Casadidio Cristina, Fens Marcel H A M, Fliervoet Lies A L, Censi Roberta, Vermonden Tina
School of Pharmacy, Drug Delivery Division, University of Camerino, ChIP Research Center, Via Madonna delle Carceri, 62032 Camerino, Macerata, Italy; Department of Pharmaceutical Sciences, Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3508, TB, Utrecht, the Netherlands.
Department of Pharmaceutical Sciences, Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3508, TB, Utrecht, the Netherlands.
J Control Release. 2025 Aug 10;384:113890. doi: 10.1016/j.jconrel.2025.113890. Epub 2025 May 26.
Patients diagnosed with advanced-stage ovarian cancer often suffer from metastases. To date, several therapies have been investigated for treating ovarian cancer and metastatic nodules, including nucleic acid-based drugs. In this study, hydrogels were explored as nucleic acid reservoirs for the local and prolonged release of siRNA in the intraperitoneal cavity of mice bearing ovarian tumors. The siRNA was first complexed with a cationic methoxypoly(ethylene glycol) poly(2-(dimethylamino)ethyl methacrylate) (PD) diblock copolymer, forming polymeric nanoparticles known as polyplexes. To investigate biodistribution, residence time, and tumor accumulation after local administration, dually labeled polyplexes (siRNA-Cy5.5 and PD-Cy7) were prepared. These siRNA polyplexes were then physically entrapped into an injectable thermosensitive hydrogel made of a poly(N-isopropylacrylamide)-poly(ethylene glycol)-poly(N-isopropylacrylamide) (NPN) triblock copolymers, enabling in situ prolonged release of the cargo. In vitro rheological tests of the NPN hydrogel using ascitic fluid derived from a patient with ovarian cancer were performed to ensure its stability and performance in tumor environment. Then, polyplex-hydrogels were injected intraperitoneally in a murine ovarian cancer orthotopic model, and their retention was monitored over seven days. The results demonstrated progressive intra-abdominal release of siRNA polyplexes from the hydrogel, driven by hydrogel erosion, with subsequent accumulation of nanoparticles within the ovarian nodules. Therapeutic studies further revealed that siRNA-STAT3 polyplexes released from the NPN hydrogel achieved a significant tumor growth delay compared to the control groups following 28 days of treatment and 56 days after tumor inoculation. In conclusion, the novel dual delivery system, comprising siRNA-STAT3 polyplexes loaded into an injectable thermosensitive hydrogel, demonstrated effective deposition and penetration of the siRNA polyplexes into ovarian primary tumors and nodules, significantly delaying tumor growth in advanced ovarian cancer.
被诊断为晚期卵巢癌的患者常伴有转移。迄今为止，已经研究了多种治疗卵巢癌和转移瘤的疗法，包括基于核酸的药物。在本研究中，水凝胶被用作核酸储存库，用于在荷卵巢肿瘤小鼠的腹腔内局部和长期释放小干扰RNA（siRNA）。首先将siRNA与阳离子甲氧基聚（乙二醇）聚（甲基丙烯酸2-（二甲氨基）乙酯）（PD）二嵌段共聚物复合，形成称为多聚体的聚合物纳米颗粒。为了研究局部给药后的生物分布、停留时间和肿瘤蓄积情况，制备了双标记多聚体（siRNA-Cy5.5和PD-Cy7）。然后将这些siRNA多聚体物理包裹到由聚（N-异丙基丙烯酰胺）-聚（乙二醇）-聚（N-异丙基丙烯酰胺）（NPN）三嵌段共聚物制成的可注射热敏水凝胶中，实现货物的原位长期释放。使用来自卵巢癌患者的腹水对NPN水凝胶进行体外流变学测试，以确保其在肿瘤环境中的稳定性和性能。然后，将多聚体-水凝胶腹腔注射到小鼠卵巢癌原位模型中，并在7天内监测其滞留情况。结果表明，水凝胶侵蚀驱动siRNA多聚体在腹腔内逐渐释放，随后纳米颗粒在卵巢结节内蓄积。治疗研究进一步表明，与对照组相比，在治疗28天和肿瘤接种56天后，从NPN水凝胶释放的siRNA-STAT3多聚体实现了显著的肿瘤生长延迟。总之，由负载到可注射热敏水凝胶中的siRNA-STAT3多聚体组成的新型双递送系统，证明了siRNA多聚体在卵巢原发性肿瘤和结节中的有效沉积和渗透，显著延迟了晚期卵巢癌的肿瘤生长。
