Researchers from United States and Ireland have formed a partnership to advance nanoparticle-based delivery systems that would not only drive sustained-release of cytotoxic agents, but also could improve penetration of these treatments within the tumor and allow them to continue working for days or weeks.
Wen Wee Ma, MD
Researchers from United States and Ireland have formed a partnership to advance nanoparticle-based delivery systems that would not only drive sustained-release of cytotoxic agents, but also could improve penetration of these treatments within the tumor and allow them to continue working for days or weeks, according to the University at Buffalo (UB).1
Funding for the partnership comes from 5-year grants totaling $3.8 million, awarded by the US-Ireland R&D Partnership Program, a funding mechanism that supports projects across the United States, the Republic of Ireland, and Northern Ireland, with each country funding the research performed within its borders.2Two-year survival is 10% for patients with pancreatic cancer; therefore, novel treatments and approaches are urgently needed.3,4 One challenge of treatment is that the epithelium of pancreatic cancer harbors an almost impenetrable, fibrous stroma that often limits the delivery of drug to the tumor.5
Recent research has identified drug pretreatments that increase delivery of conventional small-molecule drugs into the tumors helping the blood vessels to become more ‘leaky,’” according to UB experts.1 This US-Ireland research collaboration won’t focus on conventional small-molecule drugs; the drug’s delivery system will include liposomes, which are nano-sized, fat-soluble, drug-delivery packets.1 “In our specific research, we are pairing a drug that appears to affect the tumor in such a way as to increase the ‘leakiness’ of a tumor, so that a second agent, timed appropriately to take advantage of the ‘leakiness,’ can undergo greater deposition in the tumor,” said Robert M. Straubinger, PhD, professor of pharmaceutical sciences at UB and principal investigator of the US effort in an interview with OncLive. “We refer to the step of increasing the leakiness of the tumor as priming. The project is studying two types of priming drugs, and two types of the follow-on drug carriers.” The research teams involved in this partnership are investigating how to sequence these drugs so that the effects of these agents complement each other.
“A central hypothesis of our work is that the follow-on drug should be incorporated in nanoparticles, rather than given in its conventional free (unencapsulated) form, because nanoparticles differ from conventional small-molecule drugs in the way they undergo tumor deposition and persist in the tumor,” Straubinger said.“The next steps are to understand in detail how tumor priming works. For example, the two priming drugs we are studying initially work on two different time scales (1-3 days vs 7-10 days). Other priming approaches will have different time scales. We need to understand what is going on in the tumor while the priming response is going on, so that we can optimize the administration of the second chemotherapy agent,” Straubinger said. The researchers plan to use a mathematical model for simulation to help them understand the events that lead to tumor priming.
“If we quantify and interrelate the magnitude and time course of events going on in the tumor, for example, when the tumor becomes leaky, how leaky it becomes, how long it remains leaky, how much of the priming drug is needed to cause that much leakiness, we can build a mechanistic model to explain our data,” said Straubinger.
“If the model doesn’t capture the data we are obtaining for various tumor responses, then we don’t yet understand the key mechanisms involved, and we have to go back and figure out what we are ignoring that is important to know about,” he said.
Once the model captures tumor responses under different experimental conditions, then the team can use the model to simulate how changing the conditions may change the outcomes, forming a testable hypothesis for predicting circumstances that may produce the greatest tumor response. First by simulation and then by experiment, the team will test the interval between administration of the priming agent and administration of the nanoparticle drug.
“Once we understand how priming works, the model can potentially be modified to incorporate actual individual patient factors to predict the best conditions for therapy,” Straubinger said. Testing the hypothesis that incorporating chemotherapy drugs in the nanoparticle will produce better antitumor effects (under priming conditions) than free-form chemotherapy, is an important part of this research, according to Straubinger.
Partnership to Penetrate the Impenetrable “Finally, we can attach antibodies to the nanoparticles that bind to the tumor cell surface,” said Straubinger. “We hypothesize they may be retained better in the tumor compared with nanoparticles that don’t bind the tumor cells. This also is very important to test. “If this research suggests that there may be some advantage to administering two drugs with some specific interval between them, this may be something oncologists may want to test in the future.” Straubinger said.
Under this grant, UB’s School of Pharmacy and Pharmaceutical Sciences and Roswell Park Cancer Institute (RPCI) will share $2.2 million from the National Institutes of Health (NIH), and collaborators at Queens University, Belfast, will receive the equivalent of $1.13 million from the UK Health and Social Care R&D Division; collaborators at Dublin City University will receive the equivalent of $506,000 from Science Foundation Ireland.1,2
“The tumor microenvironment has been found to be a major obstacle to treating pancreatic cancer, partly by blocking the penetration of anticancer drugs,” said co-principal investigator Wen Wee Ma, MD, associate professor of oncology at Roswell Park Cancer Institute in an interview with OncologyLive.
“This research grant brings together an international multidisciplinary team to investigate how best to prime, or soften, this stromal barrier and then deliver macromolecules carrying cytotoxic payload to greatly increase cancer cell kill,” said Ma. “This approach is very different from how we treat pancreatic cancer currently and, if successful, will be an exciting new way of treating this devastating disease.”