Rakovina Therapeutics Inc. (RKV:TSX.V), a British Columbia-based artificial intelligence (AI)-powered cancer therapy developer, signed a letter of intent earlier this month with NanoPalm, a lipid nanoparticle innovator in Saudi Arabia, in regards to formulation of Rakovina's anticancer drug kt3283, reported Dr. Douglas Loe, managing director and analyst at Leede Financial Inc., in an Aug. 22 Week in Review note.
"It is no surprise that the firm consummated a letter of intent with one lipid nanoparticle innovator that has documented expertise in cancer drug delivery," Loe wrote.
This is because Rakovina has been looking for a novel formulation or drug delivery modalities that could modify kt3283's pharmacokinetics to be more tumor targeted. The prospects are nanoparticle technologies and cancer antigen-targeted monoclonal antibodies to which kt3283 could be covalently bound.
Tumor Targeting is Goal
Loe explained that Rakovina's kt3283 is a first-generation drug that inhibits both PARP and HDAC enzymes, well validated as being relevant to cancer cell growth and division. PARP, or poly-ADP ribose polymerase, is involved in DNA replication. HDAC, or histone deacetylase, removes acetyl groups from DNA-wrapped histones. Rakovina seeks to identify small molecules that inhibit these two targets at the same time. The inhibition of each enzyme is involved in several U.S. Food and Drug Administration (FDA)-approved therapies.
The pharmacokinetics of kt3283 were published in Clinical Cancer Research in 2023. The paper noted the drug showed "enhanced" cytotoxicity in at least one cancer model, a mouse model for an aggressive bone cancer affecting children and young adults called Ewing's sarcoma. This means kt3283 exhibited greater anti-tumor activity than representative PARP inhibitors like AstraZeneca's Lynparza (olaparib) and HDAC inhibitors such as Merck's Zolinza (vorinostat) did individually. Further, kt3283 did so at a lower concentration than Lynparza and Zolinza would require to show their clinical anticancer activity.
What NanoPalm Does
Since its founding in 2022, NanoPalm's researcher Dr. A.H. Alhasan has been using AI tools to develop lipid nanoparticles as vehicles for delivering gene therapies and small molecules in a disease-targeted, organ-specific way, reported Loe. For many years, Alhasan has researched various drug formulation and drug delivery modalities, not just lipid-based technologies. Reportedly, NanoPalm's AI engine EnsaliX can develop stable lipid nanoparticles target specific organs and cells, something current lipid nanoparticle-based therapies cannot do.
Little to no published information exists on this technology of NanoPalm or on the AI engine behind it. However, one study published in iScience in 2022 explains that the company's methodologies create nanopalms. These are supramolecular lipid particles, or lipid micelle precursors formed into various secondary structures (sheets, discs, tubes, ribbons, cochleates/shell shapes). To guide lipid assembly into a shape, whichever one a particular application requires, NanoPalm uses "patterning-mediated self-assembly and polymer pen lithography." In past work, the shapes remained stable for at least four months after they were formed.
"It is far too early to predict if NanoPalm-derived lipid structures could be useful in facilitating kt3283's tumor-targeted delivery," Loe wrote. That said, "the concept of formulating kt3283 in a lipid nanoparticle is certainly a plausible path forward."
Secondary Structure is Key
Loe noted that a number of FDA-approved lipid nanoparticle-based anti-cancer drugs exist already. Ones mentioned in a 2023 article in the International Journal of Molecular Sciences, for example, include Marqibo (discontinued in 2020), Doxil, Onivyde and Vyxeos. The lipid composition in them varies from drug to drug, but little to no mention is made of the secondary structure of the lipid formulations themselves.
"We will be interested to see if NanoPalm's focus on lipid nanoparticle secondary structure does indeed facilitate tissue targeting of kt3283 in ways not currently achievable with conventional liposome formulations," wrote Loe.
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