Borgheti-Cardoso Livia N, Kooijmans Sander A A, Fens Marcel H A M, van der Meel Roy, Vicentini Fabiana T M C, Fantini Marcia C A, Bentley Maria Vitória L B, Schiffelers Raymond M
School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo , Avenida do Café, s/n, 14040-903 Ribeirão Preto, São Paulo, Brazil.
Laboratory of Clinical Chemistry and Haematology, University Medical Center Utrecht , Heidelberglaan, 100, 3584 CX Utrecht, The Netherlands.
Mol Pharm. 2017 May 1;14(5):1681-1690. doi: 10.1021/acs.molpharmaceut.6b01141. Epub 2017 Mar 28.
An effective short interfering RNA (siRNA) delivery system protects the siRNA from degradation, facilitates its cellular uptake, and promotes its release into the cytoplasm. Local administration of siRNA presents advantages over systemic administration, such as the possibility to use lower doses and allow local and sustained release. In this context, in situ solidifying organogels based on monoglycerides (MO), polyethylenimine (PEI), propylene glycol (PG) and tris buffer are an attractive strategy for intratumoral delivery of siRNA. In this study, precursor fluid formulation (PFF) composed of MO/PEI/PG/tris buffer at 7.85:0.65:76.5:15 (w/w/w/w) was used to deliver siRNA to tumor cells. The internal structure of the gel obtained from PFF was characterized using small angle X-ray scattering (SAXS). In addition, its ability to complex siRNA, protect it from degradation, and functionally deliver it to tumor cells was investigated. Moreover, in vivo gel formation following intratumoral injection was evaluated. The gel formed in excess water from PFF was found to comprise a mixture of hexagonal and cubic phases. The system was able to complex high amounts of siRNA, protect it from degradation, promote siRNA internalization, and induce gene silencing in vitro in a variety of tumor cell lines. Moreover, a gel formed in situ following intratumoral injection in a murine xenograft model. In conclusion, PFF is a potential delivery system for local and sustained delivery of siRNA to tumor tissue after intratumoral administration.
一种有效的小干扰RNA（siRNA）递送系统可保护siRNA不被降解，促进其细胞摄取，并促进其释放到细胞质中。与全身给药相比，局部给药的siRNA具有诸多优势，例如可以使用更低的剂量，并实现局部和持续释放。在这种情况下，基于甘油单酯（MO）、聚乙烯亚胺（PEI）、丙二醇（PG）和三羟甲基氨基甲烷缓冲液的原位固化有机凝胶是一种有吸引力的肿瘤内递送siRNA的策略。在本研究中，使用由7.85:0.65:76.5:15（w/w/w/w）的MO/PEI/PG/三羟甲基氨基甲烷缓冲液组成的前体流体配方（PFF）将siRNA递送至肿瘤细胞。使用小角X射线散射（SAXS）对从PFF获得的凝胶的内部结构进行了表征。此外，还研究了其与siRNA复合、保护其不被降解以及将其功能性递送至肿瘤细胞的能力。此外，还评估了肿瘤内注射后体内凝胶的形成情况。发现由PFF在过量水中形成的凝胶包含六方相和立方相的混合物。该系统能够复合大量的siRNA，保护其不被降解，促进siRNA内化，并在体外多种肿瘤细胞系中诱导基因沉默。此外，在小鼠异种移植模型中肿瘤内注射后原位形成了凝胶。总之，PFF是一种在肿瘤内给药后将siRNA局部和持续递送至肿瘤组织的潜在递送系统。
