Wednesday, October 11, 2017 at 9:00am
Designer Synthetic Polypeptides and Polymeric siRNA for Cancer Therapeutics
The design of nanoparticles for the delivery of drugs to tumors and other specific regions of the body requires versatile chemistry and the ability to manipulate nanoparticle surfaces with the high level of control needed multiple kinds of targeting. Synthetic polypeptides provide the basis for new biomacromolecules that can be modified to achieve a broad range of biologically relevant function. We have designed poly(propargyl-L-glutamate) (PPLG) synthetic polypeptides to which different molecules can be “clicked” to achieve dense brush polypeptide backbone structures. A unique aspect of these new amine-functionalized polypeptides is the ability to buffer, and in some cases, change solubility with degree of ionization, over biologically relevant pHs. These polymers are PPLG homopolymers and poly(ethylene glycol (PEG-b-PPLG) block copolymers substituted with various amine moieties that range in pKa and hydrophobicity. These systems can be further functionalized to target specific cells, and make unique nanoscale drug carriers for systemic delivery in applications such as targeted cancer chemotherapy. We have recently explored adaptations to these peptide copolymers that allow encapsulation of both hydrophobic and hydrophilic drug molecules, and can exhibit tuned release in the endosomal compartment, as well as linear-dendritic formulations that enable controlled ligand presentation. New versions of peptide systems have been designed for RNAi delivery, and can be used to address the targeting of non-druggable oncogenes relevant to ovarian and non small cell lung cancer. On the other hand, interesting new biological macromolecules can be engineered from nucleic acids. Newer synthetic methods in our laboratory include the use of rolling circle transcription to create periodic-shRNA (pshRNA) consisting of hundreds of repeat units that spontaneously assemble into RNAi microsponges. We have found that these polymeric forms of siRNA can yield activation of immunological pathways that facilitate further tumor cell death, while also inducing knockdown of targeted genes. Applications of these systems toward active or responsive drug delivery applications will be discussed.
Paula Hammond received her B.S. in Chemical Engineering from MIT in 1984, her M.S. from Georgia Tech in 1988, and earned her Ph.D. from MIT in 1993. She is the David H. Koch Chair Professor of Engineering and the Head of the Department of Chemical Engineering at MIT. She is a member of MIT’s Koch Institute for Integrative Cancer Research, the MIT Energy Initiative, and a founding member of the MIT Institute for Soldier Nanotechnology. She has published over 300 papers, and holds over 20 patents based on her research at MIT. She was named a Fellow of the American Physical Society, the American Institute of Medical and Biological Engineers, and the American Chemical Society Polymer Division. Dr. Hammond’s work on multilayer tattoos for transdermal DNA vaccines was recently featured on the PBS Nova program, “Making Stuff” with David Pogue, and she was also featured in the Chemical Heritage Foundation’s Catalyst Series: Women in Chemistry. Professor Hammond is a member of the National Academy of Engineering and the National Academy of Medicine.
The core of Dr. Hammond’s work is the use of electrostatics and other complementary interactions to generate functional materials with highly controlled architecture. Her research in nanotechnology encompasses the development of new biomaterials to enable drug delivery from surfaces with spatio-temporal control. She also investigates novel responsive polymer architectures for targeted nanoparticle drug and gene delivery to address cancer and infectious disease.