digital cancer diagnostics &...

DigitalCancerDiagnostics&SurgeriesUniqueImagingAgentsWithBinaryReadout:

Cancer=ON; Healthytissue= OFF

LastModified7/31/201710:58AM

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ONCONANO|CONFIDENTIAL 2

UnmetNeedsinCancerSurgery

• Residualtumor

• Lymphnodes

• Tumormargins

Difficulttoidentifyinreal-time

duringsurgery


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ONCONANO|CONFIDENTIAL

EffectofInadequatetumorremovalandhealthyorganandnervedamage

ImpactofPoorCancerSurgery

• TissueandorgandamageParalysisandneurologicaldamageSexualfunctiondamageIncontinenceSpeechandswallowingfunctionissues

• Re-operations20-40%breastsurgeryre-operationsSecondsurgeriesforthisalonemaycostthehealthcaresystemcloseto$1Bannually

• Recurrence30%to55%ofpatientswithNSCLCdeveloprecurrenceanddieoftheirdiseasedespite“curative”resection

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KeyInsight:TumorsHaveAcidicpH


• All256humantumorstestedwereacidic

TumorpH~6.8

BloodpH=7.4

LowtumorpHisauniversalcancer

hallmarkacrossdiversecancer

genotypesandhistologyphenotypes-

Duetowellknown“Warburgeffect”

TumorpH BloodpH

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pH-TransistorNanoprobe™BinaryResponse



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OncoNano AccuracyandSpecificitySuperiortoState-Of-ArtPETImaging

PETimagingconfoundedby“brownfat”limitingresolution

BigTumor

SmallTumor

WhiteLight PET/10FDG Fluorescence/I-UPS



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ONM-100:TumorImagingAcrossMultipleCancerTypes


NatureMater.,2014,13,204-212

Red:Tumorsofdifferenttypesandorgansites

Green:Normaltissuebackground

Transgenicbreastcancer

Breastcancer

Prostatecancer

Headandneckcancer

Headandneckcancer

LungCancer

LungCancer

BrainCancer

BrainCancer

BrainCancer

TransgenicPancreaticCancer


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SurgicalTargetMarket:$2BOpportunity


BCC/SCCSkin:Incidence3.5million.756,000/yr.treatedwithMohssurgery.

Melamoma:Incidence76,000.Virtuallyalltreatedsurgically

Brain:Incidence22,000.Surgeryinmajorityofcases(15,000/year).

HeadandNeck:Incidence53,000.Surgeryperformedfor~50%patients.

Breast:Incidence229,000.Virtuallyalltreatedwithsurgery.Lumpectomies(150,000/year).

RectalCancer:Incidence40,000.Overwhelmingmajoritytreatedsurgically.

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~1MMcancersurgeriesinUSALONEeveryyear;5MMsurgeriesworldwide


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CancerPrecisionMedicineAndSurgery:DynamicSectorsforDealsinLast10Months


Spun-outfromIllumina- $900MMSeriesBPrecisioncancerdiagnosticsandearlydetection

HealthcareGmbHacquiredNEONewOncologyAGMay17,2016MolecularprofilingassaysbasedonNGS(NextGenerationSequencing),bothfor

tissuespecimensandbodyliquids.

RoboticcancersurgeryspaceveryactivewithnewentrantsNewwell-fundedcompetitorslookingfordifferentiatedproducts

AcquiredNovadaq for$700MillionSept2017

OnTargetfundedbyJJDC

$40MMOct2017


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Competition



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SharpTumorMarginsDuetoDigitalON-OFFEffectofONM-100

EGFR-IRFluorescentDyeTraditional“analogfluorescentprobe”

ONM-100“digitalfluorescentprobe”

NIR H&E NIR H&E


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PlatformTechnologyWithMultipleProductOpportunities


er than those without the fluorescence quenchers (SupportingInformation Figures S17 and S18).UPS Library Spanning a Large Range of pH

Transitions and Fluorescence Emissions. On the basis ofthe above results, we produced a representative UPS libraryconsisting of 10 nanoprobes each encoded with a differentfluorophore. The composition for each nanoprobe follows thatfrom Figure 4d (see Supporting Information Tables S3 and S4for details), which resulted in a collection with 0.3 pHincrements in the pH span of 4 to 7.4. For each nanoprobe, aseries of aqueous solutions of the copolymer at the samepolymer concentration (i.e., 0.1 mg/mL) but different pHvalues was prepared. For 4.4-AMCA, 4.7-MB, 5.0-BDY493,and 6.2-BDY630 nanoprobes, the corresponding copolymerswere mixed with the same equivalent of FQ-conjugatedmatching copolymers to achieve high on/off contrast. Figure6 shows the emission image of the UPS nanoprobe library at

the excitation/emission wavelengths corresponding to eachfluorophore. To evaluate the potential toxic effects of the UPSnanoprobes, we performed MTT assay in the H2009 lungcancer cells. H2009 cells were incubated with increasingconcentrations (from 0.1 to 100 μg/mL) of differentnanoprobes in the cell culture medium for 48 h at 37 °C(typical imaging dose is below 100 μg/mL). Results showedminimal toxicity (cell viability > 90%) for a majority of thenanoprobes (Supporting Information Figure S26). UPS7.1 and

UPS6.8 showed slightly higher toxicity (80% viability) at 100μg/mL. Current work is in progress to study the pH-dependentperturbation of lysosome catabolism and oncogenic signalingpathway and their impact on cell viability at higher doses (>400μg/mL) of the UPS nanoparticles.Results from Figure 6 illustrate the exquisite pH sensitivity of

the UPS nanoprobes to the external environment spanning theentire physiologic pH of 4−7.4. In the lowest pH range, the4.4-AMCA nanoprobe was off at pH 4.55 but can be turned onat pH 4.25. This nanoprobe can be useful in detection offunctional lysosomal pH where hydrolases require a lower pHfor enzyme activity. The on/off characteristics of the nanop-robes make them particularly useful in high-throughputscreening applications to identify molecular pathways or smallmolecular perturbators that affect lysosomal function. Thenanoprobes covering the higher pH range (e.g., 6.5−7.1) can beuseful for differentiation of the acidic pHe of tumors withdifferent glycolysis rates of the cancer cells.22,36 The nanop-robes in the intermediate range (e.g., 5.0−6.5) may be usefulfor study of the maturation of endosomes/lysosomes and toestablish organelle-specific compositions for subcellular imagingor drug delivery applications.

■ CONCLUSIONSWe report a robust method for development of ultra-pH-sensitive (UPS) micellar nanoprobes with significantlyimproved pH control and broadened fluorophore selectionover the previous methods.19,20 Through a copolymerizationstrategy for synthesis of the ionizable block, we demonstrate theability to achieve an operator-predetermined control of thetransition pH of the UPS nanoprobes based on standard curves.Importantly, matching of the hydrophobicity of the twomonomers is critical to ensure the sharpness of pH transition(i.e., <0.25 pH between the on and the off states). Introductionof fluorescence quenchers in the core of the UPS nanoprobesfurther broadens the fluorophore choice to those with largeStokes shifts. On the basis of these findings, we established aUPS nanoprobe library consisting of 10 components with 0.3pH increment that span the entire physiologic range of pH (4−7.4). Each nanoprobe maintained exquisite sensitivity to theenvironmental pH. The availability of the UPS library opens upmany exciting opportunities for basic biological research (e.g.,endosome/lysosome biology) as well as for translational studiesin tumor imaging and drug delivery.

■ ASSOCIATED CONTENT

*S Supporting InformationMaterials, methods, detailed experimental procedures (syn-thesis, characterization, and biological assays), and supple-mentary figures. This material is available free of charge via theInternet at http://pubs.acs.org.

■ AUTHOR INFORMATION

Corresponding AuthorE-mail: [email protected]

Author Contributions‡These authors contributed equally to this work.

NotesThe authors declare no competing financial interest.

Figure 6. Exemplary UPS library consisting of 10 nanoprobesspanning a wide pH range (4−7.4) and large fluorescent emissions(400−820 nm). Each nanoprobe is encoded by its transition pH andfluorophore. Images of 4.4-AMCA and 4.7-MB were taken by acamera at an excitation light of 365 nm. Images of the rest of thenanoprobe solutions were taken on a Maestro Imaging system.

Journal of the American Chemical Society Article

dx.doi.org/10.1021/ja5053158 | J. Am. Chem. Soc. 2014, 136, 11085−1109211091

Monetizenon-coreproductsva partnershipsi

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CancerSurgery

(ONM-100)

CancerRadionuclide-diagnostics

(ONM-200)

In-VitroDiagnostics(ONM-300)

Therapeutics(lysosomepHtarget,pancreaticcancer)


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OncoNanoTeamBackground


• RaviSrinivasanPhD– CEOSerialhealthcareentrepreneur,StrataGent LifeSciences(acquiredbyCorium-Nasdaq:CORI)andStemPar Sciences(IVoncologytherapeutic);ForSightVision5(acquiredbyAllergan);MITPhDinChemicalEngineering

• Yalia JayalakshmiPhD– HeadClinicalDevelopmentSr.Dir.Amgen/Onyx,JohnsonandJohnson,Genentech.DevelopedDoxil,Lucentis,TNKase

• NarmadaShenoyPhD– HeadCMCCMCheadSugen,Pfizer.DevelopedSutent

• DuaneReavesMD- RegulatoryconsultantPreviousHead,DivisionofImagingProductsFDA

• CarlAlden,PhDHeadToxicologyVPTox Millenium/Takeda.DevelopedVelcade,Celebrex

• FrankLee,PhDHeadPharmocologyVPMillenium/Takeda.DevelopedVelcade,Celebrex

• TianZhaoPhD– DirectorofResearchInventorofONM-100


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ScientificAdvisoryBoard


• Prof.Jinming Gao,PhDFounder,SABMemberProfessorofUTSWChairofNIHGeneandDrugDeliveryStudySectionPhDChemistryHarvard,Post-docMIT

• Prof.Baran Sumer,MDFounder,SABMemberFacultyandsurgicaloncologistatUTSWHeadandNeckCancerTeamLeaderUTSW

• Prof.CharlesBalch,MD• KeyStrategicAdvisor,SABMember

CancersurgeryandimmunotherapythoughtleaderEx-CEOASCO,ex-CEOCityofHopeHospitals,EVPMDAnderson

• Dr.JohnNeiderhuber,M.D.KeyOpinionLeader,SABMemberEx-head,NationalCancerInstituteEx-head,DepartmentofSurgeryatStanfordandJohnsHopkins

BusinessAdvisors

• AlGuillem,Ph.D.FounderZSPharma

• Paritosh Dhawale,PhDHeadofImagingBusinessUnit,GEHealthcare

• StevenShak,M.D.Founder,GenomicHealth


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OpportunitySummary


• UnmetNeedsAddressed:Tumor&lymphnodedetection,stagingandsurgicalimaging

• OncoNano Solutions:IVinjectabletumorimagingproductsthatturnONintumorsandstayOFFinhealthytissue

• OncoNano CoreTechnology:Uniquemicellenanoprobe basedpHnanotransistorsultrasensitivetotumoracidity,auniversaltumorbiomarker(Warburgeffect)

• Market:Cancerimaging>$5Bandrapidlygrowing

• Competition:PET,CT,MRI,ultrasoundplusseveralimagingagentsalllesssensitiveandspecificandneedexpensivehardwarepurchases

• Team:Experiencedexecutivesandkeyopinionleadersinthefieldfoundingcompanyanddrivingeffort

• IP:Inventionandapplicationsprotected,IPissued

• Exit:Activedealmaking M&A+partnerships+IPOinmarketspace

Contact:RaviSrinivasan|[email protected]

“Mostinnovativetechnologyseeninlast25years”

Prof.CharlesBalch- ex-CEOASCO,EVPMDAnderson,Past-presidentSocietyofSurgicalOncology

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