November 2017 Webinar: Novel Contrast Agents for Photoacoustic Imaging of Cancer

Hi, everyone thanks for joining, my name is Drew Heinmiller i’m the product manager for our photoacoustic. Line of products here at FUJIFILM VisualSonics and I’m happy to present, today Dr. Martina Capozza from the university of Turin She’s going to be talking about novel contrast agents for photoacoustic imaging of cancer a few things before We get started, we are recording this webinar and a recording will be made available afterwards so if you’re not able to stay on for the whole thing you can catch it later All of the lines are muted for the duration of the webinar If you have any questions that come up during the webinar, we will be having a Question session at the end so Please type your questions into the Questions box on the side panel there and they will try to go through as many as, we can at the end This presentation will be anywhere from you know 30 to 45 minutes and then 10 to 15 minutes of questions at the end I’d like to introduce Dr. Martina Capozza she received her MS and molecular biotechnology in 2013 and her Ph.D in pharmaceutical and biomolecular science In a collaboration between braco Imaging research center in the center for molecular imaging at the university of torino She’s defending she defended I should say in march of 2017 her Thesis, was titled, nano sized systems for imaging of focus on photoacoustic imaging? And from May she’s a postdoctoral fellow in the laboratory for preclinical image imaging at the university of torino and she he’s pursuing her Interest in photoacoustic imaging and the development of novel contrast agents And that’s what she’s going to be talking about today, and she’s talking about these Some icg based contrast agents nanoparticles and dyes for targeted molecular imaging today and I’m getting to hand it over to to Dr. Capozza now. Okay take it away Action and for the opportunity to share my results, about not contest agent for for the prosecuting your cancer So human concept frequently display substantial intra tumor an interpreter or jannetty that can accurately responds The aim of the in the research project, that i presented a it’s the develop a new, mythology fly with molecular and physiological feature of tumour to characterize altimeter jannetty the ideal technique to reach this goal should be characterized, by a special resolution, good penetration depth good sensitivity and Mac insertion is cheap, and involved the use of an ionizing radiation – hello repeated image in acquisition during time The technique that twister expert for this study he is acoustic imaging that is a, new? imaging technique that combines the high contrast and complicated specificity of Fluorescence imaging with the high spatial resolution and penetration depth of the press Compared to the other imaging modality for acoustic imaging is characterized, by a low Spatial resolution, through penetration, tack and will succeed evp Another advantage is the use of know your ideal radiation Precocity machines based on two toxic effects so basically, we have a Passive laser beam that irradiate issues of interest then we have absorption of photon that cause Thermal accidents function, that general expression waves that are detected by ultrasonic transducer thank to the presence of a tunable passive laser we can, perform of the spectral imaging we can, perform suspect, the limiting of Endogenous cranford, like oxy and of similar beam over melanin and we can find information about Dish boxia or vascular volume as shown in this clinical application or in this clinical application this complication the signal of a modeling, was used for diagnosis of active crown disease the introduction of exogenous contrast agent, carry on specificity and sensitivity and you provide, new tools for devaluation of summa theologiae But an efficient fat acoustic context agent should have Higher molar extinction coefficient in order to maximize the amount of light that is absorbent and low Fluorescence quantum eld to maximize the amount of energy that is converted to heat and for sure – stability for example in this clinical Application icg has been injected to the texts americans hands in an infant in melanoma patient for this application Demonstrate that proxy imaging has enough penetration depth and specialized evolution for clinical translation So in this research project in order to improve my Distribution and to marketing properties over a icg, we propose two different ict based contrast agent one for passive Targeting and one for active targeting but, we must investigate different So the optical and producing properties of different small molecule new. York dyes and also the nanorods Of all these control agent mineral with in vitro the Main properties that infants the generation of photo caustic signal such as marks ashok efficient and flora system together The passive signal is also Investigates is in vitro in different media violence of an avocado this on the a buffer army parameter s subset of Contrast agent is identified and tested in vivo in health in mice and in tumor very nice? Meal to perform optical imaging provided the results obtained with, acoustic imaging So these are the icg basic photo gusta contrast agent some Icg is an efficient of different opposite contrast agent but it suffers or below photos, stability and as well blood clearance so in order to improve the by distribution and the properties of The, same dream, we develop these two novel prophase on ict for the two more ballistic imaging exploring me on Epr effect molecular targeting mechanism So i cg, what’s carpet to an integral binding factor the in this case the Cyclic rtd to try a molecular imaging approach and ict was loaded on these solidly with Nanoparticles for a sitar clicking approach So in the same in green This, is the synthesis and characterization of our icy gog he quit so i cg Was kinetic to the alpha beta three elevating molecule and? The reaction product, was purified and catalyzed? we also observed that the optical properties of our ict I’m not affected, by the hair to be binding indeed the absorption and focused expect enough are Comparable between the ict and ict ltd in both in Also in boxer and also in sara but, also the flora system to me aldo, was not affected by the presence of algae Both in mokpo and in senate District, we pick nanoparticles only load icg On solid lipid nanoparticles this manna system Are characterized, by snippet code, we have phospholipid around And they are family today so in order to avoid, my profit you have take We know these, not we know that these, nano particles with different Imaging probes, like fluorescent molecule or gadda lynnium compass or mri experiment The fluorescent molecule in this case is icg these mathematical have a diameter of 50 i mean that they have a negative to the potential and we observed, that the Start loading the over icg the corporation so our our ict in the currently paternal Particles and as the optical properties of ict and we can confirm this results, we have search from measurement but Also, we are used for the stability of the? Measurement, we also observe that the? loading of icg in the nano particles increase the fluorescence quantum yield of ict this is Not optimal for photo christa complication so in order to decrease the amount the forest is quantum yield of icg We increase the amount of icg throw. This in the nano particles in order to decrease in the flow access continuum of Ycg and so we optima is the? The amount of ict that should be loaded in our nano particles for acoustic. Application Yarn icg we also explore the optical and photo boosting properties of other food acoustic contrast agent like Sian in 5×5 and others Among all the tested eyes there is also these automatic Signing that is an iodine furniture purchase By, life–all for practice i mean since this molecule don’t show Any, fluorescence with the side to test that Is molecule for to the physical education So the first type and evaluation process of normal contrast agent for photo costa committee is the characterization of their optical properties so the or the measure of molar Axis should be efficient and flex is quantum yield of sunlight as we evaluate the first? discontinuity in serum and in boxer From these data, we select Those guys, that shown the higher molar extinction coefficient and the wherefores is convenient Another contrast agent that, we investigate are not spherical Purchase it by non-hybrid they have an extinction coefficient several orders of magnitude greater Than that of small molecule dies due to a. Local, eye surface plasmon resonance phenomena Dependent and maximum or the us represent the maximum absorption at 800 nanometers m in order to measure the Total boosting signal indicator we obtain a contrast agent the optimize We optimize, and onaga phantom this is super center console with polyethylene tube inside so we can load our? Conversation in the tube and we start injecting as reference? We select other fan so in order to have a productive Media for our hunter so these are the in vitro produced exceeded we can, observe that the most We needed 16 early investor and ceo in order to evaluate six senior after all the remaining of our contrast agent and we can Observe in this case the max defer to be six signal at the maximum absorption wavelength of each dye Was divided, by the reference engineering solution than normalize data were prophets versus the dye concentration Ict ftp and icg showed A, high focus Succeeded in buffered but in searing the signal decreases substantially And this is probably due to the strong interaction with government protein and consummate increase of her exes quantum mia But when icg is loaded and? excited nanoparticle the photo p16 i was always likely affected, by the other impact and in This is can Be due to the fact that the after the loading of icg on the 33 15 of our people the army mining can be a relative preventative For the financial and for the gold nanorods of the seeking us Hi, brother i’m not drastically affected, by the presence of serum This, can be explained and consider that the fluorescence was very low. Him off medium So in rockford and also in serum So i’m often, we can observe that the most promising contrast agent, where icg and ice-t gl piggy About ict significant practicals and the friendship, where the most promising for the caustic contrast agent in serum in the end we can observe that the signal of ict 3 divisional particle would double comparator a signal of icg in zoom After pill in vitro evaluation with performa in vivo First preliminary experiments in alstom eyes we intravenously injected icg i have 783 Ict 780 the nanoparticles and gold nanorods in healthy mouse and observe the blood films and by distribution In order to observe that clear so we prefer for the whisky application the, mystic imaging at the maximum Absorption wavelength of the dye before during, and after the injection in the neck region We can, observe that to be 6. Signal abaya 783 how to in less than 2 minutes, why Ict clearance was only slightly faster than that of for ict loaded on the solid it is nanoparticles But blood animation of course cameras, was much lower slower than the other contrast agent We then move the transducer in the river region, and we look at the liver uptake so We observed at higher 783 showed a very low Signal at all the time for pointer observe why i see she showed the Maximum signal at 20 minutes which remains stable up to one hour Ict loaded inside little particles show the slightly later uptake compared to ict So, we have a maximum signal our city said internet park back 40 minutes under the injection My, good, nanorods showed the maxim signal after per hour, which remains stable up to 24 hour for room this, data, suggests that i are 783 it was not good for the political of the station and this is probably due to its high fluorescence quantum yield of a plasma plasma protein binding and we’ve done perform optical imaging This, panel Divided the results of 10 a treat for the woodstick imaging so we perform optical imaging after a two-hour and 24-hour close injection We can, observe that, was the signal of icg and icg longer the disparities nanoparticles Is high at 2:00 hour, after the injection but, while 24 hour the optical signal decreased, by 10 times i have 753 show the sun signal after 2 hour and 24 hour first injection For good measure of the signal wall thus weaker than the other guys at So it’s very low, compared to the other guys We, also after this the criminal silence eeeh nice view of healthy minds we prefer a to, optic experiment in tumor very nice so the two martini uptake, was validly in Most model of soup can a beautiful stone usd 7 mg Swimming, jack’s icg icg icg icg say terrific about And the friendship molecule in the u-87 mg tumor very nice and we look at the tumor uptake So these are our thoughts could fill regarding the good manners we observed. That, hey, weak signal is detected at i Was observed, after 15 minutes percent. Jack Action but no photo 16 and were detected in usa 72 words at little pastime finds these are the last of concern leader i the Yeah, the friendship so the automatic Sihanouk i am that showed a low-mass developed a keen unit 57 mg to the This, data, suggested the further investigation on this class of red, friendship for the pacific imaging Maybe for some tyrosine because this is an targeted molecule but We can target it with the sun factor and perform as a molecular imaging to seek energy Concerning the ict base for acoustic contrast agent From the emitter evaluation another fountain, we have certain that to the signal of hcg salon Was double confirm the signal of a ict or ict a cheeky for this reason We injected half those of ict loaded in the nanoparticles calm self-directed eyes in order to have a Similar of cereal in for all the three contrast agent So these are the results of icg icg is already be done remarkable and icg icg They, showed high photo 60 gallons humans already, after 15 minutes of the injection Suggesting that in this only once per face all the contrast agent if used similarly About to an hour after the Injection i ct showed a 70% signal reduction compared to the signal after 15 minutes while the signal of ict salon, was hi, up to one hour and this is So me such as fellating Prove the by distribution under premiums of icd loading ict in the 60 nano particles The signal of an ict ltd, was elevated up 24 hour after the injection a 24 hour after the injection this is likely defensively mediated accumulation of the problem So for in order to validate that it’s, also these results, we ingest On gtr tv foreign Aid or three war funds you were very nice that is the couture model – at very low alpha, beta the expression so i city of tv show the different behavior of the injection in 841 and in you 87 mg to bear in mind the photo 260 of all i see Do tv name for free one to force rapidly decrease when the signal all In our cto tv injected in you 87 mg Our, main stable up to 24 hour So, we in order to confirm, these are dance we perform optical imaging spec and? After 2 hour and 24 hour, after the injection we can Observe from this result that did it is a nice signal for all the injected contrast agent after to our first injection But after 24 hour for send. Jack come on kill the signal over ict and ict said Injected mice was low But we can observe that there is a nice signal both in a 4:3 one and you 87 mg Very nice and visit you Towards, lower front clears of icg lgd Contract-free icg but we can, also observe that The signal derived from you 87 in fiji is the greater than the the signal that i promise hey for 3/1 Please confirm the results of tinted with, mystic energy To, have more information about problem, by distribution in this tool, we Press section were obtained from u-87 mgq, was injected with ict and the icg and the Icsd d and we can observe that a, weak signal falls of? Derive from the tour injected with the Ict while a strong signal home that i found The disk you were injected doing the icg icg I’ll confirm the imaging findings in this magnified image, we can, also observe that the signal derived how My cto, city Seems to be from the parenchymal that you were not calling, from the pure face So in conclusion we evaluate different for the visit contrast agent and Regard is no molecule near dies? we Last medical eyes died quentin that showed a lobe of developed 1887 mg and so thinkin In the future we can? perform further investigation of the class dog on this class of Contrast agent for photo to stick imaging application The gold, nanorods shown a strong livers signal but the Tumor in the signal in the tumor was very low regard i mean a cd-based come to station 2 We observe that as it is solid a snippet on a particle square of human eyes the perfect Acoustic application increasing, gamma of icg flow the ignorant of octopus and they showed a good to an integrator for the customer announcement compared to the free dye and Also its lower blood blood clearance the north targeted The hi-c gfgg Report and anonymity volunteer under jannetty has showed that some single up to 24. Hour post injection The sun didn’t appear to of be a valid, starting point for targeting strategies strategies for more accessible security i Would like to thank all of you for your attention, and visual thanks for the opportunity to share my results Great thanks so much dr. Campos, de that was a that was a great presentation I just like to remind everybody that, we? Will be taking questions now so if you got any questions please just type them into the questions box, and we’ll try and get through some of those questions I’m gonna start by asking a couple here First just generally, why Why, use multi modal agents in this case, why is this important for the firm for cancer imaging Or not yeah i guess just just multimodal agents so being able to see them with, more than just photo acoustics alone so photoacoustic yeah Yeah, and i think that the optical imaging he has the opportunity to have information about the whole body and my sis also devised distribution so we can study by distribution of the Our imaging products in order to have information about the target organs and In order to hide it the results obtained with food Festivity so it is a clinical approach i think that to happen ahem a comb a probe that can give you a Signal in both in optical imaging and photo boosted imaging is a it’s a great opportunity so for example for the gold nanorods, we don’t have any signal in your tumor We are focusing imaging but they, don’t give us any cena in optical images so we can, say if this gold, nanorods give goes in the tumor or not i think, that this is an important case and it’s important to have information From off2kali videos okay? Yeah great so a. Question, that’s come, in that’s related to that is and you mentioned you know using Another modality to validate some of these results a question is coming in saying in the u-87 model You’re, talking, about uptake in the two more but they they’re Saying it seems that the icg rgd is localized around the tumor and in the rim around the rim of the tumor Do you, won’t want to just give us some some explanation of that if possible Yeah of course, we select two tumor models that? Yeah, that’ll have different alpha beta 3 expression but, we? Also know that the hisagi, beta 3 is also spread tested, by the Neon, tjanus investors and in these extenders models i think that they’re important components of a mobility Expression is also being prompted it also is profound the vessels of the name use Neon the genesis vessels so we can observe a difference in us e7 mg and 851 Because they express different They, have different expression over v with the 3 but we also to take in consideration, that, we have also other? facets from the mouse Okay, great yeah, and and just you know in my experience as, well i’ve seen You know there is this rim effect with, these tumors, where You know there may be you know Neo, angiogenesis happening around the rim of the tumor and therefore as you mentioned you get this distribution but i think, also You know because that’s sort of where these larger feeder vessels are you tend to get more distribution around around that rim as, well There’s another question here let’s see Do you have an explanation for why untargeted qc1 When went into the tumor when the structurally similar, dyes like icg did not Probably due to Binding so if we yeah with, what, we think that happened? Is that when he injected through cruncher it probably binds to augment and so Via a prf fact, we can have an Accumulation in the tumors the passive targeting in the tumor icd Of course but and so how, women but is characterized By very fast as, well as clear so it’s difficult to see icg after for example one hour in the tumor Okay, so you’re, saying that the clearance of icp is likely just Responsible it’s cleared so much faster than it just doesn’t have the chance to have this nonspecific you malaysian versus kisi, one okay Is there any reason Why, you see such a long Circulation time of the of the gold nanorods versus you know. These other dyes and things i feel It should be due to their dimension Because the gold nanorods are our metallic nanoparticles so they And they are fig-leaf so they are not they have a very low Blood, clearance and they accumulate in the liver so it’s a Whole this feature are typical of nanoparticles and in this case metallic nanoparticles while Other molecules like icg have a pastor had clearance as we already told her or when, we ingest ice in the Mouth, they, bound to albumin, and will increase their First respond, to me and we expected this decrease the acoustic signal so This or this factor affect, the blood clearance that, we measure, we have to seek energy Okay, but i mean you’re you’re Solid lipid nanoparticles were also pegylated right, why, why, do you think the blood clearance of those Was faster than the gold nanorods? This is a question that, we? They are so they different nanoparticles so the The icg are made of phospholipids moreover so this i think that this kind of fact that clears but, moreover the loading of icg yes Could be not as stable as the good not and this can affect of course the black spheres Okay, i see i see you’re Saying so related to that are the are your solid Lipid nanoparticles are those biodegradable so for example if they you know get into the tumor and a nonspecific way Will they biodegrade and sort of release the the free free die at that point so i really can’t answer for these permission but, what i think that they are biodegradable of course, we are country We don’t have a Ability in vivo of these and of course Okay, yeah understood it’s a complex question It’s a difficult question to answer i understand but okay another question There’s a somebody asking a question About the recommendation for the best agents for visualizing metastatic tumors so in your In your experience you know with your particles that you’ve created here be good for trying to image metastases i’m sorry, we done we just try these nanoparticles and sarah that is of course not i Think, my suspect so i am no i don’t know. If we can do it Okay, but but i mean the The reason for developing these kinds of agents is is one of the applications to be able to you know Image image sites of metastases so if you have a targeted particle you know if you know where the Tumor is you can you can see the Distribution of the the molecule that you’re interested in but it is one of the applications as, well to be able to develop These types of particles so you can ingest it just inject them systemically and be able to detect metastasis of course we observe that This is more? of Icg ftd because because, we observed that the melanoma is the Parameter 3, so we can do something about, we can increase the specificity of i see a diagnosis of melanoma of Using, high ctr. Can be compared food on the icg without any target Okay, okay great thanks um that’s a actually one more question, about the optical imaging i Noticed and and i may need to go back to that slide because i can’t exactly remember but it seemed there was actually a lot of signal in the kidneys And and usually icg is cleared through the liver and then through the gut, so here we go, yeah thanks so is there a reason that the targeted icg seems to be Really, highly! sort of taken up in the Kidneys, do you have an explanation for that Yeah, we think that of course the icg and the cg. Are tv we expected a totally different. By distribution Because again, they are different molecules of course the dye path Feels the same but their tv binding is could affect. The Clearance of the molecule of course, and yeah we expect, me and were surprised, by, these kidney Kidney, clearance but Yeah, we think that maybe because it’s a small molecule we can, do some clearance from Kidney instead huh believer ok, interesting so this is just a difference in you know biochemistry and and the resulting sort of from distribution of that yeah also
Because for example after 24 hour the signal from the wall mouse if or there i found i cg is lower Compared to the seen on their iphone mycgs vd so it’s Obvious in this case you have different. By distribution, these different blood clearance, also because you can, see that in the case of Isolated ingested mind the wall mount is Give signal compared to the greater signal compared to the icg Right did you take a look With photoacoustic imaging at at any biodistribution so did you take a look at the kidneys of this of these animals In vitro you mean In in vivo in vivo cuz. I guess at the different time points you could, also you know You, have the organs excited here obviously but yet the different time points you could look in vivo and just see differences in bio distribution potentially Yeah, ok, ok? alright, well thanks thanks so much dr. Carpoza thanks everybody for Thinks i’m ruined for attending if You know if you, do have more questions please Send us an email you can, go to our website too to find our contact information is wwe visual, sonic’s calm and just go to the contact page and Send us your questions I’ve got a couple short slides to to show here we’ve got a couple of Promotions that that were working on right now one is the the vive micro marker giveaway so If you’re, interested in doing targeted molecular imaging We’ve got ultrasound contrast agents, so these are phospholipids shale, bubbles with a Four floor butane core gas core And they’re stripped avidin aidid so you can put about unrelated antibodies on them and do targeted imaging within the vasculature and We’re doing a giveaway of these bubbles right now so if you have a targeted Imaging study that you’re that you you’re interested in in exploring Please submit via the website here you can, go to the link at the bottom of the page there Submit your idea for how. You would use the targeted bubbles for your study, and we’re evaluating them here and you could win a supply of owls i Just, also, want to point out, some resources, we have on our website if you go to our vevo blog You can, see how. These bubbles can be used for molecular imaging So, again, these are these are fda approved Bubbles abraço that braco, makes that were used in a study for detection of essentially liver liver cancer So you can, see how. They’re being used in the clinic and how. You might be able to apply them to your preclinical models I, also, want to point to our april 2016 webinar so if you go under our resources page on our website under webinars The data, that dr. composer Was presenting here this is sort of a? Workflow of how to use the the vivo laser, system the system that she was using to? Gather this data this is how, to use this it’s sort of like a tutorial of how, going, through a Molecular imaging study for cancer research looking at micro distribution and pharmacokinetics very similar to the kinds of things that dr. carpoza Was doing using different particles in this case but this is just a really nice sort of? Walkthrough, stepping through, each step of the study from Characterizing these agents in vitro to to going in vivo doing the multispectral imaging doing the spectral and mixed thing Quantification and all of that so if you want they’re really sort of in-depth details of how This study or these types of studies are conducted you can, check out that webinar Again, it’s under our resources page Under education webinars that’s april 2016 webinar Finally although dr. Raposa, was using the vivo laser we do have a, new? System which is the vive laser x this, was launched back in february And there’s a few and you’ll notice right away it looks quite different than the vivo laser system It’s really up this multi modal system for doing co registered multimodal imaging you get anatomy function molecular information all in one platform It’s got a touch screen for for a really, smooth workflow it can be customized for a particular user or study We have new, laser technology for faster more sensitive acquisition We also have an expanded wavelength range so in addition to the 680 to 970 nanometer range We also have the 1200 to 2000 nanometer range And we’ve customized the light delivery so on the the probes that director proposes it was using? We integrate the light into the housing of the transducer and permanently in this case we’re taking our transducers and were able to snap a jacket over top and and Change the different fibers to get either a wide field of view or a narrower field of view with increased depth and sensitivity So you can, use the the Illumination that suits the application We’ve talked a lot here about molecular imaging but there’s, also applications for neuro Cardiovascular applications looking at things, like ischemia oxygen saturation that kind of thing And finally you know Again dr. Carpoza is talking Pretty much about just the Photoacoustic imaging aspects. And she’s of course showing. These images co registered with, high resolution Anatomical detail with the ultrasound But it should, also be noted that you know. There are many other tools on the system as, well so going from You know this in depth you know multispectral imaging for doing the molecular imaging Right down to just doing plane you know Tumor, sizing seeing the anatomy, also doing hypoxia and ischemia measurements there’s blood flow And perfusion measurements, using the micro bubbles as, well and then targeted imaging, using the micro bubbles, so there’s there’s lots of? features and Ways of quantifying, your data, using the system, again, please reach out to us if you have, any any questions about About the technology thank you, again dr. Herb poza thank you everyone who’s attending and? Again, we’ll be we’ve recorded this webinar and we’ll be distributing it within the next week or so thanks very much everyone have a great day

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