A Molecular Mystery: Cracking the Case of the Ideal Nasal Spray Candidate
My workspace was silent, but my mind was racing. I had a case to solve – a molecule to catch. Its offense? Being a viable candidate to create a nasal spray formula for a neurological condition, since nasal sprays allow for fast, targeted delivery via nose-to-brain transport and bypass the Blood Brain Barrier (BBB).
I sifted through the evidence – carefully examining chemical properties, solubility rates, and bioavailability data, as I searched for our suspect. The case had been open for a week, and real human lives were on the line, so I needed answers. Fast.
The suspects were lined up– each with unique qualities that could make or break the case.
The first suspect, Tauroursodeoxycholic Acid, alias TUDCA, was a neuroprotective, meaning it protected neurons from damage and degeneration. It also had anti-inflammatory and anti-apoptotic (cell death prevention) properties — making it an effective treatment for several neurodegenerative diseases. However, further investigation revealed that TUDCA was already available on the market as a common oral nutritional supplement. Usually, the drawback of oral medications is that high doses are administered to compensate for the significant proportion of the medication that is lost through first-pass metabolism. However, since TUDCA is a naturally occurring bile salt in the body, excess dosing poses no harm— eliminating the need for alternatives to oral administration. Furthermore, TUDCA requires long-term use to display neuroprotective properties, decreasing patient compliance. Suspect Eliminated.
The next suspect, Erythropoietin (EPO), seemed more promising for Traumatic Brain Injury indications as an anti-inflammatory, but it too had its flaws. EPO is a large, complex glycoprotein, posing issues with permeability at the Blood Brain Barrier (BBB). Furthermore, as a protein, it faced difficulty in maintaining structure and stability outside its natural environment — essential qualities for a good nasal spray. Another dead end.
Just like that, one by one, the weak links were eliminated.
Then there was Temozolomide (TMZ) — a relatively modern chemotherapy drug, that quickly earned a reputation as the standard treatment for Glioblastoma multiforme (GBM). Not only is GBM the most common type of brain cancer in adults, it is also the most aggressive, accounting for the highest proportion of malignancy, with a median survival of 14.6 months, despite treatment.
It seemed promising, so I took a closer look at its profile.
TMZ is an alkylating agent– which means it adds an alkyl group to the DNA of cancer cells, causing DNA damage that triggers apoptosis (cell death) in these cancer cells. However, TMZ is currently only available on the market in oral and IV forms, causing several problems:
- A 100% of TMZ, administered orally and through IV is absorbed by the body and enters systemic circulation. However, only 30% is bioavailable, by the time the medication reaches the brain, meaning 70% is over administered, causing side effects in the body. A nasal spray alternative could mean a reduction in administered dosage and targeted delivery.
- Nausea and vomiting are common side effects of chemotherapy, making oral administration of TMZ ineffective.
- TMZ has a short half life (1.5 hours), meaning it is metabolized by the liver very quickly when administered orally/ through IV. This necessitates frequent administration, decreasing patient compliance.
Furthermore, TMZ’s lipophilic properties give it an advantage in bypassing the BBB.
Finally! I had identified my prime suspect.
Case closed? Not yet. The next phase of investigation will test the molecule’s real-world potential across three categories: solubility, stability, and permeability. Will it pass, or will it be uncovered as a theoretical decoy, requiring me to reopen the case?
The investigation continues….
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