NanotechnologyNanotechnology forfor CancerCancer MedicineMedicine andand ResearchResearch

MauroMauro Ferrari,Ferrari, Ph.D.Ph.D.

Professor,Professor, BrownBrown InstituteInstitute ofof MolecularMolecular MedicineMedicine ProfessorProfessor ofof InternalInternal MedicineMedicine Chairman,Chairman, BiomedicalBiomedical EngineeringEngineering UniversityUniversity ofof TexasTexas HealthHealth SciencesSciences Center,Center, HoustonHouston Professor,Professor, ExperimentalExperimental Therapeutics,Therapeutics, MDMD AndersonAnderson Professor,Professor, Bioengineering,Bioengineering, RiceRice UniversityUniversity President,President, AllianceAlliance forfor NanoHealthNanoHealth

CERN – June 12, 2007 8 10 Tennis ball 7 10 6 10 A period 5 10 4 Cancer cell 10 3 10 Bacteria Nanodevices: Nanopores Dendrimers Nanotubes Quantum dots Nanoshells 2 Virus 10 Antibody 110 Glucose -1 10 Water Nanotechnology in Perspective Nanotechnology in Perspective Nanometers NanotechnologiesNanotechnologies WhatWhat isis thethe AllianceAlliance forfor NanoHealth?NanoHealth?

„„ ConsortiumConsortium ofof sevenseven institutionsinstitutions governedgoverned byby memorandummemorandum ofof understandingunderstanding ofof 12/16/2004.12/16/2004.

„„ VirtualVirtual collectioncollection ofof 500+500+ investigatorsinvestigators

„„ MechanismMechanism forfor funding:funding: aaSharedShared infrastructureinfrastructure aaCollaborativeCollaborative researchresearch aaConferences/workshopsConferences/workshops aaStudentStudent programsprograms Office: The Fayez S. Sarofim Research Building (IMM) 537 at UTHSC-H. MissionMission

To Bring Nanotechnologies to the Clinic ANHANH OrganizationOrganization ChartChart ANHANH TimelineTimeline ANHANH SeedSeed GrantsGrants

•Ten seed grants awarded •Grants selected by external peer review board (AIMBE – Dr. C. Montemagno)

Nanorods-mediated gene therapy in bladder cancer P.I.: Liana Adam, M.D., Ph.D. (University of Texas MD Anderson Cancer Center) Co-P.I.’s: Jason Hafner, Ph.D. (Rice University) Colin Dinney, M.D. (University of Texas MD Anderson Cancer Center) Corazon Bucana, M.D. (University of Texas MD Anderson Cancer Center) Self-assembling peptide-amphiphile nanofibers as a scaffold for dental stem cells P.I.: Jeffrey D. Hartgerink, Ph.D. (Rice University) Co-P.I.’s: Rena D’Souza, D.D.S., Ph.D. (University of Texas MD Anderson Cancer Center) Biomodally-targeted, magnetically-responsive nanoparticles as drug carriers P.I.: Jim Klostergaard, Ph.D. (University of Texas MD Anderson Cancer Center) Co-P.I.’s: Waldemar Priebe, Ph.D. (University of Texas MD Anderson Cancer Center) Joan Bull, M.D. (University of Texas Health Science Center at Houston) David Gorenstein, Ph.D. (University of Texas Medical Branch at Galveston) Charles Seeney, M.S. (Nanobiomagnetics, INC.) ANHANH SeedSeed GrantsGrants

Feasibility of selective laser elimination of leukemia cells targeted with gold and silver nanorods P.I.: Marina Konopleva, M.D., Ph.D., (University of Texas MD Anderson Cancer Center) Co-P.I.’s: Bahman Anvari, Ph.D. (Rice University) Alexander Oraevsky, Ph.D. (Fairway Medical Technologies, Inc.)

On-command control of blood pool residence time for nanoparticle-based molecular imaging P.I.: Vikas Kundra, M.D., Ph.D. (University of Texas MD Anderson Cancer Center) Co-P.I.’s: Ananth Annapragada, Ph.D. (University of Texas Health Science Center at Houston)

Nanomagnetic biosensor array for few-cell cancer diagnostics P.I.: Dmitri Litvinov, Ph.D. (University of Houston) Co-P.I.’s: Richard Willson, Ph.D. (University of Houston) John C. Wolfe, Ph.D. (University of Houston) Mini Kapoor, Ph.D. (University of Texas MD Anderson Cancer Center)

Guided microvascular formation and cellular infiltration for tissue regeneration applications in nano-structured silk fibroin-chitosan scaffolds P.I.: Anshu B. Mathur, Ph.D. (University of Texas MD Anderson Cancer Center) Co-P.I.: Rebecca Richards-Kortum, Ph.D. (Rice University) Collaborators: Peter C. Gascoyne, Ph.D. (University of Texas MD Anderson Cancer Center) Gregory P. Reece, M.D. (University of Texas MD Anderson Cancer Center) MFMF -- The The PiecesPieces ofof thethe PuzzlePuzzle

„„ AppointmentAppointment 100%100% atat UTHSC-UTHSC- H, H, withwith inter-inter- institutionalinstitutional salarysalary reimbursementreimbursement agreementsagreements „„ AtAt UTHSC-H:UTHSC-H: aa DirectorDirector ofof NanomedicineNanomedicine Center Center ofof thethe IMMIMM aaChairmanChairman ofof BMEBME @@ UTHSCUTHSC (Three-(Three- institutionalinstitutional departmentdepartment withwith UTAustin,UTAustin, MDACC)MDACC) AAcknowledgmentscknowledgments -- Our Our NanomedicineNanomedicine Group Group Professors: Mauro Ferrari (Director), Fredi Robertson (MDACC) Associate Professor: Vittorio Cristini (SHIS – UTHSC) Assistant Professors: Mark Cheng, XueWu Liu, Takemi Tanaka Visiting Scholars: Prof. Milos Kojic (Harvard), Prof. Paolo Decuzzi (UMG Italy), Prof. Fazle Hussain (University of Houston) PostDocs: Ennio Tasciotti, Rohan Bhavane, Rita Serda, Dan Fine, + 6 Students: Alessandro Grattoni, Fabio Fais, Cynthia Chmielewski, Tony Hu Kevin Plant, Sung Kim, Zongxing Wang, Sandra Saldana, Ciro Chiappini, MariaSilvia Peluccio, Francesco Gentile + 5 Research Staff: Amber Jimenez, Li Li; Advocacy Director: D. Johnson Executives: Jason Sakamoto (ANH), Tong Sun (BME) Administration: Dee Fegans, Ramona Thomas, Victoria Herrera Key Collaborations: Profs. A. Annapragada, J. Conyers (UTHSC); Prof. Juri Gelovani, Josh Fidler, Garth Powis, Anil Sood, Gabe Lopez, R. Pasqualini and Wadih Arap (MDACC), Prof. Jim Tour (Rice University), Prof. Wah Chiu (Baylor), Prof. N. Peppas (UT Austin), Prof. S. Pricl (Trieste Italy), Prof. R. Caprioli (Vanderbilt) Prof. Venuta (UMG Italy), Sematech (Austin) Startups in progress: Leonardo Biosystems Funding: NCI, NIH, NASA, DoD, State of Texas, Office of the President UTHSC NanochanneledNanochanneled Delivery Delivery SystemsSystems (nDS)(nDS)

FinancialFinancial Support:Support: NCI;NCI; DepartmentDepartment ofof DefenseDefense (ARMY(ARMY –– TATRC; TATRC; DARPA);DARPA); NASA;NASA; StateState ofof TexasTexas EmergingEmerging TechnologyTechnology FundFund (ETF)(ETF) NanochanneledNanochanneled Implants Implants forfor thethe ControlledControlled ReleaseRelease ofof TherapyTherapy

Membrane holder Donor well

Silicon sealant Acceptor well Silicon Membrane NDS1NDS1 2-layer2-layer structurestructure

3D3D modelmodel

SEMSEM imageimage ofof AFMAFM image image microchannelsmicrochannels ofof 70nm70nm texturetexture NanochannelNanochannel SubstrateSubstrate NDS1NDS1 innerinner structurestructure && flowflow MULTISCALE Math Model – Fully Predictive (2003-…)

100 80 60 40 20 0 -20 -40

E (kJ/M) -60 -80 -100 012345678910 d (Å) ν

π η

ν π η ν

π η ⎛ ⎞ ⎛ ⎞ ⎜ ⎟ 2 ⎜ ⎟ ⎜ 2b 2a ⎟⎛ ⎞ ⎜ ν 2aπ ν ⎟ 2 ∂ = ⎜ kT 0 − 0 ⎟⎜ ∂ ⎟ + ⎜ kT 1 − 0η ⎟ ∂ ν ∂t ⎜ 6 r 3 6 r ⎟⎜ ∂x ⎟ ⎜ 6 r 2 6 r ⎟ 2 ⎜ ⎛ ⎞ ⎟⎝ ⎠ ⎜ ⎛ ⎞ ⎟ ∂x ⎜ ⎜1−b ⎟ ⎟ ⎜ ⎜1−b ⎟ ⎟ ⎝ ⎝ 0 ⎠ ⎠ ⎝ ⎝ 0 ⎠ ⎠ AA definitiondefinition ofof nanotechnanotech

nan’nan’ o o••techtech••nol’nol’ o o••gy,gy, NatureNature NanotechnologyNanotechnology (2006)(2006) 1:8-10.1:8-10. R T m' V π = 2 []1+ ()1+V m'2 m'1

PredictivePredictive TheoryTheory ofof OsmoticOsmotic PressurePressure

Osmotic pressure data for sucrose aqueous solutions at 20°C

240

220 Experimental data

200

180 Maximum Likelihood 160 Regression

140 van't Hoff Theory 120

100

80 Morse Theory

Osmotic pressure [bar] 60

40 Granik - Ferrari Theory 20

0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Molality

Granik,V.T., Ferrari, M. Osmotic Pressures for R T m'2 V Binary Solutions of Non- π = electrolytes, Biomedical []1+ ()1+V m'2 m'1 Microdevices (2002). (Grattoni and Ferrari unpubilshed) PlentyPlenty ofof SPACESPACE toto fitfit “Nano”“Nano” CHALLENGESCHALLENGES „„ MinimumMinimum 21-2821-28 MonthMonth RoundRound TripTrip toto MarsMars „„ NONO HospitalsHospitals „„ MinimalMinimal cargocargo capacitycapacity forfor meds.meds. „„ FAILUREFAILURE NOTNOT ANAN OPTION!OPTION! SmartSmart ImplantsImplants „„ nDS1:nDS1: PassivePassive ReleaseRelease NearestNearest HospitalHospital„„ nDS2:nDS2: ActiveActive Toxicity ReleaseRelease –– (Earth)(Earth)PreprogrammedPreprogrammed Therapeutic Range PlasmaPlasma Drug Drug

ConcentrationConcentration Toxicity „„ nDS3:nDS3: ActiveActive Diminished Activity ReleaseRelease –– Time nDS1 RemotelyRemotely ActivatedActivated nDS2 „„ nDS4:nDS4: ActiveActive ReleaseRelease –– Self- Self- regulatedregulated

Image Credit: NASA/JPL/Cornell/Texas A&M CancerCancer isis thethe #1#1 killerkiller ofof AmericansAmericans underunder 8585 andand aa majormajor killerkiller worldwideworldwide 570,280570,280 AmericansAmericans willwill diedie ofof cancercancer thisthis yearyear aa 1,372,9001,372,900 AmericansAmericans thisthis yearyear willwill hearhear thethe wordswords “you“you havehave cancer…”cancer…” aa $192$192 billionbillion == CostsCosts ofof cancercancer inin 20042004 More Progress is Needed to Reduce Death Rates

586.8 600 1950 500 2002

400

300 240.1

100,000 193.9 193.4 200 180.7 Death Rate Per 100 56.0 48.1 22.5 0 Heart Cerebrovascular Pneumonia/ Cancer Diseases Diseases Influenza

Source: American Cancer Society. InterventionIntervention inin thethe CancerCancer ProcessProcess PreventPrevent DetectDetect ModulateModulate EliminateEliminate

TumorTumor Colorectal Colorectal Micro-Micro- BRCA-1BRCA-1 MutationMutation Cancer Screening Cancer Screening EnvironmentEnvironment

DeathDeath duedue toto CancerCancer

MetastaticMetastatic ProgressionProgression

MalignantMalignant Transformation SusceptibilitySusceptibility Transformation Pre-CancerousPre-Cancerous ChangesChanges

NaturalNatural BirthBirth LifeLife SpanSpan DeathDeath MechanismsMechanisms ofof thethe CancerCancer ProcessProcess TheThe SixSix EssentialEssential AberrationsAberrations ofof CancerCancer

Self-SufficiencySelf-Sufficiency inin GrowthGrowth SignalsSignals EvadingEvading ApoptosisApoptosis InsensitivityInsensitivity toto Anti-GrowthAnti-Growth SignalsSignals

SustainedSustained TissueTissue InvasionInvasion AngiogenesisAngiogenesis andand MetastasisMetastasis

LimitlessLimitless ReplicativeReplicative PotentialPotential AfterAfter HanahanHanahan & & Weinberg,Weinberg, CellCell 100:57100:57 (2000)(2000) moviemovie NanotechnologyNanotechnology andand CancerCancer ApplicationsApplications

FERRARI M: Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer (2005) 5(3):161-171. At National Cancer Institute, 2003-2005

ProteomicProteomic NanochipsNanochips for for thethe EarlyEarly DetectionDetection ofof DiseaseDisease fromfrom BloodBlood andand OtherOther BiologicalBiological FluidsFluids

FinancialFinancial Support:Support: NCI;NCI; DepartmentDepartment ofof DefenseDefense (ARMY(ARMY –– TATRC); TATRC); NASA;NASA; StateState ofof TexasTexas EmergingEmerging TechnologyTechnology FundFund (ETF)(ETF) BloodBlood Proteomics/PeptidomicsProteomics/Peptidomics TheThe HypothesisHypothesis

LIOTTALIOTTA LA,LA, FERRARIFERRARI M,M, PETRICOINPETRICOIN E:ClinicalE:Clinical proteomics:proteomics: writtenwritten inin blood.blood. NatureNature(2003)(2003) MultiplexingMultiplexing proteomicproteomic detection:detection: ManyMany proteinprotein channelschannels atat samesame timetime

Nanoscale Cantilevers

Cantilevers detect Cancer biomarkers of cancer cell

Proteins

Antibodies

Binding events change cantilever shape, and properties

Arun Majumdar, University of California at Berkeley; Tom Thundat, ORNL NanotechNanotech andand thethe systemsystem approachapproach toto cancercancer biologybiology

Nanowire Sensor

Particles flow through the microfluidic channel

Electrodes Nanowire sensor

Nanowires detect biomarkers of cancer

Charles Lieber, Harvard; Jim Heath, California Institute of Technology, & Lee Hood, ISB mfluidics-mfluidics- massivelymassively multiplexedmultiplexed plumbingplumbing TheThe NanolabNanolab forfor nanotechnologiesnanotechnologies

ElectrophysiologyElectrophysiology

HIT-T15HIT-T15 whole-cellwhole-cell recordingsrecordings Ca+2Ca+2 bufferbuffer (2mM(2mM EGTA)EGTA) NanowireNanowire SensorsSensors

HIT-T15HIT-T15 cellcell onon chipchip SignaturesSignatures ofof genegene && proteinprotein expressionexpression NanomechanicsNanomechanics Protein-proteinProtein-protein && Protein-DNAProtein-DNA interactionsinteractions ElectrophysiologyElectrophysiology sensors:sensors: signaturessignatures ofof cellularcellular processes.processes.

Dendritic EffectorEffector Dendritic MacrophageMacrophage Heath,Heath, cellcell TT cellcell CalTechCalTech UTHSC/MDACCUTHSC/MDACC ProteomicProteomic NanochipNanochip

Plasma 80 1898.1

1741.7 A

% Intensity % Intensity % Intensity % Intensity 2662.1 943.0 6638.0 331 9.0 4582.5 6598.6 9147.1 0 800 10000 Mass (m/z)

Silica type A Silica type B

2485.7 4569.6 9138.7 20 3868.5 2485.7 9430.3 30 1848.0 1848.0 2863.0 4713.2 B C 8919.3 2108.3 2357.5 9385.2 8769.3 1053.2 3283.7 861.7 1078.81866.3 3316.3 6632.0 % Intensity % Intensity % Intensity % Intensity

% Intensity % Intensity % Intensity % Intensity 8693.4 3519.4 4967.3 3868.32 7673.8 4575.0 9140.6 0 0 10000 800 10000 Surface patterning 800 M ass (m/z) Mass (m/z) Surface porosity

Ferrari, Nature Reviews Cancer (2005) LMWP EnrichmentofNanochip-BasedSerum Proteomics MALDI LMWP elution Size exclusion Protein spotting

% Intensity % Intensity % Intensity % Intensity % Intensity 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 9. 69447. 3028160.6 6320.2 4479.8 2639.4 799.0 8160.6 6320.2 4479.8 8160.6 2639.4 6320.2 799.0 4479.8 2639.4 799.0 9. 69447. 3028160.6 6320.2 4479.8 2639.4 799.0 10000 8160.6 6320.2 4479.8 2639.4 799.0 erdcblt Sensitivity Reproducibility as(mz) m/z Mass ( 10000 10000 10000 10000 100 100 100 50 0 0 0 0 8034 2032 704000 3760 3520 4000 3280 3760 3040 3520 2800 4000 3280 % Intensity 3760 3040 3520 2800 4000 3280 % Intensity 3760 3040 3520 2800 3280 % Intensity 3040 2800 % Intensity 20 ng/mL 50 ng/mL 200 ng/mL 1000 ng/mL 3420.1 3419.6 3420.5 3419.8 calcitonin Nanochip-Based Proteomics of Serum from Invasive Human Breast Tumor Xenografts

Injection of 5 x 106 MCF-7/Cox-2 human The animal model breast tumor cells into mammary fat pads female nude mice

Invasive human breast tumor in mammary fat pads of nude mice Palpable tumors in 15 days, metastatic human breast tumor xenografts in 42-60 days

10 µL serum/plasma Nanoporous silicon/silica film 1. Binding

Silicon chip 2. Wash The nanotech strategy

3. Extract LMW Nanochip-based MS/MS identification of peptides serum derived proteins from mice bearing human breast tumor xenografts 4. MS analysis High MW proteins MALDI-TOF Low MW proteins/peptides Human Vascular Endothelial Growth Factor (VEGF) family

Dimerization Plasmin Neuropilin Inhibitory Sites Cleavage Binding Activity

1 2 3 4 5 6a 6b 7 8 9 Signal VEGFR-1 VEGFR-2 Heparin Peptide Binding Binding Binding

1 2 3 4 5 6a 6b 7 8 VEGF206

1 2 3 4 5 6a 7 8 VEGF189

1 2 3 4 5 7 9 VEGF165b

1 2 3 4 5 7 8 VEGF165

1 2 3 4 5 6a 8 VEGF145

1 4 VEGF121 2 3 5 8

1 2 3 3b VEGF117

(Robertson et al.) Time dependent increase of Fibrinogen alpha chain polypeptide

17000 16000 Identified Peptide fragment of Control 0 days 15000

14000 fibrinogen alpha chain polypeptide

13000 Tumor 28 days

12000 Sequence TDTEDKGEFLSEGGGVR 11000 Tumor 42 days 10000

9000 8000 Tumor 60 days 7000 *1798.96 6000

5000 Control 60 days

4000

3000

2000 1806.79 (1) 1805.74 (1) 1000 *1804.82 (1) *1808.19 *1784.43 *1785.23 (1) 1786.25 (1) *1790.21 *1810.1 *1788.62 *1792.37 0 1784 1785 1786 1787 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 1 Mass/Charge, amu ABSTRACT BloodBlood Proteomics/PeptidomicsProteomics/Peptidomics TheThe HypothesisHypothesis

LIOTTALIOTTA LA,LA, FERRARIFERRARI M,M, PETRICOINPETRICOIN E:ClinicalE:Clinical proteomics:proteomics: writtenwritten inin blood.blood. NatureNature(2003)(2003) NanoVectorsNanoVectors for for thethe LocalizedLocalized (Directed)(Directed) TreatmentTreatment ofof CancerCancer

Keywords: • Rational design • Multistage • BioBarrier Avoidance • Nanoporous Silicon

Funding: NCI, NASA, DoD (Army) PharmacologicPharmacologic TherapyTherapy:Therapy:: PastPast,Past,, PresentPresent,Present,, FutureFuture

cisplatin

Doxorubicin Liposome Pegylated Liposome DirectingDirecting TherapyTherapy OnlyOnly WhereWhere NeededNeeded

PEG-thiol

TNF targe molecu

Therapeutic payload

Colloidal Gold Nanoparticle NanoparticleNanoparticle delivery: delivery: CentralCentral Issue#1:Issue#1: BioBarriersBioBarriers

„„ EndothelialEndothelial andand EpithelialEpithelial BarriersBarriers „„ Reticulo-EndothelialReticulo-Endothelial SystemSystem (RES)(RES) „„ EnzymaticEnzymatic DegradationDegradation „„ Hemo-RheologyHemo-Rheology „„ Tumor-AssociatedTumor-Associated OsmoticOsmotic && InterstitialInterstitial FluidFluid PressuresPressures „„ CellCell MembraneMembrane „„ NuclearNuclear MembraneMembrane Reference: M. Ferrari, Cancer „„ IonicIonic && MolecularMolecular PumpsPumps Nanotechnologies, Nature Reviews Cancer, March 2005 ScanningScanning EMEM ofof NormalNormal VasculatureVasculature vsvs AbnormalAbnormal TumorTumor BloodBlood VasculatureVasculature

Normal vasculature

Tumor vasculature

McDonald and Choyke. Nat Med. 2003;9:713. MorphologyMorphology ofof TumorTumor VesselsVessels

Luminal surface Luminal surface of normal blood vessel of tumor vessel Endothelial sprout on tumor vessel

Barriers are impediments but also opportunities: Enhanced Permeation and Retention (EPR)

Baluk et al. Curr Opin Genet Dev. 2005;15:102. WeWe notice…notice…

„„ TheThe existingexisting clinicalclinical NP-basedNP-based therapiestherapies (liposomes,(liposomes, Abraxane)Abraxane) areare notnot basedbased onon biologicalbiological targetingtargeting // molecularmolecular recognitionrecognition

„„ TheyThey areare “Directed”“Directed” and and provideprovide concentrationconcentration benefitsbenefits byby interactionsinteractions withwith biologicalbiological barriersbarriers

„„ BioBarriersBioBarriers may may bebe suitablesuitable forfor imagingimaging Delivery Strategies

¾ Targeting the tumor vasculature: Multi-stage particle phase 1: circulating particle (sub-micrometer) adheres firmly to the walls of the tumor microvasculature; phase 2: smaller particles release and diffusion into the tumor micro- environment towards the target cells phase 3: internalization by the tumor cell

Margination, Adhesion and Endocytosis RationalRational designdesign ofof NanoparticlesNanoparticles based based on:on: Margination,Margination, AdhesiveAdhesive StrengthStrength (Specific(Specific andand NonSpecific),NonSpecific), EndocytosisEndocytosis

The adhesive strength of a particle is controlled by: ¾ specific interactions: ligand-receptor binding; ¾ non-specific interactions: vdW, electrostatic, steric.

t[s] Time for Margination 200 Rc 150 100 Δρ = 1000 kg/m3 70 50

30 20 15 R[nm] 50 100 500 1000 5000 10000

(Decuzzi, …, Ferrari, Annals of Biomed Engr 2004, 2005; Biomaterials 2006) Optimization of Particle Design

-2 Example I: capillaries with μS = 1 Pa and mr = 100 μm , the -2 3 optimal volume for a spherical particle would be Vopt = 5×10 μm , corresponding to a diameter of about 500 nm.

Example II: under the same physiological conditions, an oblate

particle (γ=2) with the same Pa of a spherical particle with a diameter 3 of 500 nm, would have a volume Vopt = 3.5 μm : a carrying capacity about 50 times larger. DesignDesign mapsmaps

(Decuzzi & Ferrari) Transition to Multi-Stage Vectors FirstFirst StageStage Vector:Vector: NanoporousNanoporous SiliconSilicon ParticlesParticles

Back Side Front Side Cross Section

200 1 µm 1 µm 200 nm 1 m nm Pores Nucleation Layer Cross Section

Large Pores (LP)

20 nm 20 nm 20 nm Back Side Front Side Cross Section

100 nm

1 µm 1 µm 200 nm Pores Nucleation Layer Cross Section

20 Small Pores (SP) nm

20 nm 20 nm 20 nm 20 nm is tg etr aooosSiliconParticles First StageVector:Nanoporous

Large Pore in Large Pore in Cell Culture TRIS buffer +

Media Saline

0 hours 0 hours

0 hours5 0 hours5

LP 48hours

LP 48hours Biodegradation: SEMimaging

5 hours 5 hours

18 hours 18 hours

8 hours 8 hours

SP 48hours SP 48hours

24 hours

24 hours 11 hours 11 hours Silicon Particles Silicon Particles Nanoporous Nanoporous Biocompatibility

12 hours 24 hoursSP oxidized 48 hours 72 hours SP Aptes LP oxidized LP Aptes First Stage Vector: First Stage Vector: SecondSecond StageStage NanoparticlesNanoparticles:: IntroductionIntroduction

Quantum dots (Q-dots)

Liposomes

Hydrophobic molecules

Hydrophilyc molecules

Water Lipid bilayer

Single Wall carbon Nano Tubes (SWNT) SummarySummary

„„ NanochanneledNanochanneled Delivery Delivery SystemsSystems aa PassivePassive TransportTransport (nDS-1)(nDS-1) inin commercialcommercial translationtranslation stagestage withwith SematechSematech aa ActiveActive SystemsSystems (nDS-n)(nDS-n) inin techtech developmentdevelopment

„„ PeptidomePeptidome Enrichment Enrichment NanochipsNanochips for for MSpecMSpec aa BiomarkerBiomarker identificationidentification –– BRCA BRCA

„„ RationalRational DesignDesign ofof MultistageMultistage NanovectorsNanovectors aa Conjugation/TargetingConjugation/Targeting Biodegradation Biodegradation aa Loading/ReleaseLoading/Release Biocompatibility Biocompatibility Thanks!Thanks!

[email protected]@uth.tmc.edu