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POTENTIAL APPLICATION OF NANOPARTICLES IN MEDICINE: Cancer Diagnosis and Therapy Diego A. Gomez-Gualdron Midterm Project Nanotechnology; CHEN 689-601 Texas.

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Presentation on theme: "POTENTIAL APPLICATION OF NANOPARTICLES IN MEDICINE: Cancer Diagnosis and Therapy Diego A. Gomez-Gualdron Midterm Project Nanotechnology; CHEN 689-601 Texas."— Presentation transcript:

1 POTENTIAL APPLICATION OF NANOPARTICLES IN MEDICINE: Cancer Diagnosis and Therapy Diego A. Gomez-Gualdron Midterm Project Nanotechnology; CHEN Texas A&M University March 11 th, 2010

2 OUTLINE SECTION I Nanomedicine overview SECTION II Nanotechnology potential in oncology SECTION III Promising works SECTION IV Assessment

3 SECTION I Nanomedicine Review

4 Nanomedicine Premise: Nanometer-sized particles have optical, magnetic, chemical and structural properties that set them apart from bulk solids, with potential applications in medicine. Potential applications DRUG DELIVERYMEDICAL IMAGING DIAGNOSIS & SENSINGTHERAPY

5 Interesting facts about nanomedicine A. Interest in the area has grown exponentiallyB. Drug delivery is the most productive area C. Drug delivery is the most established technology in the nanomedicine market Nature Biotechnology 2006, Vol. 4, pp

6 Drug Delivery )A nanoparticle carries the pharmaceutical agent inside its core, while its shell is functionalized with a binding agent 2)Through the binding agent, the targeted nanoparticle recognizes the target cell. The functionalized nanoparticle shell interacts with the cell membrane 3)The nanoparticle is ingested inside the cell, and interacts with the biomolecules inside the cell 4)The nanoparticle particles breaks, and the pharmaceutical agent is released Source: Comprehensive Cancer Center Ohio University A. Because of their small sizes, nanoparticles are taken by cells where large particles would be excluded or cleared from the body

7 A Drug Delivery Nanoparticle A. Nanoparticles for drug delivery can be metal-, polymer-, or lipid-based. Below (left) an example of the latter, containing SiRNA encapsulated, and functionalized with an specific antibody. SiRNA can control often lethal inflammatory body responses, as shown in the microscopic images below (right) Science 2008, Vol. 316, pp antibody lipid SiRNA Healthy tissue Sick tissue treated with non-targeted nanoparticles Sick tissue treated with targeted nanoparticles B. C.

8 Medical Imaging A. Optical properties of nanoparticles depend greatly on its structure. Particularly, the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter. C. The quantum dots (QD) can be injected to a subject, and then be detected by exciting them to emit light Source: Department of immunology, University of Toronto Solutions of CdSe QDs of different diameter CdSe nanoparticle (QD) structure Source: Laurence Livermore Laboratories Imaging of QDs targeted on cellular structures Nano Letters 2008., Vol. 8, pp B.

9 A Quantum Dot Nanoparticle A. The quantum dot itself (the semiconductor nanoparticle) is toxic. Therefore some typical modifications has to be made for it to become biocompatible. 1)The core consist of the semiconductor material that emits lights 2)The shell consist of an insulator material that protects the light emitting properties of the QD in the upcoming functionalization 3)The shell is functionalized with a biocompatible material such as PEG or a lipid layer 4)Additional functionalization can be done with several purposes (e.g. embed a drug for drug delivery, or assemble an antibody to become the QD target-specific Source: The scientist (2005), Vol. 19, p. 35

10 Targeting QDs for intracellular imaging Ligand coated QDNC QD release Ingestion Decomposition labeling Nano Letters 2008., Vol. 8, pp A. Using a drug-delivery-like mechanism, a targeted lipid-based nanoparticle (TNP) encapsulating QDs specifically attacks a cell having the receptors that pair with its ligand coating. Upon ingestion and destruction of the TNP, the QDs are set free and accumulate on intracellular structures C. QD (red)intracellular uptake is enhanced when using the QDNC instead of the free QDs B. D. Imaging of nucleus (blue) and cytoplasm (other) after 30 min (left) and 3 hours after uptake

11 Diagnosis and Sensing A. Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers). Huffman, Nanomedicine and Nanobiotechnology, Vol. 1, 1, 2009 D. molecular signature of sick cell of infecting agent (e.g. an antibody) Cell membrane Nanoparticle Coating molecule specifically attracted to the molecular signature C. A nanoparticle can be functionalized in such a way that specifically targets a biomarker. Thus, the detection of the nanoparticle is linked to the detection of the biomarker, and to the diagnosis of a disease B. Each cell type has unique molecular signatures that differentiate healthy and sick tissues. Similarly, an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

12 Nanoparticles in action A. Modifying a ferromagnetic nanoparticle with human immunoglobulin G (IgC), which specifically binds the protein A in the cellular wall of staphylococcus, the bacteria can be detected through a MRI test Accumulation of functionalized ferromagnetic nanoparticles on staphylococcus Negligible accumulation of nanoparticles in absence of functionalization B. Analytical Chemistry 2004, Vol. 76, pp C. Directed accumulation of dangerous bacteria by conjugation with functionalized magnetic nanoparticles National Research Council, Canada

13 A Chemical Nose (Multiplex Detection) A. Determining if a an apple is rotten or not, doing a thorough chemical analysis can be a very frustrating job. Due to the complex chemistry of the membrane, so can it be determining if a cell is sick or healthy. B. As well as our noses response to the overall chemistry of the apple, we can device an experiment that responses to the overall chemistry of the cell using the elements below C.D. Three sets (NP1,NP2,NP3) of functionalized gold nanoparticles A fluorescence reporter polymer PNAS 2009, Vol. 106, pp

14 A Chemical Nose (Multiplex Detection) D. PNAS 2009, Vol. 106, pp E. The polymer fluorescence is turned off while conjugated to the nanoparticle. Due to the interaction with the cell, the polymeric traces detach from the nanoparticle an emit a fluorescence signal NP1 NP2 NP3 F. The responses from a NP1, NP2 and NP3 are different due to the different functional group. Thus, the combination of the three signals is characteristic of each cell polymer detached polymer G. Cell membrane Fluorescence change Metastatic cell Normal cellCancerous cell

15 Therapy A. Nanometer-sized particles are particularly responsive to electromagnetic and acoustic excitations through a variety of phenomena (e.g. plasmon resonance) that lead to local extreme conditions (e.g. heating). The nanoparticle is able to tolerate this condition, but no so the biological material nearby B. Intramuscular injections of colloidal gold, a suspension of gold nanoparticles, has been used for decades to alleviate pain linked to rheumatoid arthritis. The mechanism is still unknown Colloidal gold Source: Source: John Hopkins Center C. An infrared beam illuminates two mice specimens. The local temperature increases for the mouse that received and injection of gold nanorods. Adv. Mater. 2009, 21, 3175–3180

16 Gold Nanoparticles vs. Alzheimer A. Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein. D. Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis) Functionalized nanoparticle Source: Chemical structure of Aβ-protein Source: C. B. Alzheimers brain Healthy brain Source: Berkeley Lab

17 Gold Nanoparticles vs. Alzheimer A. The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein. The microwaves of certain frequency are irradiated on the sample. Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate Nanoletters 2006, Vol. 6, pp Before irradiationAfter irradiation

18 SECTION II Nanotechnology potential in oncology

19 Cancer Nanotechnology A. It is an interdisciplinary area merging science, engineering and medicine with the sole purpose of provide humanity new tools to fight cancer B.C. Annu. Rev. Biomed. Eng Vol. 9, pp. 257–88 Cancer nanotechnology, as a particular area of nanomedicine, is based upon the same premise that nanoparticles display unique properties potentially useful in medical (oncological) applications. Nanoparticles in the size range of 5-100nm have enough surface area to be properly functionalized to bind specific targets, with a variety of ulterior purposes PREMISE

20 Cancer Facts B. Lung cancer is the overwhelming lead cause of cancer-related deaths. BEWARE SMOKERS!!!! A. The second main cause of death in the US, and certainly the diseases that lower the life quality of the patient the most

21 Motivation A. The only factor that really correlates to the patient survival is early cancer detection B. Chemotherapy and radiotherapy kill healthy and sick cells indiscriminately C. Cancer resurgence after surgery occurs due to failure to recognize and remove all cancerous colonies DIAGNOSIS THERAPY IMAGING

22 Cancer: Too complex to handle? A. If you are an engineer, you can think of cancer as a living organism finally succumbing to entropy. Therefore, cancer is not one disease but million of diseases characterized by the disordered an uncontrolled growth of cells B. entropy C. There are a myriad of metabolic/biological events that can unleash the growth of cancer cells. We must completely understand all the complex biochemistry of cancer to improve both diagnosis and treatment D. The key is full biomarker characterization of a different types of cancer

23 Biomarker Research Status TODAY PSA biomarkers Hmmm!! I see you have abnormal PSA levels. You might have some problems in your prostate. We must check for cancer Oh!! You have abnormal PSA levels. Also, your levels of BM1,BM2,BM3 are off, and BM4 levels are subnormal. You are starting to develop prostate cancer of the A phenotype. But dont worry your BM5 is fine, so metastasis hasnt occurred yet. Lets start treatment PSA ? ? ?? BM1 BM2 BM3 BM4 BM5 THE FUTURE

24 Nanoprobes: The usual suspects Quantum DotsGold Nanoparticles Liposomes Polymeric Nanoparticles functionalized to achieve biocompatibility and cell targeting Nanotubes Nanorods

25 QD Localization of a Tumor A. It is possible to overlap X-ray images with infrared images to localize a tumor. The X-ray images give the images an anatomical context, while the infrared images detect the QDs emission, which correlates to the tumor location (see B.) Annu. Rev. Biomed. Eng Vol. 9, pp. 257–288 B. C. 560-QD-Streptadivin targets and images In-vitro breast cancer cells having the IgG factor characteristic of chemotherapy responsive cells Nature Biotechnology Vol. 9, pp

26 Gold Nanoparticle Tumor Detection A. The common strategy to detect the tumor is the functionalization of the nanoparticle with an antibody specific to the tumor antigens, and then detect the nanoparticle by some spectroscopic technique B. Tumor photograph Imaging with gold nanoparticles as contrast agent Nanotechnology Vol. 20,

27 Diagnosis A. It must be multiplexed, i.e. multiple biomarkers must be detected simultaneously B. A specific phenotype of cancer cells has a particular combination of biomarkers on its membrane D. C. Different phenotypes show different aggressiveness on their metastatic behavior tumor Blood vessels Cancer cells metastasis Source:

28 Multiplex Diagnosis Nature Protocols Vol. 2, pp A. Four quantum dots of different diameter (i.e. different color) are respectively functionalized with four different antigens. Allowing for the distinction of two distinct phenotypes Each peak correspond to the emission of a specific QD/antigen The peak intensity correlates to the concentration of a specific QD Aggressive cancer cells Mild cancer cells As a result cancer cells of different phenotype are colored differently

29 Diagnosis using Nanothermometers A. Cancer cells appears to have a more elevated temperature than normal cells. Therefore, a local temperature mapping can be used to determine the spread of a tumor B. A gold nanoparticle is functionalized with a PEG coating, which itself is assembled to a layer of smaller QDs. The emission properties of the nanoparticle change with temperature due to the stretching/contraction of the PEG C. Correlation between emission and temperature D. Thermal image of a healthy and cancerous breast healthysick Source: 9th European Congress of Thermology, Krakow, Poland Angew. Chem. Int. Ed. 2005, Vol. 44, 7439 –7442

30 Therapy A. There is a search dual-mode nanoparticle that can detect a tumor (imaging)and destroy it (therapy) B. There is two action modes for therapeutical nanoparticles Passive Targeting Active Targeting Based on nanoparticle functionalization for specific targeting of cancerous cells Based on retention effect of particle of certain hydrodynamic size in cancerous tissues

31 Taking advantage of retention A. Tumorous tissues suffer of Enhanced Permeability and Retention effect B. Nanoparticles injected in the blood stream do not permeate through healthy tissues C. Blood vessels in the surrounding of tumorous tissues are defective and porous D. Nanoparticles injected in the blood permeate through blood vessels toward tumorous tissues, wherein they accumulate Annu. Rev. Biomed. Eng Vol. 9, pp. 257–88

32 A Targeted Polymer Nanoparticle A. A dual Nanoparticle, the targeting ligand allow it to diagnose if a cell is healthy or sick, and bind specifically to the tumorous cell B. Once inside the cell, the polymeric nanoparticle degrades and the anticancer agent is set free C. An imaging agent can be added as well Imaging agent Annu. Rev. Biomed. Eng Vol. 9, pp. 257–88

33 A commercial Anticancer Nanoparticle A. The nanoparticle drug ABRAXANE is one of the fruits of nanomedicine applied to cancer therapy. It consist in nanoparticles carrying an agent interfering with the feeding mechanism of cancerous cell. Click on the video to see action mechanism

34 SECTION III Promising work


36 Nanotubes Source: A. Carbon nanotubes have been found to have a very interesting property, they release heat when exposed to radio frequencies B. Chemical properties of nanotubes allow them to be easily functionalized C. For this studies the nanotubes were produced by the CoMoCAT procedure, and functionalized with the polymer Kentera Source: Southwest nanotechnologies CoMoCAT nanoparticles with grown nanotubes

37 Heat Release Tests Nanotube suspension Source:Hamamatsu Nanotechnology Radiowaves Cancer 2007;Vol.110, pp. 2654– mg/L 50mg/L 0mg/L A. Suspensions of nanotubes at different concentrations were remotely irradiated with radio waves, resulting in heating correlated to the concentration of nanotubes in suspension

38 Heat Release Tests Cancer 2007;Vol.110, pp. 2654–2665 A. There is a linear increase of the heating rate with the source power, and a non- linear increase with the nanotube concentration. The irradiation frequencies were previously shown not to cause damage in normal tissues 600W SWCNT RF

39 Cytotoxicity tests A. The following human cells were grown with 24h contact with 500mg/L nanotube solutions: Hepatocellular carcinoma Hep3B Hepatocellular carcinoma HepG2 Panc-1 pancreatic adenocarsinoma B. The results shown correspond to fluorescence cytometric results, the segments represent stages of cellular growth, which appear unaltered despite the presence of the nanotubes. NO CITOTOXICITY Cancer 2007;Vol.110, pp. 2654–2665

40 Intracellular Collection of Nanotubes nanotubes A. Despite the lack of cytotoxicity, bright field images clearly shows the accumulation of nanotube structure inside the cellular structure Culture without SWCNTs Culture with SWCNTs B. Also, the optical response of the cultures to other imaging techniques is shown by this IR image Cancer 2007;Vol.110, pp. 2654–2665

41 Cytotoxic induced effect A. Now, the cytotoxic effect of the SWCNTs during the irradiation of with radio waves on carcinoma cultures is tested Hepatocellular carcinoma Hep3B No Irradiation 2 min Irradiation B. The counts of cells in phases M1,M2, and M3 is negligible indicating the mortality rate of the cultured cells after irradiation Control Cancer 2007;Vol.110, pp. 2654–2665

42 In vitro induced cytotoxicity A.The cytotoxicity correlates with the nanotube concentration B.Some carcinomas are more susceptible to death (HepG2) after radiation C.Remarkably, the control (the polymer alone) showed some degree of cytotoxicity D. In vitro test successful!!! HepG2 Hep3B Panc-1 Cancer 2007;Vol.110, pp. 2654–2665

43 In Vivo cytotoxicity test A.In the top panel, the photomicrograph of a hepatic tumor on a rabbit. The black stains correspond to nanotube accumulation on the tumorous cell B.The purple staining is characteristic of live tissues C.In the bottom panel, the photomicrograph of the same hepatic tumor after 2 min. radio frequency waves irradiation. D.The brownish color is indicative of necrosis (tissue death) Cancer 2007;Vol.110, pp. 2654–2665


45 Raman Scattering Incoming light Outcoming light hv 1 hv 2 hv 1 A weak effect hv 2 hv 1 Vibrational energy Source: Earth System Research Laboratory A. Raman Scattering occurs when incoming light hits a sample. Most of the light scatters elastically (same wavelength as the incoming light), but a small fraction scatters inelastically (changes wavelength/color)

46 Raman Enhancement A. When a molecule is coupled with a metallic surface its Raman signal is enhanced n orders of magnitude B. The localization of the different peaks constitute the fingerprint of a molecule. For instance, malachite green isothiocyanite, a raman reporter. Microfluid Nanofluid 2009;Vol.6, pp. 285–297

47 Design Considerations A. Raman Reporter (malachite green) with a characteristic Raman signal B. A 60nm gold nanoparticle that enhances the reporter Raman signal 14 orders of magnitude C. A PEG polymer to coadsorb on the gold nanoparticle (together with the reporter) and improves biomobility of the nanoparticle D. A Hetero-PEG polymer to coadsorb with the PEG and the reporter, and easily functionalized E. A ScFv EGFR antibody functionalized on the hetero-PEG to become the nanoparticle target specific

48 Synthesizing the nanoparticle Colloidal gold solution Raman Reporter solution mixing Heterofunctional PEG solution mixing PEG solution mixing ScFv EGFR antibody solution mixing Resulting nanoparticle Nature Biotechnology 2008;Vol.26 pp. 83–90

49 Optical Characterization A. Gold nanoparticles and QDs both emit light after excitation with near infrared light, however, the gold nanoparticle SERS signal is much sharper than the QD fluorescence signal B. The contrast of SERS gold nanoparticles is much better than that of QDs Gold QD Nature Biotechnology 2008;Vol.26 pp. 83–90

50 In Vitro Test A. Targeting mechanism: The ScFv EFGR antibody of the nanoparticle bind to the EFG antigen of the cancer cell B. No response C. Only when the cancer cell had the antigen corresponding to the nanoparticle antibody there was response, which can be compared to the signal of the pure reporter Nature Biotechnology 2008;Vol.26 pp. 83–90

51 Technique Penetration In vivo B. The skin spectrum has to be magnified 210-fold to be distinguishable C. After subcutaneous injection, the Raman signal fo the reporter can be collected and is ~50- fold stronger than that of the skin D. After deep injection the Raman signal is only ~10- fold stronger than that of the skin A. The nanoparticle solution is injected to a mouse and after 4h… E. It is concluded that the technique penetration is about 2cm… Nature Biotechnology 2008;Vol.26 pp. 83–90

52 In Vivo Tumor Detection A.A sick mouse was injected with the targeted nanoparticle solution B.The illumination of the liver produced a weak Raman signal C.The illumination of the tumor immediately produces a strong Raman signal, with the signature characteristic of the reporter…the tumor has been detected!!! Nature Biotechnology 2008;Vol.26 pp. 83–90

53 SECTION IV Assesment

54 What have we learned? Nanoparticles have very special properties that make them attractive for nanomedicine Nanoparticles can be functionalized with antibodies to target their binding toward specific cells Nanoparticles can be used in diagnosis through the detection of biomarkers

55 What have we learned? Nanoparticles can respond to external radiation and release heat, killing cells around them Nanoparticles can be made of lipids or polymers than decompose once a target is reached and deliver a pharmaceutical agent Quantum dots are special nanoparticles that emit light of different colors according to its diameter, and can be used for complex diagnosis

56 What have we learned? PEG is the most used polymer to coat nanoparticles due to the biocompatibility and biomobility that confers to the nanoparticle Targeted nanoparticles offer a light of hope for the fight against cancer An ideal nanoparticle is three-modal: detects, diagnoses and attacks tumorous cells

57 Unsolved issues Long-term toxicity Biomarkers library Success in human trials 3-D spatial resolution Signal penetration

58 Challenges Multiple modality and functional nanoparticles Fight against the tendency of nanoparticles to be adsorbed by reticuloendothelial system Avoid aggregation of nanoparticles for in vivo viability Improve retention times of the nanoparticles inside the body to allow the therapeutic effect Substitute potentially toxic elements

59 Challenges Compromise between coating and hydrodynamic radius Eliminate the inflammatory and immune response triggered by some polymer coatings Avoid undesired degradation exposing toxic elements (QD) or untimely delivering cargo Increase contrast for human medical imaging (tissues are naturally fluorescent)

60 Challenges Real-time monitoring of drug distribution, action mechanism and patients response Fast detection of biomarkers at lower limits Understanding the mechanism of cancer Diagnosis leading to personalized treatments Detection of deep tumors Selective targeting in extremely heterogeneous tissues.

61 Thanks!

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