Jiaming Zhuang

Multi-stimuli responsive macromolecules and their assemblies

In this review, we outline examples that illustrate the design criteria for achieving macromolecular assemblies that incorporate a combination of two or more chemical, physical or biological stimuli-responsive components. Progress in both fundamental investigation into the phase transformations of these polymers in response to multiple stimuli and their utilization in a variety of practical applications are highlighted. Using these examples, we aim to explain the origin of employed mechanisms of stimuli responsiveness which may serve as a guideline to inspire future design of multi-stimuli responsive materials.

Protein AND Enzyme Gated Supramolecular Disassembly

An amphiphilic nanoassembly was designed to respond to the concurrent presence of a protein and an enzyme. We present herein a system, where in the presence of these two stimuli supramolecular disassembly and molecular release occur. This molecular release arises in the form a fluorescence response that has been shown to be specific. We also show that this system can be modified to respond only if light stimulus is also present in addition to the protein and the enzyme. Demonstration of such supramolecular disassembly principles could have broad implications in a variety of biological applications.

Concurrent Binding and Delivery of Proteins and Lipophilic Small Molecules Using Polymeric Nanogels

Supramolecular nanoassemblies, which are capable of binding and delivering either lipophilic small molecules or hydrophilic molecules, are of great interest. Concurrently binding and delivering this combination of molecules is cumbersome, because of the opposing supramolecular host requirements. We describe the development of a versatile nanoassembly system that is capable of binding and delivering both, a protein and a lipophilic small molecule, simultaneously inside the cells.

Ligand-Decorated Nanogels: Fast One-Pot Synthesis and Cellular Targeting

Nanoscale vehicles for delivery have been of interest and extensively studied for two decades. However, the encapsulation stability of hydrophobic drug molecules in delivery vehicles and selective targeting these vehicles into disease cells are potential hurdles for efficient delivery systems. Here we demonstrate a simple and fast synthetic protocol of nanogels that shows high encapsulation stabilities. These nanogels can also be modified with various targeting ligands for active targeting. We show that the targeting nanogels (T-NGs), which are prepared within 2 h by a one-pot synthesis, exhibit very narrow size distributions and have the versatility of surface modification with cysteine-modified ligands including folic acid, cyclic arginine-glycine-aspartic acid (cRGD) peptide, and cell-penetrating peptide. T-NGs hold their payloads, undergo facilitated cell internalization by receptor-mediated uptake, and release their drug content inside cells due to the reducing intracellular environment. Selective cytotoxicity to cells, which have complementary receptors, is also demonstrated.

Field Guide to Challenges and Opportunities in Antibody–Drug Conjugates for Chemists

Antibody-drug conjugates have attracted a great amount of attention as a therapeutic strategy for diseases where targeting specific tissues and cells are critical components, such as in cancer therapy. Although promising, the number of approved ADC drugs is relatively limited. This emanates from the challenges associated with generating the conjugates and the complexities associated with the stability requirements for these conjugates during circulation and after reaching the target. Here, we provide a comprehensive overview of the design challenges facing the ADC field. These challenges also provide several unique research and development opportunities, which are also highlighted throughout the review.

Templated Self-Assembly of a Covalent Polymer Network for Intracellular Protein Delivery and Traceless Release

Trafficking proteins inside cells is an emerging field with potential utility in basic cell biology and biological therapeutics. A robust and sustainable delivery strategy demands not only good protection of the cargo but also reversibility in conjugation and activity. We report a protein-templated polymer self-assembly strategy for forming a sheath around the proteins and then tracelessly releasing them in the cytosol. The versatility of the approach, demonstrated here, suggests that the strategy is compatible with a wide array of biologics.

Multi-Stimuli-Responsive Amphiphilic Assemblies through Simple Postpolymerization Modifications

A strategy to construct different stimuli responsive polymers from post polymerization modifications of a single polymer scaffold via thiol-disulfide exchange has been developed. Here, we report on a random copolymer that enables the design and syntheses of a series of dual or multi-stimuli responsive nanoassemblies using a simple post-polymerization modification step. The reactive functional group involves a side chain monopyridyl disulfide unit, which rapidly and quantitatively reacts with various thiols under mild conditions. Independent and concurrent incorporation of physical, chemical or biologically responsive properties have been demonstrated. We envision that this strategy may open up opportunities to simplify the synthesis of multi-functional polymers with broad implications in a variety of biological applications.

Activatable Dendritic 19F Probes for Enzyme Detection

We describe a novel activatable probe for fluorine-19 NMR based on self-assembling amphiphilic dendrons. The dendron probe has been designed to be spectroscopically silent due to the formation of large aggregates. Upon exposure to the specific target enzyme, the aggregates disassemble to give rise to a sharp 19F NMR signal. The probe is capable of detecting enzyme concentrations in the low nanomolar range. Response time of the probe was found to be affected by the hydrophilic–lipophilic balance of dendrons. Understanding the structural factors that underlie this design principle provides the pathway for using this strategy for a broad range of enzyme-based imaging.

Programmable Nanoassemblies from Non-Assembling Homopolymers Using Ad Hoc Electrostatic Interactions

Robust nanostructures were obtained from polymers that otherwise do not assemble by using a novel approach based on electrostatic self-assembly. The essence of this strategy involves the use of divalent counterions to temporarily perturb the packing features of the ionic groups in a homopolymer, which results in a vesicle-like structure that is captured in situ through a simple crosslinking reaction. The fidelity of the assembly has been tested for molecular transport across the nanomembrane, both for the molecules encapsulated in the lumen and for those trapped in the membrane itself. The membranes are addressable for robust multifunctionalization of their surfaces and for tunable transmembrane molecular transport.

Self-assembly of random co-polymers for selective binding and detection of peptides

Amphiphilic random co-polymers, which form stable reverse micelle-type assemblies, have been designed and synthesized. We demonstrate that the reverse micelles, formed by these co-polymers are capable of selectively binding peptides through electrostatic interactions, indicating that these random polymers can self-organize into functionally selective materials. Moreover, these random co-polymers also enable the ordered co-crystallization of matrix and extracted guest molecules, giving rise to substantial signal enhancements during MALDI-MS detection. Together, these observations represent an excellent example of how random polymers can self-assemble into ordered, functional materials.