Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy, Dorothy M. Davis Heart and Lung Research Institute, James Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, Ohio 43210, United States.
Mol Pharm. 2021 Aug 2;18(8):2924-2934. doi: 10.1021/acs.molpharmaceut.1c00035. Epub 2021 Jul 2.
Therapeutic efficiency and toxicity are two of the three critical factors in molecular therapy and pharmaceutical drug development. Specific tumor targeting and rapid renal excretion contribute to improving efficiency and reducing toxicity. We recently found that RNA nanoparticles display rubber-like properties, enabling them to deliver therapeutics to cancer with high efficiency. Off-target RNA nanoparticles were rapidly cleared by renal excretion, resulting in nontoxicity. However, previous biodistribution studies relied mainly on fluorescent markers, which can cause interference from fluorophore quenching and autofluorescence. Thus, the quantification of biodistribution requires further scrutiny. In this study, radionuclide [H] markers were used for quantitative pharmacokinetic (PK) studies to elucidate the favorable PK profile of RNA nanoparticles. Approximately 5% of [H]-RNA nanoparticles accumulated in tumors, in contrast to the 0.7% tumor accumulation reported in the literature for other kinds of nanoparticles. The amount of [H]-RNA nanoparticles accumulated in tumors was higher than that in the liver, heart, lung, spleen, and brain throughout the entire process after IV injection. [H]-RNA nanoparticles rapidly reached the tumor vasculature within 30 min and remained in tumors for more than 2 days. Nontargeting [H]-RNA nanoparticles were found in the urine 30 min after IV injection without degradation and processing, and more than 55% of the IV-injected radiolabeled RNA nanoparticles were cleared from the body within 12 h, while the other 45% includes the radiative counts that cannot be recovered due to whole-body distribution and blood dilution after intravenous injection. The high specificity of tumor targeting, fast renal excretion, and low organ accumulation illustrate the high therapeutic potential of RNA nanoparticles in cancer treatment as efficient cancer-targeting carriers with low toxicity and side effects.
治疗效果和毒性是分子治疗和药物开发的三个关键因素中的两个。特异性肿瘤靶向和快速肾脏排泄有助于提高效率和降低毒性。我们最近发现，RNA 纳米颗粒具有橡胶状特性，能够高效地将治疗剂递送到癌症部位。非靶向 RNA 纳米颗粒被肾脏快速排泄清除，从而没有毒性。然而，之前的生物分布研究主要依赖于荧光标记物，这可能会导致荧光团猝灭和自发荧光的干扰。因此，生物分布的定量需要进一步研究。在这项研究中，放射性核素 [H] 标记物用于定量药代动力学 (PK) 研究，以阐明 RNA 纳米颗粒的有利 PK 特征。大约 5%的 [H]-RNA 纳米颗粒在肿瘤中积累，而其他类型的纳米颗粒在文献中报道的肿瘤积累量为 0.7%。与肝、心、肺、脾和脑中的 RNA 纳米颗粒积累量相比，[H]-RNA 纳米颗粒在整个 IV 注射后过程中在肿瘤中的积累量更高。[H]-RNA 纳米颗粒在 30 分钟内迅速到达肿瘤血管，并在肿瘤中停留超过 2 天。在 IV 注射后 30 分钟，非靶向 [H]-RNA 纳米颗粒在尿液中被发现，没有降解和处理，超过 55%的 IV 注射放射性标记的 RNA 纳米颗粒在 12 小时内从体内清除，而其余 45%的放射性计数则由于静脉注射后全身分布和血液稀释而无法回收。肿瘤靶向的高特异性、快速的肾脏排泄和低器官积累表明，RNA 纳米颗粒作为高效的癌症靶向载体，具有低毒性和副作用，在癌症治疗中具有很高的治疗潜力。
