CONSPECTUS As a semi-permeable barrier that controls the flux of biomolecules in and out the cell, the plasma membrane is critical in cell function and survival. Many proteins interact with the plasma membrane and modulate its physiology. Within this large landscape of membrane-active molecules, researchers have focused significant attention on two specific classes of peptides, antimicrobial peptides (AMPs) and cell penetrating peptides (CPPs) because of their unique properties. In this account, we describe our efforts over the last decade to build and understand synthetic mimics of antimicrobial peptides (SMAMPs). These endeavors represent one specific example of a much larger effort to understand how synthetic molecules interact with and manipulate the plasma membrane. Using both defined molecular weight oligomers and easier to produce, but heterogeneous, polymers, it has been possible to generate scaffolds with biological potency superior to the natural analogs. In one case, a compound has progressed through a phase II clinical trial for pan)staph infections. Modern biophysical assays highlighted the interplay between the synthetic scaffold and lipid composition leading to negative Gaussian curvature, a requirement for both pore formation and endosomal escape. The complexity of this interplay between lipids, bilayer components, and the scaffolds remains to be better resolved, but significant new insight has been provided. It is worthwhile to consider the various aspects of permeation and how these are related to ‘pore formation.’ More recently, our efforts have expanded toward protein transduction domains, or cell penetrating peptide, mimics. The combination of unique molecular scaffolds and guanidinium) rich side chains has produced an array of polymers with robust transduction (and delivery) activity. Being a new area, the fundamental interactions between these new scaffolds and the plasma membrane are just beginning to be understood. Negative Gaussian curvature is important but the detailed relationships between molecular structure, self)assembly with lipids, and translocation require more investigation. It has become clear that the combination of molecular design, biophysical models, and biological evaluation provide a robust approach to the generation and study of novel proteinomimetics.

A family of nine poly(ether−thioethers) (PETEs) were synthesized by the radical coupling of a dithiol and a divinyl ether to investigate the importance of organosulfur incorporation in solid polymer electrolytes. Two series of four polymers each were synthesized to probe both the effect of the carbon spacer length between thioether units and of the ratio of ether to thioether units. PETE samples from these two series had low T g values, ranging from −50 to −75 °C, and all but two PETEs displayed crystallinity. Molecular weights between 7 and 13 kg/mol were obtained for all polymers. Taking advantage of the sulfur-centered functional group, a single polymer, PETE-1, was selectively oxidized to the poly(ether−sulfoxide) PESO-1 and the poly(ether−sulfone) PES-1. Oxidation increased the T g of PETE-1 from −64 °C to −36 and −26 °C for PESO-1 and PES-1, respectively, while all three were amorphous. Of the nine new PETE polymers, two were amorphous and the addition of LiTFSI decreased the extent of crystallinity for the other seven PETE samples. An increase in T g was also observed for PETE-1, PESO-1, and PES-1 with the addition of salt. PETE samples with carbon spacers of two, four, and six methylene units had generally uniform ion conductivity, near 5 × 10 −5 S/cm at 80 °C, while the sample with eight methylene units had a lower conductivity that was further decreased by crystallinity at lower temperatures. Samples with varied ether and thioether ratios also had very uniform conductivities, similar in magnitude to samples with varied carbon spacers. Within the oxidized series, PETE-1 outperformed PES-1, which in turn outperformed PESO-1 in terms of ion mobility. The highest observed conductivity (10 −4 S/cm) at 80 °C was for PETE-1 with a salt loading of r = 0.05. The synthetic approach described here will enable a wealth of new polymer structures to be produced with controlled functional group placement and density providing novel materials for solid polymer electrolytes, broad functional group variation, and comprehensive structure− activity relationships.

To fully explore bottlebrush polymer networks as potential model materials, a robust and versatile synthetic platform is required. Ring-opening metathesis polymerization is a highly controlled, rapid, and functional group tolerant polymerization technique that has been used extensively for bottlebrush polymer generation but to this point has not been used to synthesize bottlebrush polymer networks. We polymerized a mononorbornene macromonomer and dinorbornene cross-linker (both poly­(n-butyl acrylate)) with Grubbs’ third-generation catalyst to achieve bottlebrush networks and in turn demonstrated control over network properties as the ratio of macromonomer and cross-linker was varied. Macromonomer to cross-linker ratios ([MM]/[XL]) of 10 to 100 were investigated, of which all derivative networks yielded gel fractions over 90%. Because of its amenability toward small samples, contact adhesion testing was used to quantify dry-state shear modulus G, which ranged from 1 to 10 kPa, reinforcing that bottlebrush polymer networks can achieve low moduli in the dry state compared to other polymer network materials through the mitigation of entanglements. A scaling relationship was found such that G ∼ ([MM]/[XL])−0.81, indicating that macromonomer to cross-linker ratio is a good estimator of cross-linking density. The swelling ratio in toluene, Q, was compared to dry-state modulus to test the universal scaling relationship for linear networks G ∼ Q –1.75, and a measured exponent of −1.71 indicated good agreement. The synthetic platform outlined here represents a highly flexible route to a myriad of different bottlebrush networks and will increase the accessibility of materials critical to applications ranging from fundamental to biomedical.

Uncharged bottlebrush polymer melts and highly charged polyelectrolytes in solution exhibit correlation peaks in scattering measurements and simulations. Given the striking superficial similarities of these scattering features, there may be a deeper structural interrelationship in these chemically different classes of materials. Correspondingly, we constructed a library of isotopically labeled bottlebrush molecules and measured the bottlebrush correlation peak position q*=2π/ξ by neutron scattering and in simulations. We find that the correlation length scales with the backbone concentration, ξ∼cBB−0.47, in striking accord with the scaling of ξ with polymer concentration cP in semidilute polyelectrolyte solutions (ξ∼cP−1/2). The bottlebrush correlation peak broadens with decreasing grafting density, similar to increasing salt concentration in polyelectrolyte solutions. ξ also scales with sidechain length to a power in the range of 0.35–0.44, suggesting that the sidechains are relatively collapsed in comparison to the bristlelike configurations often imagined for bottlebrush polymers.

Multiblock copolymers, composed of different combinations and number of blocks, offer appreciable opportunities for new advanced materials. However, exploring this parameter space using traditional block copolymer synthetic techniques, such as living polymerization of sequential blocks, is time-consuming and requires stringent conditions. Using thiol addition across norbornene chemistry, we demonstrate a simple synthetic approach to multiblock copolymers that produces either random or alternating architectures, depending on the choice of reactants. Past reports have highlighted the challenges associated with using thiol−ene chemistry for polymer−polymer conjugation; however, using norbornene as the "ene" yielded multiblock copolymers at least four or five blocks. Preparation of new multiblock copolymers containing two or three block chemistries highlights the versatility of this new approach. These materials were thermally stable and showed microphase separation according to characterization by DSC, SAXS, and AFM. This chemical platform offers a facile and efficient route to exploring the many possibilities of multiblock copolymers.

A new use of the thiol-ene reaction to generate functional, redox-tunable polymers is described. To illustrate the versatility of this approach, tailored divinyl ether monomers were polymerized with triethylene glycol dithiol to yield polymers containing either a carbonate or zwitterionic phosphocholine within the polymer backbone. Similarly, dithioerythritol was polymerized with triethylene glycol divinyl ether to yield a polymer with pendant diols and show how functional groups can be designed into either the divinyl ether or dithiol monomer. Using the thioether functional group inherent to this polymerization, all three polymers were selectively and quantitatively oxidized to either sulfoxides or sulfones by treatment with dilute hydrogen peroxide or mCPBA, respectively. With these illustrative examples, it is shown that the thiol-ene polymerization is a broad-reaching method to access a class of new redox-active polymers which contain varied and dense functional-group compositions.

Cell-penetrating peptides are an important class of molecules with promising applications in bioactive cargo delivery. A diverse series of guanidinium-containing polymeric cell-penetrating peptide mimics (CPPMs) with varying backbone chemistries was synthesized and assessed for delivery of both GFP and fluorescently tagged siRNA. Specifically, we examined CPPMs based on norbornene, methacrylate, and styrene backbones to determine how backbone structure impacted internalization of these two cargoes. Either charge content or degree of polymerization was held constant at 20, with di-guanidinium norbornene molecules being polymerized to both 10 and 20 repeat units. Generally, homopolymer CPPMs delivered low amounts of siRNA into Jurkat T cells, with no apparent backbone dependence; however, by adding a short hydrophobic methyl methacrylate block to the guanidinium-rich methacrylate polymer, siRNA delivery to nearly the entire cell population was achieved. Protein internalization yielded similar results for most of the CPPMs, though the block polymer was unable to deliver proteins. In contrast, the styrene-based CPPM yielded the highest internalization for GFP (~40% of cells affected), showing that indeed backbone chemistry impacts protein delivery, specifically through the incorporation of an aromatic group. These results demonstrate that an understanding of how polymer structure affects cargo-dependent internalization is critical to designing new, more effective CPPMs.

An ew use of the thiol-ene reaction to generate functional, redox-tunable polymers is described. To illustrate the versatility of this approach,t ailored divinyl ether monomers were polymerizedw ith triethylene glycol dithiol to yield polymers containing either ac arbonate or zwitterionic phosphocholine within the polymer backbone.S imilarly,d ithioerythritol was polymerizedwith triethylene glycol divinyl ether to yield apolymer with pendant diols and showhow functional groups can be designed into either the divinyl ether or dithiol monomer.Using the thioether functional group inherent to this polymerization, all three polymers were selectively and quantitatively oxidized to either sulfoxides or sulfones by treatment with dilute hydrogen peroxideo rm CPBA, respectively.W ith these illustrative examples,i ti ss hown that the thiol-ene polymerization is ab road-reaching method to access ac lass of new redox-active polymers which contain varied and dense functional-group compositions.The union of synthetic organic chemistry and polymer science over the last 20 years has enabled the generation of new materials containing practically every chemical moiety conceivable. [1] These advances promise new macromolecules with av ery high degree of chemical functionality which is expected to rival naturesb iopolymers such as proteins and DNA. Major progress in tailor-made polymers has been facilitated by new synthetic methods such as controlled radical polymerization [2] and ring-opening metathesis polymerization (ROMP), [3] as well as post-polymerization functionalization techniques such as so-called click reactions and activated ester methodologies. [4] Despite the many differences among these strategies,m ost aim to generate new polymers with unprecedented degrees of functionalization and precise control over the placement of that functionality.Many of these new methods have inherent limitations, with oxygen and water sensitivity being the most common. Moreover,b ecause of the chain-growth nature of many polymerizations,functional groups are generally incorporated as side chains pendant to the polymer backbone.H owever, there are numerous opportunities,r anging from lithium ion conductivity by poly(ethylene oxide) [5] to selective degradability of poly(lactic acid) [6] where functional-group incorporation into the polymer backbone (main chain) is preferred. With these challenges in mind, we present the thiol-ene stepgrowth (TES) polymerization and demonstrate its ability to incorporate both main-chain functional groups (zwitterion, carbonate) and pendant functional groups (diol) under ambient reaction conditions.T his approach, which exploits the thiol-ene reaction to generate novel polymers,d iffers from the originally reported and most widely employed use of click reactions in the context of macromolecular science,that is,tofunctionalize existing materials. [7,8] Theability to utilize both functional dienes and dithiols indicates an ear infinite combination of possible polymer chemistries.A dditionally, the thioethers wit...