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)

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