Longyu Li

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.

Surface charge generation in nanogels for activated cellular uptake at tumor-relevant pH

Nanocarriers that can be effectively transported across cellular membranes have potential in a variety of biomedical applications. Among these, materials that are capable of changing their surface properties and thus gain entry into a cell, in response to a specific tissue environment, are of particular interest. In this manuscript we report a facile route to prepare nanogels, which generate surface charge with pH as stimulus. This is achieved by designing a polymeric nanogel containing 2-diisopropylamino (DPA) moieties. The choice of DPA nanogel is based on its pKb, which causes this functional group to be rapidly protonated upon change in pH. It is noteworthy that the pH change at which the surface charge is generated in the nanogel corresponds to the slightly acidic conditions observed in the extracellular environment of solid tumor. We show that the pH at which the charge is generated, i.e. the isoelectric point (pI) of the nanogel, can be adjusted by varying the percentage of DPA units in the nanogel, its preparation process and crosslinking density. Intracellular delivery of these nanogels was greatly enhanced in an acidic pH environment due to the surface charge generation. This study demonstrates the versatile nature of the nanogels to introduce specific functionalities with relative ease to achieve desired functional behavior.

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.

Responsive single-chain polymer nanoparticles with host–guest features

We report a facile approach to form ultra-fine single-chain polymer nanoparticles (SCPNs) via disulfide-based intrachain crosslinking of single polymer chains of a random copolymer poly(HEMA-co-PDSEMA). The SCPNs, which were prepared under mild reaction conditions and at normal reaction concentrations (up to 10 mg mL−1), have been characterized by 1H nuclear magnetic resonance (1H NMR) spectroscopy, atomic force microscopy (AFM), differential scanning calorimetry (DSC), gel permeation chromatography (GPC), and dynamic light scattering (DLS). The influences of the crosslinking density, the molecular weight and the initial concentration of the polymer upon the formation of SCPNs are also reported. In order to investigate the hydrophobic interior of SCPNs, we trace the emission spectrum of a pyrene probe. We highlight that these SCPNs exhibit host–guest properties to stably encapsulate hydrophobic guest molecules and release them in response to a redox stimulus.

pH responsive soft nanoclusters with size and charge variation features

Size and surface properties of a drug delivery vehicle play a very crucial role in determining its biological fate. The success of nanotherapeutic systems depends on several features such as deeper tumor tissue penetration, good retention and rapid cellular uptake. These properties are strongly influenced by the size and surface properties of the delivery vehicles. In this study, we demonstrate a polymeric nanoparticle that exhibits the size and surface charge variation features in response to slight changes in pH, which are biologically relevant (pH 7.4 to 6.5). These features have been demonstrated using a pH sensitive interparticle crosslinking by dynamic covalent imine bond formation between nanogels. The pH sensitive interparticle crosslinking is demonstrated using DLS, TEM, SEC, fluorescamine assay and cell uptake study.

Environment-Dependent Guest Exchange in Supramolecular Hosts

Dynamic exchange of guest molecules, encapsulated in host assemblies, is a phenomenon in supramolecular chemistry that has important implications in several applications. While the mechanism of exchange in micellar assemblies has been previously investigated, the effect of host and guest environment upon the guest-exchange dynamics has received little attention, if any. In this paper, we study the guest-exchange mechanism in pH-sensitive nanogels along with pH-insensitive nanogels as a control. By systematically comparing the behavior of these nanogels, we show that size, concentration, and hydrophobicity can all play a critical role in guest-exchange dynamics. More importantly, these studies reveal that the dominant mechanism of guest exchange can intimately depend on environmental factors.

Utilizing Reversible Interactions in Polymeric Nanoparticles To Generate Hollow Metal–Organic Nanoparticles

The use of reversible linkers in polymers has been of interest mainly for biomedical applications. Herein, we present a novel strategy to utilize reversible interactions in polymeric nanoparticles to generate hollow metal-organic nanoparticles (MOPs). These hollow MOPs are synthesized from self-assembled polymeric nanoparticles using a simple metal-comonomer exchange process in a single step. The control over the size of the polymer precursor particles translates into a straightforward opportunity for controlling MOP sizes. The shell thickness of the MOPs could be easily tuned by the concentration of metal ions in solution. The underlying mechanism for the formation of these hollow MOPs has been proposed. Evidence for the generality of the method is provided by its application to a variety of metal ions with different coordination geometries.

Biodistribution Analysis of NIR-Labeled Nanogels using In Vivo FMT Imaging in Triple Negative Human Mammary Carcinoma Models

The purpose of this study is to evaluate the biodistribution properties of random-copolymer-based core-cross-linked nanogels of various sizes and surface poly(ethylene glycol) composition. Systematic variations of near-IR labeled nanogels, comprising varying particle sizes (28-135 nm), PEG corona quantity (0-50 mol %), and PEG length (PEG Mn 1000, 2000, and 5000), were prepared and injected in mice that had been subcutaneously implanted with MDA-MB-231-luc-D3H2LN human mammary carcinoma. In vivo biodistribution was obtained using fluorescence molecular tomography imaging at 0, 6, 24, 48, and 72 h postinjection. Retention of total body probe and percentages of total injected dose in the tumor, liver, spleen, lungs, heart, intestines, and kidneys were obtained. Smaller nanogels (∼30-40 nm) with a high PEG conjugation (∼43-46 mol %) of Mn 2000 on their coronas achieved the highest tumor specificity with peak maximum 27% ID/g, a statistically significant propensity toward accumulation with 16.5% ID/g increase from 0 to 72 h of imaging, which constitutes a 1.5-fold increase. Nanogels with greater tumor localization also had greater retention of total body probe over 72 h. Nanogels without extensive PEGylation were rapidly excreted, even at similar sizes to PEGylated nanogels exhibiting whole body retention. Of all tissues, the liver had the highest % ID, however, like other tissues, it displayed a monotonic decrease over time, suggesting nanogel clearance by hepatic metabolism. Ex vivo quantification of individual tissues from gross necropsy at 72 h postinjection generally correlated with the FMT analysis, providing confidence in tissue signal segmentation in vivo. The parameters determined to most significantly direct a nanogel to the desired tumor target can lead to improve effectiveness for nanogels as therapeutic delivery vehicles.