Lipid Nanocarriers of a Lipid-Conjugated Estrogenic Derivative Inhibit Tumor Growth and Enhance Cisplatin Activity against Triple-Negative Breast Cancer: Pharmacokinetic and Efficacy Evaluation
| Autor: | Rajkumar Banerjee, Mandip Singh, Apurva R. Patel, Terrick Andey, G. Sudhakar, Srujan Marepally |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Cell Survival
Administration Oral Mice Nude Pharmaceutical Science Antineoplastic Agents Triple Negative Breast Neoplasms Cell Separation Pharmacology Rats Sprague-Dawley Inhibitory Concentration 50 Mice Breast cancer Cell Line Tumor Drug Discovery Solid lipid nanoparticle medicine Animals Humans Viability assay Particle Size Triple-negative breast cancer Cisplatin Drug Carriers Liposome Estradiol Chemistry Cell Cycle Drug Synergism Estrogens Cell cycle Flow Cytometry medicine.disease Lipids In vitro Rats Liposomes Nanoparticles Molecular Medicine Female Caco-2 Cells Neoplasm Transplantation medicine.drug |
| Zdroj: | Molecular Pharmaceutics. 12:1105-1120 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp5008629 |
| Popis: | Breast cancer is the leading cause of malignancies among women globally. The triple negative breast cancer (TNBC) subtype is the most difficult to treat and accounts for 15% of all cases. Targeted therapies have been developed for TNBC but come short of clinical translation due to acquired tumor resistance. An effective therapy against TNBC must combine properties of target specificity, efficient tumor killing, and translational relevance. The objective of this study was to formulate a nontoxic, cationic, lipid-conjugated estrogenic derivative (ESC8), with demonstrated anticancer activity, for oral delivery in mice bearing triple negative breast cancer (TNBC) as xenograft tumors. The in vitro cell viability, Caco-2 permeability, and cell cycle dynamics of ESC8-treated TNBC cells were investigated. ESC8 was formulated as liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) and characterized for size, zeta potential, entrapment efficiency, size stability, and tumor biodistribution. Pharmacokinetic modeling of plasma concentration-time course data was carried out following intravenous and oral administration in Sprague-Dawley rats. In vivo efficacy investigation of ESC8-SLNC was carried out in Nu/Nu mice bearing MDA-MB-231 TNBC as xenograft tumors, and the molecular dynamics modulating tumor growth inhibition was analyzed by Western blot. In vitro ESC8 inhibited TNBC and non-TNBC cell viability with IC50 ranging from 1.81 to 3.33 μM. ESC8 was superior to tamoxifen and Cisplatin in inhibiting MDA-MB-231 cell viability; and at 2.0 μM ESC8 enhanced Cisplatin cytotoxicity 16-fold. Intravenous ESC8 (2.0 mg/kg) was eliminated at a rate of 0.048 ± 0.01 h(-1) with a half-life of 14.63 ± 2.95 h in rats. ESC8 was orally bioavailable (47.03%) as solid lipid nanoparticles (ESC8-SLN). ESC8-SLN (10 mg/kg/day, ×14 days, p.o.) inhibited breast tumor growth by 74% (P0.0001 vs control) in mice bearing MDA-MB-231 cells as xenografts; and when given in combination with Cisplatin (2.0 mg/kg/biweekly, ×2 weeks, IV), tumor growth was inhibited by 87% (P = 0.0002, vs ESC8-SLN; 10 mg/kg/day, ×14 days, p.o). ESC8-SLN tumor growth inhibition was associated with increased expression of p21 and Caspase-9; as well as by inhibition of EGFR, Slug, p-Akt1, Vimentin, NFkβ, and IKKγ. These results show the promise of ESC8 as an oral adjuvant or neoadjuvant against triple negative breast cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|