Alpha-tocopheryl succinate improves encapsulation, pH-sensitivity, antitumor activity and reduces toxicity of doxorubicin-loaded liposomes
Alpha-tocopheryl succinate improves encapsulation, pH-sensitivity, antitumor activity and reduces toxicity of doxorubicin-loaded liposomes
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DOI：
10.1016/j.ejps.2019.105205
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发表时间：
2020-03-01
影响因子：
4.6
通讯作者：
Leite, E. A.
中科院分区：
文献类型：
--
作者：
Boratto, F. A.;Franco, M. S.;Leite, E. A.
阿霉素(DOX)在肿瘤治疗中发挥着重要作用，但其心脏毒性大、实体肿瘤渗透率低是其应用的主要局限性。已经开发出了减轻DOX毒性的脂质体配方，但脂质体配方的技术改进以及另一种具有抗肿瘤特性的试剂的加入，如维生素E的半合成类似物α-生育酚琥珀酸酯(TS)，肯定会带来好处。因此，本研究提出了DOX和TS(PHSL-TS-DOX)脂质体的研制。开发了一种新的DOX包封法，该方法不使用经典的硫酸铵梯度法，包封率高。小角X射线散射(SAXS)分析和释药研究证明了所开发的处方的pH敏感性。与游离DOX相比，使用PHSL-TS-DOX可以稳定肿瘤生长。毒性试验表明，该制剂安全，治疗后体重初步恢复，对DOX毒性的主要靶器官心脏和肝脏无害。开发的配方还避免了DOX的典型不良反应--骨髓抑制的发生。因此，PHSL-TS-DOX具有足够的抗肿瘤活性和安全的毒性，是治疗乳腺癌的一种有前途的替代方案。
Doxorubicin (DOX) plays an important role in cancer treatment; however, high cardiotoxicity and low penetration in solid tumors are the main limitations of its use. Liposomal formulations have been developed to attenuate the DOX toxicity, but the technological enhancement of the liposomal formulation as well as the addition of another agent with antitumor properties, like alpha-tocopheryl succinate (TS), a semi-synthetic analog of vitamin E, could certainly bring benefits. Thus, in this study, it was proposed the development of liposomes composed of DOX and TS (pHSL-TS-DOX). A new DOX encapsulation method, without using the classic ammonium sulfate gradient with high encapsulation percentage was developed. Analysis of Small Angle X-ray Scattering (SAXS) and release study proved the pH-sensitivity of the developed formulation. It was observed stabilization of tumor growth using pHSL-TS-DOX when compared to free DOX. The toxicity tests showed the safety of this formulation since it allowed body weight initial recovery after the treatment and harmless to heart and liver, main target organs of DOX toxicity. The developed formulation also avoided the occurrence of myelosuppression, a typical adverse effect of DOX. Therefore, pHSL-TS-DOX is a promising alternative for the treatment of breast cancer since it has adequate antitumor activity and a safe toxicity profile.