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Programming in situ accelerated DNA walkers in diffusion-limited microenvironments.

ABSTRACT: Macromolecule diffusion in cellular microenvironments dictates the kinetics of biochemical processes, yet inevitably limiting the assembly and operation of biomimetic motors. Herein we program in situ accelerated DNA walkers in diffusion-limited microenvironments such as molecularly crowded solutions and cytoplasm. All DNA components, including single-foot walkers, chemically damaged tracks and calibration elements, are anchored on individual gold nanoparticles. Two endogenous enzymes participating in base repair pathways are used to actuate on-particle walking via a base excision/hydrolyzation coupled reaction. The walkers are in situ driven without requiring external drivers and accelerated several times. They also avoid low-efficiency diffusion/assembly procedures and respond to heterogeneous cellular milieus with calibration function. We further regulated the walking kinetics via DNA densities and sets of enzymes, and demonstrated cytoplasmic behaviors of three kinds of walkers. They were utilized to profile DNA repair pathways and monitor enzyme catalysis in living cells.

SUBMITTER: Chen F

PROVIDER: S-EPMC6432271 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Programming <i>in situ</i> accelerated DNA walkers in diffusion-limited microenvironments.

Chen Feng F Xue Jing J Bai Min M Qin Jing J Zhao Yongxi Y

Chemical science 20190122 10

Macromolecule diffusion in cellular microenvironments dictates the kinetics of biochemical processes, yet inevitably limiting the assembly and operation of biomimetic motors. Herein we program <i>in situ</i> accelerated DNA walkers in diffusion-limited microenvironments such as molecularly crowded solutions and cytoplasm. All DNA components, including single-foot walkers, chemically damaged tracks and calibration elements, are anchored on individual gold nanoparticles. Two endogenous enzymes par ...[more]

PMID: 30996893

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Project description:BackgroundAntibodies revolutionized cancer treatment over the past decades. Despite their successfully application, there are still challenges to overcome to improve efficacy, such as the heterogeneous distribution of antibodies within tumors. Tumor microenvironment features, such as the distribution of tumor and other cell types and the composition of the extracellular matrix may work together to hinder antibodies from reaching the target tumor cells. To understand these interactions, we propose a framework combining in vitro and in silico models. We took advantage of in vitro cancer models previously developed by our group, consisting of tumor cells and fibroblasts co-cultured in 3D within alginate capsules, for reconstruction of tumor microenvironment features.ResultsIn this work, an experimental-computational framework of antibody transport within alginate capsules was established, assuming a purely diffusive transport, combined with an exponential saturation effect that mimics the saturation of binding sites on the cell surface. Our tumor microenvironment in vitro models were challenged with a fluorescent antibody and its transport recorded using light sheet fluorescence microscopy. Diffusion and saturation parameters of the computational model were adjusted to reproduce the experimental antibody distribution, with root mean square error under 5%. This computational framework is flexible and can simulate different random distributions of tumor microenvironment elements (fibroblasts, cancer cells and collagen fibers) within the capsule. The random distribution algorithm can be tuned to follow the general patterns observed in the experimental models.ConclusionsWe present a computational and microscopy framework to track and simulate antibody transport within the tumor microenvironment that complements the previously established in vitro models platform. This framework paves the way to the development of a valuable tool to study the influence of different components of the tumor microenvironment on antibody transport.

Dataset Information

Programming in situ accelerated DNA walkers in diffusion-limited microenvironments.

Publications

Programming <i>in situ</i> accelerated DNA walkers in diffusion-limited microenvironments.

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