CICS-UBI, Health Sciences Research Center, University of Beira Interior, 6200-506 Covilhã, Portugal.
Centre de Biophysique Moléculaire, CNRS UPR4301, Inserm et Université d'Orléans, 45071 Orléans cedex 02, France.
J Control Release. 2014 Sep 10;189:90-104. doi: 10.1016/j.jconrel.2014.06.040. Epub 2014 Jun 28.
The design of nanocarriers for the delivery of drugs and nucleic-acids remains a very challenging goal due to their physicochemical differences. In addition, the reported accelerated clearance and immune response of pegylated nanomedicines highlight the necessity to develop carriers using new materials. Herein, we describe the synthesis of amphiphilic triblock poly(2-ethyl-2-oxazoline)-PLA-g-PEI (PEOz-PLA-g-PEI) micelles for the delivery of minicircle DNA (mcDNA) vectors. In this copolymer the generally used PEG moieties are replaced by the biocompatible PEOz polymer backbone that assembles the hydrophilic shell. The obtained results show that amphiphilic micelles have low critical micellar concentration, are hemocompatible and exhibit stability upon incubation in serum. The uptake in MCF-7 cells was efficient and the nanocarriers achieved 2.7 fold higher expression than control particles. Moreover, mcDNA-loaded micelleplexes penetrated into 3D multicellular spheroids and promoted widespread gene expression. Additionally, to prove the concept of co-delivery, mcDNA and doxorubicin (Dox) were simultaneously encapsulated in PEOz-PLA-g-PEI carriers, with high efficiency. Dox-mcDNA micelleplexes exhibited extensive cellular uptake and demonstrated anti-tumoral activity. These findings led us to conclude that this system has a potential not only for the delivery of novel mcDNA vectors, but also for the co-delivery of drug-mcDNA combinations without PEG functionalization.
由于药物和核酸在物理化学性质上存在差异，因此设计用于输送药物和核酸的纳米载体仍然是一个极具挑战性的目标。此外，据报道，经聚乙二醇（PEG）修饰的纳米药物的清除速度加快，免疫反应增强，这凸显了开发使用新材料的载体的必要性。在此，我们描述了两亲性三嵌段聚（2-乙基-2-恶唑啉）-PLA-g-PEI（PEOz-PLA-g-PEI）胶束的合成，用于递送微小环 DNA（mcDNA）载体。在该共聚物中，通常使用的 PEG 部分被生物相容性的 PEOz 聚合物主链取代，该主链组装了亲水性外壳。所得结果表明，两亲性胶束具有低临界胶束浓度，具有血液相容性，并在血清孵育时表现出稳定性。在 MCF-7 细胞中的摄取效率高，纳米载体的表达水平比对照颗粒高 2.7 倍。此外，负载 mcDNA 的胶束复合物能够穿透 3D 多细胞球体，并促进广泛的基因表达。此外，为了证明共递药的概念，mcDNA 和多柔比星（Dox）同时被高效包封在 PEOz-PLA-g-PEI 载体中。Dox-mcDNA 胶束复合物具有广泛的细胞摄取，并表现出抗肿瘤活性。这些发现使我们得出结论，该系统不仅具有递送新型 mcDNA 载体的潜力，而且还具有共递药-DNA 复合物的潜力，而无需 PEG 功能化。
