Spadea Alice, Tirella Annalisa, Rios de la Rosa Julio Manuel, Lallana Enrique, Mehibel Manal, Telfer Brian, Tirelli Nicola, Lawrence Margaret Jayne, Williams Kaye J, Stratford Ian J, Ashford Marianne
NorthWest Centre for Advanced Drug Delivery (NoWCADD), School of Health Science, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Pharmaceutics. 2024 Sep 30;16(10):1286. doi: 10.3390/pharmaceutics16101286.
Conventional anticancer therapies often lack specificity, targeting both cancerous and normal cells, which reduces efficacy and leads to undesired off-target effects. An additional challenge is the presence of hypoxic regions in tumors, where the Hypoxia Inducible Factor (HIF) transcriptional system drives the expression of pro-survival and drug resistance genes, leading to radio- and chemo-resistance. This study aims to explore the efficacy of targeted nanoparticle (NP)-based small interfering RNA (siRNA) therapies in downregulating these genes to enhance treatment outcomes in pancreatic cancer, a tumor type characterized by high CD44 expression and hypoxia. We utilized hyaluronic acid (HA)-displaying nanoparticles composed of positively charged chitosan (CS) complexed with siRNA to target and knock down HIF-1α in pancreatic cancer cells. Two NP formulations were prepared using either low molecular weight (LMW) or high molecular weight (HMW) CS. These formulations were evaluated for their internalization by cells and their effectiveness in gene silencing, both in vitro and in vivo. The study found that the molecular weight (MW) of CS influenced the interaction between HA and CD44, as well as the release of siRNA upon internalization. The LMW CS formulation shows faster uptake kinetics, while HMW CS is more effective in gene knockdown across different cell lines in vitro. In vivo, both were able to significantly knockdown HIF-1α and some of its downstream genes. The results suggest that HMW and LMW CS-based NPs exhibit distinct characteristics, showing that both MWs have potential for targeted pancreatic cancer therapy by influencing different aspects of delivery and gene silencing, particularly in the hypoxic tumor microenvironment.
传统的抗癌疗法往往缺乏特异性，会同时靶向癌细胞和正常细胞，这降低了疗效并导致不良的脱靶效应。另一个挑战是肿瘤中存在缺氧区域，缺氧诱导因子（HIF）转录系统在该区域驱动促生存和耐药基因的表达，导致放疗和化疗耐药。本研究旨在探索基于靶向纳米颗粒（NP）的小干扰RNA（siRNA）疗法在下调这些基因以提高胰腺癌治疗效果方面的疗效，胰腺癌是一种以高CD44表达和缺氧为特征的肿瘤类型。我们利用由带正电荷的壳聚糖（CS）与siRNA复合而成的展示透明质酸（HA）的纳米颗粒来靶向并敲低胰腺癌细胞中的HIF-1α。使用低分子量（LMW）或高分子量（HMW）的CS制备了两种NP制剂。对这些制剂进行了细胞内化评估以及它们在体外和体内的基因沉默有效性评估。研究发现，CS的分子量（MW）影响HA与CD44之间的相互作用以及内化后siRNA的释放。LMW CS制剂显示出更快的摄取动力学，而HMW CS在体外对不同细胞系的基因敲低更有效。在体内，两者都能够显著敲低HIF-1α及其一些下游基因。结果表明，基于HMW和LMW CS的NP表现出不同的特性，表明两种分子量通过影响递送和基因沉默的不同方面，特别是在缺氧肿瘤微环境中，都具有靶向胰腺癌治疗的潜力。
