Abstract Mammary gland tumour has the highest incidence rate and mortality in women, worldwide. The present study envisaged a molecularly targeted nanostructured lipid carrier (NLCs) for doxorubicin (Dox) delivery capable of inducing cellular apoptosis in mammary gland tumour. NLCs were prepared utilizing Perilla frutescens oil (54–69% ω3-fatty acid) as liquid lipid to enhance entrapment of Dox through molecular ion pairing. Biotin decorated NLCs (b-Dox-NLCs) were evaluated in vitro and in vivo. The b-Dox-NLCs showed particle size of 105.2 ± 3.5 nm, zeta potential −35 ± 2 mV, entrapment 99.15 ± 1.71%, drug content 19.67 ± 2.6 mg.g−1, biotin content 5.85 ± 0.64 µg.g−1 and drug release 98.67 ± 2.43% (facilitated by acidic microenvironment) respectively. MTT assay and Flow cytometric analysis revealed higher anti-proliferative capability of b-Dox-NLCs to force apoptosis in MCF-7 cell line vis-à-vis marketed Dox, evidenced by reactive oxygen species level and mitochondrial membrane potential mediated apoptosis. Enhanced antitumor targeting, therapeutic safety and efficacy was exhibited by b-Dox-NLCs, as investigated through tumour volume, animal survival, weight variation, cardiotoxicity and biodistribution studies in 7,12-Dimethylbenz[a]anthracene induced mammary gland tumour. Immunoblotting assay demonstrated b-Dox-NLCs downregulated anti-apoptotic proteins, i.e. bcl-2, MMP-9 while upregulated pro-apoptotic proteins, i.e. caspase-9, p16 and BAX. The experimental results suggest that biotinylated ω3-fatty acid augmented NLCs loaded with Dox are capable of inducing programmed cell death in mammary tumour and can be utilized as safe and effective delivery system with enhanced potential for mammary gland carcinoma therapy.

中文翻译：

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生物素锚定纳米结构脂质载体通过凋亡调节剂的调节靶向递送阿霉素治疗乳腺癌


摘要 乳腺肿瘤是全球女性中发病率和死亡率最高的肿瘤。本研究设想了一种分子靶向纳米结构脂质载体（NLC），用于输送阿霉素（Dox），能够诱导乳腺肿瘤细胞凋亡。使用紫苏油（54-69% ω3-脂肪酸）作为液体脂质制备 NLC，以通过分子离子配对增强 Dox 的包封。在体外和体内评估了生物素修饰的 NLC（b-Dox-NLC）。 b-Dox-NLC 的粒径为 105.2 ± 3.5 nm，zeta 电位为 -35 ± 2 mV，包封率为 99.15 ± 1.71%，药物含量为 19.67 ± 2.6 mg.g−1，生物素含量为 5.85 ± 0.64 µg.g−1和药物释放分别为 98.67 ± 2.43%（酸性微环境促进）。 MTT 测定和流式细胞术分析显示，与市售 Dox 相比，b-Dox-NLC 具有更高的抗增殖能力，可迫使 MCF-7 细胞系发生凋亡，这通过活性氧水平和线粒体膜电位介导的细胞凋亡得到证明。通过对 7,12-二甲基苯并[a]蒽诱导的乳腺肿瘤的肿瘤体积、动物存活、体重变化、心脏毒性和生物分布研究进行研究，b-Dox-NLC 表现出增强的抗肿瘤靶向性、治疗安全性和有效性。免疫印迹分析表明，b-Dox-NLC 下调抗凋亡蛋白，即 bcl-2、MMP-9，同时上调促凋亡蛋白，即 caspase-9、p16 和 BAX。实验结果表明，负载Dox的生物素化ω3-脂肪酸增强NLC能够诱导乳腺肿瘤中的程序性细胞死亡，并且可以用作安全有效的递送系统，增强乳腺癌治疗的潜力。