Use of a Lipid-Coated Mesoporous Silica Nanoparticle Platform for Synergistic Gemcitabine and Paclitaxel Delivery to Human Pancreatic Cancer in Mice

Abstract

Recently, a commercial albumin-bound paclitaxel (PTX) nanocarrier (Abraxane) was approved as the first new drug for pancreatic ductal adenocarcinoma in almost a decade. PTX improves the pharmaceutical efficacy of the first-line pancreatic cancer drug, gemcitabine (GEM), through suppression of the tumor stroma and inhibiting the expression of the GEM-inactivating enzyme, cytidine deaminase (CDA). We asked, therefore, whether it was possible to develop a mesoporous silica nanoparticle (MSNP) carrier for pancreatic cancer to co-deliver a synergistic GEM/PTX combination. High drug loading was achieved by a custom-designed coated lipid film technique to encapsulate a calculated dose of GEM (40 wt %) by using a supported lipid bilayer (LB). The uniform coating of the 65 nm nanoparticles by a lipid membrane allowed incorporation of a sublethal amount of hydrophobic PTX, which could be co-delivered with GEM in pancreatic cells and tumors. We demonstrate that ratiometric PTX incorporation and delivery by our LB-MSNP could suppress CDA expression, contemporaneous with induction of oxidative stress as the operating principle for PTX synergy. To demonstrate the in vivo efficacy, mice carrying subcutaneous PANC-1 xenografts received intravenous (IV) injection of PTX/GEM-loaded LB-MSNP. Drug co-delivery provided more effective tumor shrinkage than GEM-loaded LB-MSNP, free GEM, or free GEM plus Abraxane. Comparable tumor shrinkage required coadministration of 12 times the amount of free Abraxane. High-performance liquid chromatography analysis of tumor-associated GEM metabolites confirmed that, compared to free GEM, MSNP co-delivery increased the phosphorylated DNA-interactive GEM metabolite 13-fold and decreased the inactivated and deaminated metabolite 4-fold. IV injection of MSNP-delivered PTX/GEM in a PANC-1 orthotopic model effectively inhibited primary tumor growth and eliminated metastatic foci. The enhanced in vivo efficacy of the dual delivery carrier could be achieved with no evidence of local or systemic toxicity. In summary, we demonstrate the development of an effective LB-MSNP nanocarrier for synergistic PTX/GEM delivery in pancreatic cancer.

Neoadjuvant chemotherapy for pancreatic cancer: Effects on cancer tissue and novel perspectives

“…A number of studies have focused on the inhibition of tumor EMT and stromal cell activation using paclitaxel (74,86,87). The results of these studies are consistent with the observation of tumor shrinkage and a decrease in stroma in tumors treated with nab-paclitaxel and GEM (88,89). Finally, HDACis have been tested in clinical trials of pancreatic cancer treatment combined with valproic acid and oral S-1 (90).…”

Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer

“…We have developed a multifunctional mesoporous silica nanoparticle (MSNP) platform (16,(23)(24)(25) that has recently been adapted to provide high-dose PDAC chemotherapy using a supported lipid bilayer (LB) for drug encapsulation (26,27). This carrier has also been designated as a "silicasome" to distinguish it from morphologically similar liposomal carriers, which contain a nonsupported LB.…”

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

“…182 Meng et al developed a MSNP for co-delivery of gemcitabine and paclitaxel to take advantage of paclitaxel's ability to inhibit CDA expression to increase tumor response to gemcitabine. 183 …”