School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.
School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, United Kingdom.
Mol Pharm. 2022 Dec 5;19(12):4601-4611. doi: 10.1021/acs.molpharmaceut.2c00439. Epub 2022 Aug 8.
Delivery of chemotherapy drugs specifically to cancer cells raises local drug doses in tumors and therefore kills more cancer cells while reducing side effects in other tissues, thereby improving oncological and quality of life outcomes. Cubosomes, liquid crystalline lipid nanoparticles, are potential vehicles for delivery of chemotherapy drugs, presenting the advantages of biocompatibility, stable encapsulation, and high drug loading of hydrophobic or hydrophilic drugs. However, active targeting of drug-loaded cubosomes to cancer cells, as opposed to passive accumulation, remains relatively underexplored. We formulated and characterized cubosomes loaded with potential cancer drug copper acetylacetonate and functionalized their surfaces using click chemistry coupling with hyaluronic acid (HA), the ligand for the cell surface receptor CD44. CD44 is overexpressed in many cancer types including breast and colorectal. HA-tagged, copper-acetylacetonate-loaded cubosomes have an average hydrodynamic diameter of 152 nm, with an internal nanostructure based on the space group Im3m. These cubosomes were efficiently taken up by two CD44-expressing cancer cell lines (MDA-MB-231 and HT29, representing breast and colon cancer) but not by two CD44-negative cell lines (MCF-7 breast cancer and HEK-293 kidney cells). HA-tagged cubosomes caused significantly more cell death than untargeted cubosomes in the CD44-positive cells, demonstrating the value of the targeting. CD44-negative cells were equally relatively resistant to both, demonstrating the specificity of the targeting. Cell death was characterized as apoptotic. Specific targeting and cell death were evident in both 2D culture and 3D spheroids. We conclude that HA-tagged, copper-acetylacetonate-loaded cubosomes show great potential as an effective therapeutic for selective targeting of CD44-expressing tumors.
递送至癌细胞的化疗药物会在肿瘤中提高局部药物剂量，从而杀死更多的癌细胞，同时减少对其他组织的副作用，从而改善肿瘤学和生活质量的结果。立方液晶脂质纳米粒（Cubosomes）是递呈化疗药物的潜在载体，具有生物相容性、稳定包封和高载药率（亲脂性或亲水性药物）的优点。然而，与被动积累相比，载药立方液晶脂质纳米粒对癌细胞的主动靶向仍然相对未被充分探索。我们制备并表征了载有潜在癌症药物乙酰丙酮铜的立方液晶脂质纳米粒，并通过点击化学与透明质酸（HA，细胞表面受体 CD44 的配体）偶联对其表面进行功能化。CD44 在包括乳腺癌和结直肠癌在内的许多癌症类型中过表达。HA 标记的、载有乙酰丙酮铜的立方液晶脂质纳米粒的平均水动力直径为 152nm，其内部纳米结构基于空间群 Im3m。这些立方液晶脂质纳米粒被两种表达 CD44 的癌细胞系（MDA-MB-231 和 HT29，代表乳腺癌和结肠癌）有效摄取，但不被两种 CD44 阴性细胞系（乳腺癌 MCF-7 和肾细胞 HEK-293）摄取。HA 标记的立方液晶脂质纳米粒在 CD44 阳性细胞中引起的细胞死亡明显多于未靶向的立方液晶脂质纳米粒，证明了靶向的价值。CD44 阴性细胞对两者均具有相对抗性，证明了靶向的特异性。细胞死亡被表征为凋亡。在 2D 培养和 3D 球体中均观察到了特异性靶向和细胞死亡。我们得出结论，HA 标记的、载有乙酰丙酮铜的立方液晶脂质纳米粒具有很大的潜力成为针对 CD44 表达肿瘤的有效治疗方法。
