Epithelial cell adhesion molecule targeted nutlin-3a loaded immunonanoparticles for cancer therapy.
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.
Das
Manasi
M
Institute of Life Sciences, Bhubaneswar, India.
Sahoo
Sanjeeb K
SK
D000951:Antigens, Neoplasm / Q000276:immunology*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D055598:Chemical Phenomena / Q000187:drug effects; D003374:Coumarins / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000627:therapeutic use* / Q000648:ultrastructure; D009369:Neoplasms / Q000628:therapy*; D010316:Particle Size; D010879:Piperazines / Q000494:pharmacology*; D011098:Polyglactin 910 / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D012996:Solutions
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D003374:Coumarins; D000071858:Epithelial Cell Adhesion Molecule; D007093:Imidazoles; D010879:Piperazines; D011956:Receptors, Cell Surface; D012996:Solutions; D011098:Polyglactin 910; C482205:nutlin 3; C030123:coumarin