Because of the synergistic effects of drugs and minimal drug dose for cancer therapy, combination chemotherapy is frequently used in the clinic. In this study, hyaluronic acid-modified amine-terminated fourth-generation polyamidoamine dendrimer nanoparticles were synthesized for systemic co-delivery of cisplatin and doxorubicin (HA@PAMAM-Pt-Dox). In vitro data showed that HA@PAMAM-Pt-Dox can enter the cells through the lysosome mediated-pathway in a time-dependent manner. Cell viability studies indicated that HA@PAMAM-Pt-Dox exhibited a higher anticancer activity on MCF-7 and MDA-MB-231 breast cancer cells at a relative low concentration. HA@PAMAM-Pt-Dox not only efficiently inhibited tumor growth but also significantly reduced the toxicity of Dox. Moreover, intravenous administration of HA@PAMAM-Pt-Dox to MDA-MB-231 tumor-bearing BALB/c nude mice resulted in the accumulation of HA@PAMAM-Pt-Dox at the tumor site, thereby significantly inhibiting tumor growth without apparent toxicity. These results suggested that HA@PAMAM-Pt-Dox has great potential to improve the chemotherapeutic efficacy of cisplatin and doxorubicin in breast cancer. STATEMENT OF SIGNIFICANCE: One of the main problems in cancer treatment is the development of drug resistance. To date, it is believed that combination chemotherapy might be an effective strategy for the above problem. However, for two completely different drugs, combination chemotherapy faces huge difficulties including the antagonistic nature of drugs, variations in drugs in terms of solubility, and limited tumor targeting. Recent developments in nanoscience and nanotechnology provide an effective approach for such disadvantages. Considering the advantages of dendrimers such as control of size and molecular weight, bioavailability, and biosafety, we used fourth-generation dendrimers modified by HA as drug vectors by covalently conjugating them with anticancer drugs (cisplatin and doxorubicin) to form a nanodrug delivery system, named HA@PAMAM-Pt-Dox. We observed that the HA@PAMAM-Pt-Dox system can effectively kill breast cancer cells both in vitro and in vivo, which showed a favorable synergistic effect. This strategy can be extended to other drugs, thus providing a highly effective strategy for cancer treatment.

中文翻译：

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通过与聚酰胺酰胺树状大分子共价共价联运顺铂和阿霉素，以增强协同性癌症治疗。

由于药物的协同作用和最小剂量的药物可用于癌症治疗，因此临床上经常使用联合化疗。在这项研究中，透明质酸修饰的胺封端的第四代聚酰胺型胺树枝状聚合物纳米粒子被合成用于顺铂和阿霉素（HA @ PAMAM-Pt-Dox）的系统共递送。体外数据显示，HA @ PAMAM-Pt-Dox可以以时间依赖性的方式通过溶酶体介导的途径进入细胞。细胞活力研究表明，HA @ PAMAM-Pt-Dox在相对低的浓度下对MCF-7和MDA-MB-231乳腺癌细胞表现出较高的抗癌活性。HA @ PAMAM-Pt-Dox不仅有效地抑制了肿瘤的生长，而且还大大降低了Dox的毒性。而且，向带有MDA-MB-231荷瘤的BALB / c裸鼠静脉注射HA @ PAMAM-Pt-Dox导致HA @ PAMAM-Pt-Dox在肿瘤部位积聚，从而显着抑制肿瘤生长而无明显毒性。这些结果表明，HA @ PAMAM-Pt-Dox具有提高顺铂和阿霉素对乳腺癌的化学治疗功效的巨大潜力。意义声明：癌症治疗中的主要问题之一是耐药性的发展。迄今为止，据信联合化疗可能是解决上述问题的有效策略。然而，对于两种完全不同的药物，联合化疗面临着巨大的困难，包括药物的拮抗性质，药物在溶解度方面的差异以及有限的肿瘤靶向性。纳米科学和纳米技术的最新发展为解决这些缺点提供了一种有效的方法。考虑到树状聚合物的优势，例如控制大小和分子量，生物利用度和生物安全性，我们使用了HA修饰的第四代树状聚合物作为药物载体，将它们与抗癌药物（顺铂和阿霉素）共价结合以形成纳米药物递送系统，名为HA @ PAMAM-Pt-Dox。我们观察到HA @ PAMAM-Pt-Dox系统可以在体内外有效杀死乳腺癌细胞，表现出良好的协同作用。该策略可以扩展到其他药物，从而为癌症治疗提供了一种高效的策略。生物利用度和生物安全性方面，我们使用了HA修饰的第四代树状聚合物作为药物载体，将它们与抗癌药物（顺铂和阿霉素）共价结合，形成了纳米药物递送系统，称为HA @ PAMAM-Pt-Dox。我们观察到HA @ PAMAM-Pt-Dox系统可以在体内外有效杀死乳腺癌细胞，表现出良好的协同作用。该策略可以扩展到其他药物，从而为癌症治疗提供了一种高效的策略。生物利用度和生物安全性方面，我们使用了HA修饰的第四代树状聚合物作为药物载体，将它们与抗癌药物（顺铂和阿霉素）共价结合，形成了纳米药物递送系统，称为HA @ PAMAM-Pt-Dox。我们观察到HA @ PAMAM-Pt-Dox系统可以在体内外有效杀死乳腺癌细胞，表现出良好的协同作用。该策略可以扩展到其他药物，从而为癌症治疗提供了一种高效的策略。表现出良好的协同作用。该策略可以扩展到其他药物，从而为癌症治疗提供了一种高效的策略。表现出良好的协同作用。该策略可以扩展到其他药物，从而为癌症治疗提供了一种高效的策略。