From the nose to the lungs

Although vaccination campaigns against COVID-19 are in full swing, research is ongoing to find treatments for the disease. Indeed, there is a most convenient route to deliver drugs to the lungs without affecting the rest of the body: the nose and the airways. Professors Antonella Badia’s and Christine DeWolf’s teams have joined forces to develop a carrier which delivers a drug from the nose to diseased lung cells.

Their research, however, does not focus on COVID-19 but lung cancer, and Christine DeWolf banks on a peptide featuring both anticancer and antimicrobial properties. “The peptide carries a positive charge and targets the negatively charged membranes of cancer and microbial cells,” explains Christine DeWolf. As lung infections often affect lung cancer patients as comorbidities, delivering this peptide to the lungs would be a doubly smart move. The problem is that, on the way, the peptide runs into proteolytic enzymes that digest it. To protect the peptide, Christine DeWolf and Antonella Badia have chosen to load it into a phytoglycogen nanoparticle. Extracted from corn, phytoglycogen has another interesting feature: it forms dendrimers, i.e. spheres with an internal tree-like structure. “The nanoparticles are modified to carry a positive charge. Electrostatic interactions, along with the dendrimer shape itself, explain how the nanoparticle can trap the drug inside,” explains Laurianne Gravel-Tatta, MSc student working on this project. By modifying the chemical groups at the dendrimer surface, it is even possible to fine-tune the peptide loading and mobility.

But once it arrives at the lungs, the peptide-loaded dendrimer comes across another obstacle: lung surfactant. A layer made of lipids and proteins, the surfactant keeps the alveoli together during expiration while also helping them to expand during inspiration. The dendrimer must cross this surfactant without hindering breathing. At Université de Montréal’s Department of Chemistry, Antonella Badia provides her expertise in microscopy to observe the configuration acquired by the surfactant upon contact with the dendrimers. At Concordia University’s Department of Chemistry and Biochemistry, Christine DeWolf applies her expertise in x-rays to shed light on the molecular-level organisation of the surfactant. In addition, Prof. DeWolf’s expertise in rheology allows her to study the mechanical properties of the surfactant. “One has to pin down the dendrimer concentration threshold above which the dendrimer starts to have negative effects on the surfactant,” describes Antonella Badia. “And we also want to maximise the drug loading in the dendrimer, while still keeping it to a safe level to avoid harmful effects,” adds Christine DeWolf.

Lastly, the dendrimer must not only cross the surfactant without hindering breathing—it must also release peptides. “There are enzymes breaking down glucose in phytoglycogen and when the dendrimer is degraded, it frees the peptides,” explains Christine DeWolf. And these enzymes are more active in tumour cells than in healthy ones.

Like in a jigsaw puzzle, all the pieces are there but the challenge lies in putting them together.

This research project was supported by a QCAM collaborative research grant and has resulted in a paper published in Langmuir: “Are Plant-Based Carbohydrate Nanoparticles Safe for Inhalation? Investigating Their Interactions with the Pulmonary Surfactant Using Langmuir Monolayers“.

Original French text by Valérie Levée.

Translated by Matteo Duca, Development and scientific affairs director of QCAM

Read the original post (in French)

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