SRINIVAS SRIDHARNANOMEDICINE SCIENCE AND TECHNOLOGY CENTERNANOMEDICINE SCIENCE AND TECHNOLOGY CENTER

ELECTRONIC MATERIALS RESEARCH INSTITUTE DEPARTMENT OF PHYSICS, NORTHEASTERN UNIVERSITY,RADIATION ONCOLOGY , HARVARD MEDICAL SCHOOL

www.igert.neu.edu

Director : Srinivas Sridhar, Ph.D.CAS Distinguished Professor of PhysicsDirector : Srinivas Sridhar, Ph.D.CAS Distinguished Professor of Physics

sagar.physics.neu.eduwww igert neu edu

Nanotechnology for Radiation OncologyNanotechnology for Radiation Oncology Magnetic Theranostic NanoplatformsMagnetic Theranostic Nanoplatforms

Visiting Professor of Radiation Oncology, Harvard Medical SchoolVisiting Professor of Radiation Oncology, Harvard Medical School

Funded by NIH, NSF, Hospitals

www.igert.neu.edu

With Harvard Medical School• Smart Implants for BIS‐IGRT• Gold Nanoparticles for Radiotherapy• Green Quantum Dots for Xray Photodynamic 

With Harvard Medical School• Smart Implants for BIS‐IGRT• Gold Nanoparticles for Radiotherapy• Green Quantum Dots for Xray Photodynamic 

Magnetic Theranostic Nanoplatforms• MR Contrast Enhancement• Magnetic Targeting• Magnetic Hyperthermia

Magnetic Theranostic Nanoplatforms• MR Contrast Enhancement• Magnetic Targeting• Magnetic Hyperthermia

TherapyTherapy

Multi‐modal Imaging Platforms• MR, SPECT, CT, PET• Nanotechnology in the Operating Room of the

Multi‐modal Imaging Platforms• MR, SPECT, CT, PET• Nanotechnology in the Operating Room of the

Dental and Orthopedic NanomedicineWith Harvard School of Dental Medicine•Smart Implants for Bone Regeneration •Slow release agents for cements and

Dental and Orthopedic NanomedicineWith Harvard School of Dental Medicine•Smart Implants for Bone Regeneration •Slow release agents for cements and• Nanotechnology in the Operating Room of the 

Future• Nanotechnology in the Operating Room of the Future

•Slow release agents for cements and membranes•Slow release agents for cements and membranes

Nanoparticles in k l

MR Imaging of Theranostic Magnetic

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skin using multi‐modal imaging

Theranostic Magnetic Nanoiposomes

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From nano to micro

NNATUR

DNA base DNA turn Protein Virus CellsBacteria

RAL

1nm 10nm 100nm m0.1nm m

Metal MIcelleNanoassembly Liposome

DNA t h

SYNT

16nm4nm

DNA nanotechTHETI

www.igert.neu.edu

IC

Designing Utili k l d fDesigning Nano: The 

computation revolution

• Utilize knowledge of interactions to design nanoelements

e o ut o

Making Nano: The 

nanofabricatio n revolution 

• Top‐down nanolithograpjy• Bottom up Self – assembly

Seeing  Nano: The imaging revolution

• Atomic, Electron Microscopies

• Optical microscopies, d

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quantum dots

NANOMEDICINE A di i di i d th

NANOMEDICINE

A new paradigm in diagnosis and therapy

NANOTECHNOLOGY:NANOMATERIALS, NANOFABRICATION

GENOMICS, PROTEOMICS, MOLECULAR BASIS OF 

DISEASE

Early  Early Detection

NANOFABRICATION DISEASE

Diagnostics!

Targeted

yTargeted delivery of multiple therapies

Targeted DeliveryReal‐time efficacy assessments

Symptomatic management

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ARTISTS CONCEPTIONS OF AARTISTS CONCEPTIONS OF A FANTASTIC FUTURE FOR NANOMEDICINE

NANOBOTS TO CLEAN ARTERIES

NANOHUMVEES TO 

Tim Fonseca

DESTROY TUMOR CELLS

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NANOMEDICINE 

NANOTECHNOLOGY APPLIED TO: 

•Cancer•Cardiovascular Diseases•Infectious Diseases•Orthopedics•Genomics•ProteomicsO th l l•Opthalmology

•Neuroscience•

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• ………..

THERANOSTIC NANOPLATFORMS 

EARLY REAL‐TIME MONITORING

TARGETED 

DIAGNOSTICS MONITORINGTHERAPY

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Figure: Opensource Handbook of Nanoscience and Nanotechnology

Cellular andNanoplatforms

•Polymers, lipids, ll lf

Characterization toolkit

•Nanoscale Mi i SEM

Cellular  and Phyiological Mechanisms

•Apoptosis

Medical Challenge

• Image guided drug d liorganelles, self‐

assembling ampiphiles, 

•Magnetic nanoparticles

Microscopies: SEM, TEM, AFM, STM, NSOM, 

• Fluorescence confocal and optical 

•Delivery to nucleus, mitochondria or ribosome

•Endocytosis, Cellular uptake

delivery• Localized energy delivery

•Nano‐enhanced implants

•Metallic nanoparticles 

•Quantum dots•Nanoporous coatings on implants

microscopy• Spectroscopies: Femtosecond optical spectroscopy, XAFS,

• Zeta Potential, 

•Gene Silencing• Organ biodistribution and pharmacokinetics

•Radiation Oncology•Dental and Orthopedic Nanomedicine

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coatings on implants ,SQUID, Coulter

Multi‐functional Nanoplatforms

PEGSpacerAntibody Endosome

BufferingAgent

HIV TATP tid

NANOCOATED IMPLANTS

TAT

d

Peptide

pDNA orOligonucleotide

pH‐SensitiveFluorescentLabel

Radioactive Label

Magnetic core40 nm 30 nm40 nm40 nm40 nm 30 nm30 nm30 nm

SENSING DRUG ELUTINGSENSING, DRUG ELUTING PLATFORMS, SCAFFOLDS AND 

TEMPLATES, NEUROCHIP

Au or Fe‐Au NP1‐100nm

Micelles10‐50nm

Liposomes100‐250 nm

Polymeric NP~ 20nm – 10 m

SENSING TARGETING DELIVERY

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SENSING, TARGETING, DELIVERY

NANOPARTICLE FORMULATIONS OF DRUGS

www.igert.neu.edu

www.igert.neu.edu

Ferrari, Nature 

Table 1. Examples of Nanomaterials in Clinical Use.* Nanomaterial Trade Name Application Target Adverse Effects Manufacturer Current Status

Examples of Nanomedicine in Clinical Use Kim, et. al. NEJM 2010

Nanomaterial Trade Name Application Target Adverse Effects Manufacturer Current Status Metallic Iron oxide Feridex MRI contrast Liver Back pain, vaso- Bayer Schering FDA approved

dilatation Resovist MRI contrast Liver None Bayer Schering FDA approved Combidex MRI contrast Lymph nodes None Advanced Magnetics In phase 3 clin-

ical trials NanoTherm Cancer therapy Various forms Acute urinary MagForce In phase 3 clin-

retention ical trials Gold Verigene In vitro diag- Genetic Not applicable Nanosphere FDA approved

nostics Aurimmune Cancer therapy Various forms Fever CytImmune Sciences In phase 2 clin-

ical trials Nanoshells Auroshell Cancer therapy Head and neck Under investigation Nanospectra In phase 1 clin-

Biosciences ical trials Semiconductor

Quantum dot Qdots, EviTags, Fluorescent con- Tumors, cells, Not applicable Life Technologies, Research

semiconductor trast, in vitro tissues, and eBioscience, use only t l di ti l l Nnanocrystals diagnostics molecular Nanoco,

sensing CrystalPlex, structures Cytodiagnostics

Organic Protein Abraxane Cancer therapy Breast Cytopenia Abraxis Bioscience FDA approved Liposome Doxil/Caelyx Cancer therapy Various forms Hand–foot syndrome, Ortho Biotech FDA approved

stomatitisstomatitis Polymer Oncaspar Cancer therapy Acute lymphoblas- Urticaria, rash Rhône-Poulenc Rorer FDA approved

tic leukemia CALAA-01 Cancer therapy Various forms Mild renal toxicity Calando In phase 2 clin-

ical trials Dendrimer VivaGel Microbicide Cervicovaginal Abdominal pain, Starpharma In phase 2 clin-

dysuria ical trials

www.igert.neu.edu

dysuria ical trials Micelle Genexol-PM Cancer therapy Various forms Peripheral sensory Samyang For phase 4

neuropathy, clinical neutropenia trials

Theranostic Magnetic Nanoplatforms

Other options for targeting:

TARGETING IMAGING  GUIDED  DRUG  & ENERGY DELIVERY

Solid tumor

Apply magnetic field

p g g1 ‐ Direct injection into tumor site2 ‐ Coating NMP with antibodies to target tumorApply magnetic field 

to concentrate particles

Inject NMPs IV,NMP ill i l h h

g

Modulate field to release drug from particles

NMP will circulate through the blood stream

particles

From Biophan

www.igert.neu.edu

SuperParamagnetic Iron Oxide Nanoparticles (SPIONS)

M vs B

Nanoparticles (SPIONS)

0.E+001.E-052.E-053.E-054.E-05

mu/

uL)

hexanemicelle

SPION in hexane at 100 Oe

4.E-05

-4.E-05-3.E-05-2.E-05-1.E-05

-0.5 -0.3 -0.1 0.1 0.3 0.5

M (e

3.E-05

3.E-05

4.E-05

4.E 05u/

ul)

ZFCFC

Blocking

temperature (TB) of

SPIONs

B (T)

5 E-06

1.E-05

2.E-05

2.E-05

M (e

muSuperparamagnetism

No hysteresis in M‐H curves

www.igert.neu.edu

0.E+00

5.E 06

0 50 100 150 200 250 300 350T (K)

Magnetic Nanoplatforms @ NU

TAT

Y

TAT

Y

I id ldIron oxide NPs

Iron oxide‐goldCore‐shell NPs MagNP + polyelectrolye MagNP + antibody

Magnetic NanoLiposome SPION‐micellew. Torchilin

Magnetic NanoLiposomew. Campbell

Magnetic NanoEmulsionw. Amiji

For hydrophilic drugs eg

www.igert.neu.edu

For hydrophobic drugs, e.g. taxanesdrugs, eg. Adriamycin

MULTI‐FUNCTIONAL MAGNETIC NANOPLATFORM: MAGNETIC CATIONIC LIPOSOMEMAGNETIC CATIONIC LIPOSOME

Typical size : 100 – 250 nm

PEG (Circulation)

Fluorescent Label

Magnetic guidanceMRI contrast enhancement

With Robert Campbell

MCLformulated andcharacterized inprevious work.

All components are FDA 

www.igert.neu.edu

= PEG approvedsiRNA

MULTI‐MODAL IN VIVO IMAGING

Apply Magnet

Inject cancer cells

No magnet

Inject MCL IV or IT

Dr. Zhenghong

Lee, Case W

Bi di t ib ti t d SPECT/CT Fl

Western U

niversity

MR imaging Biodistribution study using radio‐tagged MCL

SPECT/CT Fluorescence imaging

www.igert.neu.edu

STABLE FORMULATIONS OF ML, EXTENSIVELY CHARACTERIZEDDPPC:DOTAP:CHOL and DOPE‐PEG5000 Campbell , et. al.p

Vigorous uptake in HMVEC‐D cellsLiposomes

MagnetoLiposomes

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Cationic liposomes preferentially target tumor vessels (dorsal skin fold chamber)vessels (dorsal skin fold chamber)

Same image zoomedSame image zoomed

www.igert.neu.edu

Campbell RB et al., Cancer Research 2002.

Vinblastine‐loaded MCLs improved melanoma treatment: in vivo therapeutic benefit

Mechanism of action:

Campbell , et. al.

Mechanism of action: Vinblastine sulfate- binds to the microtubular proteins of the mitotic spindle, causing mitotic arrest and cell

death

Magnet improvedTreatment outcomeTreatment outcome

www.igert.neu.edu

T1‐scan of healthy animal before and i di l f i j iimmediately after injection.

LiverLiver

Spleen

Melanoma tumor model

www.igert.neu.edu

Melanoma tumor modelMNL ARE LONG CIRCULATING AND CAN BE OBSERVED FOR > 48 HOURS

MAGNETIC LIPOSOMESMAGNETIC GUIDANCE LEADS TO INCREASED ACCUMULATION IN TUMNOR

T2‐scan of intravenous injected mouse with magnet

Magnet placed externally for 1 hour

T2‐scan of intravenous injected mouse with magnet applied for 1hr imaged 24 and 48 hours after injection.

Gultepe, et. al., Nanomedicine (2010)

www.igert.neu.edu

With Robert Campbell, Craig Ferris, Praveen Kulkarni

NANOMAGNETIC THERMAL THERAPY

MAGNETIC NANOPARTICLES ABSORB

THERMAL ABLATION > 45CCOAGULATION, NECROSIS

MAGNETIC NANOPARTICLES ABSORB ENERGY FROM AC MAGNETIC FIELDSRELEASE ENERGY TO TUMOR

NON INVASIVEHYPERTHERMIA  41‐45 CREVERSIBLE, SENSITIZATION

•NON‐INVASIVE •LOCALIZED •CAN BE IMAGED

NANOTECHNOLOGY AND NEWMAGNETIC SOURCES HAVE LED TO A REVIVALNANOTECHNOLOGY, AND NEW MAGNETIC SOURCES, HAVE LED TO A REVIVAL OF INTEREST IN MAGNETIC HYPERTHERMIACLINICAL TRIALS IN EUROPEDARTMOUTH CANCER NANOTECH CENTER ESTABLISHED

www.igert.neu.edu

IN VITRO HEATING USING MAGNETIC  NANOLIPOSOMES

Hyperthermia of Mag C - Liposomes

110 0

20 mg/ml10 mg/ml5 mg/ml2 5 mg/ml

80 0

90.0

100.0

110.0

)

2.5 mg/mlBlank liposomes

50.0

60.0

70.0

80.0

pera

ture

(CRAPID TEMPERATURE 

THERMAL ABLATION

20.0

30.0

40.0

50.0Te

mINCREASE WITH APPLICATION OF AC MAGNETIC FIELD360 kHz, 70 kA drive

HYPERTHERMIA 

10.00 5 10 15 20 25 30

Time (minutes)

www.igert.neu.eduTHERMAL THERAPY FEASIBLE  WITH MNL

SPECT /CT  Single photon emission computed tomography  (SPECT)Xray computed tomography (CT)

M i Li I 111 di l b lMagnetic Liposome  +  In111 radiolabel

IT‐no magnet‐24hrs post‐i j ti

IT‐magnet‐ 24hrs post‐injection

injection

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MULTI‐FUNCTIONAL NANOPLATFORMS FOR THE OPERATING ROOM OF THE FUTURE

MRI

Ch th ti

SPECT/CT

ChemotherapeuticsBiologics, siRNA

SPECT/CT

PET

Radio TherapyHardware Integration – MRI, PET, CT, ..In vivo fiducial marker – not on the table, but in the aorta 

www.igert.neu.edu

,or tumor!Improved image registration for treatment planning

CLINICAL TRANSLATION OF NANOMEDICINES

Valley of death

SAFETY

I go home today They cured me

SAFETY POLICYETHICS

I go home today. They cured meusing this new miracle drug. Itwill be years before it isapproved for humans.

COMMERCIALIZATION

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Nanotechnology for Smart Implants

Reasons for implant failures:  Scar tissue formation; Inflammatory response; Lack of tissue integration; Infection Nanotechnology based 

techniques offer solution

Non‐erodible coatings on TiO2 for cardiovascular stents  and other implantsimplants

Smart implants for Image Guided Radio Therapy

http://www.alberox.com/articles/MAC_MedicalImageFINAL.jpg

www.igert.neu.edu30

Gold TiO2

RADIATION ONCOLOGYRADIATION ONCOLOGYIMAGE‐GUIDED RADIATION THERAPY

5 MeV XraysBRACHYTHERAPY

125In radioactive seeds

Gold Fiducial Markers Radioactive seeds and spacers

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spacers

Nanotechnology for Radiation OncologyBIOLOGICAL IN SITU IMAGE‐GUIDED RADIATION THERAPY (BIS‐IGRT)

Cormack, Makrigiorgos, D’Amico, Nguyen, Kumar, Sridhar

BIOLOGICAL IN SITU IMAGE‐GUIDED RADIATION THERAPY (BIS‐IGRT)

Dual drug release strategies for localized delivery over 8 weeks

Brachytherapy spacers of IGRT coated with radiosensitizer-releasing nanoparticles, lead to a radiosensitized volume resulting in increased efficacy of radiation therapy.

Combined chemo + radiation therapy i ffi i t i ti ll

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is more efficient synergistically

Join us at

www igert neu edu

Join us atTim Fonseca

www.igert.neu.edusagar.physics.neu.edu

s.sridhar@neu.eduwww.igert.neu.edu