The delivery of nitric oxide (NO) specifically to solid tumours was explored in this study as a strategy to augment the passive accumulation of nanomedicines in tumours induced by the Enhanced Permeability and Retention (EPR) effect. An increase in accumulation was achieved by the binding of the chemical precursor of NO, based on an organic nitrate, to a water-soluble synthetic polymer drug carrier. Four structurally different N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer NO donors were synthesized. Depending on their chemical structure, two of these donors were hydrolytically stable, while two rapidly released the parent nitrate under acidic conditions, mimicking the intracellular environment. The polymer NO donors were shown to overcome the drawbacks related to low-molecular-weight NO releasing compounds, namely systemic toxicity, lack of site specificity, and fast blood clearance. The NO donors showed intracellular NO release upon incubation with tumour cells. In vivo, they potentiated the EPR effect, resulting in an increased accumulation of polymer-bound cytotoxic drug doxorubicin (Dox) in EL4 T-cell lymphoma inoculated in mice. This led to a better therapeutic outcome in the treatment of lymphoma with the high-molecular-weight polymer conjugates carrying Dox but not in the treatment with the free Dox. The localized augmentation of the EPR effect via the tumour-specific NO delivery system can be viewed as a promising strategy to potentiate polymer-based tumour therapy without increasing systemic toxicity.

一氧化氮（NO）专门向实体瘤的传递被研究作为一种策略，以增强由增强的渗透率和保留（EPR）效应诱导的纳米药物在肿瘤中的被动积累。通过将基于有机硝酸盐的NO的化学前体与水溶性合成聚合物药物载体结合，可以增加积累量。四个结构不同的N合成了基于-（2-羟丙基）甲基丙烯酰胺（HPMA）的聚合物NO供体。根据它们的化学结构，这些供体中的两个是水解稳定的，而两个在酸性条件下迅速释放了母体硝酸盐，从而模拟了细胞内环境。聚合物NO供体显示出克服了与低分子量NO释放化合物有关的缺点，即全身毒性，缺乏位点特异性和血液快速清除。NO供体在与肿瘤细胞孵育后显示出细胞内NO释放。体内，他们增强了EPR效应，导致在小鼠中接种的EL4 T细胞淋巴瘤中与聚合物结合的细胞毒性药物阿霉素（Dox）的积累增加。这导致在使用带有Dox的高分子量聚合物结合物治疗淋巴瘤中获得更好的治疗效果，但是在使用游离Dox的治疗中却没有得到更好的治疗效果。通过肿瘤特异性NO释放系统的EPR效应的局部增强可以被视为增强基于聚合物的肿瘤治疗而不增加全身毒性的一种有前途的策略。