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  1. 1. Nanomedicine
  2. 2. Premises • Since the human body is basically an extremely complex system of interacting molecules (i.e., a molecular machine), the technology required to truly understand and repair the body is the molecular machine technology : NANOTECHNOLOGY • A natural consequence of this level of technology will be the ability to analyze and repair the human body as completely and effectively as we can repair any conventional machine today.
  4. 4. Feynman: "There is plenty of room at the bottom" • Seminal speech on December 1959 at CalTech • " Why can’t be compress 24 volumes of Encyclopedia Britannica on a pin head ?“ • " The biological example of writing information on a small scale has inspired me to think of something that should be possible " • In 1990, IBM scientists wrote the logo IBM using 35 xenon atoms on nickel.
  5. 5. NANO ≈ < 100 nm
  6. 6. Nanomedicine: EC European Technology Platform (ETP)
  7. 7. E.C.-ETP “Nanomedicine, is defined as the application of nanotechnology to achieve breakthroughs in healthcare. It exploits the improved and often novel physical, chemical and biological properties of materials at the nanometer scale. Nanomedicine has the potential to enable early detection and prevention, and to essentially improve diagnosis, treatment and follow-up of diseases. ………………………. Diagnostics, targeted drug delivery and regenerative medicine constitute the core disciplines of nanomedicine.”
  8. 8. Nanomedicine: European Science Foundation (ESF) “The field of Nanomedicine is the science and technology of diagnosing, treating and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using molecular tools and molecular knowledge of the human body. It embraces subdisciplines which are in many ways overlapping and are underpinned by common technical issues.”
  9. 9. The numbers of nanomedicine The total market for nanobiotechnology products is $19.3 billion in 2010 and is growing at a compound annual growth rate (CAGR) of 9% to reach a forecasted market size of $29.7 billion by 2015.
  10. 10. Number of publications containing “nanoparticles” in Medline 14000 12000 10000 8000 6000 4000 2000 0 1990 1995 1999 2001 2003 2005 2007 2009 2011
  11. 11. 1966
  12. 12. Topics in nanomedicine • Therapy: Drug Delivery: Use nanodevices specifically targeted to cells, to guide delivery of drugs, proteins and genes Drug targeting : Whole body, cellular , subcellular delivery Drug discovery : Novel bioactives and delivery systems
  13. 13. Topics in nanomedicine • Diagnosis: Prevention and Early Detection of diseases: Use nanodevices to detect specific changes in diseased cells and organism.
  14. 14. Nanoparticles (NP): Smart Nanostructures for diagnosis and therapy
  15. 15. Why Nanoparticles 1) Drugs, contrast agents, paramagnetic or radiolabeled probes can be vehiculated by NPs 2) NPs can be multi-functionalized to confer differents features on them
  16. 16. • Targeting: nanoparticles control over delivery. • Drugs are concentrated to target. Less systemic toxicity. • Less drug is necessary • Drugs are protected inside NPs and are not degraded. Longer halflife
  17. 17. • Multi-functionalization: Control over delivery location, drug dosage, and drug release characteristics is possible
  18. 18. An ideal Multi-functional nanoparticle vector Anticorpo Polietilenglicol Evita che NP venga (PEG) digerita nei lisosomi Indirizza la NP verso un antigene specifico sulla la NP venga Evita che cellula da colpire rimossa dal circolo Tat peptide Determina Fusione e Probe magnetico ingresso della NP nella cellula Permette imaging tramite MRI Farmaco
  20. 20. Carbon-based: Buckyballs and Nanotubes C60 1nm
  21. 21. What are Carbon Nanotubes? Carbon nanotubes are hexagonally shaped arrangements of carbon atoms that have been rolled into tubes.
  22. 22. Nanotubes are members of the fullerene structural family, which also includes the spherical buckyballs. The ends of a nanotube might be capped with a hemisphere of the buckyball structure. Their name is derived from their size, since the diameter of a nanotube is on the order of a few nanometers, while they can be up to 18 centimeters in length (as of 2010). Nanotubes are categorized as single-walled nanotubes (SWNTs) and multi-walled nanotubes (MWNTs) Human hair fragment (the purplish thing) on top of a network of single-walled carbon nanotubes
  23. 23. Single-walled • Most single-walled nanotubes (SWNT) have a diameter of close to 1 nanometer, with a tube length that can be many millions of times longer..
  24. 24. • Single-walled nanotubes are an important variety of carbon nanotube because they exhibit electric properties that are not shared by the multi-walled carbon nanotube (MWNT) variants.One useful application of SWNTs is in the development of the first intramolecular field effect transistors (FET). • (Used for nanobiosensors). Armchair (n,n)
  25. 25. • • • Multi-walled nanotubes (MWNT) consist of multiple rolled layers (concentric tubes) of graphite. In the Russian Doll model, sheets of graphite are arranged in concentric cylinders, e.g. a (0,8) single-walled nanotube (SWNT) within a larger (0,10) single-walled nanotube. In the Parchment model, a single sheet of graphite is rolled in around itself, resembling a scroll of parchment or a rolled newspaper. The interlayer distance in multi-walled nanotubes is close to the distance between graphene layers in graphite, approximately 3.4 Å. Multi-walled
  26. 26. Properties of Carbon Nanotubes Nanotubes have a very broad range of electronic, thermal, and structural properties that change depending on diameter, length. They exhibit extraordinary strength and unique electrical properties, and are efficient conductors of heat.
  27. 27. • Carbon nanotubes are the strongest and stiffest materials yet discovered in terms of tensile strength and elastic modulus respectively. This strength results from the covalent sp2 bonds formed between the individual carbon atoms. In 2000, a multi-walled carbon nanotube was tested to have a tensile strength of 63 gigapascals (GPa). (This, for illustration, translates into the ability to endure tension of a weight equivalent to 6422 kg on a cable with cross-section of 1 mm2.) Since carbon nanotubes have a low density for a solid of 1.3 to 1.4 g·cm−3, its specific strength of up to 48,000 kN·m·kg−1 is the best of known materials, compared to high-carbon steel's 154 kN·m·kg−1. Strength
  28. 28. Electrical properties • Depending how the graphene sheet is rolled up, the nanotube can be metallic; semiconducting or moderate semiconductor.
  29. 29. Thermal property • All nanotubes are expected to be very good thermal conductors along the tube, exhibiting a property known as "ballistic conduction," but good insulators laterally to the tube axis.
  30. 30. Defects • As with any material, the existence of a crystallographic defect affects the material properties. Defects can occur in the form of atomic vacancies. High levels of such defects can lower the tensile strength by up to 85%. Crystallographic defects also affect the tube's electrical properties. A common result is lowered conductivity through the defective region of the tube.
  31. 31. Natural, incidental, and controlled flame environments • Fullerenes and carbon nanotubes are not necessarily products of high-tech laboratories; they are commonly formed in such places as ordinary flames,produced by burning methane,ethylene,and benzene,and they have been found in soot from both indoor and outdoor air. However, these naturally occurring varieties can be highly irregular in size and quality because the environment in which they are produced is often highly uncontrolled.
  32. 32. Potential and current applications of CNT
  33. 33. In electrical circuits • Nanotube based transistors have been made that operate at room temperature and that are capable of digital switching using a single electron.The first nanotube integrated memory circuit was made in 2004. Nanotube Transistor
  34. 34. Proposed as a vessel for transporting drugs into the body. The drug can be attached to the side or trailed behind, or the drug can actually be placed inside the nanotube Nanotube Nanocap
  35. 35. Covalent Functionalization Non-Covalent Functionalization
  36. 36. Funzionalizzazione non covalente (DNA)
  37. 37. final usage, however, may be limited by their potential toxicity. Under some conditions, nanotubes can cross membrane barriers and can induce harmful effects: inflammation, epithelioid granulomas (microscopic nodules), fibrosis,and biochemical/toxicological changes in the lungs. Determining the toxicity of carbon nanotubes has been one of the most pressing questions in nanotechnology.Unfortunately such research has only just begun and the data are still fragmentary and subject to criticism. Preliminary results highlight the difficulties in evaluating the toxicity of this heterogeneous material. Parameters such as structure, size distribution, surface area, surface chemistry, surface charge, and agglomeration state as well as purity of the samples, have considerable impact on the reactivity of carbon nanotubes.. Their Toxicity
  38. 38. Lipid-based NPs :Liposomes and solid lipid nanoparticles (SLN) 50 – 500 nm 40-1000nm
  39. 39. •LIPOSOMES are the smallest spherical structure technically produced by natural non-toxic phospholipids and cholesterol.
  40. 40. Metal-core nanoparticles
  41. 41. gold nanoparticles (1-20 nm) are produced by reduction of chloroauric acid (H[AuCl4]), To the rapidly-stirred boiling HAuCl4 solution, quickly add 2 mL of a 1% solution of trisodium citrate dihydrate, Na3C6H5O7.2H2O. The gold sol gradually forms as the citrate reduces the gold(III). Remove from heat when the solution has turned deep red or 10 minutes has elapsed.
  42. 42. In cancer research, colloidal gold can be used to target tumors and provide detection using SERS (Surface Enhanced Raman Spectroscopy) in vivo. They are being investigated as photothermal converters of near infrared light for in-vivo applications, as ablation components for cancer, and other targets since near infrared light transmits readily through human skin and tissue
  43. 43. Polymeric/Dendrimers (e.g.PLGA, PAA, PACA) spherical polymers of uniform molecular weight made from branched monomers are proving particularly adapt at providing multifunctional modularity.
  44. 44. Polymeric PLGA POLY-LACTIC-GLYCOLIC ACID PLGA Poly-Lactic-Glycolic Acid
  45. 45. Polyacrylamide (PACA)
  46. 46. In solvente organico In acqua
  47. 47. Dendrimers are repetitively branched molecules. PAA= POLI AMMINO AMMIDE PLGA PAA
  48. 48. Polyamidoamines (PAA or PAMAM)
  49. 49. HYDROGELS Polymers or co-polymers (e.g. acrylamide and acrylic acid) create water-impregnated nanoparticles with pores of well-defined size. Water flows freely into these particles, carrying proteins and other small molecules into the polymer matrix. By controlling the pore size, huge proteins such as albumin and immunoglobulin are excluded while smaller peptides and other molecules are allowed. The polymeric component acts as a negatively charged "bait" that attracts positively charged proteins, improving the particles' performance.
  50. 50. Mesoporous silica (SiO2)
  51. 51. Mesoporous silica particles: nano-sized spheres filled with a regular arrangement of pores with controllable pore size from 3 to 15nm and outer diameter from 20nm to 1000 nm . The large surface area of the pores allows the particles to be filled with a drug or with a fluorescent dye that would normally be unable to pass through cell walls. The MSN material is then capped off with a molecule that is compatible with the target cells. When are added to a cell culture, they carry the drug across the cell membrane. These particles are optically transparent, so a dye can be seen through the silica walls. The types of molecules that are grafted to the outside will control what kinds of biomolecules are allowed inside the particles to interact with the dye. EM
  52. 52. Quantum dots • Crystalline fluorophores • CdSe semiconductor core • ZnS Shell 3 nm
  53. 53. A quantum dot is a semiconductor whose excitons are confined in all three spatial dimensions. An immediate optical feature of colloidal quantum dots is their coloration First attempts have been made to use quantum dots for tumor targeting under in vivo conditions. Generically toxic
  54. 54. Quantum Dot Properties High quantum yield compared to common fluorescent dyes Broadband absorption: light that has a shorter wavelength than the emission maximum wavelength can be absorbed, peak emission wavelength is independent of excitation source Tunable and narrow emission, dependent on composition and size High resistance to photo bleaching: inorganic particles are more photostable than organic molecules and can survive longer irradiation times Long fluorescence lifetime: fluorescent of quantum dots are 15 to 20 ns, which is higher than typical organic dye lifetimes. Improved detection sensitivity: inorganic semiconductor nanoparticles can be characterized with electron microscopes 58
  55. 55. Quantum Dots • Raw quantum dots are toxic • But they fluoresce brilliantly, better than dyes (imaging agents) • Only way of clearance of protected QDs from the body is by slow filtration and excretion through the kidney
  56. 56. Quantum Dots QD technology helps cancer researchers to observe fundamental molecular events occurring in the tumor cells by tracking the QDs of different sizes and thus different colors, tagged to multiple different biomoleules, in vitro by fluorescent microscopy. QD technology holds a great potential for applications in nanobiotechnology and medical diagnostics where QDs could be used as labels.
  57. 57. Quantum Dots for Imaging of Tumor Cells Figure 2. Phase contrast images (top row) and fluorescence image NIH-3T3 cells incubated with QDs2; (c) SKOV3 cells were incubated with QDs2 FPP-QDs specifically bind to tumor cells via the membrane expression of FA receptors on cell surface Y. Zhao et al. Journal of Colloid and Interface Science 350 (2010) 44–50. 62
  58. 58. Quantum dots conjugated with folate–PEG–PMAM for targeting tumor cells Folate–poly(ethylene glycol)–polyamidoamine ligands encapsulate and solubilize CdSe/ZnS quantum dots and target folate receptors in tumor cells. Dendrimer ligands with multivalent amino groups can react with Zn2+ on the surface of CdSe/ZnS QDs based on direct ligand-exchange reactions with ODA ligands Y. Zhao et al. Journal of Colloid and Interface Science 350 (2010) 44–50. 63
  59. 59. Nano-particulate pharmaceuticals Brand name Emend (Merck & Co. Inc.) Rapamune (Wyeth-Ayerst Laboratories) Abraxane (American Biosciences, Inc.) Rexin-G (Epeius Biotechnology corporation) Olay Moisturizers (Procter and Gamble) Trimetaspheres (Luna Nanoworks) Description Nanocrystal (antiemetic) in a capsule Silcryst (Nucryst Pharmaceuticals) Nano-balls (Univ. of South Florida) Enhance the solubility and sustained release of silver nanocrystals Nano-sized plastic spheres with drugs (active against methicillin-resistant staph (MRSA) bacteria) chemically bonded to their surface that allow the drug to be dissolved in water. Nanocrystallized Rapamycin (immunosuppressant) in a tablet Paclitaxel (anticancer drug)- bound albumin particles A retroviral vector carrying cytotoxic gene Contains added transparent, better protecting nano zinc oxide particles MRI images
  60. 60. Company Product CytImmune Gold nanoparticles for targeted delivery of drugs to tumors Nucryst Antimicrobial wound dressings using silver nanocrystals Nanobiotix Nanoparticles that target tumor cells, when irradiated by xrays the nanoparticles generate electrons which cause localized destruction of the tumor cells. Oxonica Disease identification using gold nanoparticles (biomarkers) Nanotherapeutics Nanoparticles for improving the performance of drug delivery by oral, inhaled or nasal methods NanoBio Nanoemulsions for nasal delivery to fight viruses (such as the flu and colds) and bacteria BioDelivery Sciences Oral drug delivery of drugs encapuslated in a nanocrystalline structure called a cochleate NanoBioMagnetics Magnetically responsive nanoparticles for targeted drug delivery and other applications Z-Medica Medical gauze containing aluminosilicate nanoparticles which help bood clot faster in open wounds.
  61. 61. Some liposome -based pharmaceuticals
  62. 62. Open Problems Manufacturing NPs for medical use: Putting the drug on the particle Maintaining the drug in the particle Making the drug come off the particle once application is done Purity and homogeneity of nanoparticles SOLUTION: Assessment of NPs: Dynamic structural features in vivo Kinetics of drug release Triggered drug release
  63. 63. Open Problems Toxicity: short term - no toxicity in animals long term- not known Toxicity for both the host and the environment should be addressed
  64. 64. Open Problems Delivery: Ensuring Delivery to target organ/cell Removal of nanoparticles from the body SOLUTION: detection of NPs at target, organs , cells , subcellular location et al. Tissue distribution
  65. 65. Open Problems: Targeting the brain • Brain micro-vessel endothelial cells build up the blood brain barrier (BBB) • The BBB hinders water soluble molecules and those with MW > 500 from getting into the brain
  66. 66. The blood-brain barrier (BBB) NPs
  67. 67. Open Problems GMP Challenges • No standards for: Purity and homogeneity of nanoparticles Manufacturing Methods Testing and Validation
  68. 68. Summary • Toxicities of nanomaterials are unknown • to best target the nanomaterials so that systemic administration can be used • to uncage the drug so it gets out at the desired location • to “re-cage” the drug when it is no longer desired • Removal of nanoparticles from the body • Mathematical modeling of nanostructures • Barrier crossing (BBB, G.I., et al.)