Ovarian cancer affects tens of thousands of women each year, many of whom do not show symptoms until the disease has advanced significantly. With an increased challenge in treating patients exhibiting resistance to chemotherapeutics, targeted siRNA therapy offers great promise as a complementary or standalone treatment. Unfortunately, while RNA interference has been studied for at least 15 years, there are still no FDA approved vehicles for siRNA. Amongst the liposomes, micelles, cationic polymers, and other vectors currently being investigated, issues related to toxicity, specificity, and stability are all too common. Cationic polymers synthesized with precise lengths, sequences, tacticity, and chirality would offer an improvement of the status quo by being able to control structure with atomistic precision from the ?bottom up?. Structurally precise polymers, though ubiquitous in Nature, still remain as synthetic challenges for organic chemists. While Nature creates polypeptides to catalyze specific transformations and polynucleotides to store genetic information, both from a small catalog of building blocks, there is still a need to develop biomimetic syntheses of structurally precise artificial polymers. Iterative exponential growth (IEG) techniques have been known since the 1980?s and allow for highly efficient coupling between two monomers/oligomers, doubling the chain length after each iteration. While such methods have produced numerous examples of uniform high molecular weight (MW) oligomers with high degrees of polymerization, their applications for sequence-controlled synthesis have been scarce due to limitations in incorporating functionality. Recent advances have allowed for the introduction of functionalized chiral side-chains into the IEG platform (IEG+) to synthesize high MW (~ 6.5 kDa) oligotriazoles, providing a unique avenue to explore novel ?unimacromolecular? structure-function relationships. The IEG+ methodology represents a landmark in molecular architecture that combines efficient reactions (CuAAC) to access high MW structrues, highly soluble products, and complete control of backbone stereochemistry/sequence. As a consequence of the high yielding CuAAC reactions, triazoles are available for post-polymerization alkylation. In this work, IEG+ methodology will be exploited to synthesize and characterize 24 triazolium-containing polymers, all with precise lengths, sequences, tacticity, and chirality. It is expected that the diffuse nature of the positive charge throughout the heterocycle will confer decreased toxicity compared to traditional ammonium-based delivery agents. Upon evaluating these structures? affinity for ID4 siRNA, complexation will be correlated with the identity of each polymer. These data will then be utilized for the in vitro delivery to OVCAR8 cells and the in vivo treatment of subcutaneous xenograft tumor-bearing female mice. While chirality is expected to play a major role in binding helical siRNA, our ability to precisely tune so many additional structural parameters will provide great insight to the design principles that govern the development of siRNA nanotherapeutics for the treatment of ovarian cancer.
RNA interference therapy offers an alternative to chemotherapeutic cancer treatments, but there are currently no FDA-approved vehicles for siRNA delivery. Through the synthesis of monodisperse, well-defined polycationic vectors with precise lengths, sequences, tacticity, and chirality, the proposed research will establish a structure/function relationship for a novel class of nanotherapeutics aimed at challenging ovarian cancer, thereby improving human health.
| Golder, Matthew R; Jiang, Yivan; Teichen, Paul E et al. (2018) Stereochemical Sequence Dictates Unimolecular Diblock Copolymer Assembly. J Am Chem Soc 140:1596-1599 |
