Perfluorocarbon Materials As Drug Delivery Vehicles

描述（由申请人提供）：全氟辛基溴（PFOB）已被临床研究作为液体通气的呼吸介质。这种呼吸支持技术采用PFOB作为运输氧气到肺部的载体。PFOB也被设想为一种肺部药物递送载体，它允许(a)在受损肺实质处以高浓度直接将药物递送到肺部，(b)在肺内均匀分布，以及(c)有限的全身分布（减少全身毒性）。不幸的是，典型的药物分子不溶于PFOB，这限制了它作为药物递送载体的用途。为了克服烟酸的溶解度问题，我们合成了一系列烟酸前药模型。这些前药在PFOB中具有高溶解度，同时也是水溶性的，在酯酶的存在下容易水解，并且几乎没有细胞毒性。我们的工作假设是，由于这些特性，前体药物，例如烟酸的前体药物，可以成功地输送到肺部，在那里它们将分解到肺组织中，从而达到比传统药物输送方法更高的组织水平。母体药物将在组织内通过化学或酶降解释放出来。在此，我们提出(i)利用线性自由能关系（LFER）研究和模拟与细胞摄取相关的烟酸前药的分配行为，（ii）研究烟酸前药在全氟碳(PFOB)-组织界面的细胞培养模型中的转运，以及（iii）通过研究雄性大鼠PFOB给药后C-14标记前药的摄取和分布来评估体内药物传递系统。该提案汇集了化学家、细胞/分子生物学家和化学工程师组成的多学科研究团队。我们采用线性自由能关系（LFER）结合细胞培养和动物研究来评估PFOB组织界面上的分裂行为，这将使我们能够更好地理解和预测基于PFOB的药物制剂中药物释放的相关参数。这些发现将使我们能够以PFOB为载体设计适合肺给药的（亲）药物，从而为肺损伤部位靶向给药提供一种新颖而优越的方法。

DESCRIPTION (provided by applicant): Perfluorooctyl bromide (PFOB) has been clinically studied as a respiratory medium for liquid ventilation. This respiratory support technique employs PFOB as a vehicle for the transport of oxygen to the lung. PFOB is also envisioned as a pulmonary drug delivery vehicle that allows (a) direct delivery of a drug to the lung in high concentrations at the injured lung parenchyma, (b) equal distribution within the lung, and (c) limited systemic distribution (which reduces systemic toxicity). Unfortunately, typical drug molecules are insoluble in PFOB, which currently limits its usefulness as drug delivery vehicle. To overcome the solubility problem, we have synthesized a series of model prodrugs of nicotinic acids. These prodrugs show a high solubility in PFOB and are also water soluble, readily hydrolyzed in the presence of esterases and show little cytotoxicity. Our working hypothesis is that, because of these properties, prodrugs, for example prodrugs of nicotinic acid, can be successfully delivered to the lung where they will partition into the lung tissue, thus achieving higher tissue levels compared to conventional drug delivery approaches. The parent drug will be released by chemical or enzymatic degradation within the tissue. Herein we propose to (i) investigate and model the partition behavior of nicotinic acid prodrugs relevant to cellular uptake using a linear free energy relationship (LFER), (ii) study the transport of nicotinic acid prodrugs in a cell culture model of the perfluorocarbon (PFOB)-tissue interface, and (iii) evaluate the drug delivery system in vivo by investigating the uptake and distribution of C-14 labeled prodrugs after administration with PFOB in male rats. This proposal brings together a multidisciplinary research team of chemists, cell/molecular biologists and chemical engineers. Our approach of employing a linear free energy relationship (LFER) to assess the partition behavior at the PFOB tissue interface in combination with cell culture and animal studies will allow us to better understand and predict the parameters relevant for the release of drugs from a PFOB-based drug formulation. These findings will allow us to design (pro-)drugs suitable for pulmonary administration using PFOB as vehicle, thus providing a novel and superior method for the targeted administration of drugs to the injured sites of the lung.