INSPIRE: Neutrophil Delivery of Apoptosis-Inducing Anticancer Drugs

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This INSPIRE award to Kansas State University at Manhattan is partially funded by the Biomaterial program in the Division of Materials Research in the Directorate for Mathematical and Physical Sciences. The other two interdisciplinary programs that are partially funding this award are the Biophotonic program in the Division of Chemical, Bioengineering, Environmental, & Transport Systems, and the Materials for Surface Engineering program in the Division of Civil, Mechanical and Manufacturing Innovation, both from the Directorate for Engineering. With this award, targeted protease-activatable polymer-caged liposomes (PPCLs) will be designed and synthesized for rapid uptake by neutrophils from peripheral blood. The liposomes prepared will be loaded with a metal binding anticancer drug (4,4-dimethyl-1-(di(pyridine-2-yl)methylene) (Dp44mT), which destabilizes liposomes. This metal chelating agent will be conjugated with a mitochondria inactivating peptide D[KLAKLAK]2 before the conjugate is loaded in the liposomes. This new class of liposomes with loaded drugs are expected to remain intact in the neutrophil while being transported by blood to the brain cancer cells (glioblastoma multiforme). PPCLs will be activated by caspases and discharge their payload once the neutrophils have reached their target and undergo apoptosis. Synergy between the two drugs loaded in the liposomes is anticipated and that will start apoptotic cascades in primary tumors and metastases. It is important to note that neutrophils are able to cross the blood brain barrier, and will be able to kill cancer cells even if these brain cancer cells are small and in the early stages of development. The proposed cell-based cancer treatment strategies are potentially superior to the ones that use nanoparticles and other drug carriers, because the proposed neutrophil-based therapies can treat early tumors, and they are selective, efficient, and fast. Additionally, the use of autologous cells has the potential of significantly lowering the regulatory barriers generally seen with cell-based human cancer therapies. In addition, this strategy could be expanded to other applications for targeting numerous cell types using different oligopeptides as targeting sequences. The targeting principles of a single cell-type would have the potential to evolve into targeted therapies for viral, bacterial and protozoal infections, and biophotonic approaches for different applications. In addition, a successful outcome from this INSPIRE project could lead to a new interdisciplinary research approach at the interface of materials science, surface processing, synthetic biology, molecular engineering, nanotechnology and biophotonics. As part of teaching, training and outreach activities, the PI plans to develop and teach a course entitled 'Theranostics' at Kansas State University. In addition, the PI and Co-PI will alternately lead a workshop on developing skills in writing manuscripts, and this workshop will be offered to all undergraduates, graduate students and postdoctoral scientists in their groups. Currently, the PI and Co-PI have five female graduate students, four Developing Scholars' Program students, one Summer Undergraduate Research Opportunity Program student and two Research Experience of Undergraduates students in their laboratories. These recruiting, mentoring and training activities will be enlarged and enhanced with this award.This research is directed at developing new materials for the treatment for brain tumors (glioma or glioblastoma multiforme). A new treatment concept will be developed, which utilizes the patients' own white blood cells as "transport ships" for anticancer drugs. These drugs will be released once the white blood cells have reached the tumor. Using whole blood from cancer patients, this project will target the white blood cells to load them with anticancer drugs, and then re-inject their blood. The white blood cells will then travel to the sites of tumors. Classic liposomes are not taken up selectively by the various cell types in blood. They either burst after uptake or the fuse with the cells. In either case, the drugs that are supposed to stay within the liposomes are released prematurely, thus killing the transport cells and not the tumors. However, the proposed novel protease-activatable polymer-caged liposomes (PPCLs) are expected to be stable during transport within white blood cells, and become activated once these white cells become integrated into the tumor cells. The drugs will then cause programmed cell death (apoptosis). They will be able to kill the fast growing tumor cells and the slower growing cancer stem cells. The latter are responsible for the reappearance of tumors and the formation of metastases. The use of patient derived cells will provide a pathway to truly personalized medicine, free of concerns about the potential of stem cells causing cancer, and also free of ethical concerns. Three education thrusts will be carried out during the period of this project: (i) the PI will develop and teach a block course entitled 'Theranostics'. This course will be open to all graduate and undergraduate students in veterinary medicine, chemistry, biochemistry, biology and physics; (ii) the PI and Co-PI will alternately lead a workshop on writing research papers, and will be offered to all undergraduates, graduate students and postdoctoral scientists in the PIs' research team; and (iii) the research will also create opportunities for incoming Research Experience of Undergraduates, Summer Undergraduate Research Opportunity Program and Developing Scholars? Program students at Kansas State University. Both PI and Co-PI will continue to work with graduate and undergraduate students from underrepresented groups, as well as veterans. In addition, this research will help extend the efforts to ongoing collaborative efforts in materials chemistry, cancer therapy and diagnostics at Kansas State University.