Internalization pathways into cancer cells of gadolinium-based radiosensitizing nanoparticles.

Over the last few decades, nanoparticles have been studied in theranostic field with the objective of exhibiting a long circulation time through the body coupled to major accumulation in tumor tissues, rapid elimination, therapeutic potential and contrast properties. In this context, we developed sub-5 nm gadolinium-based nanoparticles that possess in vitro efficient radiosensitizing effects at moderate concentration when incubated with head and neck squamous cell carcinoma cells (SQ20B). Two main cellular internalization mechanisms were evidenced and quantified: passive diffusion and macropinocytosis. Whereas the amount of particles internalized by passive diffusion is not sufficient to induce in vitro a significant radiosensitizing effect, the cellular uptake by macropinocytosis leads to a successful radiotherapy in a limited range of particles incubation concentration. Macropinocytosis processes in two steps: formation of agglomerates at vicinity of the cell followed by their collect via the lamellipodia (i.e. the "arms") of the cell. The first step is strongly dependent on the physicochemical characteristics of the particles, especially their zeta potential that determines the size of the agglomerates and their distance from the cell. These results should permit to control the quantity of particles internalized in the cell cytoplasm, promising ambitious opportunities towards a particle-assisted radiotherapy using lower radiation doses.

[1]  Harvey F. Lodish,et al.  MOLECULAR.CELL.BIOLOGY 5TH.ED , 2003 .

[2]  Line Claude,et al.  Protective role of Hsp27 protein against gamma radiation-induced apoptosis and radiosensitization effects of Hsp27 gene silencing in different human tumor cells. , 2008, International journal of radiation oncology, biology, physics.

[3]  S. Yadav,et al.  Cellular interactions of therapeutically delivered nanoparticles , 2011, Expert opinion on drug delivery.

[4]  A. Malik,et al.  Size and dynamics of caveolae studied using nanoparticles in living endothelial cells. , 2009, ACS nano.

[5]  P. Perriat,et al.  Hybrid gadolinium oxide nanoparticles: multimodal contrast agents for in vivo imaging. , 2007, Journal of the American Chemical Society.

[6]  Tayyaba Hasan,et al.  Intracellular drug delivery by poly(lactic-co-glycolic acid) nanoparticles, revisited. , 2009, Molecular pharmaceutics.

[7]  Hak Soo Choi,et al.  Design considerations for tumour-targeted nanoparticles. , 2010, Nature nanotechnology.

[8]  Sandra L. Schmid,et al.  Regulated portals of entry into the cell , 2003, Nature.

[9]  O Tillement,et al.  Synthesis and properties of europium-based phosphors on the nanometer scale: Eu2O3, Gd2O3:Eu, and Y2O3:Eu. , 2004, Journal of colloid and interface science.

[10]  P. Perriat,et al.  Multi-luminescent hybrid gadolinium oxide nanoparticles as potential cell labeling. , 2009, Journal of nanoscience and nanotechnology.

[11]  O. Tillement,et al.  Nanosystems for medical applications : Biological detection, drug delivery, diagnosis and therapy , 2006 .

[12]  Sancey Lucie,et al.  Clustering and Internalization of Integrin αvβ3 With a Tetrameric RGD-synthetic Peptide. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  Jun Fang,et al.  Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. , 2003, International immunopharmacology.

[14]  A. Jones,et al.  Intracellular trafficking pathways and drug delivery: fluorescence imaging of living and fixed cells. , 2005, Advanced drug delivery reviews.

[15]  Wolfgang Löscher,et al.  Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases , 2005, Progress in Neurobiology.

[16]  M. Ferrari.  Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.

[17]  J. Hainfeld,et al.  The use of gold nanoparticles to enhance radiotherapy in mice. , 2004, Physics in medicine and biology.

[18]  Francis Vocanson,et al.  Gadolinium chelate coated gold nanoparticles as contrast agents for both X-ray computed tomography and magnetic resonance imaging. , 2008, Journal of the American Chemical Society.

[19]  H. Lodish.  Molecular Cell Biology , 1986 .

[20]  K. Uvdal,et al.  Effects of gadolinium oxide nanoparticles on the oxidative burst from human neutrophil granulocytes , 2012, Nanotechnology.

[21]  F. Maxfield,et al.  Endocytic recycling , 2004, Nature Reviews Molecular Cell Biology.

[22]  J. Hainfeld,et al.  Radiotherapy enhancement with gold nanoparticles , 2008, The Journal of pharmacy and pharmacology.

[23]  F Lux,et al.  In vitro radiosensitizing effects of ultrasmall gadolinium based particles on tumour cells. , 2011, Journal of nanoscience and nanotechnology.

[24]  M. Edidin,et al.  Shrinking patches and slippery rafts: scales of domains in the plasma membrane. , 2001, Trends in cell biology.

[25]  C. Souchier,et al.  Clustering and internalization of integrin alphavbeta3 with a tetrameric RGD-synthetic peptide. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[26]  O. Tillement,et al.  Nanosized hybrid particles with double luminescence for biological labeling , 2005 .

[27]  N. Swanson,et al.  Squamous cell carcinoma of the skin (excluding lip and oral mucosa). , 1992, Journal of the American Academy of Dermatology.

[28]  Thierry Epicier,et al.  Toward an image-guided microbeam radiation therapy using gadolinium-based nanoparticles. , 2011, ACS nano.

[29]  Jean-Luc Coll,et al.  Ultrasmall rigid particles as multimodal probes for medical applications. , 2011, Angewandte Chemie.

[30]  Zongxi Li,et al.  Aspect ratio determines the quantity of mesoporous silica nanoparticle uptake by a small GTPase-dependent macropinocytosis mechanism. , 2011, ACS nano.

[31]  Z. Salehi,et al.  Significance of eIF4E expression in skin squamous cell carcinoma , 2007, Cell biology international.

[32]  P. Perriat,et al.  Size-induced effect upon the Néel temperature of the antiferro/paramagnetic transition in gadolinium oxide nanoparticles , 2011 .

[33]  Taeghwan Hyeon,et al.  Multifunctional nanostructured materials for multimodal imaging, and simultaneous imaging and therapy. , 2009, Chemical Society reviews.

[34]  N. Herlin‐Boime,et al.  In vitro investigation of oxide nanoparticle and carbon nanotube toxicity and intracellular accumulation in A549 human pneumocytes. , 2008, Toxicology.

[35]  Jean-Luc Coll,et al.  Physico-chemical parameters that govern nanoparticles fate also dictate rules for their molecular evolution. , 2012, Advanced drug delivery reviews.

[36]  T. Paunesku,et al.  Endocytosis of titanium dioxide nanoparticles in prostate cancer PC-3M cells. , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[37]  R. Jain,et al.  Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  T. Park,et al.  Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[39]  K Kobayashi,et al.  Enhancement of radiation effect by heavy elements. , 2010, Mutation research.

[40]  Ralph Weissleder,et al.  Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells , 2000, Nature Biotechnology.

[41]  Scott C. Brown,et al.  Gd nanoparticulates: from magnetic resonance imaging to neutron capture therapy , 2007 .

[42]  Mauro Ferrari,et al.  Emerging applications of nanomedicine for the diagnosis and treatment of cardiovascular diseases. , 2010, Trends in pharmacological sciences.