Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstrasse 14, Vienna A 1090, Austria.
Int J Pharm. 2013 Jun 25;450(1-2):163-76. doi: 10.1016/j.ijpharm.2013.04.058. Epub 2013 Apr 26.
The urgent demand for more potent treatment schedules in bladder cancer (BCa) therapy calls for a refinement of the intravesical administration modalities. However, progress on drug delivery systems tailored to the penetration-hostile urothelial barrier lags behind the advancements in comparable fields. This study reports on a multimodal, carrier-based delivery concept that combines biorecognitive targeting with modified release strategies for improved intravesical chemotherapy. The plant lectin wheat germ agglutinin (WGA) was immobilized on poly(lactide-co-glycolide) (PLGA) microparticles (MP) to induce stable cytoadhesion via cellular carbohydrate chains, similar to the specific attachment mechanism utilized by uropathogenic bacteria. A panel of DNA-selective chemotherapeutics with established track record in uro-oncology was screened for physicochemical compatibility with the polymeric carrier formulation. Critical limitations in encapsulation efficiency were found for mitomycin C (MMC), doxorubicin (DOX), and gemcitabine hydrochloride (GEM), despite multiparametric optimization of the preparation conditions. In contrast, the amphiphilic 4-(N)-stearoyl prodrug of gemcitabine (GEM-C18) exhibited excellent processability with PLGA. In vitro bioassays on 5637 human BCa cells showed that the enhanced cytoadhesion of WGA-GEM-C18-PGLA-MP traces back to the specific lectin/carbohydrate interaction, and is not easily disrupted by adverse environmental factors. Owing to several synergistic effects, the combined prodrug/targeting approach resulted in strong cytostatic response even when adjusting the exposure scheme to the confined temporal conditions of instillative treatment. Our results highlight the importance of fine-tuning both pharmacokinetic and pharmacologic parameters to gain adequate impact on urothelial cancer cells, and assign promising potential to glycan-targeted delivery concepts for the intravesical route.
膀胱癌（BCa）治疗中对更有效治疗方案的迫切需求要求改进膀胱内给药方式。然而，针对穿透性差的尿路上皮屏障的药物输送系统的进展落后于可比领域的进展。本研究报告了一种多模式、基于载体的递药概念，该概念将生物识别靶向与改良释放策略相结合，以提高膀胱内化疗效果。植物凝集素麦胚凝集素（WGA）固定在聚（乳酸-共-乙醇酸）（PLGA）微球（MP）上，通过细胞碳水化合物链诱导稳定的细胞黏附，类似于尿路致病性细菌利用的特定附着机制。一系列在尿路上皮肿瘤学中具有既定记录的 DNA 选择性化疗药物与聚合物载体配方的理化相容性进行了筛选。尽管对制备条件进行了多参数优化，但米托蒽醌（MMC）、阿霉素（DOX）和盐酸吉西他滨（GEM）的包封效率存在关键限制。相比之下，吉西他滨的亲脂性 4-（N）-硬脂酰前药（GEM-C18）与 PLGA 具有优异的加工性能。在 5637 个人膀胱癌细胞的体外生物测定中，WGA-GEM-C18-PLGA-MP 的增强细胞黏附可追溯到特定的凝集素/碳水化合物相互作用，并且不易受到不利环境因素的干扰。由于多种协同作用，即使调整暴露方案以适应灌输治疗的受限时间条件，联合前药/靶向方法也会导致强烈的细胞抑制反应。我们的结果强调了精细调整药代动力学和药效学参数以对尿路上皮癌细胞产生足够影响的重要性，并为糖靶向递药概念用于膀胱内途径赋予了有希望的潜力。
