Project Update – 11/20/2020

It’s been a while again – midterms put a damper on updating this site, but now that I’m done with that, I’m planning to start rifling through tons of papers – we’ve already found a couple things that we’re looking to talk about in our video that I’ll cover here, and once we have more information about the script and direction of our video I’ll be sure to update this website accordingly!

Firstly, we’ve shifted away from polymer and non-organic nanoparticles. There’s a not a lot of research dedicated to the edibility of these types of nanoparticles, which makes it difficult for us to figure out if it’s even possible to have targeted drug absorption and releasure. Plant-based nanoparticles, however, are inherently edible and relatively less toxic – and have been recently looked at as a possibility for nanovectors for biologically active components, which is exactly what our siRNA treatments aim to be. After doing some more paper research, we’ve found a couple of really interesting things that we plan to focus on going forward for our video and final presentation:

Firstly, plant-derived nanoparticles are nontoxic and relatively more hypoallergenic compared to other types of nanoparticles. This makes them a prime candidate for long-term, large-scale production as treatment, as the particles don’t need to be tailored to specific patients in the same vein as experimental cancer treatments today.

Secondly, plant-derived nanoparticles are already edible but have also been proven to be extremely effective as drug transport for chemotherapy drugs (and miRNA/siRNA, but we’re currently looking into the feasibility of these specifically), and are very effective in their staying power within the bloodstream.

We just need to hone in on siRNA targets to implant into our nanoparticles, but beyond that the majority of our research should be finished! I’ll update this post once more when we have that more concretely down, along with starting a script for our video!

Project Update – 11/07/2020

I had a meeting with Dr. Qiaobing, an expert in the field of nanoparticle drug delivery over the week on Wednesday, and it was extremely useful! We ended up not talking for as long as I expected, but he asked a lot of questions that made me think about the feasibility of our project and exactly what we need to consider during our research. Feasibility is not just one of the biggest problems when considering a project of this scale – rather, Dr. Qiaobing pointed me to looking toward the niche my treatment would fulfill.

More specifically, he asked me to think long and hard why such an edible treatment would be necessary – what types of benefits would it bring compared to current treatments in the market. And, additionally, would such a treatment accomplish enough/occupy enough of a niche to be able to justify its development and manufacturing costs?

Furthermore, Dr. Qiaobing directed me to different technical nanoparticle synthesis types:

Nanoparticle Synthesis — 

  • Different people use different approaches, lipid-based, polymer-based, inorganic particles. 
  • Lipid-based
  • Synthesize lipid, throw into aqueous solution — makes nanoparticle
  • Polymer-based
  • Depending on properties, you can do something similar to lipid-based
  • Inorganic-based
  • AuNPs, similar, etc.

along with a bunch of new research avenues to look at! I’m starting to look at papers this weekend, and we hope to have a sizable knowledge base by next weekend to begin presentation/video scripting.

Project Development – 11/02/2020

It’s been a while since I updated this, mostly due to the fact that I didn’t think about anything worth updating – but now that I have a group, along with a slightly-edited idea (more on that below), I’m expecting to have a lot more stuff to write about in the coming weeks! Also, the video’s coming up – and that’s going to be an entirely separate beast to tackle…

So, as I might have mentioned earlier, my original plan was to use siRNA-infused nanoparticles to create a novel cancer treatment that would have clear translational possibilities into clinical trials. However, after talking with Professor Kaplan in a meeting, he told us to dream bigger – look into something you might not be able to directly take into research, but has much, much bigger impacts.

So, he suggested an idea (and I came up with another one), and our updated PDR has a slightly bigger vision – a baseline NP therapy to prevent cancer before it happens. Think about iodine salt – iodine deficiency was one of the leading causes of intellectual and developmental disorders before the widespread introduction of salt fortified with micrograms of iodine. In a similar vein, Professor Kaplan and our group are starting to look into edible NPs, which would carry siRNAs not targeted at one specific cancer, but rather a wide variety of oncogenes in an effort to silence mutated cells that may evade immune detection before they get out of control. We would have to look into how to synthesize NPs that can both survive the digestive tract without destruction, while also capable of absorption through the intestine or stomach wall. We currently have a meeting with Dr. Qiaobing Xu, who is an expert in this field, which can hopefully point us in a direction for this!

The idea I had – which is lower priority, but still an interesting expansion that we can look into should we have time/space in our video – surrounded an “adaptive” NP. Something like a synthetic immune cell, that could target cancer or viruses with siRNA or more targeted therapies and is capable of “switching” its target and drug delivery to match a different cancer or threat. Such a technology would be incredibly difficult to make, as development of that sort on the nano-scale would likely have to be entirely chemical in nature, while simultaneously avoiding denaturing of siRNA or other drugs within the NP. Further research pending on both these topics.

One-Page Project Summary/PDR

PRELIMINARY DESIGN REVIEW: Nanoparticle Lung Cancer Therapy

DATE: 10/13/2020

TEAM: Justin Wang, Jordan Berke, Zayn Jacob Ratzliff, Zayn Merzouk

CRITICAL ISSUE

Cancer has been one of the most prevalent and dangerous incurable diseases in the past century — and has acted as a major barrier in the advancement of medicine. However, cancer therapies from different angles have promised to change the way we approach cancer treatment — at current, cancer treatments are mostly focused on blanket therapy, preventing all manner of rapid replication, but with side effects that greatly reduce patient quality of life. Genetic therapies have offered a promising alternative, with targeted therapy that reduces side effects and can be exceptionally effective depending on the type of cancer and the physiological method of the treatment. siRNA, or small interfering RNA (a dsRNA strand that can silence mRNAs and mark them for cleavage and degradation), has been a promising avenue for genetic research — with very narrow targeting, very reliable success rate, and post-transcriptional modification that extrapolates easily to other forms of cancer. However, due to the thermodynamically unstable nature of the molecular structure of siRNA (with an exposed 3’ end, and the degradable nature of dsRNA in general), transport and execution of the treatment is the most difficult aspect of siRNA targeted therapy. We propose a relatively novel solution in the scenario of lung cancer: nanoparticle mediated transport of siRNA through an inhalable therapy, likely utilizing gold-based nanoparticles (AuNPs). Nanoparticles, or small particles with a diameter < 1-100 nm, are both relatively nontoxic and highly customizable — the shell of an AuNP can be coated in a multitude of ligands and receptors, making identification of cancer cells for directed dosage much easier than through other dosing strategies. In addition, NP encapsulation of siRNA for treatment drastically reduces probability that either the immune system or general chemical interactions will degrade siRNA to an unfunctional state before entry into the cancer cell.

STATE OF THE ART TECHNOLOGY:
At the moment, state of the art technology regarding this specific treatment is not well defined — reviews only mention the possibility of siRNA delivery using a variety of synthesized NPs, but our group was unable to find any full-scale trials of this in either in vitro, or in vivo settings. However, synthesis of NPs has become increasingly specified — ligands and receptor proteins can now be implanted onto the surface of NPs, a fact that we will be taking advantage of to specify our NP treatment to only cancer cells. Furthermore, siRNA treatments for cancer have already been investigated in vitro research, and are proceeding to clinical trials with widespread success — however, the majority of these siRNA treatments, whether it be for cancer or other settings like respiratory viruses (respiratory syncytial virus) mostly function on topical or local installations of siRNA, rather than a more holistic approach that NPs may provide. Furthermore, immune intervention into  siRNA treatments is a widespread factor influencing possible delivery mechanisms — phagocytes are designed to degrade/consume siRNA on contact, as some viral infections utilize similar processes. At the moment, lipid or polymer-based delivery systems are the most effective, which may influence the synthesis of our NPs. 

FUTURE IMPLICATIONS

Future implications of this research are widespread — by meshing together two major areas of research, we can pave the way for not only additional research into NP therapies surrounding RNAi, but also open the door to less invasive cancer therapies. Even genetic treatments, that have vastly reduced side effects compared to traditional chemotherapy, are both extremely selective on biological characteristics of the patient and still relatively invasive, requiring administration and constant monitoring by medical professionals. An inhaled treatment utilizing NP-mediated siRNA therapy hopes to solve both these problems — an inhaler is a much simpler method to administer treatment, and can be done without the help of a medical professional. Additionally, RNAi does not necessarily have as many genetic prerequisites for treatment — siRNAs function on mRNA cleavage, rather than the DNA code itself, so RNAi treatment eliminates the need for restrictive binding sites or specialized gene mapping for direct gene editing (although the mRNA sequence for the targeted protein/proteins does need to be known for siRNA binding to be effective). 

PRO/CON TABLE

PROSCONS
Easily administered dose — inhalation, as with an asthma inhaler, that can be administered without a medical professionalHighly effective should siRNA be configured correctly for a complementary mRNA and transported correctly into cancer cellsLow chance of side effects — if nanoparticles are synthesized correctly, nanoparticle entry should only occur in cancerous cells, with different surface coatings, rather than noncancerous cells.No direct genetic editing, so genetic intervention is both more specific and less prone to unintended side effects.NPs and especially siRNA are degraded quickly, even inside cytoplasm — multiple doses or higher dose values may be necessary to compensate for low siRNA half-life.High concentrations of NPs in the body (depending on NP shell material) can be toxic, balancing required between siRNA half-life and NP concentration in final therapy.Inhalation contamination — much more specified treatment than other inhaler-based therapies, there may be unforeseen circumstances between the contamination of a inhaler-based treatment rather than a direct injection. 

REFERENCES: 

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681865/
  1. Low-level explanation of nanoparticle endocytosis
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214025/
    1. Higher-level explanation of nanoparticle cancer therapies
  3. https://www.nature.com/articles/nrd2742
    1. General review in siRNA delivery mechanisms and applications 

(TO BE ADDED TO, SHOULD ADDITIONAL REFERENCES BE FOUND/UTILIZED)

Project Development – 10/10/20

I’d like to first apologize for the long downtime between posts – in the meantime, I’ve done research into reviews surrounding nanoparticles and siRNAs, and have recruited 3 more people to join me as a 4-person group on the nanoparticle siRNA project (though a better name is pending if one of my groupmates comes up with a flashier title). Overall, we are currently still working on the presentation on Tuesday for a general project overview, however we believe that our project will likely be focused on nanoparticle therapies targeting either the lungs, liver, or kidneys – these are organs that accumulate large percentages of nanoparticles naturally, which assists in reducing dosage and/or ease of delivery into the cancer site. However, before in-depth research can be done onto this topic, we must first clarify both the mechanism of action and the previous research and therapies created through siRNA. In addition, we must also investigate research on the creation, development, and delivery mechanisms of nanoparticles, in order to better understand the context surrounding nanoparticles. Finally, we must bring both sides together by investigating current research into siRNA nanoparticle therapies, and the interactions between unstable dsRNA and nanoparticle interiors – and furthermore, how to manufacture particles around unstable dsRNA samples.

Professor Kaplan has directed me towards Professor Qiaobing Xu, an expert in the field of nanoparticles and siRNA research – and he relayed a review to me that will be invaluable in producing the upcoming introductory presentation. However, Prof. Xu has unfortunately not been able to reply to my attempts to directly reach him through email – but I hope to develop a relationship between him and this team so that we may ask him questions and clarification for some of the more complex aspects of the project as a whole.

Finally, as per requirements of the class, I have also created a project-centric website at sites.tufts.edu/nanoparticlesirna that will be the home for most of our technical progress updates on research and creation of the final-video-project.