Nanomedicine Laboratory, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400076, India.
Radiopharmaceuticals Division, BARC, Trombay, Mumbai 400085, India.
Biomacromolecules. 2020 Jul 13;21(7):2645-2660. doi: 10.1021/acs.biomac.0c00358. Epub 2020 Jun 22.
Galectin-3 (gal-3) plays a crucial role in various cellular events associated to tumor metastasis and progression. In this direction, gal-3 binding core-shell glyconanoparticles based on citrus pectin (CP) have been designed for targeted, trigger-responsive combination drug delivery. Depolymerization via periodate oxidation in heterogeneous medium yielded low-molecular weight dialdehyde oligomers (CPDA) of CP with a gal-3 binding property ( = 160.90 μM). CPDA-based core-shell nanoparticles prepared to enhance the gal-3 binding specificity via a multivalent ligand presentation have shown to reduce homotypic cellular aggregation, tumor cell binding with endothelial cells, and endothelial tube formation, the major steps involved in the progression of cancer. Immune-fluorescence and flow cytometric analysis confirmed significant reduction in gal-3 expression on MDA-MB 231 cancer cells upon incubation with nanoparticles. An on-demand tumor microenvironment-responsive release of drugs at low pH and high concentrations of glucose and glutathione prevailing in tumor milieu was achieved by introducing a cleavable Schiff's base, a boronate ester, and disulfide linkages within the shell of the nanoparticles. Nanoparticles with encapsulated sulindac in the core and doxorubicin (DOX) in the shell demonstrated target specificity and enhanced internalization with synergistic cytotoxic effects with a 30-fold reduction in IC in DOX-resistant, triple-negative MDA-MB 231 breast cancer cells. Nanoparticles were radiolabeled with I radioisotopes with ≥80% efficiency while retaining its gal-3 binding property. Biodistribution studies of radiolabeled placebo nanoparticles and drug-loaded CPDA nanoparticles demonstrated proof of concept of gal-3 targeting seen as preferential accumulation in the gal-3-expressing tissues of the gastric tract. The CPDA core-shell nanoparticles are thus promising platforms for gal-3 targeting and inhibition of gal-3-mediated processes involved in cancer progression with a potential of radiolabeling for in vivo monitoring or delivering therapeutic doses of radiation and on-demand triggered, target-specific drug release.
半乳糖凝集素-3（gal-3）在与肿瘤转移和进展相关的各种细胞事件中发挥着关键作用。在这方面，基于柑橘果胶（CP）的 gal-3 结合核壳糖纳米粒子已被设计用于靶向、触发响应的组合药物递送。在非均相介质中通过高碘酸盐氧化进行解聚，得到具有 gal-3 结合特性的 CP 低分子量二醛低聚物（CPDA）（ = 160.90 μM）。通过呈现多价配体来增强 gal-3 结合特异性制备的 CPDA 基于核壳纳米粒子已显示出降低同种细胞聚集、肿瘤细胞与内皮细胞的结合以及内皮管形成，这是癌症进展中的主要步骤。免疫荧光和流式细胞术分析证实，在用纳米粒子孵育后 MDA-MB 231 癌细胞上 gal-3 的表达显著降低。通过在壳内引入可裂解的席夫碱、硼酸酯和二硫键，实现了在肿瘤微环境中低 pH 值、高葡萄糖和谷胱甘肽浓度下按需释放药物，这是肿瘤环境中的主要步骤。载有 sulindac 的核芯和载有阿霉素（DOX）的壳芯的纳米粒子表现出靶向特异性和增强的内化作用，对 DOX 耐药、三阴性 MDA-MB 231 乳腺癌细胞的协同细胞毒性作用降低了 30 倍。纳米粒子用 I 放射性同位素进行放射性标记，效率≥80%，同时保留其 gal-3 结合特性。放射性标记的安慰剂纳米粒子和载药 CPDA 纳米粒子的生物分布研究证明了 gal-3 靶向的概念，这被视为在胃组织中表达 gal-3 的组织中的优先积累。因此，CPDA 核壳纳米粒子是用于 gal-3 靶向和抑制与癌症进展相关的 gal-3 介导过程的有前途的平台，具有放射性标记用于体内监测或递送治疗剂量的辐射和按需触发、靶向特定的药物释放的潜力。
