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Enhanced tumor uptake and activity of nanoplex-loaded doxorubicin

阿霉素 药理学 细胞凋亡 化学 心脏毒性 脂质体 癌症研究 神经肽1 化疗 毒性 生物 医学 内科学 生物化学 有机化学 血管内皮生长因子受体 血管内皮生长因子
作者
Na Zhao,Qixin Leng,Martin C. Woodle,A. James Mixson
出处
期刊:Biochemical and Biophysical Research Communications [Elsevier]
卷期号:513 (1): 242-247 被引量:7
标识
DOI:10.1016/j.bbrc.2019.03.190
摘要

Doxorubicin (Dox) has widespread use as a cancer chemotherapeutic agent, but Dox is limited by several side effects including irreversible cardiomyopathy. Although liposomal Dox formulations, such as Doxil, mitigate side effects, they do not prolong survival in many patients. As a result, efforts have continued to discover improved formulations of Dox. We previously found that a peptide-based nanoplex delivered plasmid DNA efficiently to tumors in murine models. Unlike the majority of nanoparticles that depend solely on enhanced permeability and retention (EPR) for their transport into the tumor, our peptide-based nanoplex has a potential advantage in that its uptake primarily depends on neuropilin-1 receptor targeting. Because Dox binds to DNA, we tested whether this delivery platform could effectively deliver Dox to tumors and reduce their size. The nanoplexes increased the levels of Dox in tumors by about 5.5-fold compared to aqueous (free) Dox controls. Consistent with enhanced levels in the tumor, the nanoplex-Dox treatment had significantly greater anti-tumor activity. Whereas low dose free Dox did not reduce the size of tumors compared to untreated controls, the low dose nanoplex-Dox reduced the size of tumors by nearly 55% (p < 0.001). The high dose nanoplex-Dox also inhibited the size of tumor significantly more than the comparable high-dose free Dox (p < 0.001). Furthermore, apoptosis and proliferation markers (Ki67) of tumors observed in the different treatment groups correlated with their ability to inhibit tumor size. This study shows the efficacy of an NRP-1 targeted nanoplexes to deliver Dox to tumors in vivo and lays the groundwork for more complex and effective formulations.

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