Development of multifunctional nanoparticles validated by an intravital tumor model.

摘要

Cancer is a major public health problem, and although significant therapeutic advances have been achieved for some types of malignancy, many tumors are still challenging to treat. The main therapeutic obstacles include tumor cell resistance to standard chemo-radiotherapy at clinically feasible doses, and treatment effects that are limiting due to normal tissue toxicity. Despite research spanning several decades, the goal of specifically destroying tumor cells, while sparing normal tissues, has remained difficult to attain. Recently however, the growth of the nanotechnology field offers new strategies and is promising in terms of early detection and the targeted therapy of cancer. Separate nanoparticles can carry a drug payload, can be targeted to tumors, and can be bound to MRI and CT contrast agents. A recent concept is that of "theranostics", viz., the ability of one nanoplatform to integrate several functions so that these are co-localized. For instance, the imaging enhancement property can be used in conjunction with drug delivery for real-time monitoring of drug distribution and to follow the therapeutic effects. Moreover, imaging capability may facilitate activation of a pro-drug payload at an optimum time, for example at the point of maximum nanoplatform accumulation at the tumor. This dissertation describes the design, fabrication and testing of two novel multifunctional nanoplatforms; a liposome containing dextran hydrogel and iron oxide, and a liposome containing perfluorocarbon (PFC) gas microbubble.;A key limitation of nanoengineering in medicine is the lack of practical in vivo models, so that many nanoplatforms, while creatively engineered, are not biologically useful. This dissertation discusses and presents the development of an in vivo test-bed that allows optical and MRI imaging of nanoplatforms within a tumor and its blood vessels, and is a versatile system for guiding nanovehicle design.