Title: Polyacetal
Description: This dissertation focuses on the synthesis and characterization of an exciting new family of thermoresponsive polyacetal polymers with remarkable properties that are well suited for a myriad of applications. The new polyacetals are the first, intrinsically biodegradable polymers to exhibit a lower critical solution temperature (LCST). Their LCSTs are linearly dependent on the number of carbon and oxygen atoms in the repeat units, which can be easily adjusted over a wide range of temperatures. The LCSTs can be precisely and predictably tuned to any temperature ranging from 7-80°C by simply using mixtures of monomers during synthesis. The LCST transition of polyacetals is sharp and shows no hysteresis. These new materials have the potential to be used in a broad range of technologies that are important not only economically, but also affect the quality of life. In particular, they have the potential to be used as a drug delivery carrier for treatment of pancreatic cancer; an illness that has a dismal prognosis, for which other treatments have proven ineffective.

Polyacetals are known to be chemically inert; the primary thesis objectives presented here are to develop frameworks for polyacetal functionalization for use in a variety of applications. Chapter 3 explores strategies to prepare water-soluble polyacetal-drug conjugates from three HIF-1 inhibitors; a highly hydrophobic class of cancer therapeutics. HIF-1 inhibitors explored in this chapter have simple structures containing di-hydroxy functionalities, which can be used for polyacetal main-chain attachment. Step-growth polymerization is used to prepare, for the first time, main-chain drug conjugates that are temperature responsive and pH degradable. Furthermore, the temperature response of main-chain polyacetal-drug conjugates is precisely tuned with the amount of the HIF-1 in the polymer backbone. The pH dependent backbone degradation of the drug conjugates show that pristine HIF-1 inhibitors evolve from the polymer at long degradation times, showing promise for use of this material as a drug delivery vehicle.

Strategies outlined in Chapter 3 require specific di-hydroxy functionalities in the molecules of interest, without which, functionalization is not possible. Therefore, Chapter 4 considers polyacetal functionalization of molecules with mono- or poly- hydroxy functional groups, further expanding the scope of these new materials. Two strategies of functionalization are presented, namely, end group functionalization and pendent-chain polyacetal-conjugation using click chemistry. End group functionalization of polyacetal is achieved during step-growth polymerization, in situ, using mono-hydroxy functional molecules. Pendent-chain polyacetal-conjugates are prepared using backbone alkyne functional polyacetal with specialized heterobifunctional linkers that enable the use of orthogonal chemistries such as click-chemistry. Importantly, end group and pendent-chain functional polyacetals retain their temperature response and degradation properties. Both polyacetals evolve pristine mono- functional payloads at the onset of the degradation cycle in contrast to main-chain polyacetal-drug conjugates, which evolve the payload towards the end of the degradation cycle.

Knowledge of both degradation mechanisms allows for precise control over the degradation profile of the resulting polyacetals. Chapter 5 further expands on the thesis objectives by the synthesis of ABA type polyacetal block co-polymers and micelles. Polyacetal block co-polymers encapsulate virtually any type of hydrophobic molecule of interest, significantly expanding the number of molecules that can be incorporated into polyacetals. For this purpose, click-functional polyacetal macromonomers are prepared and end-linked with the polymer. The resulting polyacetal micelles show remarkable temperature response, by a second-order θ collapse exhibited by base-polyacetals, and by coacervation of the individual micelles. The temperature response for polyacetal block co-polymers is sharp and reversible, with minimal hysteresis. Pyrene encapsulation studies conducted with polyacetal micelles show that, upon degradation, 99% the encapsulated pyrene is released, showing great promise for use of polyacetal block co-polymers as a delivery vehicle for a variety of applications.

Using the methods outlined in Chapter 3-5, virtually any molecule of interest can be incorporated into the polyacetal chain. Lastly, the fundamental origins of the LCST behavior of PAs are explored using molecular dynamic simulations in Chapter 6. For this purpose, PA chains of 10,000 g/mol are accurately modeled using coarse-graining techniques. The experimental LCST transition is reproduced with an accuracy of ±20°C using the coarse grained model, which allows for precise prediction of the temperature response using simulations. The model is further expanded to obtain sequence transferability; that is, the LCST behavior of any sequence or architecture that consists of poly(ethylene oxide) and methylene units can be modeled with precision using this model. We also present sample conformations of the polyacetal during its coil-globule transition, which provides a degree of insight into the mechanism of the LCST.