Achieving excellent anti-cancer effects in a small package

CCommon cancer treatments can have off-target effects that cause unwanted toxicities and debilitating side effects. To help therapeutics accumulate specifically at tumor sites, researchers are developing new nanomedicines made with polymers that more precisely deliver and release drugs.

Soon Jin JinA nanotechnologist and cancer researcher at the University of Nebraska Medical Center, he works to improve tumor targeting and penetration of nanomedicines so that they can be more successful in human clinical trials. . Her team recently developed a small nanocarrier It actively delivers poly(ADP-ribose) polymerase (PARP) inhibitor and demethyltransferase 1 (DNMT1) inhibitor to tumors in murine cancer models.¹

What are the advantages of polymer-based drug delivery systems?

Polymers are unique due to their versatile properties. The polymer structure and repeat units can be easily modified to allow the carrier to deliver hydrophobic drugs, hydrophilic drugs, or therapeutic nucleic acids. It's fascinating because small adjustments to units can cause big changes. Polymer parameters can be improved to create optimal nanocarriers for the chosen purpose.

How do nanocarriers typically target tumors?

One method is through a passive targeting mechanism called the enhanced permeability and retention (EPR) effect. Compared to normal tissues, solid tumors have leaky vasculature, which allows small nanoparticles to easily penetrate. Another method is to add targeting ligands to polymeric nanoparticles, allowing them to specifically interact with receptors on the surface of tumor cells.

Why did you develop a treatment that contains both a PARP inhibitor (BMN673) and a demethyltransferase inhibitor (AZA)?

Many PARP inhibitors have been approved to treat BRCA-mutated cancer types, including some breast and pancreatic cancers. However, BRCA mutations occur in only a small percentage of cancer patients. My team wanted to expand the application of PARP inhibitors to both BRCA-mutant and wild-type cancer patients. Studies from our laboratory and others have shown that combining PARP inhibitors with demethylation inhibitors can enhance DNA damage and cytotoxicity to tumors.

We have developed a new polymer that combines hydrophilic AZA. This polymer serves as a prodrug polymer nanocarrier for loading various hydrophobic drugs such as BMN673. In this system, PARP inhibitors are co-delivered with AZA to enhance therapeutic efficacy. Although our nanoparticles are small, they have high drug loading capacity and excellent formulation stability.

How does this nanocarrier target tumors?

People often think that small nanoparticles selectively accumulate within tumors due to the EPR effect. We found that this is not the primary mechanism for nanoparticles. After intravenous injection, the nanoparticles were coated with serum proteins. Proteomic analysis shows that the major protein present in small nanoparticles compared to large nanoparticles is fibronectin (FN), which plays an important role in mediating tumor-mediated nanoparticle transcytosis. It was done. FN interacts with the integrin receptor ITGA5 on cancer cells and promotes active targeting. Through extravasation assays and in vivo tumor permeation studies, we confirmed that our nanoparticles were more effective in tumor permeation due to the interaction of ITGA5 and FN rather than the commonly assumed EPR effect.

How effective was your treatment?

We tested the efficacy of our nanocarrier formulations in several in vivo models. Compared with carrier-free free drug, our nanomedicine inhibited tumor growth more effectively. We also evaluated changes in the tumor immune microenvironment and found that treatment increased the proportion of CD8.⁺ T cells and natural killer (NK) cells within tumor tissue. This means that our nanotherapeutics stimulated anti-tumor immune responses better compared to free drugs alone or in combination.

What are your future efforts regarding this nanomedicine?

In the future, we would like to further elucidate the mechanism of this combination drug and optimize its dosage. In our study, we used both AZA and BMN673 at low doses in a fixed ratio of 1:1. Perhaps a different ratio would be more effective, such as less AZA and more PARP inhibitors.

This nanoparticle is not unique to AZA. Can be used with many nucleoside analogs, including gemcitabine. My team has previously used this gemcitabine-conjugated polymer to: pancreatic cancer treatmentand it was very successful in the lab.² We would like to move this drug into clinical trials. The drug has received orphan designation from the FDA and EMA, and manufacturing is being expanded. My dream is to conduct useful research and turn the results into products that benefit patients.

This interview has been condensed and edited for clarity.