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Nanotechnology Applications in Cancer
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ANRV317 BE09 09 ARI 7 June 2007 17 40, INTRODUCTION 258. The Cancer Problem 258, Cancer Nanotechnology 259, Cancer Biomarkers 259. Personalized Oncology 260, NANOPARTICLE PROBES 261. Dual Modality Probes 262, Multifunctional Platforms 263. Annu Rev Biomed Eng 2007 9 257 288 Downloaded from www annualreviews org. MOLECULAR CANCER IMAGING 263, Mapping Sentinel Lymph Nodes and Tumor Angiogenesis 264.
Tumor Targeting and Imaging 265, by University of Washington on 04 28 12 For personal use only. Correlated Optical and X Ray Imaging 265, MOLECULAR CANCER DIAGNOSIS 267. Correlation of Biomarkers with Cancer Behavior 267. EARLY CANCER DETECTION 271, Nanobarcodes 271, Nanowires 271. Carbon Nanotubes 272, TARGETED CANCER THERAPY 272, Passive Targeting 273. Active Targeting 274, Nanoparticle Drugs 275, FUTURE DIRECTIONS 278.
INTRODUCTION, The Cancer Problem, Human cancer is a complex disease caused by genetic instability and accumulation. of multiple molecular alterations 1 2 Current diagnostic and prognostic classi. cations do not re ect the whole clinical heterogeneity of tumors and are insuf. cient to make predictions for successful treatment and patient outcome 3 4 Most. current anticancer agents do not greatly differentiate between cancerous and nor. mal cells leading to systemic toxicity and adverse effects In addition cancer is of. ten diagnosed and treated too late when the cancer cells have already invaded and. metastasized into other parts of the body At the time of clinical presentation for. example more than 60 of patients with breast lung colon prostate and ovar. ian cancer have hidden or overt metastatic colonies 5 At this stage therapeutic. modalities are limited in their effectiveness Due to these problems cancer has over. taken heart disease as the leading cause of death for adults in the United States. United States Cancer Statisics Centers for Disease Control and Prevention CDC. http www cdc gov cancer npcr uscs, 258 Nie et al, ANRV317 BE09 09 ARI 7 June 2007 17 40. Current problems and unmet needs in translational oncology include a advanced. technologies for tumor imaging and early detection b new methods for accurate. diagnosis and prognosis c strategies to overcome the toxicity and adverse side ef. Prognosis prediction of, fects of chemotherapy drugs and d basic discovery in cancer biology leading to new how a patient s disease will. knowledge for treating aggressive and lethal cancer phenotypes such as bone metas progress and its clinical. tasis Advances in these areas will form the major cornerstones for a future medical outcome. practice of personalized oncology in which cancer detection diagnosis and therapy Superparamagnetic often. are tailored to each individual s tumor molecular pro le and also for predictive on associated with. cology in which genetic molecular markers are used to predict disease development single domain iron. nanoparticles that become, progression and clinical outcomes. ferromagnetic in the, Annu Rev Biomed Eng 2007 9 257 288 Downloaded from www annualreviews org.
presence of an external, magnetic eld but lose, Cancer Nanotechnology magnetization when the. Cancer nanotechnology is emerging as a new eld of interdisciplinary research cut magnetic eld is removed. by University of Washington on 04 28 12 For personal use only. ting across the disciplines of biology chemistry engineering and medicine and is Biomarkers any. expected to lead to major advances in cancer detection diagnosis and treatment 6 biomolecules or analytical. features associated with a, 7 The basic rationale is that metal semiconductor and polymeric particles have. disease or its behavior, novel optical electronic magnetic and structural properties that are often not avail. able from individual molecules or bulk solids 8 10 Recent research has developed. functional nanoparticles that are covalently linked to biological molecules such as pep. tides proteins nucleic acids or small molecule ligands 11 18 Medical applications. have also appeared such as the use of superparamagnetic iron oxide nanoparticles as a. contrast agent for lymph node prostate cancer detection 19 and the use of polymeric. nanoparticles for targeted gene delivery to tumor vasculatures 20 New technologies. using metal and semiconductor nanoparticles are also under intense development for. molecular pro ling studies and multiplexed biological assays 21 25. Cancer Biomarkers, Biomolecular markers or biomarkers include altered or mutant genes RNAs pro. teins lipids carbohydrates and small metabolite molecules and their altered ex. pressions that are correlated with a biological behavior or a clinical outcome Most. cancer biomarkers are discovered by molecular pro ling studies based on an asso. ciation or correlation between a molecular signature and cancer behavior In the. cases of both breast and prostate cancer a deadly step is the appearance of so called. lethal phenotypes such as bone metastatic hormone independent and radiation. and chemotherapy resistant phenotypes It has been hypothesized that each of these. aggressive behaviors or phenotypes could be understood and predicted by a de ning. set of biomarkers By critically de ning the interrelationships among these biomark. ers it could be possible to diagnose and prognosticate cancer based on a patient s. molecular pro le leading to personalized and predictive medicine That is a unique. molecular pro le can be used to predict the tumor s invasive and metastatic potential. its ability to survive and grow under androgen deprived and hypoxia and metabolic. stress conditions and the potential of certain cancer cells to evade host immune. surveillance, www annualreviews org Nanotechnology Applications in Cancer 259.
ANRV317 BE09 09 ARI 7 June 2007 17 40, One of the rst molecular pro ling studies was reported by Golub et al 26 who. showed that gene expression patterns could classify tumors yielding new insights into. tumor pathology such as stage grade clinical course and response to treatment Gene. expression studies of cell lines further revealed that the molecular signature of each. tumor is a result of the combined tumoral stromal and in ammatory factors of the. original heterogeneous tumor 27 The rst clinical correlation of gene expression. patterns with clinical outcome was reported for diffuse large B cell lymphoma 28. a clinically heterogeneous disease Whereas most 60 of the patients succumbed. to the disease the remainder responded well to therapy and had prolonged survival. This variability in disease progression was correlated with a distinct pattern of gene. expression The concept of a speci c molecular portrait for each patient s tumor was. Annu Rev Biomed Eng 2007 9 257 288 Downloaded from www annualreviews org. later validated by Perou et al 29 and Bittner et al 30. Most recent work on cancer molecular pro ling by Rubin Chinnaiyan and their. coworkers has combined cDNA microarrays with tissue microarrays for biomarker. by University of Washington on 04 28 12 For personal use only. discovery and immunohistochemical validation 31 38 For prostate cancer a. number of gene and protein biomarkers have been identi ed including p504S. methylacyl coenzyme A racemase or AMAC an enzyme involved in oxidation of. fatty acids hepsin HPN a transmembrane serine protease Pim 1 protease KLK4. prostein EHZ 2 and STEAP 39 40 These markers appear to be excellent indica. tors of aggressive cancer behavior such as metastasis and androgen independence. Personalized Oncology, For applications in individualized therapy biomarkers enable the characterization. of patient populations and quanti cation of the extent to which new drugs reach. their intended targets 41 42 One example is the drug trastuzumab Herceptin. Genentech Roche a monoclonal antibody designed to target ampli ed and overex. pressed ERBB2 also known as HER2 tyrosine kinase receptor found in 25 30. of breast cancers FDA approval of trastuzumab was predicated on the availability. of a test to detect ERBB2 overexpression Both an immunohistochemistry assay for. the expressed protein HercepTest Dako and a nucleic acid based uorescence in. situ hybridization FISH test PathVysion Abbott have been approved as in vitro. diagnostics to guide trastuzumab treatment decisions In another example the clini. cal response of lung cancer patients to the epidermal growth factor receptor EGFR. tyrosine kinase inhibitor ge tinib IressaTM AstraZeneca is associated with a small. number of genetic mutations 43 44 Thus a molecular diagnostic test could be used. to identify patients that are most likely to respond to this drug. Despite these advances critical studies that can clearly link biomarkers with can. cer behavior remain a signi cant challenge One dif culty is that most cancer tumors. especially prostate and breast cancer are highly heterogeneous containing a mix. ture of benign cancerous and stromal cells Current technologies for molecular. pro ling including RT PCR gene chips protein chips two dimensional 2 D gel. electrophoresis and biomolecular mass spectrometry e g MALDI MS ES MS. and SELDI MS are not designed to handle this type of heterogeneous sample 45. 46 Furthermore a limitation shared by all these technologies is that they require. 260 Nie et al, ANRV317 BE09 09 ARI 7 June 2007 17 40. Nanotechnology Schematic diagram showing, nanotechnology. applications in cancer, through molecular tumor, imaging early detection.
molecular diagnosis, targeted therapy and cancer, bioinformatics. Therapeutics, Diagnostics, Informatics, Annu Rev Biomed Eng 2007 9 257 288 Downloaded from www annualreviews org. by University of Washington on 04 28 12 For personal use only. destructive preparation of cells or tissue specimens into a homogeneous solution. leading to a loss of valuable 3 D cellular and tissue morphological information as. sociated with the original tumor The development of nanotechnology especially. bioconjugated nanoparticles provides an essential link by which biomarkers could. be functionally correlated with cancer behavior Figure 1 illustrates nanotechnology. applications in cancer through molecular imaging diagnosis early detection tar. geted therapy and cancer bioinformatics In the following we describe the design. and development of nanoparticle probes and their applications in cancer. NANOPARTICLE PROBES, A prototype nanoparticle is semiconductor quantum dots QDs tiny light emitting. particles on the nanometer scale that are emerging as a new class of uorescent probes. for in vivo biomolecular and cellular imaging 11 18 Figure 2 In comparison with. organic dyes and uorescent proteins QDs have unique optical and electronic prop. erties QDs have molar extinction coef cients that are 10 50 times larger than that of. organic dyes which make them much brighter in photon limited in vivo conditions Quantum dots QDs. tiny particles on the, Further QD emission wavelengths are size tunable For example CdSe Zns QDs of. nanometer scale with, approximately 2 nm in diameter produce a blue emission whereas QDs approximately quantum con nement.
7 nm in diameter emit red light 47 In recent work researchers have extended the properties such as. emission wavelength into the near infrared 650 nm to 950 nm to take advantage of size tunable light emission. the improved tissue penetration depth and reduced background uorescence at these most often made of. semiconductors such as, wavelengths 48 A key property for in vivo imaging is the unusual QD Stokes shift. which can be as large as 300 400 nm depending on the wavelength of the excitation. www annualreviews org Nanotechnology Applications in Cancer 261. ANRV317 BE09 09, Annu Rev Biomed Eng 2007 9 257 288 Downloaded from www annualreviews org ARI 7 June 2007 17 40. Semiconductor quantum dots with quantum con nement and size tunable optical properties. This image shows ten distinguishable emission colors of ZnS capped CdSe quantum dots. by University of Washington on 04 28 12 For personal use only. excited with a near UV lamp From left to right blue to red the emission maxima are located. at 443 473 481 500 518 543 565 587 610 and 655 nm, light 49 In conjunction with broadband absorption and narrow emission peaks of. QDs this property allows multiplexed imaging applications in which one light source. is used to simultaneously excite multicolor QDs without the need for complicated. instrumentation Another important feature is the long term photostability of QD. imaging probes which opens the possibility of investigating the dynamics of cellular. processes over time such as continuously tracking cell migration differentiation and. metastasis These properties have made QDs a topic of intensive interest in cancer. biology molecular imaging and molecular pro ling, Dual Modality Probes. Optical imaging is highly sensitive but its applications in vivo and in human are ham. pered by a limited penetration depth in tissue and the lack of anatomic resolution and. spatial information Although near infrared wavelengths can be used to improve the. penetration depth and 3 D uorescence tomography can be used to provide spatial. information 50 51 other imaging modalities such as magnetic resonance imaging. MRI are much better for tomography and 3 D imaging Thus there has been con. siderable interest in developing dual modality contrast agents for combin. Figure 1 illustrates nanotechnology applications in cancer through molecular imaging diagnosis early detection tar geted therapy and cancer bioinformatics In the following we describe the design and development of nanoparticle probes and their applications in cancer NANOPARTICLE PROBES

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