Flores-Colón Marienid, Rivera-Serrano Mariela, Peterson-Peguero Esther A, Vivas-Rivera Pablo E, Valiyeva Fatima, Vivas-Mejía Pablo E
Department of Biochemistry, University of Puerto Rico, Medical Sciences Campus, San Juan 00936, Puerto Rico.
Comprehensive Cancer Center, University of Puerto Rico, San Juan 00936, Puerto Rico.
Pharmaceuticals (Basel). 2025 Jul 17;18(7):1053. doi: 10.3390/ph18071053.
Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer that accounts for 1-5% of BC patients and regularly affects women under 40 years of age. Approximately 50% of IBC cases are HER2+ and can be treated with the monoclonal antibody-based therapy Herceptin (trastuzumab). However, resistance to Herceptin develops within a year, and effective second-line targeted therapies are currently unavailable for IBC patients. Lipocalin-2 (LCN2) is a promising therapeutic target for IBC due to its role in promoting tumor invasiveness, angiogenesis, and the inflammatory tumor microenvironment characteristic of IBC. We developed Herceptin-conjugated liposomes loaded with LCN2-targeted small-interference RNA (siRNA) for HER2+ IBCs. We synthesized DSPE-PEG(2000)-maleimide-Herceptin in a three-step process and formulated the liposomes together with DOPC, PEG(2000)-PE, cholesterol, and siRNA. Dynamic light scattering confirmed the liposome size distribution, which was 66.7 nm for the Herceptin-conjugated liposome versus 43.0 nm in a non-functionalized liposome. Here, we report efficient internalization of this formulation into HER2+ IBC cells, reducing LCN2 levels by 30% and disrupting tumor emboli formation. RNA sequencing revealed 139 genes that were differentially expressed upon LCN2 knockdown, with 25 canonical pathways identified through Ingenuity Pathway Analysis. : These findings suggest that LCN2-targeted siRNA within Herceptin-targeted liposomes represents a promising therapeutic strategy for IBC.
炎性乳腺癌（IBC）是一种罕见且侵袭性强的乳腺癌亚型，占乳腺癌患者的1%-5%，且常影响40岁以下的女性。大约50%的IBC病例为HER2阳性，可采用基于单克隆抗体的赫赛汀（曲妥珠单抗）治疗。然而，对赫赛汀的耐药性在一年内就会出现，目前IBC患者尚无有效的二线靶向治疗方法。脂联素-2（LCN2）因其在促进肿瘤侵袭、血管生成以及IBC特有的炎性肿瘤微环境中所起的作用，成为IBC一个有前景的治疗靶点。我们开发了负载LCN2靶向小干扰RNA（siRNA）的赫赛汀偶联脂质体，用于治疗HER2阳性的IBC。我们通过三步法合成了DSPE-PEG(2000)-马来酰亚胺-赫赛汀，并将脂质体与DOPC、PEG(2000)-PE、胆固醇和siRNA一起配制。动态光散射证实了脂质体的大小分布，赫赛汀偶联脂质体的大小为66.7nm，而非功能化脂质体为43.0nm。在此，我们报告了该制剂能有效内化进入HER2阳性IBC细胞，使LCN2水平降低30%，并破坏肿瘤栓子形成。RNA测序揭示了139个在LCN2敲低后差异表达的基因，通过通路分析确定了25条经典通路。这些发现表明，赫赛汀靶向脂质体内的LCN2靶向siRNA是一种有前景的IBC治疗策略。
