To improve the efficacy of antibody drug conjugates (ADCs), there has been significant focus on increasing the drug-to-antibody ratio (DAR) in order to deliver more payload. However, due to the hydrophobicity of many cytotoxics, highly-loaded conjugates often have lower physicochemical stability and poorer pharmacokinetic outcomes, requiring the development of new hydrophilic linkers. Herein, we report a platform for the preparation of functional, sequence-defined polymers for conjugation to antibodies. We demonstrate the successful synthesis of novel diazido macrocyclic sulfate monomers of varied size ranging from 4 to 7 ethylene glycol repeat units. These monomers were then successively ring-opened to produce sequence-defined polymers that contained either 4 or 6 azides for post-synthesis functionalization. Given the hydrophilic ethylene glycol backbone and chemically defined nature of the polymers, we envisioned this as a useful strategy in the preparation of highly-loaded ADCs. To demonstrate this, we prepared a model polymer-fluorophore scaffold composed of 4 coumarin molecules and conjugated it to Herceptin. We fully characterized the conjugate via mass spectrometry, which yielded a polymer-to-antibody ratio of 6.6, translating to a total of 26 fluorophores conjugated to the antibody at the inter-chain disulfides. We believe this technology to not only be a meaningful contribution to the field of sequence-defined polymers and conjugates, but also as a general and tunable platform for drug delivery.

Chemical synthesis typically relies on reactions that generate complexity through elaboration of simple starting materials. Less common are deconstructive strategies toward complexity-particularly those involving carbon-carbon bond scission. Here, we introduce one such transformation: the hydrodealkenylative cleavage of C(sp³)-C(sp²) bonds, conducted below room temperature, using ozone, an iron salt, and a hydrogen atom donor. These reactions are performed in nonanhydrous solvents and open to the air; reach completion within 30 minutes; and deliver their products in high yields, even on decagram scales. We have used this broadly functionality tolerant transformation to produce desirable synthetic intermediates, many of which are optically active, from abundantly available terpenes and terpenoid-derived precursors. We have also applied it in the formal total syntheses of complex molecules.

Enzyme nanogels (ENGs) offer a convenient method to protect therapeutic proteins from in vivo stressors. Current methodologies to prepare ENGs rely on either covalent modification of surface residues or the noncovalent assembly of monomers at the protein surface. In this study, we report a new method for the preparation of noncovalent ENGs that utilizes a heterobifunctional, photocleavable monomer as a hybrid approach. Initial covalent modification with this monomer established a polymerizable handle at the protein surface, followed by radical polymerization with poly(ethylene glycol) methacrylate monomer and ethylene glycol dimethacrylate crosslinker in solution. Final photoirradiation cleaved the linkage between the polymer and protein to afford the noncovalent ENGs. The enzyme phenylalanine ammonia lyase (PAL) was utilized as a model protein yielding well-defined nanogels 80 nm in size by dynamic light scattering (DLS) and 76 nm by atomic force microscopy. The stability of PAL after exposure to trypsin or low pH was assessed and was found to be more stable in the noncovalent nanogel compared to PAL alone. This approach may be useful for the stabilization of active enzymes.