Cancer patients dread the hours spent hooked to intravenous lines that send toxic chemotherapy medications like Paclitaxel into their bodies, treating the tumors but also producing problematic side effects.
Now, Katarzyna Slowinska, an associate professor of chemistry at California State University, Long Beach (CSULB), is investigating how collagen, a naturally occurring bodily substance, can be manipulated into carrying and releasing cancer drugs directly at or even inside tumor cells.
She received a four-year, $433,500 grant from the National Institute of Health’s (NIH) National Institute of General Medical Sciences to pursue using short strands of amino acids called peptides to serve as drug nanocarriers. The grant also supports the work of CSULB graduate students Aparna Shinde and Mona Oumais as well as five undergraduates, Rose Pham, Myungeun Oh, Lien Uong, Steven Tu and Krista Godlasky.
“The project really came to life because we work a lot with collagen and collagen peptides,” Slowinska said. “We have about six different projects but each of the projects are related to the fact that collagen has this beautiful structure of a triple helix, so it looks like DNA, but instead of having two helices, it has three strands twisted together. This triple helix gives collagen its properties of a rigid, rod-like character, so it’s strong. This is why collagen is a main component of scaffolds that support organs and make connective tissues.”
She said that the large size of collagen molecules is difficult to work with, so they use shorter peptides. “If you look at the dimensions, it’s really a perfect nanoparticle structure because it’s rigid—you cannot bend it—and you can exchange the amino acids, so you can attach anything you like to it.”
Moreover, compared with some other types of nanoparticles, their new peptide is safe because, “it’s part of you—it’s part of the collagen structure. You’re made of amino acids, so it’s very safe to use it,” she said.
“There were several issues that we had to address to design a drug carrier,” Slowinska continued. “The first is how do you deliver it? Normally most of the drugs on the market now are delivered through an intravenous line or you swallow it. But you may ask yourself, why is the cancer killed but your healthy tissues are not? The reason is that the tumor grows really fast so the endothelial cells, which line the vascular system, don’t fit together tightly, so they’re leaky. You have spaces between them so a small particle like our carrier can sneak through. A small molecule is more efficiently delivered to a tumor rather than to other tissues because of the leaky vasculature.”
Another difficulty is that many cancer drugs don’t dissolve very well, so Slowinska’s team learned to attach molecules of Paclitaxel to their soluble peptide in the hope of increasing the medication’s effectiveness. Cell membranes also are designed to keep out intruders, so Slowinska and her students used a molecule called polyarginine to help deliver their peptide directly to cell nuclei in order to destroy the cells. And, “Normally, short peptides have about a 15-minute lifespan in the circulatory system because of enzymatic digestion,” she said, so they discovered that their peptide has the beneficial quality of a long lifespan.
“This is really the beginning of the idea of the platform—how you can stabilize the peptides to use them for many different things. Paclitaxel is the model for us, but there are many things you can deliver,” she said.
Their method could potentially do away with intravenous delivery by designing the peptides in certain ways that include molecular anchors and enclosing them in a collagen gel. “You could implant this stabilized collagen into a spot very close to a tumor, so you can also accomplish local delivery without going to a systemic circulation and limit the side effects,” Slowinska explained.
“Our hypothesis—but we haven’t tried it yet—is that our nanocarrier that we designed could be delivered from the collagen in a very controllable manner, which is what we hope for, by changing the length of the anchor. If that happens, you can control the concentration of the drug so that it’s therapeutic in tumor proximity, but nontoxic on the systemic level. And, the gel will protect the molecule from digestion. So, that’s the possibility.”
Additionally, she said, “When you heat collagen, you get gelatin and you cannot go back. But with a peptide you can—it’s just the temperature that controls the transition, so you can build completely new materials by simply manipulating the temperature. It’s like a puzzle. You can take it apart and put it back together and change the components.”
They are acquiring seven lines of cancer cells known to be affected by Paclitaxel in order to study the effectiveness of their work.
“This is only one of our projects,” Slowinska said, “but all our research goes around the presence of the collagen triple helix and how we can use it as a biomaterial, not necessarily as nature intended, but how we can learn from biology to use it as a functional material.”