Self-targeting visualizable hyaluronate nanogel for synchronized intracellular release of doxorubicin and cisplatin in c
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Self-targeting visualizable hyaluronate nanogel for synchronized intracellular release of doxorubicin and cisplatin in combating multidrug-resistant breast cancer Wen Ma1,§, Qiling Chen1,§, Weiguo Xu2,§, Meng Yu1, Yuanyuan Yang1, Binhua Zou1, Yu Shrike Zhang3 (), Jianxun Ding2 (), and Zhiqiang Yu1 () 1
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China 2 Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China 3 Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge MA 02139, USA § Wen Ma, Qiling Chen, and Weiguo Xu contributed equally to this work. © Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 19 July 2020 / Revised: 9 September 2020 / Accepted: 12 September 2020
ABSTRACT Multidrug-resistance (MDR) featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic. Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR. However, the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites. In the present study, a type of self-targeting hyaluronate (HA) nanogels (CDDPHANG/DOX) to reverse drug resistance through the synchronized pharmacokinetics, intratumoral distribution, and intracellular release of topoisomerase II inhibitor doxorubicin (DOX) and DNAcrosslinking agent cisplatin (CDDP) is developed. With prolonged circulation time and enhanced intratumoral accumulation in vivo, CDDP HANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity. Besides, fluorescence imaging of DOX combined with the micro-computed tomography (micro-CT) imaging of CDDP facilitates the visualization of this combination tumor chemotherapy. With visualizable synchronized drug delivery, the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.
KEYWORDS hyaluronate nanogel, self-targetability, intracellular drug codelivery, multimodal imaging, reversal of multidrug resistance
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Introduction
In the clinics, chemotherapy often fails due to the low selectivity of therapeutic agents and rapid efflux of small-molecule drugs by drug-transporting proteins, e.g., P-glycoprotein (P-gp), present in the membranes of tumor cells, which always cause severe toxicity and multidrug resistance (MDR), respectively [1]. Numerous nanoparticles with various targeting ligands have been developed to selectively deliver the antitumor drugs to tumor tissues by ligand-receptor recognition and tumor cells by endocytosis, which down-regulate the efflux of drugs and suppress th
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