Nanoparticles are being extensively studied as carriers for drug delivery, but they often have limited penetration inside tumor.  In this presentation, we report that transcytosis mediated by CD44 can be utilized to facilitate tumor penetration and drug delivery by nanoparticles.  We synthesized hyaluronan coated silica nanoparticles and magnetic nanoparticles to target CD44 over-expressed on cancer cell surface.  Although prior studies have primarily focused on CD44 mediated endocytosis to facilitate cellular uptake of hyaluronan nanoparticles, we discovered that once internalized, the hyaluronan coated nanoparticles could be transported out of the cells with its cargo.  The exported nanoparticles could be taken up by neighboring cells.  This enabled the nanoparticles to penetrate deeper inside tumor and reach much greater number of cells in 3D tumor models, presumably through tandem cycles of CD44 mediated endocytosis and exocytosis.  When doxorubicin was loaded onto the nanoparticles, better penetration of multilayered tumor cells was observed with much improved cytotoxicites against both drug sensitive and drug resistant cancer spheroids compared to free doxorubicin.  Furthermore, in vivo studies were performed using an ovarian cancer xenograft model.  Hyaluronan coated nanoparticles penetrated deep into tumor enabling imaging of tumor by magnetic resonance imaging as well as enhanced toxicity of doxorubicin delivered. Thus, receptor mediated transcytosis can become a general strategy to enhance tumor penetration by nanoparticles and their theranostic potential.

CD44 mediated transcytosis for enhancement of drug delivery by hyaluronan coated nanoparticles

247th National Meeting (2014)

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