NSERC/MRI, guided delivery and controlled release of core/shell superparamagnetic nanoparticle-based submicron-sized respiratory and systemic drug carriers

药物的溶解性仍然是药理学科学家的终极追求，也是降低医疗保健成本的一个非常可取的目标。药物制剂与其给药途径密切相关。一些药物从未上市，由于它们的化学不稳定性、毒性及其代谢途径的无处不在，在进行重大手术之前，例如一氧化氮(NO)，它们的药理作用仍未得到开发。人们已经提出了许多策略来解决药物溶解性差的问题，例如使用含有药物的聚合物支架，但由于它们的降解动力学未知，任何定制药物剂量学的尝试都受到了阻碍。为了真正实现其治疗效果，该药物还必须克服两个进一步的挑战：靶向和受控释放。针对特定细胞群体的靶向减少了全身副作用；因此，将新的医疗应用扩展到无数患者类别，到目前为止，使用特别有毒的化学物质进行治疗是不可能的。给老年病人、新生儿和婴儿使用麻醉药就是这样一个例子。控释将确保药物在必要的时间内持续存在，以证明治疗效果。在这个项目中，我们试图证明肺部给药的可行性，这种药物结合到可以磁性靶向的超顺磁性纳米颗粒上；药物必须以适当的速度、在适当的时间内给药，并且纳米颗粒不能对健康构成风险。我们通过将NO气体与功能化的Fe3O4纳米颗粒(FDA批准)进行化学结合来实现这一点，然后将其装载到大到足以通过呼吸道进入肺深部的亚微米级聚合物颗粒中，以释放NO。磁场用于将颗粒定向到肺壁，使它们在那里保持较长的治疗期。这将是一个两部分研究计划的可行性研究，涉及纳米颗粒的功能化和亚微米大小的壳聚糖颗粒的形成。第二部分将涉及到进入动物模型的交付和监测。

Drug solubility continues to be an ultimate pursuit of pharmacological scientists, and represents a highly desirable aim for health care cost reduction. Drug formulations are intimately connected to the pathway of their administration. Some drugs have never been marketed, due to their chemical instabilities, toxicities and the ubiquities of their metabolic pathways, their pharmacological benefits remaining unexploited, prior to major surgeries, such as nitric oxide (NO), are cases in point. Many strategies have been suggested to counteract the poor solubility problem, such as the use of polymeric scaffolds containing the drugs, but due to their unknown degradation kinetics, any attempts at tailoring drug dosimetry are hindered. Two further challenges will have to be overcome for the drug to truly fulfill its therapeutic effects: targeting and controlled release. The targeting of specific cell populations reduces systemic side effects; hence extending new medical applications to a myriad of patient categories, whose treatments, using particularly toxic chemicals, have so far been impossible. Such an example is the administration of anesthetics to elderly patients, neonates and infants. Controlled release would assure the continual presence of the drug for periods necessary for demonstrable therapeutic effects. In this project, we seek to demonstrate the feasibility of the pulmonary administration of therapeutic gaseous drugs bound to superparamagnetic nanoparticles that can be magnetically targeted; the drug must be delivered at an appropriate rate, for an appropriate period of time, and the nanoparticles must not present health risks. We do this by chemically binding the gas NO to functionalized Fe3O4 nanoparticles (FDA approved) that will then be loaded into submicron-sized polymer particles large enough to pass through the airway, into the deep lungs, to release the NO. Magnetic fields serve to target the particles to the lung walls, to maintain their presence there for long therapeutic periods. This will be the feasibility study of a two parts research programme, having to do with nanoparticle functionalization and the formation of submicron-sized chitosan particles. The second part will concern delivery into animal models and monitoring.