Multidimensional atomic force microscopy for drug discovery: A versatile tool for defining targets, designing therapeutics and monitoring their efficacy

Current therapeutic design involves combinatorial chemistry and system biology-based molecular synthesis and bulk pharmacological assays. Therapeutics delivery is usually non-specific to disease targets and requires excessive dosage. Efficient therapeutic discovery and delivery would require molecular level understanding of the therapeutics–effectors (e.g., channels and receptors) interactions and their cell and tissue responses. This review summarizes the application of multidimensional scanning probe techniques, especially atomic force microscopy (AFM), for drug discovery. Important features of AFM include its capability of atomic scale structural and physical properties study of live biological systems, its open architecture that allows its integration with other techniques, tools and operating environments, and its application for creating and characterizing nanocarriers and implantable vehicles for controlled delivery. Specific areas covered include: 1) the operating principle and examples of AFM integrated with electrical recording, fluorescence imaging and microfluidics, (2) examples of AFM nanoscale imaging that has provided new paradigms in pathogenesis, including protein misfolding diseases (e.g., Alzheimer's disease, cancer, diabetes) and diseases arising from environmental and life choices and thus identifies potential therapeutic targets, (3) high-throughput parallel sensors, comprising integrated cantilevered microarrays, TIRF, microfluidics and nanoelectronics, for potential rapid diagnosis of pathogens, allergens and biomarkers as well as for therapeutics design, (4) the definition target macromolecules and structures, using intermolecular interaction assays, (5) the definition of abnormal vs normal tissues and the assessment of therapeutic efficacy by monitoring biomechanics, and (6) the development and characterization of nanocarrier-based drug delivery (e.g., nanoliposomes and nanoparticles) systems that allow high efficiency in vivo or the topical administration of a small dosage of therapeutics.