Strategies for the intracellular delivery of nanoparticles.

The ability to target contrast agents and therapeutics inside cells is becoming important as we strive to decipher the complex network of events that occur within living cells and design therapies that can modulate these processes. Nanotechnology researchers have generated a growing list of nanoparticles designed for such applications. These particles can be assembled from a variety of materials into desirable geometries and configurations and possess useful properties and functionalities. Undoubtedly, the effective delivery of these nanomaterials into cells will be critical to their applications. In this tutorial review, we discuss the fundamental challenges of delivering nanoparticles into cells and to the targeted organelles, and summarize strategies that have been developed to-date.

[1]  Joshua E. Smith,et al.  Aptamer-conjugated nanoparticles for the collection and detection of multiple cancer cells. , 2007, Analytical chemistry.

[2]  Vladimir P Torchilin,et al.  Tat peptide-mediated intracellular delivery of pharmaceutical nanocarriers. , 2008, Advanced drug delivery reviews.

[3]  S. Kelley,et al.  Cell-penetrating peptides as delivery vehicles for biology and medicine. , 2008, Organic & biomolecular chemistry.

[4]  T. Allen,et al.  Targeted delivery of anti-CD19 liposomal doxorubicin in B-cell lymphoma: a comparison of whole monoclonal antibody, Fab' fragments and single chain Fv. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[5]  Na Zhang,et al.  PLGA nanoparticle--peptide conjugate effectively targets intercellular cell-adhesion molecule-1. , 2008, Bioconjugate chemistry.

[6]  F. Gisou van der Goot,et al.  Mechanisms of pathogen entry through the endosomal compartments , 2006, Nature Reviews Molecular Cell Biology.

[7]  Sudha Kumari,et al.  Endocytosis unplugged: multiple ways to enter the cell , 2010, Cell Research.

[8]  Anna M Wu,et al.  Arming antibodies: prospects and challenges for immunoconjugates , 2005, Nature Biotechnology.

[9]  James R Baker,et al.  Dendrimer-entrapped gold nanoparticles as a platform for cancer-cell targeting and imaging. , 2007, Small.

[10]  Alexander M. Klibanov,et al.  Conjugation to gold nanoparticles enhances polyethylenimine's transfer of plasmid DNA into mammalian cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Shuming Nie,et al.  Single chain epidermal growth factor receptor antibody conjugated nanoparticles for in vivo tumor targeting and imaging. , 2008, Small.

[12]  Kazunori Kataoka,et al.  Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. , 2005, Molecular bioSystems.

[13]  R. P. Andres,et al.  Synthesis and grafting of thioctic acid-PEG-folate conjugates onto Au nanoparticles for selective targeting of folate receptor-positive tumor cells. , 2006, Bioconjugate chemistry.

[14]  S. Haam,et al.  Multifunctional magneto-polymeric nanohybrids for targeted detection and synergistic therapeutic effects on breast cancer. , 2007, Angewandte Chemie.

[15]  Indrajit Roy,et al.  Covalently dye-linked, surface-controlled, and bioconjugated organically modified silica nanoparticles as targeted probes for optical imaging. , 2008, ACS nano.

[16]  Yanli Liu,et al.  Cellular trajectories of peptide-modified gold particle complexes: comparison of nuclear localization signals and peptide transduction domains. , 2004, Bioconjugate chemistry.

[17]  Xingyu Li,et al.  Intracellular delivery of quantum dots tagged antisense oligodeoxynucleotides by functionalized multiwalled carbon nanotubes. , 2007, Nano letters.

[18]  S. Schmid,et al.  Clathrin-coated vesicle formation and protein sorting: an integrated process. , 1997, Annual review of biochemistry.

[19]  P. Swaan,et al.  Endocytic mechanisms for targeted drug delivery. , 2007, Advanced drug delivery reviews.

[20]  Rongqin Huang,et al.  Efficient gene delivery targeted to the brain using a transferrin-conjugated polyethyleneglycol-modified polyamidoamine dendrimer , 2007 .

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

[22]  H. Dai,et al.  In vivo quantum dot labeling of mammalian stem and progenitor cells , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[23]  R Pepperkok,et al.  The many ways to cross the plasma membrane , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. Scheinberg,et al.  Conscripts of the infinite armada: systemic cancer therapy using nanomaterials , 2010, Nature Reviews Clinical Oncology.

[25]  Igor L. Medintz,et al.  Intracellular bioconjugation of targeted proteins with semiconductor quantum dots. , 2010, Journal of the American Chemical Society.

[26]  Weibo Cai,et al.  Nanoplatforms for targeted molecular imaging in living subjects. , 2007, Small.

[27]  T. Xia,et al.  Understanding biophysicochemical interactions at the nano-bio interface. , 2009, Nature materials.

[28]  B. Cui,et al.  One at a time, live tracking of NGF axonal transport using quantum dots , 2007, Proceedings of the National Academy of Sciences.

[29]  Christophe Danelon,et al.  Multifunctional lipid/quantum dot hybrid nanocontainers for controlled targeting of live cells. , 2006, Angewandte Chemie.

[30]  L. Chen,et al.  Aptamer-based silver nanoparticles used for intracellular protein imaging and single nanoparticle spectral analysis. , 2010, The journal of physical chemistry. B.

[31]  P. Hudson,et al.  Engineered antibody fragments and the rise of single domains , 2005, Nature Biotechnology.

[32]  Mark E. Davis,et al.  Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles , 2009, Proceedings of the National Academy of Sciences.

[33]  D. Pang,et al.  Imaging viral behavior in Mammalian cells with self-assembled capsid-quantum-dot hybrid particles. , 2009, Small.

[34]  David Putnam,et al.  Polymers for gene delivery across length scales , 2006, Nature materials.

[35]  E. Giralt,et al.  Cytosolic targeting of macromolecules using a pH-dependent fusogenic peptide in combination with cationic liposomes. , 2009, Bioconjugate chemistry.

[36]  M. El-Sayed,et al.  Why gold nanoparticles are more precious than pretty gold: noble metal surface plasmon resonance and its enhancement of the radiative and nonradiative properties of nanocrystals of different shapes. , 2006, Chemical Society reviews.

[37]  Pier Paolo Di Fiore,et al.  The endocytic matrix , 2010, Nature.

[38]  Chitta Ranjan Patra,et al.  Attaching folic acid on gold nanoparticles using noncovalent interaction via different polyethylene glycol backbones and targeting of cancer cells , 2007 .

[39]  Warren C W Chan,et al.  Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. , 2007, Nano letters.

[40]  Forrest M Kievit,et al.  PEI–PEG–Chitosan‐Copolymer‐Coated Iron Oxide Nanoparticles for Safe Gene Delivery: Synthesis, Complexation, and Transfection , 2009, Advanced functional materials.

[41]  C. Batt,et al.  Gold hybrid nanoparticles for targeted phototherapy and cancer imaging , 2010, Nanotechnology.

[42]  Robert Langer,et al.  Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA–PEG nanoparticles , 2008, Proceedings of the National Academy of Sciences.

[43]  Maurizio Prato,et al.  Synthesis and characterization of a carbon nanotube-dendron series for efficient siRNA delivery. , 2009, Journal of the American Chemical Society.

[44]  L. Malerød,et al.  Clathrin-dependent endocytosis. , 2004, The Biochemical journal.

[45]  Arezou A Ghazani,et al.  Assessing the effect of surface chemistry on gold nanorod uptake, toxicity, and gene expression in mammalian cells. , 2008, Small.

[46]  Igor L. Medintz,et al.  Delivering quantum dots into cells: strategies, progress and remaining issues , 2009, Analytical and bioanalytical chemistry.

[47]  Shuming Nie,et al.  Semiconductor nanocrystals: structure, properties, and band gap engineering. , 2010, Accounts of chemical research.

[48]  Erkki Ruoslahti,et al.  Targeted quantum dot conjugates for siRNA delivery. , 2007, Bioconjugate chemistry.

[49]  A. Marcus,et al.  Imaging and tracking of tat peptide-conjugated quantum dots in living cells: new insights into nanoparticle uptake, intracellular transport, and vesicle shedding. , 2007, Journal of the American Chemical Society.

[50]  P. Low,et al.  Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Philip S Low,et al.  Folate receptor-mediated drug targeting: from therapeutics to diagnostics. , 2005, Journal of pharmaceutical sciences.

[52]  Weihong Tan,et al.  DNA aptamer–micelle as an efficient detection/delivery vehicle toward cancer cells , 2009, Proceedings of the National Academy of Sciences.

[53]  A. Lu,et al.  Magnetic nanoparticles: synthesis, protection, functionalization, and application. , 2007, Angewandte Chemie.

[54]  Sangeeta N. Bhatia,et al.  Intracellular Delivery of Quantum Dots for Live Cell Labeling and Organelle Tracking , 2004 .

[55]  Robert J. Lee,et al.  Synthesis of cetuximab-immunoliposomes via a cholesterol-based membrane anchor for targeting of EGFR. , 2007, Bioconjugate chemistry.

[56]  J. Szostak,et al.  In vitro selection of RNA molecules that bind specific ligands , 1990, Nature.

[57]  J. Nam,et al.  Lipid-gold-nanoparticle hybrid-based gene delivery. , 2008, Small.

[58]  Yong Zhang,et al.  Upconversion fluorescence imaging of cells and small animals using lanthanide doped nanocrystals. , 2008, Biomaterials.

[59]  R. Parton,et al.  Lipid Rafts and Caveolae as Portals for Endocytosis: New Insights and Common Mechanisms , 2003, Traffic.

[60]  Valérie Cabuil,et al.  Fluorescence-modified superparamagnetic nanoparticles: intracellular uptake and use in cellular imaging. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[61]  Igor L. Medintz,et al.  Intracellular delivery of quantum dot-protein cargos mediated by cell penetrating peptides. , 2008, Bioconjugate chemistry.

[62]  Thommey P. Thomas,et al.  Dendrimer-epidermal growth factor conjugate displays superagonist activity. , 2008, Biomacromolecules.

[63]  Jesus M de la Fuente,et al.  Tat peptide as an efficient molecule to translocate gold nanoparticles into the cell nucleus. , 2005, Bioconjugate chemistry.

[64]  J Aaron,et al.  Directional conjugation of antibodies to nanoparticles for synthesis of multiplexed optical contrast agents with both delivery and targeting moieties , 2008, Nature Protocols.

[65]  Yu-Cheng Lin,et al.  A nonviral transfection approach in vitro: the design of a gold nanoparticle vector joint with microelectromechanical systems. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[66]  Arezou A Ghazani,et al.  Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. , 2006, Nano letters.

[67]  Satyajit Mayor,et al.  Pathways of clathrin-independent endocytosis , 2007, Nature Reviews Molecular Cell Biology.

[68]  A. Verkman Solute and macromolecule diffusion in cellular aqueous compartments. , 2002, Trends in biochemical sciences.

[69]  Betty Y. S. Kim,et al.  Biodegradable quantum dot nanocomposites enable live cell labeling and imaging of cytoplasmic targets. , 2008, Nano letters.

[70]  M. Dahan,et al.  Probing cellular events, one quantum dot at a time , 2010, Nature Methods.

[71]  Stefaan C De Smedt,et al.  High intracellular iron oxide nanoparticle concentrations affect cellular cytoskeleton and focal adhesion kinase-mediated signaling. , 2010, Small.

[72]  Ning Wang,et al.  Nanoneedle: a multifunctional tool for biological studies in living cells. , 2010, Nanoscale.

[73]  Sanjiv S Gambhir,et al.  Cys-diabody quantum dot conjugates (immunoQdots) for cancer marker detection. , 2009, Bioconjugate chemistry.

[74]  Sangjin Park,et al.  Carbon nanosyringe array as a platform for intracellular delivery. , 2009, Nano letters.

[75]  Shuming Nie,et al.  Proton-sponge coated quantum dots for siRNA delivery and intracellular imaging. , 2008, Journal of the American Chemical Society.

[76]  Yu Matsumoto,et al.  Polyplex micelles with cyclic RGD peptide ligands and disulfide cross-links directing to the enhanced transfection via controlled intracellular trafficking. , 2008, Molecular pharmaceutics.

[77]  H. Harashima,et al.  Learning from the Viral Journey: How to Enter Cells and How to Overcome Intracellular Barriers to Reach the Nucleus , 2009, The AAPS Journal.

[78]  Florian Beck,et al.  Correlative microscopy: bridging the gap between fluorescence light microscopy and cryo-electron tomography. , 2007, Journal of structural biology.

[79]  Tomaso Zambelli,et al.  FluidFM: combining atomic force microscopy and nanofluidics in a universal liquid delivery system for single cell applications and beyond. , 2009, Nano letters.

[80]  Miqin Zhang,et al.  Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI. , 2006, Journal of biomedical materials research. Part A.

[81]  R. A. Ezekowitz,et al.  Phagocytosis: elegant complexity. , 2005, Immunity.

[82]  S Gordon,et al.  Macrophage receptors and immune recognition. , 2005, Annual review of immunology.

[83]  Tae Gwan Park,et al.  Target-specific cellular uptake of PLGA nanoparticles coated with poly(L-lysine)-poly(ethylene glycol)-folate conjugate. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[84]  Eva Syková,et al.  Poly(L-lysine)-modified iron oxide nanoparticles for stem cell labeling. , 2008, Bioconjugate chemistry.

[85]  Kazuo Maruyama,et al.  Transferrin-modified liposomes equipped with a pH-sensitive fusogenic peptide: an artificial viral-like delivery system. , 2004, Biochemistry.

[86]  Kostas Kostarelos,et al.  Lipid-quantum dot bilayer vesicles enhance tumor cell uptake and retention in vitro and in vivo. , 2008, ACS nano.

[87]  M. Morris,et al.  Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics , 2009, British journal of pharmacology.

[88]  Mathias Brust,et al.  Uptake and intracellular fate of surface-modified gold nanoparticles. , 2008, ACS nano.

[89]  Ya-jun Guo,et al.  Preparation and characterization of PE38KDEL-loaded anti-HER2 nanoparticles for targeted cancer therapy. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[90]  G. Adams,et al.  Monoclonal antibody therapy of cancer , 1999, Nature Biotechnology.

[91]  Long-chuan Yu,et al.  Microinjection as a tool of mechanical delivery. , 2008, Current opinion in biotechnology.

[92]  Paras N Prasad,et al.  Folate-receptor-mediated delivery of InP quantum dots for bioimaging using confocal and two-photon microscopy. , 2005, Journal of the American Chemical Society.

[93]  Seungpyo Hong,et al.  Nanoparticle interaction with biological membranes: does nanotechnology present a Janus face? , 2007, Accounts of chemical research.

[94]  Xiangling Xiong,et al.  Nanoparticle-mediated IgE-receptor aggregation and signaling in RBL mast cells. , 2009, Journal of the American Chemical Society.

[95]  Shuming Nie,et al.  Cell-penetrating quantum dots based on multivalent and endosome-disrupting surface coatings. , 2007, Journal of the American Chemical Society.

[96]  Warren C W Chan,et al.  Nanoparticle-mediated cellular response is size-dependent. , 2008, Nature nanotechnology.

[97]  Hua Ai,et al.  Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems. , 2006, Nano letters.

[98]  Vincent Noireaux,et al.  In Vivo Imaging of Quantum Dots Encapsulated in Phospholipid Micelles , 2002, Science.

[99]  Michael V. Mirkin,et al.  Electrochemical attosyringe , 2007, Proceedings of the National Academy of Sciences.

[100]  Daniele Gerion,et al.  Fluorescent CdSe/ZnS nanocrystal-peptide conjugates for long-term, nontoxic imaging and , 2004 .

[101]  I. Khalil,et al.  Uptake Pathways and Subsequent Intracellular Trafficking in Nonviral Gene Delivery , 2006, Pharmacological Reviews.

[102]  James A J Fitzpatrick,et al.  Cholera toxin B conjugated quantum dots for live cell labeling. , 2007, Nano letters.

[103]  Tore-Geir Iversen,et al.  Cellular trafficking of quantum dot-ligand bioconjugates and their induction of changes in normal routing of unconjugated ligands. , 2008, Nano letters.

[104]  Rebecca Richards-Kortum,et al.  Plasmonic nanosensors for imaging intracellular biomarkers in live cells. , 2007, Nano letters.

[105]  Daniel G. Anderson,et al.  Knocking down barriers: advances in siRNA delivery , 2009, Nature Reviews Drug Discovery.

[106]  John F. McDonald,et al.  Magnetic nanoparticle-peptide conjugates for in vitro and in vivo targeting and extraction of cancer cells. , 2008, Journal of the American Chemical Society.

[107]  Q. Pankhurst,et al.  Nanoparticles functionalized with recombinant single chain Fv antibody fragments (scFv) for the magnetic resonance imaging of cancer cells. , 2010, Biomaterials.

[108]  S. Ryter,et al.  Mechanisms of cell death in oxidative stress. , 2007, Antioxidants & redox signaling.

[109]  M. El-Sayed,et al.  Nuclear targeting of gold nanoparticles in cancer cells induces DNA damage, causing cytokinesis arrest and apoptosis. , 2010, Journal of the American Chemical Society.

[110]  Conroy Sun,et al.  Inhibition of tumor-cell invasion with chlorotoxin-bound superparamagnetic nanoparticles. , 2008, Small.

[111]  R. Weissleder,et al.  Cell-specific targeting of nanoparticles by multivalent attachment of small molecules , 2005, Nature Biotechnology.

[112]  Kostas Kostarelos,et al.  Functionalized-quantum-dot-liposome hybrids as multimodal nanoparticles for cancer. , 2008, Small.

[113]  Jeffrey L. Wrana,et al.  Distinct endocytic pathways regulate TGF-β receptor signalling and turnover , 2003, Nature Cell Biology.

[114]  Sung Ho Ryu,et al.  A Nucleolin-Targeted Multimodal Nanoparticle Imaging Probe for Tracking Cancer Cells Using an Aptamer , 2010, Journal of Nuclear Medicine.

[115]  Wole Soboyejo,et al.  LHRH-conjugated Magnetic Iron Oxide Nanoparticles for Detection of Breast Cancer Metastases , 2006, Breast Cancer Research and Treatment.

[116]  R. Langer,et al.  Intracellular delivery of core-shell fluorescent silica nanoparticles. , 2008, Biomaterials.