Development of specific oxygen reactive species (ROS) sensitive polymeric micelles for cancer therapy

• Main Authors: Lu-Yi Yu, 余律誼
• Other Authors: Chun-Liang Lo
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/f638fm

博士 === 國立陽明大學 === 生物醫學工程學系 === 106 === Nanoparticle delivery systems are an important and major route to deliver anticancer drugs in cancer therapy. However, most nanoparticle systems have some problems to be overcome. For example, nanoparticles are lack of selective drug delivery, efficient payload release in the cytosol and uncertain bio-compatibility of delivery materials. Herein, a reactive oxygen species (ROS)-responsive micelle composed of methoxy polyethylene glycol-b-poly(diethyl sulfide)-NH2 (mPEG-PS) copolymers that can induce specific endosome escape in cancer cells and deliver payloads into cancer cell cytosol by changing in the hydrophobicity of copolymers was developed. The experimental results indicate that the copolymers can be oxidized by high levels of H2O2, change the chemical structure of copolymers from sulfide to sulfone and sulfoxide and change the hydrophobicity of copolymers to more hydrophilic. Additionally, copolymers maintain their molecular weight and weak negative zeta-potential after oxidation. The red blood cell analysis also shows that oxidized copolymers can insert into cells and induce hemoglobin release. Because micelles encapsulate an acid-degradable drug, α‐tocopheryl succinate inside the core, the stability of this drug can be analyze to evaluate the functionality of micelles in cancer cells. The in vitro results indicate that drugs can maintain their bio-activity and selectively kill cancer cells. In the second part of my study, lysine molecules are introduced into ROS-sensitive micelles and then conjugate with dichloro(1,2-diaminocyclohexane) platinum (II) (DACHPt) to form micelles for clinical colon cancer therapy. After micelle oxidation, the hydrophobicity of copolymers can rapidly become hydrophilic and release DACHPt. Because of the rapidly responsive and drug release abilities, the released DACHPt can prevent excess interaction with intracellular glutathione and largely accumulate in lysosomes by copper transporters. The results of in vitro and in vivo test demonstrate that the rapidly responsive micelles not only increase cancer therapeutic efficacy in colon cancer but also reduce the side-effects in normal organs. Overall speaking, rapidly ROS-responsive micelles have great potential as drug carriers to overcome the limitations of acid-unstable drugs and platinum-based drugs in cancer therapy.