Dataset Information

The design and synthesis of dextran-doxorubicin prodrug-based pH-sensitive drug delivery system for improving chemotherapy efficacy.

ABSTRACT: Tumor cells show acidic conditions compared with normal cells, which further inspires scientist to build nanocarrier responsive to tumor microenvironment (TME) for enhancing tumor therapeutic efficacy. Here, we report a pH-sensitive and biocompatible polyprodrug based on dextran-doxorubicin (DOX) prodrug (DOXDT) for enhanced chemotherapy. High-density DOX component was covalently decorated on the nanocarrier and the drug molecules could be effectively released in the acidic tumor tissue/cells, improving chemotherapy efficacy. Specifically, a dextran-based copolymer was preliminarily prepared by one-step atom transfer radical polymerization (ATRP); then DOX was conjugated on the copolymer component via pH-responsive hydrazone bond. The structure of DOXDT can be well-controlled. The resulting DOXDT was able to further self-assemble into nanoscale micelles with a hydration diameter of about 32.4?nm, which presented excellent micellar stability. Compared to lipid-based drug delivery system, the DOXDT prodrug showed higher drug load capacity up to 23.6%. In addition, excellent stability and smaller size of the nanocarrier contributed to better tissue permeability and tumor suppressive effects in vivo. Hence, this amphipathic DOXDT prodrug is promising in the development of translational DOX formulations, which would be widely applied in cancer therapy.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7610203 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The design and synthesis of dextran-doxorubicin prodrug-based pH-sensitive drug delivery system for improving chemotherapy efficacy.

Zhang Xiaoli X Zhang Tian T Ma Xianbin X Wang Yajun Y Lu Yi Y Jia Die D Huang Xiaohua X Chen Jiucun J Xu Zhigang Z Wen Feiqiu F

Asian journal of pharmaceutical sciences 20191106 5

Tumor cells show acidic conditions compared with normal cells, which further inspires scientist to build nanocarrier responsive to tumor microenvironment (TME) for enhancing tumor therapeutic efficacy. Here, we report a pH-sensitive and biocompatible polyprodrug based on dextran-doxorubicin (DOX) prodrug (DOXDT) for enhanced chemotherapy. High-density DOX component was covalently decorated on the nanocarrier and the drug molecules could be effectively released in the acidic tumor tissue/cells, i ...[more]

PMID: 33193863

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Project description:In this study, we investigated the potential of a dual-targeted pH-sensitive doxorubicin prodrug-microbubble complex (DPMC) in ultrasound (US)-assisted antitumor therapy. The doxorubicin prodrug (DP) consists of a succinylated-heparin carrier conjugated with doxorubicin (DOX) via hydrazone linkage and decorated with dual targeting ligands, folate and cRGD peptide. Combination of microbubble (MB) and DP, generated via avidin-biotin binding, promoted intracellular accumulation and improved therapeutic efficiency assisted by US cavitation and sonoporation. Aggregates of prepared DP were observed with an inhomogeneous size distribution (average diameters: 149.6±29.8 nm and 1036.2±38.8 nm, PDI: 1.0) while DPMC exhibited a uniform distribution (average diameter: 5.804±2.1 μm), facilitating its usage for drug delivery. Notably, upon US exposure, DPMC was disrupted and aggregated DP dispersed into homogeneous small-sized nanoparticles (average diameter: 128.6±42.3 nm, PDI: 0.21). DPMC could target to angiogenic endothelial cells in tumor region via αvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediated via recognition of folate receptor (FR) after US exposure. In vitro experiments showed higher tumor specificity and killing ability of DPMC with US than free DOX and DP for breast cancer MCF-7 cells. Furthermore, significant accumulation and specificity for tumor tissues of DPMC with US were detected using in vivo fluorescence and ultrasound molecular imaging, indicating its potential to integrate tumor imaging and therapy. In particular, through inducing apoptosis, inhibiting cell proliferation and antagonizing angiogenesis, DPMC with US produced higher tumor inhibition rates than DOX or DPMC without US in MCF-7 xenograft tumor-bearing mice while inducing no obvious body weight loss. Our strategy provides an effective platform for the delivery of large-sized or aggregated particles to tumor sites, thereby extending their therapeutic applications in vivo.

Dataset Information

The design and synthesis of dextran-doxorubicin prodrug-based pH-sensitive drug delivery system for improving chemotherapy efficacy.

Publications

The design and synthesis of dextran-doxorubicin prodrug-based pH-sensitive drug delivery system for improving chemotherapy efficacy.

Similar Datasets

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