Conte Claudia, Monteiro Patrícia F, Gurnani Pratik, Stolnik Snow, Ungaro Francesca, Quaglia Fabiana, Clarke Philip, Grabowska Anna, Kavallaris Maria, Alexander Cameron
Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, NG7 2RD, UK.
Drug Delivery Laboratory, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy.
Nanoscale. 2021 Jul 8;13(26):11414-11426. doi: 10.1039/d1nr02179f.
Bioresponsive nanoparticles (NPs) are of interest for anticancer nanomedicines, owing to the possibility to 'design in' selective modulation of drug release at target sites. Here we describe the double emulsion formulation of redox-responsive NPs based on modified polyethylene glycol (PEG)-co-poly(lactic-co-glycolic acid) (PLGA) block copolymers and oligo (β-aminoesters) (OBAE), both of which contained disulfide linkages, for the co-delivery of a cytotoxic small molecule drug and a nucleic acid. In particular, we focused our attention on docetaxel (DTX) and a siRNA against TUBB3, a gene that encodes for βIII-tubulin, in order to have a synergistic effect in the treatment of lung cancer. Spherical NPs of around 150 nm with negative zeta potential and high loading efficiencies of both drugs were obtained. Stability and release studies showed "on demand" drug release under reducing conditions. Unloaded NPs containing PEG-disulfide-PLGA and OBAE were well-tolerated by lung cancer cells, thus masking the intrinsic cytotoxicity of OBAE, while for intracellular siRNA delivery, redox responsive NPs demonstrated a higher cell internalization with a preferential cytoplasmic accumulation of siRNA, with a subsequent fast gene-silencing efficiency. The viability of cells treated with combined DTX/TUBB3-siRNA NPs significantly decreased as compared to NPs loaded only with DTX, thus showing an efficient combined anticancer effect, due to a substantial reduction of β-tubulin expression. Finally, in an in vivo feasibility study employing an orthotopic lung cancer model, NPs formulated with an anti-luciferase siRNA distributed throughout the lungs following oro-tracheal administration, and demonstrated effective gene knockdown and no apparent cytotoxicity. Taken together, these results show that the double emulsion formulated redox responsive PEG-PLGA and OBAE systems represent a promising new therapeutic approach for the local combined chemo- and gene-therapy of lung cancer.
生物响应性纳米颗粒（NPs）因其有可能在靶位点“设计”药物释放的选择性调节而在抗癌纳米药物领域备受关注。在此，我们描述了基于修饰的聚乙二醇（PEG）-聚（乳酸-乙醇酸）共聚物（PLGA）嵌段共聚物和寡聚（β-氨基酯）（OBAE）的氧化还原响应性NPs的双乳液制剂，这两种物质均含有二硫键，用于协同递送细胞毒性小分子药物和核酸。特别地，我们将注意力集中在多西他赛（DTX）和针对TUBB3（一种编码βIII-微管蛋白的基因）的小干扰RNA（siRNA）上，以便在肺癌治疗中产生协同效应。我们获得了粒径约为150 nm、zeta电位为负且两种药物负载效率均高的球形NPs。稳定性和释放研究表明，在还原条件下药物能“按需”释放。含有PEG-二硫键-PLGA和OBAE的未负载NPs对肺癌细胞具有良好的耐受性，从而掩盖了OBAE的内在细胞毒性，而对于细胞内siRNA递送，氧化还原响应性NPs表现出更高的细胞内化能力，siRNA优先在细胞质中积累，随后基因沉默效率迅速提高。与仅负载DTX的NPs相比，用DTX/TUBB3-siRNA NPs联合处理的细胞活力显著降低，这表明由于β-微管蛋白表达大幅降低，联合用药具有高效的抗癌效果。最后，在一项采用原位肺癌模型的体内可行性研究中，用抗荧光素酶siRNA配制的NPs经口气管给药后分布于整个肺部，并显示出有效的基因敲低且无明显细胞毒性。综上所述，这些结果表明，双乳液配制的氧化还原响应性PEG-PLGA和OBAE系统代表了一种有前景的肺癌局部联合化疗和基因治疗新方法。
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