Nanocarriers utilizing target tissue-specific microenvironment

Abstract

Nanocarriers have been used in a variety of biological applications for drug delivery and diagnostic devices. This nanotechnology has great implications for clinical use through the enhanced therapeutic effect and the reduced side effects. Also, various nanocarrier targeting strategies have been tried to improve medication therapeutic effects in various diseases. Although numerous targeting techniques have made tremendous progress in developing therapy possibilities, clinical trials are still impeded by obstacles at a later stage. As a result, further work is underway to evolve for these nanotechnologies beyond the remaining obstacles to drug delivery.

A challenge to current advances in nanotechnology is to consider the diverse micro-environmental factors as advanced strategies for nanocarrier therapy. This expansion will ensure an effective point for disease targeting in the surrounding area.

In chapter 1, the use of nanocarriers in a broad strategic scope was discussed. There is a variety of targeting strategies for using nanocarriers as drug delivery systems, ranging from traditional ways to cutting-edge technologies. This nanotechnology has a substantial impact on enormous effective developments in the biological therapeutic field. There are still certain constraints that need to be addressed. Advanced nanotechnology using microenvironment factors is a sophisticated strategy that considers not only the properties of vehicles but also the adaptive aspects to microenvironment for therapy. Nanocarrier dispersion and biological consequences are heavily influenced by micro-environmental factors. Moreover, monitoring the tissue microenvironment through molecular and cellular profiles will be an essential point in identifying cellular or protein targets.

In Chapter 2, we applied a strategy to enhance the permeability of nanocarriers in the physiological and biological barriers of the microenvironment. The eye is one of the compartment tissues. To prevent hazardous compounds from reaching the eye, the ocular anatomy has both static and dynamic comparted barriers. Therefore, therapeutic molecules absorption requires overcoming barriers to permeability into the desired location. Especially, there is a retinal layer formed of a blood-retinal barrier in the posterior portion of the eye, which prevents ocular medication bioavailability. Also, the retina is affected by significant limiting factors that impede the diffusion of molecules through GAGs throughout the eye by intravenous injection. To overcome the biological barriers for ophthalmic therapy, a simple modification of nanocarrier surface has been utilized to enhance the permeability of compressed GAGs to reach the retinal layer, also to be lower the tight junction barrier of retinal pigment epithelium to penetrate therapeutic molecule across the desired location.

In Chapter 3 and 4, the strategies to exploit altered factors in disease conditions was used. Nanotechnology utilized these microenvironment changes, not only, can diagnosis with sensitive tools to read the micro-scale environment in real-time, but also can treat a medicine into a specific disease for efficient therapy.

In Chapter 3, we considered the barrier which cannot get a benefit of nanocarrier by the extremely size-dependent filtration. Because of the obstacles, nanocarriers smaller than 100 nm are unable to enter the tissue through the filter membrane. However, impairment to the filter structure has changed this nano-sized constraint. So, the strategy using that alteration was applied to the design of the nanocarrier in this chapter. The glomerular basement membrane (GBM) in the kidney structure has a very size-dependent filtration, thus it only penetrates materials smaller than 6 nm for the size threshold. However, when the microenvironment of a damaged structure is disrupted, nanosized materials can penetrate the GBM, indicating that nanocarriers allow the medicine to reach the injured structure. Furthermore, the peptide-functionalized nanocarrier exhibited the binding affinity in the proximal tubule, indicating that reduced renal clearance.

Lastly, in Chapter 4, we consider the nanoreactor system which stimuli-response from the specific disease microenvironment factor such as excess reactive oxygen species. Especially, for safer and for a specific reaction, two antioxidant enzyme cascade system was utilized for the nanoreactor. Mostly, highly reactive oxygen species is super oxide anion as substrate, superoxide dismutase (SOD) and catalase (CAT) cascade system was realized in nano-sized level with significantly increased transforming result from superoxide anion to oxygen. It shows the enhanced regenerative effect from the inflammatory bowel disease model in vivo.

In summary, this thesis describes a nanocarrier system that improves the targeting and therapeutic effects by utilizing the target tissue microenvironment.