경피전달 나노의약을 이용한 진단 및 치료시스템

Abstract

The term “theranosis” is a combination word for diagnosis and therapy. Theranostic systems can be used to deliver diagnostic agents and drugs simultaneously. It is greatly advantageous to carry out diagnostic analysis to assess the heterogeneity, morphology and cellular phenotype before and during treatment of various diseases. Accordingly, theranostic systems are one of the key technologies for a new era of personalized medicine. The ultimate goal of theranostic systems is to monitor the diseased tissue and control the drug delivery kinetics in real-time. In this context, a variety of nanomaterials have been widely investigated for theranostic systems. However, their safety issues have limited the further clinical applications. Here, several unique theranostic systems have been developed using gold nanomaterials (AuNMs), black phosphorus (BP), and hyaluronic derivatives for transdermal theranosis of several model diseases. In part I, a versatile theranostic platform of hyaluronan - goldnanorod/death receptor 5 antibody (HA-AuNR/DR5 Ab) complex was developed for photoacoustic imaging and antibody cancer therapy after its non-invasive transdermal delivery. As an anticancer therapeutic, we exploited DR5 Ab which specifically targeted death receptor 5 (DR5), highly expressed on cancer cell membrane, to induce apoptosis of cancer cells. The conjugation of negatively charged HA on the surface of AuNR could highly improve the stability of HA-AuNR/DR5 Ab complex, preventing the nonspecific interaction between AuNRs and serum protein in the body. The hygroscopic HA can hydrate stratum corneum and the hydrophobic patch domain on HA chain can enhance its permeation into the skin. AuNRs absorbing NIR lasers can be harnessed as a photoacoustic imaging platform for diagnostic applications. As a result, HA coated AuNR can serve as a transdermal nanocarrier of DR5 Ab for the treatment of skin cancer. In combination, HA-AuNR/DR5 Ab complex was successfully applied for non-invasive theranosis of skin cancers. In part II, a nanoplatform of hyaluronan - hollow gold nanosphere - adipocyte targeting peptide (HA-HAuNS-ATP) conjugate was developed for obesity therapy. The most typical treatment of obesity is to remove subcutaneous adipose tissues with laser and suction. Although laser-assisted liposuction is one of the most common methods to remove adipose tissues, this invasive method has several disadvantages, such as discomfort, pain, bleeding, long recovery time and side effect of seromas. The transdermal delivery of HA-HAuNS-ATP conjugate can resolve the invasiveness of conventional obesity therapies with the advantages of comfort, painless, less side effect and avoidance of first-pass metabolism. ATP with a sequence of CKGGRAKDC was used to increase the target-specificity of HAuNS to adipose tissues, specifically binding to prohibitin proteins on the surface of white adipose tissues. The HA-HAuNS-ATP conjugate was prepared by the gold-thiol chemistry between HAuNS, thiolated HA (HA-SH) and cysteine of ATP. HA-HAuNS-ATP conjugate appeared to penetrate the skin barrier and target-specifically accumulated in adipocytes. Finally, the photoacoustic (PA) imaging of HA-HAuNS-ATP conjugate confirmed the successful transdermal delivery and the photothermal lipolysis under NIR light illumination. In part III, a nanoplatform of hyaluronan – blackphosphorus / upconversion nanoparticle (HA-BP/UCNP) complex was developed for multimodal theranosis of skin cancer. BP which exhibits high light-to-heat conversion efficiency can be applied to photothermal cancer therapy. In addition, BP nanoparticles can generate singlet oxygen efficiently and be used for photodynamic therapy to treat cancers. UCNPs convert NIR light to blue light for enhancing light absorbtion of BP. The combination of the two treatments resulted in more effective cancer cell apoptosis. In addition, HA-BP/UCNP complex could be applied to multimodal imaging. BP has unique optical properties for photoacoustic imaging and fluorescence cell labeling. Furthermore, UCNPs can be used as an MRI imaging agent. Amidated HA (HA-DAH) and UCNPs were physically attached on the BPNS surface by the electrostatic interaction. In vitro cytotoxicity tests confirmed that HA-BP/UCNP complex successfully induced apoptosis of cancer cells. Finally, the photoacoustic (PA) imaging of HA-BP/UCNP complex confirmed the successful transdermal delivery and the therapeutic effect for multimodal cancer theranosis. In part IV, black phosphorus (BP) was harnessed as a subdermal drug delivery carrier. The facile double-coating with osteogenic dexamethasone (Dex) loaded BP and poly(lactide-co-glycolide) (PLGA) was performed for Mg subdermal implants. According to the electrochemical and biodegradation tests, the prepared Mg-Dex/BP/PLGA showed remarkably enhanced resistance against the corrosion possibly by the neutralization of basic molecules from Mg implants with acidic molecules from BP and PLGA with increasing biodegradation. Scanning electron microscopy, cell proliferation test, Alizarin red staining and alkaline phosphatase activity tests confirmed that MC3T3-E1 cells were significantly proliferated and differentiated on the Mg-Dex/BP/PLGA surface. The facile surface modification of Mg implants would be effectively harnessed for protecting the Mg surface from the corrosion and inducing the osseointegration of pre-osteoblast onto the Mg implants. Taken together, my PhD research for several unique theranostic systems using AuNMs, BP, and HA derivatives would contribute greatly for the transdermal theranosis of intractable diseases including skin cancers and obesity.