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Structure–function relationships for multivalent polymer scaffolds are highly complex due to the wide diversity of architectures offered by such macromolecules. Evaluation of this landscape has traditionally been accomplished case-by-case due to the experimental difficulty associated with making these complex conjugates. Here, we introduce a simple dual-wavelength, two-step polymerize and click approach for making combinatorial conjugate libraries. It proceeds by incorporation of a polymerization friendly cyclopropenone-masked dibenzocyclooctyne into the side chain of linear polymers or the α-chain end of star polymers. Polymerizations are performed under visible light using an oxygen tolerant porphyrin-catalyzed photoinduced electron/energy transfer-reversible addition–fragmentation chain-transfer (PET-RAFT) process, after which the deprotection and click reaction is triggered by UV light. Using this approach, we are able to precisely control the valency and position of ligands on a polymer scaffold in a manner conducive to high throughput synthesis.

From protein science, it is well understood that ordered folding and 3D structure mainly arises from balanced and noncovalent polar and nonpolar interactions, such as hydrogen bonding. Similarly, it is understood that single-chain polymer nanoparticles (SCNPs) will also compact and become more rigid with greater hydrophobicity and intrachain hydrogen bonding. Here, we couple high throughput photoinduced electron/energy transfer reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization with high throughput small-angle X-ray scattering (SAXS) to characterize a large combinatorial library (>450) of several homopolymers, random heteropolymers, block copolymers, PEG-conjugated polymers, and other polymer-functionalized polymers. Coupling these two high throughput tools enables us to study the major influence(s) for compactness and flexibility in higher breadth than ever before possible. Not surprisingly, we found that many were either highly disordered in solution, in the case of a highly hydrophilic polymer, or insoluble if too hydrophobic. Remarkably, we also found a small group (9/457) of PEG-functionalized random heteropolymers and block copolymers that exhibited compactness and flexibility similar to that of bovine serum albumin (BSA) by dynamic light scattering (DLS), NMR, and SAXS. In general, we found that describing a rough association between compactness and flexibility parameters (R(g)/R(h) and Porod Exponent, respectively) with logP, a quantity that describes hydrophobicity, helps to demonstrate and predict material parameters that lead to SCNPs with greater compactness, rigidity, and stability. Future implementation of this combinatorial and high throughput approach for characterizing SCNPs will allow for the creation of detailed design parameters for well-defined macromolecular chemistry.