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Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice.
- Source :
-
ACS nano [ACS Nano] 2015; Vol. 9 (4), pp. 3540-57. Date of Electronic Publication: 2015 Mar 31. - Publication Year :
- 2015
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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.
- Subjects :
- Albumins pharmacology
Albumins therapeutic use
Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Cell Line, Tumor
Cell Transformation, Neoplastic
Cytidine Deaminase metabolism
Deoxycytidine chemistry
Deoxycytidine pharmacology
Deoxycytidine therapeutic use
Drug Synergism
Female
Gene Expression Regulation, Neoplastic drug effects
Humans
Mice
Paclitaxel pharmacology
Paclitaxel therapeutic use
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms metabolism
Porosity
Gemcitabine
Albumins chemistry
Deoxycytidine analogs & derivatives
Drug Carriers chemistry
Lipid Bilayers chemistry
Nanoparticles chemistry
Paclitaxel chemistry
Pancreatic Neoplasms pathology
Silicon Dioxide chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1936-086X
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- ACS nano
- Publication Type :
- Academic Journal
- Accession number :
- 25776964
- Full Text :
- https://doi.org/10.1021/acsnano.5b00510