Common cancer therapies can have off-target effects that lead to unwanted toxicities and debilitating side effects. To help therapeutics accumulate specifically at tumor sites, researchers develop novel nanomedicines made of polymers that more precisely carry and release their drug cargo.
Jingjing Sun, a nanotechnologist and cancer researcher at the University of Nebraska Medical Center, works to improve the tumor targeting and penetration of nanomedicines so that they can become more successful in human clinical trials. Her team recently developed a small nanocarrier that actively delivers a poly (ADP-ribose) polymerase (PARP) inhibitor and a demethyltransferase 1 (DNMT1) inhibitor to tumors in mouse cancer models.1
What advantages do polymer-based drug delivery systems provide?
Polymers are unique because of their versatile properties. We can easily change the polymer structure and the repeating units to allow the carrier to deliver hydrophobic drugs, hydrophilic drugs, or therapeutic nucleic acids. It is fascinating because one can adjust the units just a little to cause a large change. We can improve the polymer parameters to make optimal nanocarriers for whatever purpose we choose.
How do nanocarriers typically target to tumors?
One way is through a passive targeting mechanism called the enhanced permeability and retention (EPR) effect. Compared to normal tissues, solid tumors have leaky vasculature, so small nanoparticles can easily penetrate. Another way is to add a targeting ligand to the polymer nanoparticles so that they can specifically interact with a receptor on the tumor cell surface.
Why did you build a therapeutic carrying 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 portion of cancer patients. My team wanted to expand the application of PARP inhibitors to both BRCA-mutated and wild-type cancer patients. Research from our laboratory and others showed that combining the PARP inhibitor with a demethylation inhibitor can enhance DNA damage and cytotoxicity to tumors.
We developed a new polymer that is conjugated with hydrophilic AZA. This polymer can serve as a prodrug polymeric nanocarrier to load a variety of hydrophobic drugs, such as BMN673. With this system, the PARP inhibitor is delivered together with AZA to enhance therapeutic efficacy. Our nanoparticles are small, but they have high drug loading capacity and excellent formulation stability.
How does this nanocarrier target tumors?
People often assume that small nanoparticles selectively accumulate in the tumor through the EPR effect. We found that this is not the major mechanism for our nanoparticles. After intravenous injection, our nanoparticles were coated with serum proteins. Proteomic analysis showed that the major protein present on the small nanoparticles compared to larger nanoparticles was fibronectin (FN), which plays an important role in mediating nanoparticle transcytosis through tumors. FN can interact with the integrin receptor ITGA5 on the cancer cells, facilitating active targeting. Through transmigration assays and in vivo tumor penetration studies, we confirmed that our nanoparticle was more effective at penetrating tumors due to the ITGA5 and FN interaction, not the generally assumed EPR effect.
How effective was your therapeutic?
We tested the efficacy of our nanocarrier formulation in several in vivo models. Compared to free drugs without a carrier, our nanomedicine inhibited tumor growth more effectively. We also evaluated changes in the tumor immune microenvironment and found that our treatment increased the percentage of CD8+ T cells and natural killer (NK) cells in the tumor tissues. This means that our nanotherapeutic better stimulated an anti-tumor immune response compared to the free drugs alone or in combination.
What is next for your work on this nanomedicine?
I would like to further investigate the underlying mechanism of this combination drug and optimize the dosage. In our study, we used lower dosages of both AZA and BMN673 at a fixed ratio of one to one. Perhaps different ratios, such as less AZA and more PARP inhibitor, will work better.
This nanoparticle is not AZA specific; it can work with many nucleoside analogs including gemcitabine. My team has previously used this gemcitabine-conjugated polymer for pancreatic cancer treatment, and it has been quite successful in the laboratory.2 We want to translate this drug to clinical trials—it has received FDA and EMA orphan designations, and we are scaling up its manufacture. My dream is to do useful research and have my findings result in products that are beneficial for patients.
This interview has been condensed and edited for clarity.
- Luo Z, et al. In situ formation of fibronectin-enriched protein corona on epigenetic nanocarrier for enhanced synthetic lethal therapy. Adv Sci. 2024;11(19):2307940.
- Wan Z, et al. Overcoming pancreatic cancer immune resistance by codelivery of CCR2 antagonist using a STING-activating gemcitabine-based nanocarrier. Mater Today. 2023;62:33-50.
