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.