This month, a paper published by University researchers Richard Terek and Qian Chen highlighted a potential nanotechnology therapy that targets chondrosarcoma, a rare type of bone cancer. Using nanoparticles, the team effectively delivered therapies directly into tumor cells and observed decreases in tumor volume and prolonged survival in mouse models.
Chondrosarcoma currently has no FDA approved treatments. The complex makeup of these cancer cells makes them uniquely difficult to treat. Specifically, “one challenge to (drug) delivery in chondrosarcoma is the negatively charged proteoglycan-rich extracellular matrix that needs to be penetrated to reach the tumor cells,” according to the study.
Terek, the chief of musculoskeletal oncology at Rhode Island Hospital, an orthopedic oncology surgeon with the Lifespan Cancer Institute and a professor of orthopedic surgery at Warren Alpert, studies chondrosarcoma and collaborated with Chen, a molecular and nano-medicine researcher, director of the NIH-funded Center of Biomedical Research Excellence in Skeletal Health and Repair at Rhode Island Hospital and a professor of orthopedic research and medical science, on this study. The pair aimed to develop a nanopiece delivery platform capable of penetrating the convoluted chondrosarcoma matrix.
“We develop nanomaterial (that) we call nanopieces and we found that it can deliver nucleic acid therapeutics to tissues that normally are very difficult to be penetrated,” Chen said.
In addition to getting drugs to the tumor tissue, the researchers also studied the biology of how chondrosarcoma spreads. “The other thing is we don’t totally understand what drives cancer cells to metastasize. That part of the work involves trying to disentangle which types of pathways have gone awry,” Terek said.
The underlying principle of the therapy is that miRNA, short 21-nucleotide sequences, are overexpressed in chondrosarcoma tumor cells. These miRNA end up functioning in a way similar to oncogenes, genes which drive cancer formation, by indirectly affecting other genes in the cancer pathway.
Terek’s work over the past decade has culminated in the identification of the cancer-causing, or oncogenic, miRNA involved in chondrosarcoma formation. “That process involved microarray analysis of primary human tumor tissues. We used a variety of screening techniques to identify which miRNA were overexpressed in tumors,” Terek said.
These detrimental effects of the oncogenic miRNA can be prevented by “synthesizing a molecule of the opposite sequence of nucleotides. Once delivered into the cell with the nanoparticles it will counteract and annihilate the overexpressed miRNA” Terek said.
Once the target miRNA was identified, the small, opposing sequence of RNA needed to be delivered, a process that is normally very difficult because of the charge and structure of the matrix formed by the tumor. “What we do in the lab is … formulate this nanomaterial specifically for penetrating into the matrix,” Chen said.
“The laws kind of break down when you get to these nano levels. At the nano level, these particles somehow get through the cell wall and into the cell, even though the cell wall is classically thought of as this impenetrable structure around the cell,” Terek said.
The nanomaterial delivery vehicle is composed of a small molecule, weighing about 400 daltons, which assembles into a nanotube structure that contains RNA. “The molecule itself is biomimetic. It’s half composed of nucleic bases and half of the molecule is amino acids, so it’s fused together. Because of that it also has a very low level of cell toxicity,” Chen said. The nanoparticle is designed to be comparable to a natural biological structure, enabling the particle to be generally accepted by cells, so it can enter and affect them.
In previous studies, Chen’s lab has shown successful use of nanoparticle therapy in the treatment of multiple other diseases, including rheumatoid arthritis. Recently, they also received a grant from the National Institutes of Health funding research on the treatment of Alzheimer’s disease using a similar nanopiece delivery system that can traverse the blood brain barrier.
In further developing this drug therapy, Terek said “one possibility is to combine multiple miRNA sequences with these nanoparticles to impact more pathways and get maximal inhibition of tumor spread.” This involves both counteracting overexpressed miRNA, and restoring beneficial cancer suppressor miRNAs to combine multiple therapeutics with one dose of the nanoparticles.
Another potential approach is to pair the miRNA therapy with other cancer drug therapies. Since some miRNAs prevent the effective use of typical cancer treatment drugs, this approach can be used to reverse drug resistance, allowing for the use of conventional therapies, like chemotherapy.
In order for nanoparticle therapy development to succeed, investors, pharmaceutical companies, biotech companies and other collaborators need to give time and money to projects like this, Chen said. “As far as moving it into the clinic, that’s always a big hurdle,” Terek said. One intermediate step the team might take is to collaborate with veterinarians — allowing them to incorporate their treatment method beyond mouse models.
“Brown and Lifespan have helped establish a startup called NanoDe so that we can continue the process,” Chen said. Moving forward, the team will continue to work on collaborating with other researchers and developers to advance this drug therapy for chondrosarcoma.