Development of carrier-free nanodrugs based on low molecular weight heparin-doxorubicin conjugate assembly with smart pH-triggered drug release characteristics for combinatorial antitumor therapy

Abnormal angiogenesis is a hallmark of solid tumors. The combination of cytotoxic and anti-angiogenic drugs has been proven to be more effective than single treatments. As an important platform in synergistic cancer therapy, a carrier-free nanodrug with satisfying bioactivity is very appealing, due...

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Veröffentlicht in:New journal of chemistry 2022-01, Vol.46 (2), p.82-831
Hauptverfasser: Fan, Bo, Li, Qian, Jiang, Yanping, Shen, Weiguang, Xing, Yang, Liang, Guixian, Wu, Qian, Ban, Shurong, Zhang, Ruiping
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Sprache:eng
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Zusammenfassung:Abnormal angiogenesis is a hallmark of solid tumors. The combination of cytotoxic and anti-angiogenic drugs has been proven to be more effective than single treatments. As an important platform in synergistic cancer therapy, a carrier-free nanodrug with satisfying bioactivity is very appealing, due to its avoiding of carrier-related potential toxicity. Herein, an amphiphilic drug-drug conjugate was simply synthesized from hydrophilic natural glycosaminoglycan low molecular weight heparin (LMWH) and hydrophobic doxorubicin (DOX) via a pH-responsive imine linkage. The LMWH-DOX conjugates could self-assemble into nanoscale particles in aqueous media (denominated 'LD nanodrug'), but were degraded with acidic stimulus. The LD nanodrug integrated the anti-angiogenesis activity of LMWH and the cytotoxicity of DOX and overcame the drawbacks of the free drugs. Compared with the free drugs, the LD nanodrug could accumulate in solid tumors through an enhanced permeability and retention effect, be effectively internalized by tumor cells and release bioactive agents to exert the combinational antitumor effects. Accordingly, the LD nanodrug displayed a significant inhibitory effect on tumor growth and metastasis. Furthermore, this work investigated the anti-angiogenic activity of the LD nanodrug using a tube formation assay in vitro and a chick embryo chorioallantoic membrane (CAM) in vivo to evaluate its contribution for combinational antitumor therapy. A LMWH-DOX nanodrug effectively released bioactive agents, providing a combination therapy of low molecular weight heparin and doxorubicin for angiogenesis suppression and carcinoma inhibition.
ISSN:1144-0546
1369-9261
DOI:10.1039/d1nj04224f