Integration of an LPAR1 Antagonist into Liposomes Enhances Their Internalization and Tumor Accumulation in an Animal Model of Human Metastatic Breast Cancer.
Integration of an LPAR1 Antagonist into Liposomes Enhances Their Internalization and Tumor Accumulation in an Animal Model of Human Metastatic Breast Cancer.
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DOI：
10.1021/acs.molpharmaceut.3c00348
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发表时间：
2023-10
影响因子：
4.9
通讯作者：
Rudolf G Abdelmessih;Jiaming Xu;Francisco R Hung;Debra T Auguste
中科院分区：
文献类型：
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作者：
Rudolf G Abdelmessih;Jiaming Xu;Francisco R Hung;Debra T Auguste
溶血磷脂酸受体1(LPAR1)在乳腺癌中升高。LPAR1的失控，包括其功能和表达水平，与癌症的发生、发展和转移有关。LPAR1拮抗剂AM095或Ki16425可能是有效的治疗分子，但它们有限的水溶性阻碍了体内给药。在这项研究中，我们报道了两种含有AM095或Ki16425的脂质体配方的合成，它们嵌入在脂质双层中，作为转移性乳腺癌(MBC)的靶向纳米载体。数据显示，与空白脂质体制剂(对照)相比，Ki16425脂质体制剂对MBC小鼠上皮细胞的内化作用(4T1)增加了50%，在MBC小鼠模型中的肿瘤蓄积增加了100%。同时，正常小鼠上皮细胞(Eph-4EV)对Ki16425脂质体制剂的内化比对照制剂少25%。分子动力学模拟表明，AM095或Ki16425的整合改变了脂双层的物理和机械性质，使其在这些脂质体配方中比不含药物的脂质体更具灵活性。在脂质体给药系统中加入LPAR1拮抗剂是靶向LPA-LPAR1轴的一种可行的治疗方法，这可能会阻碍MBC的进展。
Lysophosphatidic acid receptor 1 (LPAR1) is elevated in breast cancer. The deregulation of LPAR1, including the function and level of expression, is linked to cancer initiation, progression, and metastasis. LPAR1 antagonists, AM095 or Ki16425, may be effective therapeutic molecules, yet their limited water solubility hinders in vivo delivery. In this study, we report on the synthesis of two liposomal formulations incorporating AM095 or Ki16425, embedded within the lipid bilayer, as targeted nanocarriers for metastatic breast cancer (MBC). The data show that the Ki16425 liposomal formulation exhibited a 50% increase in internalization by MBC mouse epithelial cells (4T1) and a 100% increase in tumor accumulation in a mouse model of MBC compared with that of a blank liposomal formulation (control). At the same time, normal mouse epithelial cells (EpH-4Ev) internalized the Ki16425 liposomal formulation 25% lesser than the control formulation. Molecular dynamics simulations show that the integration of AM095 or Ki16425 modified the physical and mechanical properties of the lipid bilayer, making it more flexible in these liposomal formulations compared with liposomes without drug. The incorporation of an LPAR1 antagonist within a liposomal drug delivery system represents a viable therapeutic approach for targeting the LPA-LPAR1 axis, which may hinder the progression of MBC.