The root cause of low survival rate in breast cancer patients is the resistance to conventional therapies and recurrence of the disease because of unaffected stem like cells after chemotherapy. Cancer stem cells (CSCs) are reported to be controlled by pathways that are dormant in normal adult cells, e.g. PTEN, which is a negative regulator of transcription factor STAT-3. STAT-3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of significant clinical importance. Herein we describe for the first time a novel nanotherapeutic strategy to target breast cancer stem-like cells via STAT-3 inhibition and provide encompassing to chemotherapeutic agent for efficient delivery.      Our strategy to deliver CSC-directed therapy involved a well-defined polymeric nanoparticle system self-assembled from amphiphilic PS-b-PAA (2:1). Polycelles are solid core micelles comprised of condensed polyoxyethylene (20) cetyl ether surrounded by the hydrophobic polystyrene moieties.  Polycelles were prepared by a solvent evaporation method in presence of niclosamide, a FDA-approved anthelmintic used in the treatment of worm infections and a well-studied STAT-3 inhibitor. Hydrodynamic diameter of the polycelle particles (95�5) was significantly different from blank nanoparticles (70�5) and found to be significantly stable with time even in presence of serum. The drug loading pattern was established using UV-Vis spectroscopy and zeta potential measurements. Polycelles were found to be solid core spheroids under TEM and AFM investigations. Blank nanoparticles were found to be with some sort of orderness and crystallinity peaks in cast film X-ray diffraction measurement which were not seen in polycelles. Polycelles were further evaluated for their cytotoxicity studies using Trypan Blue and MTT assay in MDA-MB231 and MCF-7 cells. Polycelles were at least fourfold better in inhibiting breast cancer cell growth compared to the small molecule niclosamide, with apoptotic cell death and abolition of stem cell-subpopulation via STAT-3 pathway.

Polycelles for improved inhibition of breast cancer stem cells via STAT-3 cascade pathway

248th National Meeting (2014)

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