Compacting hyaluronan into nanogels induces an enhanced macropinocytosis in MC38 cells

IF 8.5 1区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

International Journal of Biological Macromolecules Pub Date : 2025-05-01 DOI:10.1016/j.ijbiomac.2025.143599

Wei Hou , Xinxin Hao , Jiayi Li , Xiaorong Gou , Hua Guo , Yiyi Zhang , Hong Deng , Weiqi Zhang

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Abstract

Hyaluronan (HA)-based drug delivery system including HA conjugates and nano-formulations have been intensively researched in various biomedical applications due to its excellent biocompatibility and unique biological characteristics. Currently most researches are exploring the targeted drug delivery enabled by HA receptors e.g. CD44-based cancer targeting, while the contribution of other cellular uptake pathways in HA-based delivery remains elusive especially for different HA carriers. Here, the cellular uptake of HA in linear form (HA conjugate) and nano-formulation (HA nanogels (NG)) were compared with a focus on macropinocytosis that is actively involved in nutrient scavenging for cancer cells. Considering the ease of fluorescence in evaluating cellular uptake, Rhodamine b (Rb) dye was employed as a model drug to prepare HA-Rb conjugate and HA/Rb NG. After a comprehensive physiochemical characterization, the cellular uptake of these two HA carriers were compared in MC38 cells with different transport inhibitors, HA synthesis inhibition and nutrient depletion. While macropinocytosis blockage inhibited HA/Rb NG uptake more than HA-Rb, enhancing macropinocytosis either by HA inhibition or serum starvation significantly increased HA/Rb NG uptake. These evidences clearly suggest macropinocytosis contributes differently to the cellular uptake of varied HA carriers, which provides new insights to engineer HA for different drug delivery purposes.

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将透明质酸压实成纳米凝胶诱导MC38细胞巨噬细胞增多

透明质酸（HA）基于透明质酸缀合物和纳米制剂的药物传递系统由于其优异的生物相容性和独特的生物学特性，在各种生物医学应用中得到了广泛的研究。目前，大多数研究都在探索HA受体的靶向药物递送，例如基于cd44的癌症靶向，而其他细胞摄取途径在基于HA的递送中的作用仍然难以捉摸，特别是对于不同的HA载体。本研究比较了线性形式的透明质酸（透明质酸缀合物）和纳米配方的透明质酸纳米凝胶（NG）的细胞摄取，重点研究了积极参与癌细胞营养清除的巨噬细胞作用。考虑到荧光易于评估细胞摄取，以罗丹明b （Rb）染料为模型药物制备HA-Rb缀合物和HA/Rb NG。经过全面的理化表征，比较了这两种HA载体在具有不同转运抑制剂、HA合成抑制和营养耗尽的MC38细胞中的细胞摄取情况。虽然巨噬细胞抑制比HA-Rb更能抑制HA/Rb NG的摄取，但通过HA抑制或血清饥饿来增强巨噬细胞，可显著增加HA/Rb NG的摄取。这些证据清楚地表明，巨噬细胞对各种HA载体的细胞摄取有不同的贡献，这为设计不同药物递送目的的HA提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Biological Macromolecules 生物-生化与分子生物学

CiteScore

13.70

自引率

9.80%

发文量

2728

审稿时长

64 days

期刊介绍： The International Journal of Biological Macromolecules is a well-established international journal dedicated to research on the chemical and biological aspects of natural macromolecules. Focusing on proteins, macromolecular carbohydrates, glycoproteins, proteoglycans, lignins, biological poly-acids, and nucleic acids, the journal presents the latest findings in molecular structure, properties, biological activities, interactions, modifications, and functional properties. Papers must offer new and novel insights, encompassing related model systems, structural conformational studies, theoretical developments, and analytical techniques. Each paper is required to primarily focus on at least one named biological macromolecule, reflected in the title, abstract, and text.