration of gemcitabine potentiates the effect of curcumin-loaded MSNs in vitro, but in vivo validation is lacking [47].…”