Epithelial cell adhesion molecule targeted nutlin-3a loaded immunonanoparticles for cancer therapy

Epithelial cell adhesion molecule targeted nutlin-3a loaded immunonanoparticles for cancer therapy,10.1016/j.actbio.2010.08.010,Acta Biomaterialia,Man

Epithelial cell adhesion molecule targeted nutlin-3a loaded immunonanoparticles for cancer therapy   (Citations: 7)
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Recently much attention has been given to the anti-cancer drug nutlin-3a, an antagonist of murine double minute 2 (MDM2) that actively inhibits p53–MDM2 interaction. Reactivating p53 function by nutlin-3a thus provides a promising therapeutic strategy for the treatment of cancer. Although nutlin-3a seems a potential candidate in restoring p53 activity, it has many lacunae, toxicity, poor bioavailability, nonspecific delivery, and most importantly it is a substrate of multidrug resistance protein. The objective of the present study is to prepare and characterize nutlin-3a loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), surface functionalized with epithelial cell adhesion molecule (EpCAM) antibody, with an aim to deliver encapsulated drug in a targeted manner to its site of action and to enhance its therapeutic efficacy many times over. The enhanced cellular uptake of EpCAM antibody conjugated nutlin-3a loaded NPs (EpCAM-nutlin-3a-NPs) over native nulin-3a, nutlin-3a loaded NPs (nutlin-3a-NPs) in HCT116 and A549 cells substantiate the targeting potentiality of conjugated system. IC50 values depicted superior antiproliferative activity of EpCAM-nutlin-3a-NPs over nutlin-3a-NPs and native nutlin-3a in the above studied cell lines. Cell cycle arrest, loss of mitochondrial membrane potential and apoptosis induced by above formulation were confirmed by flow cytometry. Expression of p53, p21, EpCAM, and C-myc proteins involved in cell cycle regulation and apoptosis were investigated by western blotting. The above investigation indicates the enhanced therapeutic ability of EpCAM-nutlin-3a-NPs compared to nutlin-3a or nutlin-3a-NPs. Thus, our results suggest that EpCAM-nutlin-3a-NPs could be a potentially useful drug carrier system for targeted delivery of potent anti-cancer drug nutlin-3a for cancer therapy.
Journal: Acta Biomaterialia - ACTA BIOMATER , vol. 7, no. 1, pp. 355-369, 2011
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    • ...Encapsulation efficiency was determined by the reverse phase isocratic mode of high performance liquid chromatography (RP-HPLC) method, using Agilent 1100 HPLC (Agilent technologies, Waldbronn Analytical Division, Germany) which consists of Zorbax Eclipse XDB-C18, 150×4.6 mm, i.d with internal standard of dimethylphthalate. To estimate entrapped drugs in NPs, 5 mg of freeze dried drug loaded NPs (containing single drug or dual drug) was dissolved in 5 ml of acetonitrile and kept in the shaker at 37°C and 2 g (Wadegati Labequip, India) for 2 days. The samples were then centrifuged at 17,458 g for 10 min at 25°C (SIGMA 3K30, Munich, Germany) to extract the drug present in the solution. The collected supernatant was analyzed for drug content by RP-HPLC using specific mobile phase for each drugs, at a flow rate of 1 ml/min, at 30°C with thermostat (Model No -G1316A) ...

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