nanoparticle engineering for cancer imaging and therapymotieim1/papers/%ee%e0%ee%f8%e9... ·...
TRANSCRIPT
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Nanoparticle Engineering for Cancer Imaging and Therapy
Jiang He, PhD
Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging,
University of California, San Francisco
Department of Radiology andBiomedical Imaging
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Conclusion:
Introduction:Nanotechnology and Cancer Imaging/Therapy
Advances in Nanoparticle Engineering:Novel Engineering/Design of Nanoparticles:• Self-destructive nanoparticle
Novel targeting strategies:• Rapid internalization of targeting ligand
OUTLINE
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Physical SIZE of Nano
Courtesy of the LBL, DOE
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Biological Relevant Entities Size (nM)Hydrogen atom 0.1Amino acids 0.8DNA a-helix (width) 2Globular protein 4Cell membrane 10Liposomes 50-200Lysosomes 200-500Red blood cells 9000Kupffer cells (liver) 15,000-20,000Lymphatic microvells 100,000
Relative sizes of Bio-entities in nanometer scale
•Small size: sub-cellular level•Function Assembly: multiple function modification•High surface-volume ratio: high payload•Stable assembly: carrier/shelter for drug delivery
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General construct of nanoparticle for molecular imaging and therapy
Ferrari et al, Nature Review Cancer, 2005, 5, 161
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In vivo Fate of of Nanoparticles
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Challenges of Nanoparticles for Cancer Imaging and Therapy
Toxicity
Targeting/Delivery
Degradable/biocompatible
Internalizing targeting
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Self-destructive Nanoparticle for in vivo application
Park JH, et al., NATURE MATERIALS. PUBLISHED ONLINE: 22 FEBRUARY 2009
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SEM image Photoluminescence emissionand absorbance spectra
CytotoxicityRelease profile
structure and in vivo degradation process
Characterization of LPSiNPs(Luminescent Porous Silicon Nanoparticle)
PBS solution at 37 C
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Biocompatibility and biodegradability of LPSiNPs.
In vivo biodistribution and biodegradation of LPSiNPsIn vitro cytotoxicity of LPSiNP towards HeLa cells (48h)
HistologyChange in body mass of mice injected with LPSiNPs
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In vitro, in vivo and ex vivo fluorescence imaging with LPSiNPs
D-LPSiNP: dextran coated-LPSiNP
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Fluorescence images of tumours containing D-LPSiNPs
A strong signal from D-LPSiNPs is observed in the tumor, indicating significant passive accumulation in the tumour by the enhanced permeability and retention (EPR) effect.
(Red and blue indicate D-LPSiNPs and cell nuclei)
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Nanoparticle-conjugated tumor-specific ligands/antibodies bind to surface receptors, triggering nanoparticle internalization through an endosome-dependent mechanism.
Internalization of Nanoparticles viaReceptor-mediated Endocytosis
Wang X., et al., CA Cancer J Clin 2008;58:97–110
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Detecting cancer early with targeted nano-probes for vascular signatures
NIH Nanotechnology Alliance Platform Grant (Ongoing)
Internalizing Peptide
!!! Confidential: Some of the data are not published yet!
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iRGD1 phage extensively internalize into tumor cells in vitro.
A: T7 phage displayingiRGD1 peptides, RGD-4C, orCG7C (control phage) wereincubated with various tumorcell lines at 37°C for 30 min.
B: T7 phage displaying iRGD1 peptides (main panel) or CG7C control peptides (right upper window) were incubated with PPC1 cells for 2 hours at 37°C.
Anti-T7 antibody (green);
plasma membrane marker (red);
DAPI for the nuclei (blue),
DATA deleted!!
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Inhibition of iRGD1 phage binding and internalization to tumor cells by series of anti-integrin antibodies.
Phage on cell surface
Pretreatment: 30min at 4°C
iRGD1 phage incubation:1 hour at 4°C
Phage internalized
Pretreatment: 30min at 37°C
iRGD1 phage incubation:1 hour at 37°C
A function-blocking antibody against the αV integrin subunitefficiently inhibits both the binding and internalization of the iRGD1 phage.
DATA deleted!!
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iRGD1 peptide (FAM-iRGD) internalizes into tumor cells in vitro
Protocol: Incubation for 2 hours at 37°CStaining with a plasma membrane marker (red) and nuclear stain DAPI (blue)Imaging under a confocal microscope
DATA deleted!!
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iRGD1 nanoworms labeled with Fluorescein home and spread into pancreatic tumors (confocal microscopy)
PDAC Rip-Tag2
The green signals are detected not only in the blood vessel walls (A and B; asterisks), but also inside the tumor cells (A and B; arrow heads).
The red (A) and blue (A and B) colors represent CD31 and DAPI staining respectively
DATA deleted!!
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iRGD1 micelles home to PDAC tumors.
white light image fluorescent light images
Protocol:iRGD1 micelles were labeled with fluorescein,3 hrs post-injection of PDAC mice. Perfused with 1% BSA/PBS Organs of interest were imaged.
DATA DELETED!!!
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Novel internalizing human antibody for cancer imaging and therapy
NIH Nanotechnology R01 Grant (Ongoing)
Note: Some of the data that are not published yet are deleted!
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In vitro screening In vivo evaluation
Radiochemistry:Site-specific radiolabeling with 99mTc.
Animal model:Xenograft mouse model with clinical tissue;
Xenograft mouse model with tumor cell line
Small animal Imaging:microSPECT/CT.
Biodistribution/Ex vivo staining:
Tumor cells/Tissues animals Imaging
Strategies for internalizing antibody discovery
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Biodistribution of 99mTc-UA20 in athymic mice with DU-145 subcutaneoustumor xenograft at post-injection of 3 hours.
Tumor uptake in study group was at 4.4%ID/g only lower than that of kidneys (81%ID/g) while liver at 2.7%ID/g. The remaining organ/tissue uptakes were all lower than 1%ID/g.
In control, tumor uptake was only 0.26%ID/g similar to muscle and fat.
Tumor/blood and tumor/muscle ratios were 12:1 and 70:1 as early as 3h post-injection.
DATA deleted!!
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Tumor targeting of 99mTc-UA20 at 1h and 3hs post-injection in nude mice with subcuatouse prostate cancer xenograft at lower back.
The remarkable tumor uptake and contrast (tumor/muscle at 70 at 3 hrs) are credited to the rapid internalization and clearance from normal organs.
DATA deleted!!
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microSPECT/CT image of nude mice with subcuatouse prostate cancer xenograft at lower back receiving 99mTc-UA20 3hs earlier
Coronal View Axial view
DATA deleted!!
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Internalization of scFv UA20-based liposomes into prostate cancer cells (PC3 and DU145) (microscopy and FACS analysis)
DU145
Microscopic examination
Quantification of FACS
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Summary for internalizing antibody
Internalizing antibodies showed accumulation and rapidinternalization into tumor cell.
Internalizing antibodies showed rapid homing to tumor andclearance in normal organs, providing remarkable contrast in vivoand great potential for PET cancer imaging with short half-life isotopelike 18F etc.
Nanoparticles decorated with internalizing antibody retain theinternalizing functions of scFvs, offering intracellular delivery ofimaging reporters as well as chemodrugs and other therapeuticentities such as siRNA and genes for improved imaging and therapy.
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Conclusion
Challenges Technology
Novel Chemical Engineering of nanoparticle
Internalizing targeting ligands to decorate nanoparticles
Toxicity/Biocompatibility
Efficacy/Targeting
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AcknowledgementsCenter for Molecular and Function ImagingJiang He, PhDHenry VanBrocklin, PhDYoungho Seo, PhDElla Jones, PhDDongwei Gao, MD
Department of Anesthesia, SFGHBin Liu, PhD
Lung Biology Center, Department of Medicine, SFGHCourtney Broaddus, MD
Financial Support:National Institute of Health(R01 CA135358 to JH, R01 CA118919 to BL, R01 CA119414 to DH and R01CA95671 to VCB)Mesothelioma Applied Research Foundation (to BL and VCB).American Cancer Society (to JH).Department of Defense (to BL)
Diabete Center, UCSFDouglas Hanahan, PhD
Biomedical Engineering, University of VirginiaKimberly Kelly, PhD
Department of Biopharmaceuticals, UCSFFrancis Szoka, PhD
Burnham Institute for Medical Research, UCSBEkki Ruoslahti, PhD
Radiation Oncology, UCSFLijun Ma, PhD
Benjamin Franc, MD (Left for private practice)Jinjin Feng, MSArun Iyer, PhD (Postdoctor)XiaoLi Lan, PhD/MD (Postdoctor)
Collaborators