Diaz-Diestra Daysi, Thapa Bibek, Badillo-Diaz Dayra, Beltran-Huarac Juan, Morell Gerardo, Weiner Brad R
Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR 00926, USA.
Department of Chemistry, University of Puerto Rico, San Juan, PR 00925-2534, USA.
Nanomaterials (Basel). 2018 Jun 30;8(7):484. doi: 10.3390/nano8070484.
Nanoparticle-based cancer theranostic agents generally suffer of poor dispersability in biological media, re-agglomeration over time, and toxicity concerns. To address these challenges, we developed a nanocomposite consisting of chemically-reduced graphene oxide combined with manganese-doped zinc sulfide quantum dots and functionalized with folic acid (FA-rGO/ZnS:Mn). We studied the dispersion stability, Doxorubicin (DOX) loading and release efficiency, target specificity, internalization, and biocompatibility of FA-rGO/ZnS:Mn against folate-rich breast cancer cells, and compared to its uncoated counterpart (rGO/ZnS:Mn). The results indicate that DOX is adsorbed on the graphene surface via π⁻π stacking and hydrophobic interaction, with enhanced loading (35%) and entrapment (60%) efficiency that are associated to the chelation of DOX and surface Zn ions. DOX release is favored under acidic conditions reaching a release of up to 95% after 70 h. Membrane integrity of the cells assessed by Lactate dehydrogenase (LDH) release indicate that the surface passivation caused by folic acid (FA) functionalization decreases the strong hydrophobic interaction between the cell membrane wall and the edges/corners of graphene flakes. Chemotherapeutic effect assays reveal that the cancer cell viability was reduced up to ~50% at 3 µg/mL of DOX-FA-rGO/ZnS:Mn exposure, which is more pronounced than those obtained for free DOX at the same doses. Moreover, DOX-rGO/ZnS:Mn did not show any signs of toxicity. An opposite trend was observed for cells that do not overexpress the folate receptors, indicating that FA functionalization endows rGO/ZnS:Mn with an effective ability to discriminate positive folate receptor cancerous cells, enhancing its drug loading/release efficiency as a compact drug delivery system (DDS). This study paves the way for the potential use of functionalized rGO/ZnS:Mn nanocomposite as a platform for targeted cancer treatment.
基于纳米颗粒的癌症诊疗剂通常在生物介质中分散性差、会随时间重新团聚，并且存在毒性问题。为应对这些挑战，我们开发了一种纳米复合材料，它由化学还原的氧化石墨烯与锰掺杂的硫化锌量子点组成，并通过叶酸（FA-rGO/ZnS:Mn）进行功能化。我们研究了FA-rGO/ZnS:Mn对富含叶酸的乳腺癌细胞的分散稳定性、阿霉素（DOX）负载和释放效率、靶向特异性、内化以及生物相容性，并将其与其未包覆的对应物（rGO/ZnS:Mn）进行比较。结果表明，DOX通过π-π堆积和疏水相互作用吸附在石墨烯表面，负载量（约35%）和包封率（约60%）提高，这与DOX和表面锌离子的螯合有关。在酸性条件下有利于DOX释放，70小时后释放率高达95%。通过乳酸脱氢酶（LDH）释放评估的细胞膜完整性表明，叶酸（FA）功能化引起的表面钝化降低了细胞膜壁与石墨烯薄片边缘/角落之间强烈的疏水相互作用。化疗效果分析表明，在3μg/mL的DOX-FA-rGO/ZnS:Mn暴露下，癌细胞活力降低至约50%，这比相同剂量的游离DOX更明显。此外，DOX-rGO/ZnS:Mn没有显示出任何毒性迹象。对于不高表达叶酸受体的细胞观察到相反的趋势，表明FA功能化赋予rGO/ZnS:Mn有效区分阳性叶酸受体癌细胞的能力，作为一种紧凑的药物递送系统（DDS）提高其药物负载/释放效率。这项研究为功能化rGO/ZnS:Mn纳米复合材料作为靶向癌症治疗平台的潜在应用铺平了道路。
