The development of nanoparticle‐based biomedical applications has been hampered due to undesired off‐target effects. Herein, we outline a cellular AND gate to enhance uptake selectivity, in which a nanoassembly–cell interaction is turned on, only in the concurrent presence of two different protein functions, an enzymatic reaction (alkaline phosphatase, ALP) and a ligand–protein (carbonic anhydrase IX, CA IX) binding event. Selective uptake of nanoassemblies was observed in cells that overexpress both of these proteins (unicellular AND gate). Interestingly, selective uptake can also be achieved in CA IX overexpressed cells, when cocultured with ALP overexpressed cells, where the nanoassembly presumably acts as a mediator for cell–cell communication (bicellular AND gate). This logic‐gated cellular uptake could find use in applications such as tumor imaging or theranostics.
Infrared spectroscopy has been used to analyze the microstructures of liquid‐crystalline polymers in various mesophases. It was quite evident that there is little indication of conformational order associated with the flexible polymethylene sequences in the nematic or isotropic phases. However, additional spectroscopic evidence does suggest that polyesters with an even number of methylene units have a higher degree of lateral order when compared to those with an odd number in the liquid‐crystalline state.
Targeted drug delivery using antibody–drug conjugates has attracted great attention due to its enhanced therapeutic efficacy compared to traditional chemotherapy. However, the development has been limited due to a low drug-to-antibody ratio and laborious linker-payload optimization. Herein, we present a simple and efficient strategy to combine the favorable features of polymeric nanocarriers with antibodies to generate an antibody–nanogel conjugate (ANC) platform for targeted delivery of cytotoxic agents. Our nanogels stably encapsulate several chemotherapeutic agents with a wide range of mechanisms of action and solubility. We showcase the targetability of ANCs and their selective killing of cancer cells over-expressing disease-relevant antigens such as human epidermal growth factor receptor 2, epidermal growth factor receptor, and tumor-specific mucin 1, which cover a broad range of breast cancer cell types while maintaining low to no toxicity to non-targeted cells. Overall, our system represents a versatile approach that could impact next-generation nanomedicine in antibody-targeted therapeutics.
Disulfide cross-linked nanoassemblies have attracted considerable attention as a drug delivery vehicle due to their responsiveness to the natural redox gradient in biology. Fundamentally understanding the factors that influence the drug loading capacity, encapsulation stability, and precise control of the liberation of encapsulated cargo would be profoundly beneficial to redox-responsive materials. Reported herein are block copolymer (BCP)-based self-cross-linked nanogels, which exhibit high drug loading capacity, high encapsulation stability, and controllable release kinetics. BCP nanogels show considerably higher loading capacity and better encapsulation stability than the random copolymer nanogels at micromolar glutathione concentrations. By partially substituting thiol-reactive pyridyl disulfide into the unreactive benzyl or butyl group, we observed opposite effects on the cross-linking process of BCP nanogels. We further studied the redox-responsive cytotoxicity of our drug-encapsulated nanogels in various cancer cell lines.
Polymeric nanocarriers (PNCs) are versatile drug delivery vehicles capable of delivering a variety of therapeutics. Quantitatively monitoring their uptake in biological systems is essential for realizing their potential as next-generation delivery systems; however, existing quantification strategies are limited due to the challenges of detecting polymeric materials in complex biological samples. Here, we describe a metal-coded mass tagging approach that enables the multiplexed quantification of the PNC uptake in cells using mass spectrometry (MS). In this approach, PNCs are conjugated with ligands that bind strongly to lanthanide ions, allowing the PNCs to be sensitively quantitated by inductively coupled plasma–MS. The metal-coded tags have little effect on the properties or toxicity of the PNCs, making them biocompatible. We demonstrate that the conjugation of different metals to the PNCs enables the multiplexed analysis of cellular uptake of multiple distinct PNCs at the same time. This multiplexing capability should improve the design and optimization of PNCs by minimizing biological variability and reducing analysis time, effort, and cost.
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