Nanotechnology in the diagnosis and treatment of cancer
Note
|Updated
Summary
Background
NOKC was asked by the western health region (Helse-Vest RHF) to summarize the current use of nanotechnology, especially for cancer patients. This is a rapid review mainly based on a report from "Committee of the Health Council" in Holland, published in 2006 (1).
Introduction
Materials with a size between 0,1 og 100 nm can impose different mechanical, electrical and magnetic properties compared with the same larger sized material. Nanotechnology is the manipulation of materials at the nanolevel, and has emerged as a separate scientific field. The medical application of nanotechnology is emerging in several areas, and the summary below gives an overview of current and future medical applications.
Diagnostics
Increased knowledge of the human genome has made it possible to link diseases with abnormalities at the gene- or protein level. Thus diseases might be treated before the manifestation of symptoms (2,3). Strategies for early diagnosis and disease prevention has been a focus for medical research and in particular cancer research (3). Nanotechnology may be an important technology, especially in the development of biomarkers at the DNA and protein level (4-6). Biomarkers may be used for in vitro or in vivo diagnostic strategies.
In vitro diagnostic strategies
Nanotechnology is important in the production of microarrays, and can improve the accuracy of the technology(7). Microarrays are used to assess gene expression in a sample (for instant a biopsy) to assist in setting the diagnose, and has the potential to predict patients likelihood to respond to treatments. Microarrays are used extensively in research, but to a lesser extent in clinical practice. Slike mikromatriser er i utstrakt bruk innen
An alternative technology to microarray is another relatively new nanotechnology-based strategy called "Quantum dots". "Quantum dots" are fluorescent nanocrystals that can be has improved stability compared with conventional fluorescence dyes (8). This may be applied to study identify specific DNA sequences in a sample. Quantum dots is used in research, but the clinical utilization is very limited (9).
Work are in progress to develop other methods for more rapid verification of DNA sequences. Nanopore membranes is one technology that may improve the speed by which a DNA sequence is established (10). This method may also be applied to proteins and carbohydrates, though there is an issue of instability and complexity that complicate these applications (7).
Researchers have developed a detection system for (PSA) based on this technology (11,12).
"Labs-on-a-chip" is nanotechnology based. The idea is to simplify the analysis of blood samples, by patients themselves or at the physician office. There is a chip available for home verification of litium concentration in blood (13).
"Photonic explorers for bioanalysis with biologically localised embedding" (PEBBLEs) are sensor a few hundred nanometer thick. PEBBLES are capsules containing an indicator that emit light upon contact with specific molecules(14). PEBBLEs can be used to assess intracellular concentrations of ions and molecules.
So far PEBBLEs are used to study Alzheimer and Parkinson that are characterized by abnormal concentration of sink (15). Tumor samples may also be characterized by abnormal intracellular concentrations of certain ions and small molecules (16). Thus PEPPBLEs may have a potential future application within the diagnosis of cancer.
In vivo diagnostic
In vivo use of nanotechnology is mostly connected to imaging technologies. Nanotechnology may improve current technologies, and also establish new ones.
Lipid nanoparticles can be designed to incorporate gadolinium or a radioactive isotope. The uptake and distribution of theses particles can be visualized with MRI or scintigraphy
(7,17). Such nanoparticles may be conjugated with targeting molecules (for instance antibodies) to target the uptake to specific design areas in the body.
Super paramagnetic particles of iron oxide are currently in use as contrast agent for MRI
MRI (3). These may used in the detection of lymph node metastases (18), or as molecular markers.
The development of quantum dots (described above) may also be used in imaging procedures to assess metastases (19-22).
Therapy
Nanostructured lipid carriers
The distribution and specificity of drug therapy can be improved by embedding drugs within lipid nanoparticles. Lipid carriers allows for improved transportation of water insoluble molecules in blood, and slower drug release within the body. Thus may be of interested in several areas, though improved delivery of cancer therapy is one possible application (24,25).
Nanoparticles may be designed to improve the accumulation in tumor tissue in either by modifying the size or by conjugating the particles to targeting molecules.
(27,28). Nanoparticles may also be applied to monitor treatment responses (29,30).
Nanoparticles as drugs
Nanoparticles may also be active substances themselves. Magnetic or metal containing nanoparticles that accumulates within tumor tissue may kill tumor cells therapy when exposed to oscillatory magnetic fields, (31-33), infrared radiation (34), ultrasonic vibrations (35) or heat (36-38), depending on the composition of the chosen nanoparticle. Nanotubes of carbon may also kill tumor cells when exposed to infrared radiation (42).
Passive implants and tissue systems
Artificial joints (such as hip prosthesis) has a survival of 10-15 years (7,43).
Implants coated with nanocrystals may have improved survival (44). Nanocrystals may also improve biocompatibility and the tolerance to implants.
Acktive implantats
Active implants have a have an energy source (45), and may be used for drug administration such as insulin or morphine pumps. Such implants may also have biosensors to facilitate responses to physiological changes. Nanotechnology may allow for production of smaller size implants and sensors.
An other group of active implants are those that modulate neurological functions. Examples are Cochlea implants, pacemakers and defibrillators that are in clinical use. Retinal implants though has not yet been developed.
Disinfection
The development of antibiotic resistance has enhanced the interest in using silver as an antimicrobial strategy (7,46). The antiseptic properties of silver is due to silver ions that impose bacterial metabolism, destabilize the membrane and prevent cell division.
Silver nanoparticles can be integrated with other materials, for instance implants.
Research is ongoing that incorporates silver nanoparticles in catheters (47,48), cochlea implants (7,45) and bone cement (49,50). Bandages and patches with silver nanoparticles are currently available (51,52).
Safety and risks
The size of nanoparticles may impose new safety issues. Particle toxicology has emerged as an important research area (53). There is a special attention to possible adverse effects on the airways, due to respiration of nanoparticles. Important issues for research is whether current knowledge on traditional particles also apply to nanoparticles (54-59). Current information on humans are on the respiration of nanoparticles (60,61) and use of nanoparticles for transportation of drugs or contrast agents (62).
References:
1. Health council of the Netherlands. Health significance of nanotechnologies.2006.
2. Lamerichs r, Schäffer T, Hämisch Y et al. Molecular imaging: the road to better healthcare. Medicamundi 2003; 47: 2-9.
3. European Science Foundation. Nanomedicine - an ESF - European Medical Research Councils (EMRC) forward look report. Strasbourg: European Science Foundation 2005.
4. Baumgartner, W., Jäckli, B., Schmithüsen, B., and Weber, F. Nanotechnologie in der Medizin. Bern: TASwiss 2003.
5. Emerich DF, Thanos CG. Nanotechnology and medicine. Expert Opin Biol Ther 2003; 3: 655-63.
6. Hauptman, A. and Sharan, Y. Envisioned developments in nanobiotechnology - Nano2Life expert survey report. Tel-Aviv: Interdisciplinary Center for Technology Analysis and Forecasting, Tel-Aviv University 2005.
7. Wagner, V. and Wechsler, D. Nanotechnologie II: Anwendungen in der Medizin und Pharmazie. Düsseldorf: Zukünftige Technologien XConsulting, VDI Technologiezentrum GmbH 2004.
8. Han M, Gao X, Su JZ et al. Quantum-dot-tagged microbeads for multiplexed optical coding of biomolecules. Nat Biotechnol 2001; 19: 631-5.
9. Xu H, Sha MY, Wong EY et al. Multiplexed SNP genotyping using the Qbead system: a quantum dotencoded microsphere-based assay. Nucleic Acids Res 2003; 31: e43.
10. LaVan DA, Lynn DM, Langer R. Moving smaller in drug discovery and delivery. Nat Rev Drug Discov 2002; 1: 77-84.
11. Wu G, Datar RH, Hansen KM et al. Bioassay of prostate-specific antigen (PSA) using microcantilevers. Nat Biotechnol 2001; 19: 856-60.
12. Majumdar A. Bioassays based on molecular nanomechanics. Dis Markers 2002; 18: 167-74.
13. Vrouwe EX, Luttge R, van den BA. Direct measurement of lithium in whole blood using microchip capillary electrophoresis with integrated conductivity detection. Electrophoresis 2004; 25: 1660-7.
14. Buck SM, Koo YE, Park E et al. Optochemical nanosensor PEBBLEs: photonic explorers for bioanalysis with biologically localized embedding. Curr Opin Chem Biol 2004; 8: 540-6.
15. Sumner JP, Aylott JW, Monson E et al. A fluorescent PEBBLE nanosensor for intracellular free zinc. Analyst 2002; 127: 11-6.
16. Chinje EC, Stratford IJ. Role of nitric oxide in growth of solid tumours: a balancing act. Essays Biochem 1997; 32:61-72.
17. Morawski AM, Winter PM, Crowder KC et al. Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI. Magn Reson Med 2004; 51: 480-6.
18. Torabi M, Aquino SL, Harisinghani MG. Current concepts in lymph node imaging. J Nucl Med 2004; 45: 1509-18.
19. Parak WJ, Pellegrino T, Plank C. Labelling of cells with quantum dots. Nanotechnology 2005; 16: R9- R25.
20. Jovin TM. Quantum dots finally come of age. Nat Biotechnol 2003; 21: 32-3. 6
21. Lidke DS, Arndt-Jovin DJ. Imaging takes a quantum leap. Physiology (Bethesda ) 2004; 19: 322-5.
22. Michalet X, Pinaud FF, Bentolila LA et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 2005; 307: 538-44.
23. Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug Discov Today 2003; 8: 1112-20.
24. Gabizon AA. Stealth liposomes and tumor targeting: one step further in the quest for the magic bullet. Clin Cancer Res 2001; 7: 223-5.
25. Owens DE, III, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 2006; 307: 93-102.
26. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986; 46: 6387-92.
27. Kreuter J, Shamenkov D, Petrov V et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target 2002; 10: 317-25.
28. Muller RH, Keck CM. Drug delivery to the brain--realization by novel drug carriers. J Nanosci Nanotechnol 2004; 4: 471-83.
29. Harrington KJ, Mohammadtaghi S, Uster PS et al. Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes. Clin Cancer Res 2001; 7: 243-54.
30. Quintana A, Raczka E, Piehler L et al. Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm Res 2002; 19: 1310-6.
31. Lubbe AS, Bergemann C, Riess H et al. Clinical experiences with magnetic drug targeting: a phase I study with 4'-epidoxorubicin in 14 patients with advanced solid tumors. Cancer Res 1996; 56: 4686-93.
32. Alexiou C, Jurgons R, Schmid RJ et al. Magnetic drug targeting-biodistribution of the magnetic carrier and the chemotherapeutic agent mitoxantrone after locoregional cancer treatment. J Drug Target 2003; 11: 139-49.
33. Saiyed Z, Telang S, Ramchand C. Application of magnetic techniques in the field of drug discovery and biomedicine. Biomagn Res Technol 2003; 1: 2.
34. Radt B, Smith TA, Caruso F. Optically addressable nanostructured capsules. Advanced Materials 2004; 16: 2184-9.
35. Nelson JL, Roeder BL, Carmen JC et al. Ultrasonically activated chemotherapeutic drug delivery in a rat model. Cancer Res 2002; 62: 7280-3.
36. Kong G, Braun RD, Dewhirst MW. Characterization of the effect of hyperthermia on nanoparticle extravasation from tumor vasculature. Cancer Res 2001; 61: 3027-32.
37. Meyer DE, Shin BC, Kong GA et al. Drug targeting using thermally responsive polymers and local hyperthermia. J Control Release 2001; 74: 213-24.
38. Meyer DE, Kong GA, Dewhirst MW et al. Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia. Cancer Res 2001; 61: 1548-54.
39. Johannsen M, Thiesen B, Jordan A et al. Magnetic fluid hyperthermia (MFH)reduces prostate cancer growth in the orthotopic Dunning R3327 rat model. Prostate 2005; 64: 283-92.
40. Hirsch LR, Stafford RJ, Bankson JA et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc Natl Acad Sci U S A 2003; 100: 13549-54. 7
41. O'Neal DP, Hirsch LR, Halas NJ et al. Photo-thermal tumor ablation in mice using near infraredabsorbing nanoparticles. Cancer Lett 2004; 209: 171-6.
42. Kam NW, O'Connell M, Wisdom JA et al. Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction. Proc Natl Acad Sci U S A 2005; 102: 11600-5.
43. Park GE, Webster TJ. A review of nanotechnology for the development of better orthopedic implants. J Biomed Nanotechnol 2005; 1: 18-29.
44. Catledge SA, Fries MD, Vohra YK et al. Nanostructured ceramics for biomedical implants. J Nanosci Nanotechnol 2002; 2: 293-312.
45. Morrison M. Nanotechnology and the implications for the health of the EU citizen. Nanoforum 2003.
46. Lansdown AB. Silver. I: Its antibacterial properties and mechanism of action. J Wound Care 2002; 11: 125-30.
47. Furno F, Morley KS, Wong B et al. Silver nanoparticles and polymeric medical devices: a new approach to prevention of infection? J Antimicrob Chemother 2004; 54: 1019-24.
48. Samuel U, Guggenbichler JP. Prevention of catheter-related infections: the potential of a new nano-silver impregnated catheter. Int J Antimicrob Agents 2004; 23 Suppl 1:S75-8.
49. Alt V, Bechert T, Steinrucke P et al. [Nanoparticulate silver. A new antimicrobial substance for bone cement]. Orthopade 2004; 33: 885-92.
50. Alt V, Bechert T, Steinrucke P et al. An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement. Biomaterials 2004; 25: 4383-91.
51. Dowsett C. An overview of Acticoat dressing in wound management. Br J Nurs 2003; 12: S44-S49.
52. Lansdown AB. A guide to the properties and uses of silver dressings in wound care. Prof Nurse 2005; 20: 41-3.
53. Borm PJ. Particle toxicology: from coal mining to nanotechnology. Inhal Toxicol 2002; 14: 311-24.
54. deJong, W. H., Roszek, B., and Geertsma, R. E. Nanotechnology in medical applications: possible risks for human health. Bilthoven: RIVM 2005.
55. Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 2005; 113: 823-39.
56. Borm PJ, Kreyling W. Toxicological hazards of inhaled nanoparticles--potential implications for drug delivery. J Nanosci Nanotechnol 2004; 4: 521-31.
57. Hoet PH, Bruske-Hohlfeld I, Salata OV. Nanoparticles - known and unknown health risks. J Nanobiotechnology 2004; 2: 12.
58. Reijnders L. Cleaner nanotechnology and hazard reduction of manufactured nanoparticles. J Cleaner Production 2006; 14: 124-33.
59. Nel A, Xia T, Madler L et al. Toxic potential of materials at the nanolevel. Science 2006; 311: 622-7.
60. Dockery DW, Pope CA, Xu X et al. An association between air pollution and mortality in six US cities. N Engl J Med 1993; 329: 1753-9.
61. Hoek G, Brunekreef B, Goldbohm S et al. Association between mortality and indicators of traffic-related air pollution in the Netherlands: a cohort study. Lancet 2002; 360: 1203-9. 8
62. Allen TM, Cullis PR. Drug delivery systems: entering the mainstream. Science 2004; 303: 1818-22. 9