Metal-free magnetic resonance imaging (MRI) agents could overcome the established toxicity associated with metal-based agents in some patient populations and enable new modes of functional MRI in vivo. Herein, we report nitroxide-functionalized brush-arm star polymer organic radical contrast agents (BASP-ORCAs) that overcome the low contrast and poor in vivo stability associated with nitroxide-based MRI contrast agents. As a consequence of their unique nanoarchitectures, BASP-ORCAs possess per-nitroxide transverse relaxivities up to ∼44-fold greater than common nitroxides, exceptional stability in highly reducing environments, and low toxicity. These features combine to provide for accumulation of a sufficient concentration of BASP-ORCA in murine subcutaneous tumors up to 20 h following systemic administration such that MRI contrast on par with metal-based agents is observed. BASP-ORCAs are, to our knowledge, the first nitroxide MRI contrast agents capable of tumor imaging over long time periods using clinical high-field 1H MRI techniques.

Ring-opening metathesis polymerization (ROMP) of norbornene-based (macro)monomers is a powerful approach for the synthesis of macromolecules with diverse compositions and complex architectures. Nevertheless, a fundamental limitation of polymers prepared via this strategy is their lack of facile degradability, which limits their utility in a range of applications. Here, we describe a class of readily available bifunctional silyl-ether-based cyclic olefins that copolymerize efficiently with norbornene-based (macro)monomers to provide copolymers with backbone degradability under mildly acidic aqueous conditions and degradation rates that can be tuned over several orders-of-magnitude depending on the silyl ether substituents. These monomers can be used to manipulate the in vivo biodistribution and clearance rate of PEG-based bottlebrush polymers, as well as to synthesise linear, bottlebrush, and brush-arm star copolymers with degradable segments. We expect that this work will enable preparation of degradable polymers by ROMP for biomedical applications, responsive self-assembly, and improved sustainability.

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Studies on the phase segregation of unimolecular block copolymers (BCPs) are limited by a lack of reliable, versatile methods for the synthesis of such polymers on the preparative scale. Herein, we describe an advancement of Iterative Exponential Growth (IEG) wherein chiral allyl-based IEG oligomers are subjected to thiol-ene reactions and converted into unimolecular BCPs. With this strategy we have synthesized uniform BCPs with molar masses up to 12.1 kDa on ∼1 g scale. BCPs composed of decane-based side chains and either triethyleneglycol- or thioglycerol-based side chains phase-segregate into hexagonal cylinder morphologies. The assembly is not driven by side-chain crystallization, but is instead the result of amorphous BCP assembly.

Nitroxides occupy a privileged position among plausible metal-free magnetic resonance imaging (MRI) contrast agents (CAs) due to their inherently low-toxicity profiles; nevertheless, their translational development has been hindered by a lack of appropriate contrast sensitivity. Nanostructured materials with high nitroxide densities, where each individual nitroxide within a macromolecular construct contributes to the image contrast, could address this limitation, but the synthesis of such materials remains challenging. Here, we report a modular and scalable synthetic

The polymerization of functional monomers provides direct access to functional polymers without need for postpolymerization modification; however, monomer synthesis can become a bottleneck of this approach. New methods that enable rapid installation of functionality into monomers for living polymerization are valuable. Here, we report the three-step convergent synthesis (two-step longest linear sequence) of a divalent exo-norbornene imide capable of efficient coupling with various nucleophiles and azides to produce diversely functionalized branched macromonomers optimized for ring-opening metathesis polymerization (ROMP). In addition, we describe an efficient iterative procedure for the synthesis of tri-and tetra-valent branched macromonomers. We demonstrate the use of these branched macromonomers for the synthesis of Janus bottlebrush block copolymers as well as for the generation of bottlebrush polymers with up to three conjugated small molecules per repeat unit. This work significantly expands the scalability and diversity of nanostructured macromolecules accessible via ROMP.

Single-nanoparticle (NP) combination chemotherapeutics are quickly emerging as attractive alternatives to traditional chemotherapy due to their ability to increase drug solubility, reduce off-target toxicity, enhance blood circulation lifetime, and increase the amount of drug delivered to tumors. In the case of NP-bound drugs, that is, NP-prodrugs, the current standard of practice is to assume that the subcellular mechanism of action for each drug released from the NP mirrors that of the unbound, free-drug. Here, we use an RNAi signature assay for the first time to examine the mechanism of action of multidrug-conjugated NP prodrugs relative to their small molecule prodrugs and native drug mechanisms of action. Additionally, the effective additive contribution of three different drugs in a single-NP platform is characterized. The results indicate that some platinum(IV) cisplatin prodrugs, although cytotoxic, may not have the expected mechanism of action for cisplatin. This insight was utilized to develop a novel platinum(IV) oxaliplatin prodrug and incorporate it into a three-drug-conjugated NP, where each drug’s mechanism of action is preserved, to treat tumor-bearing mice with otherwise lethal levels of chemotherapy.

Deciphering the significance of length, sequence, and stereochemistry in block copolymer self-assembly remains an ongoing challenge. A dearth of methods to access uniform block co-oligomers/polymers with precise stereochemical sequences has precluded such studies. Here, we develop iterative exponential growth (IEG) methods for the synthesis of a small library of unimolecular stereoisomeric diblock 32-mers. X-ray scattering reveals that stereochemistry modulates the phase behavior of these polymers, which we rationalize based on simulations carried out on a theoretical model system. This work demonstrates that stereochemical sequence can play a crucial role in unimolecular polymer self-assembly.