Drug delivery across the cell membrane has been widely investigated by scientists. However, not much work has been done on the fate of therapeutics in the intracellular environment. This review deals with advances in the field of nanotechnology investigating localization of agents in the intracellular environment particularly their role in imaging and diagnosis. It can be stated that subcellular organelle-specific targeting of therapeutic

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Emerging Nanotechnologies for Diagnostics, Drug Delivery, and Medical Devices

ISBN 978-0-323-42978-8,

and diagnostic agents has become the new frontier in drug delivery. A variety of pharmaceutical platforms in the nanometer size range, such as liposomes, carbon nanotubes, quantum dots, nanomicelles, and dendrimers, have been investigated for their ability to target subcellular components. Significant improvement has been achieved in the area of organelle-targeted nanocarrier. There is a need to understand the effects of size and shape of nanocarriers on intracellular trafficking and distribution. It is also of paramount importance to determine whether release of therapeutics can be controlled in the intracellular environment. If successful, nanocarriers can be directed toward intracellular organelle where the therapeutics can exert pharmacological effect. Answers to these and similar other questions will lead to a better understanding oftargeted intracellular drug delivery.

To answer these questions, the fate of nanocarriers needs to be tracked real time. A rapid enhancement in imaging technologies will allow scientists to explore this area of research. Some of the exciting technological advancements this chapter will review include state-of-the-art confocal microscopes, quantum dots, and gold nanoparticles. Such technologies will allow us to determine disposition of nanocarriers in the intracellular environment with respect to space and time. Rapid improvement in confocal and fluorescent microscopic techniques has given the scientific community an effective tool to image the entry and trafficking of drug-loaded nanocarriers in the intracellular environment. Time-lapsed and z-stacked images provide detailed information about the intracellular environment and delivery of nanoparticles and other nanocarriers. Quantum dots, also referred to as nanocrystals, are made of semiconductor materials. Gradually it has acquired an important position in nanotechnological research. A detailed discussion on quantum dots is beyond the scope if this chapter. However, their role in intracellular imaging and delivery will be examined. Similar to quantum dots, gold nanoparticle is another important imaging and delivery tool.

Pharmaceutical nanocarriers offer an ideal platform to modify disposition of a drug without modifying the molecule itself. Different chemical modifications can be carried out on the components making up the nanocarrier system, which can be loaded with therapeutics. This will lead to targeted therapy without any structural modification of the drug molecule itself.A majority of pharmaceutical nanocarriers are surface modified, which leads to targeted delivery. Another type of targeted delivery that does not involve any modification of nanocarriers is size-dependent targeting. Nanocarriers such as long circulating liposomes and nanoparticles may be able to passively target tissues and cells with leaky vasculature. This is possible due to the enhanced permeability and retention effect. These two different targeting strategies can be classified into active and passive targeting, respectively, and will be discussed in this chapter.

The internal environment of a cell varies vastly from an aqueous buffer solution. In a buffered environment therapeutic molecules have considerable freedom to diffuse and freely interact. The intracellular environment contains cytoskeletal network and numerous organelles. The cytoplasm expresses a large quantity of macromolecules such as proteins and carbohydrates. Hence the diffusion or transport of a therapeutic molecule in such a viscous and crowded environment will be different from that in a buffered solution. Usually diffusion of drug molecules in the intracellular environment is considered to be hindered diffusion reflecting the high degree of molecular crowding. Also, the viscous nature of the cytoplasmic environment and binding of drug molecules to intracellular components may affect diffusion of drugs inside a cell. Another important parameter that needs to be kept in mind while designing nanocarriers is the physicochemical properties of the therapeutic molecule. It plays an important role in the determination of the subcellular fate of drug molecule.

Another important role of nanocarriers that will be reviewed in this chapter will be targeted drug delivery of nanocarriers to different organelles. Special focus will be on nucleus as it is the site of action for many important anticancer drugs such as doxorubicin. How nanocarriers can be effectively sequestered to its targeted site ofaction inside the cell is an important concept that is discussed in this review. Different targeting moieties are used to specifically target nanocarriers into the organelle. These include peptides, antibodies, DNA, RNA, and other molecules. A detailed knowledge of these targeting moieties is essential to understand how nanotechnology can effectively lead to targeted intracellular delivery. Fig. 8.1 depicts the different parameters affecting intracellular trafficking of different nanoformulations.

Nanotechnology in Intracellular Trafficking

Nanocarriers such as nanoparticles, nanomicelles, and liposomes have been investigated widely for their ability to deliver therapeutics to intracellular compartments. It is necessary to understand the mechanism ofentry ofthese nanocarriers into the subcellular space crossing the barrier of plasma membrane. This section provides an in-depth account of these mechanisms.

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