Hollow Gold Nanosphere for Photothermal Lipolysis Obesity Therapy

Abstract

Gold nanomaterials have been widely investigated for various biomedical applications. Gold nanomaterials have great biocompatibility compared with other metal nanomaterials and can be easily surface-modified by the gold-thiol chemistry. There are many kinds of gold nanomaterials with various shapes including nanocages, naonorods, and nanoparticles. Here, we focused on hollow gold nanosphere (HAuNS) as a photothermal agent for the treatment of obesity. HAuNS can absorb near-infrared (NIR) light and generate heat by surface plasmon resonance effect. For this reason, HAuNS has been used for photothermal therapy of cancer or photoacoustic imaging of certain organ such as brain. In this work, HAuNS was synthesized and applied for photothermal lipolysis by conjugating hyaluronic acid (HA) and adipocyte target sequence (ATS, GKGGRAKDGGC). Chapter 1 describes the introduction to gold nanomaterials in terms of their various nanostructures according to the shape, size and applications. Then, HA was introduced focusing on the biological functions and unique physico-chemical properties. Also, the principle of photoacoustic (PA) imaging and its merits on tissue penetration depth and resolution were described. Chapter 2 HA-HAuNS-ATS complex was prepared for transdermal delivery and photothermal lipolysis. HAuNS was synthesized via galvanic replacement reaction of cobalt with gold. Transmission electron microscopy (TEM) and high resolution TEM (HRTEM) imaging showed the morphology of HAuNS which has thin gold layer and embedding medium within the shell. UV-vis absorbance spectrum demonstrated the absorbance of NIR light by HAuNS. The photothermal effect of HAuNS was confirmed by measuring temperature of HAuNS aqueous solution with irradiating 808nm of NIR laser. Furthermore, photoacoustic signal amplitude depending on several different wavelengths of light was measured. To attach HA and ATS to HAuNS, thiol group was introduced to end group of HA and ATS. End-thiol HA and ATS can be attached to HAuNS via gold-thiol chemistry during simply stirring. HA-HAuNS-ATS complex was assured by TEM, UV-vis absorbance, zeta potential and DLS. The MTT tests assured the negligible cytotoxicity of the complex. After differentiation of preadipocytes to mature adipotyes, in vitro cellular uptake of HA-HAuNS-ATS was visualized by dark-field imaging. Due to ATS, HA-HAuNS-ATS was efficiently internalized into adipocytes than HAuNS and HA-HAuNS. After transdermal delivery of HA-HAuNS-ATS on the skin of Balb/c nude mice, the complex could penetrate stratum corneum (SC) and accumulate within skin, which was visualized by PA imaging. After inducing obesity mice model, the same amount of HAuNS, HA-HAuNS-ATS were administered on abdominal skin and NIR light was irradiated. Then, PA imaging at 1200nm could show the decrease in fat by only using HA-HAuNS-ATS. In conclusion, after HA-HAuNS-ATS was successfully synthesized and specifically delivered to adipose tissue via skin, NIR irradiating made the complex generate heat and melt fat. This photothermal and target-specific lipolysis can achieved partial and intensive removal of adipose tissue. HA facilitated HAuNS to penetrate SC layer and be delivered to hypodermis. ATS could help HA-HAuNS-ATS complex to be internalized into adipocytes, which prevent other normal skin cells from damaging. The photothermal property of HAuNS enables the complex to be visualized within skin by PA imaging and photothermal therapy.