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Targeted Liposomes for Preterm Labor Management: Development, Optimization and Scale up towards…

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Targeted Liposomes for Preterm Labor Management: Development, Optimization and Scale up towards Clinical Translation

Thank you very much san francisco from his mitosis research institute and today i’ll be presenting a one of my project on targeting the preterm labor management and i will start with technology itself and then the second part i’ll give an update about our process on progress progress in preparing for preclinical and clinical study so as a bit of introduction as we

Know from the last few days and you all are probably working with nano medicine and i have a schematic here from a nice review in that nature nanotechnology is about a range of application for nano medicine we use different materials for different targeting and different diseases however is still missing the obstetric and gene ecology this is a very underestimated

Field i think and i was approaching fortunate enough to be involved in the study and my pa dr. brianna gordon has started this study with lb gene which because there are not a lot of people who are working in this field and a weekend itself are very what do you say like very very old fashioned the technology has been there like the medicine that have been used been

There for like decades so there are a lot of challenges actually in this field they have a lot of problems and in this study we are targeting the preterm labor and mostly to make cure that it increases safety and of the medicine that we are delivering so that they are not reaching the feeders there are a lot of other things too that we are involved in creating clamsy

A– diagnosis as one of them well as the diagnostic and therapy but for today i’m just going to limit our presentation to the preterm labor so the significance of preterm labor is is very costly actually i’m from the us where the hoof care is not the best and well it’s actually really good that it costs a lot it calls like fifty nine thousand preterm birth and then

It costs twenty six billion dollars per year by caused by the prematurity itself from the the mortality as well as the following health problems that is caused by the prematurity and in the medicine is one of the most used to politics however they can also cross the placental barrier from maternal to the fetus and it cost a lot of problems one of the main problem

Is the doctors at risk at arteriosus structure which make the artery that goes from the pulmonary system to the heart closed so this is one of the main problem that has been have that we have in the preterm labor so as we know like the most of the free drug can transferred from the mother to the fetus freely and we can change this depending on whether we want to

Treat the fetus or if we wanted to treat the mother or as in our case you want to target the placenta we can use different kind of particles and in in our study we we did the research on the previous literature and we found that liposomal formulation seems to be able to restrict the distribution to the mother site order to the uterus site and reduce the placenta

Transfer so if we can restrict by distribution until only to the motor side it can prolong the administration of the drug and also reduce the morbidity associated with a preterm birth so one of the main point that we want to have in this project is to have increased safety especially to the feeders and another one is that we we also have a increased efficacy as we

Are on not only adding the liposome with in the medicine but we also add the auto semen this is actually a drug by itself it is approved in a in europe i am a but it’s not a proof in fda in america they actually also tocolytics which reduced of contraction however in fda i did didn’t approve it just because the the efficacy is not high enough for them not because

Of the safety concern so we aim to use this and then conjugated with indomethacin liposome and this is the schematic of our system so we all have indomethacin between the lipid bilayers and we have a linker and then add a dose even for the size we have around 900 154 and really high in the medicine loading efficiency because of the they are trapped in between the

Layers and the zeta potential about minus 20 and we found that the lip endora as we call them are accumulated mostly in the uterus and we found very low amount in the fetus as we can see here we have an increase of double of the concentration of the pandora compared to nanomedicine well in the feeders we actually have our concentration of indoor eyes as we wanted

And the effect on the contractility we checked the uterine contraction and with the cell line it did increase with we use a mice model cd1 – model with a ps induction once they are inducted they increase their has an increase in the uterine contraction while deepened or actually reduced the contraction itself this is also like the comparison in the number in the

Percentage and other them that the window medicine also reduced prostaglandin concentration we checked it and it actually sorry reduces the the peak ee concentration so as a summary for the technology itself we we managed to increase the indomethacin concentration with possible the pandora as well as we reduce their fetus concentration of it removing the reducing

The exposure to the indomethacin and here is a uterine contraction as you see the lip endora cause like really lower contraction and in in fact we actually reduce it up to like almost half of them actually have reduced in the preterm birth so the second part is about the translation into the preclinical and clinical study so we did the liposome in a normal way

Before with using the thin layer formation with rock paper and then in the extra extrusion which takes the whole day basically four five six seven hours to finish so what we’re thinking is we can use the user nano assemblers michael mace by person production to simplify the whole system because as we heard from the last few days that it’s hard to to make make the

Liposome as easy as possible to make it easier to go through that to the fda and so we did like the whole month we tried different settings different flow rate different ratio of aqueous and organic phase and we found that actually our indomethacin cost some problems with the micro fluidics so according to the manufacturers side they we only have to do like washing

Steps and those washing steps were not actually sufficient to remove the indomethacin so for the longest time we only get like sighs like for some size 60 nanometers so we figure out after we changed the chip we always get better results so we found that with this ratio 1/2 1/4 ml per minute we get like really good size about 182 which is a bit larger than the

Traditionally made particles there are like round 150 and it has similar zeta potential and the next part is we did like a whole system with for the crime protection during the rifle is asian study so we tested 7 different sugars for as a cryoprotectant and we found that the sorbitol seems to have like better potential and we found that 3% sorbitol has pretty nice

Size and very low pdi and we decided to use that as our future so we are going to also plan the gelt study in non-human primates for the pdp case study in non pregnant monkeys as well as glp studies in rats for single and multiple study so as we we figured that this this field is a really untap field that we can have a lot to be done and we have successfully then

Use a live endora to target pregnant uterus and reduce the preterm birth and now we are moving to the next phase of preclinical and clinical studies and we use a nano assembler and 3% sorbitol 4life realization and we are now have a lot of ongoing works on like establishing sops as you guys probably know as a lot of regulatory regulatory systems that we have to be

Done like batch records for violin life realization and so as the qc so lastly i would like to thank my pa dr. deanna gordon tracy he’s been working in the lab doing all the cryoprotectant study as well as i was translational fair office and he mpcore in nano medicine as well as the obg insight who did all most of the animal studies and planning on the clinical

Stuff thank you very much thank you very much for this very interesting talk so we have time for some questions from the audience one at the back thanks and i also noted that the the field of genetic ecology of birth giving is a really ancient do you have to do it do you have an idea of why industry shuts away from normal products in that field yeah so a lot

Of the gene that i talked to they are very traditional and it’s not like in the cancer field where everybody’s doing nanotechnology and and also not a lot of funding as well i think probably does one of the reason but yeah i’m i’m not sure why is it maybe certain personality goes through that i have no idea but like yeah indomethacin they’ve been using it since

The 70s and they haven’t changed it so it’s but i think it’s been changing like actually in the last few the last few years actually when we started this one so we published our paper and then read in the end of that year there are also two other papers that’s coming out in this field it’s in infancy but still it’s growing so hopefully it’s getting bigger yeah

I have one question for you so what is the the pharmacological reasons for what you see is it because your lipizzans bind to the cell surface and releasing or doing something at the cell surface or they actually internalized by the cells what we’re thinking is that the size matters because the small molecules they just go past the cells like they they have the

Epithelium that goes to the to the fetus and it seems like with the size we increase the barrier and kind of reduce the passage we haven’t checked yet how exactly because it is a really complex model so we haven’t checked yet how exactly the cells oxytocin receptors expressed by the tropic last yeah in the placenta yeah but is that an internal izing receptor when

You have the you or the actor actually attached to the lipizzans yeah the point is we want to yeah i want to have it internalized by its a center but not going through the barrier so that’s you know i mean the particles won’t go through yeah i mean yeah that is the work done by by harish patel in in mid-80s an old field yeah i don’t know why is because there’s a

Lot of problem with like pregnant women they cannot take any medicine that’s actually a big merit market for it i don’t know why it’s like yeah so any other questions so that is the end of

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Targeted Liposomes for Preterm Labor Management: Development, Optimization and Scale up towards… By TAUVOD