MAEER's Maharashtra Institute of Pharmacy, Kothrud, Pune 411038, India.
Maharashtra Institute of Medical Education and Research Medical College, Talegaon Dabhade, Pune 410507, India.
J Mater Chem B. 2020 Mar 4;8(9):1852-1862. doi: 10.1039/c9tb02744k.
Cancer diagnosis and its stage-wise assessment are determined through invasive solid tissue biopsies. Conversely, cancer imaging is enriched through emission tomography and longitudinal high-resolution analysis for the early detection of cancer through altered cell morphology and cell-deformation. Similarly, in post multiple chemo-cycle exposures, the tumor regression and progression thereafter are not well understood. Here, we report chemo-cycles of doxorubicin (Dox) carrying nanoparticles (NPs) to be highly indicative of cell deformation and a progressive indicator of phenotypic expressions of acquired drug resistance (ADR). We designed graphene (G) based nanocarriers by chemically conjugating multiple components: (i) G; (ii) iron oxide (Fe3O4) NPs; and (iii) Dox through a cysteine (Cys) linker (G-Dox and G-Cys-Fe3O4-Dox). Although Dox underwent cell diffusion, the G-based nanocarriers followed a receptor-mediated endocytosis which created a profound impact on the cell membrane integrity. ADR owing to Dox and G-based nanocarriers was analyzed through a cytotoxicity assay, cell morphology deformation parameters and cellular uptake kinetic patterns. Interestingly, after the third chemo-cycle, G-Dox incubated cells showed the greatest decrease in the alteration of the nuclear surface area (NSA) of ∼28%, a ∼40% reduction of the cell surface area (CSA) and a ∼32% increase in the cell roundness (CRd). Our results suggested that the G-based nanocarriers induced the cell deformation process, subsequently resulting in ADR. Although the G-based nanocarriers initiated ADR, G-Dox was most cytotoxic to cancer cells and induced the maximum cell morphology deformation within our scope of study. This outcome implies caution is needed when using G-based nanocarriers and other multi-component nanosystems for Dox delivery as they lead to possible phenotypic expressions of drug resistance in cancer cells.
癌症的诊断及其分期评估是通过侵入性的实体组织活检来确定的。相反，通过发射断层扫描和纵向高分辨率分析，可以丰富癌症成像，以便通过改变的细胞形态和细胞变形来早期发现癌症。同样，在多次化疗周期暴露后，此后的肿瘤消退和进展情况尚不清楚。在这里，我们报告载有多柔比星（Dox）的纳米颗粒（NPs）的化疗周期高度指示细胞变形，并逐步指示获得性药物耐药（ADR）的表型表达。我们通过化学偶联多种成分设计了基于石墨烯（G）的纳米载体：（i）G；（ii）氧化铁（Fe3O4）NPs；和（iii）通过半胱氨酸（Cys）接头的 Dox（G-Dox 和 G-Cys-Fe3O4-Dox）。尽管 Dox 经历了细胞扩散，但基于 G 的纳米载体遵循受体介导的内吞作用，这对细胞膜完整性产生了深远的影响。通过细胞毒性测定、细胞形态变形参数和细胞摄取动力学模式分析了由于 Dox 和基于 G 的纳米载体引起的 ADR。有趣的是，在第三个化疗周期后，孵育 G-Dox 的细胞的核表面积（NSA）变化最大减少了约 28%，细胞表面积（CSA）减少了约 40%，细胞圆形度（CRd）增加了约 32%。我们的结果表明，基于 G 的纳米载体诱导了细胞变形过程，随后导致 ADR。虽然基于 G 的纳米载体引发了 ADR，但 G-Dox 对癌细胞最具细胞毒性，并在我们的研究范围内诱导了最大的细胞形态变形。这一结果意味着在使用基于 G 的纳米载体和其他多组分纳米系统进行 Dox 递送时需要谨慎，因为它们可能导致癌细胞中出现药物耐药的表型表达。
