2-Dimensional Inorganic Nanohybrid for Drug Delivery

Abstract

Drug delivery systems have been intensively studied in the last few decades because they enable drugs to be effectively delivered to target sites, and increase the therapeutic efficacy with minimum side effects through controlled release manner. In this study, an anticancer drug, methotrexate (MTX), has been successfully hybridized with layered double hydroxides (LDHs) through co-precipitation route to produce MTX-LDH nanohybrids. According to the X-ray diffraction, FT-IR spectroscopic, UV/vis spectroscopic and thermogravimetric analyses, it was confirmed that MTX molecules are stabilized in the interlayer space of LDHs by electrostatic interaction, maintaining their functional groups and structural integrity. According to the drug release study, the total amount of released MTX from the LDH lattice was determined to be larger in a simulated intracellular lysosomal condition (pH 5±0.5) than simulated body fluid one (pH 7.4). It is, therefore, expected that the MTX molecules in MTX-LDH can be effectively released in lysosomes, since the MTX release could be accelerated via ion-exchange reaction and decomposition of LDH in an acidic lysosomal condition. We also examined the anticancer efficacy of MTX-LDH in human osteosarcoma cells. The cellular uptake of MTX was considerably higher in MTX-LDH-treated cells than in free MTX-treated cells, giving a lower IC_(50) value for the former than the latter. Furthermore, MTX in MTX-LDH nanohybrids was better retained in the cells than free MTX. All the results demonstrated that the MTX-LDH nanohybrid allows the efficient drug delivery in cells, and thus enhances drug efficacy. In addition, venlafaxine, (+/-)-1-(alpha-((dimethylamino)methyl)-p-methoxybenzyl) cyclohexanol, is a kind of antidepressant drug which was successfully intercalated into layered aluminosilicate, montmorillonite (MMT), by ion-exchange reaction to form a venlafaxine-montmorillonite hybrid (VMH). It was again coated with enteric polymer and pH independent ones such as a methacrylic copolymer (Eudragit L 100-55), ethylcellulose (EC) and hydroxypropyl methylcellulose (HPMC), respectively, in order to control the rate of drug release from VMH as designed. According to the X-ray diffraction and infrared spectroscopic analyses, it was confirmed that venlafaxine molecules in the interlayer spaces of MMT maintained their chemical and structural properties. To realize the controlled release of venlafaxine molecules from the polymer-coated VMH, the coating polymers and the solution pHs were changed systematically. The drug release profiles, as confirmed by high performance liquid chromatography (HPLC), indicated that venlafaxine molecules were more effectively release out from VMH upon polymer coating, and its release kinetics were intentionally controlled as well.;본 연구의 제 1장에서는 항암제의 일종인 메쏘트레쎄이트(MTX)를 이온교환 반응을 통하여 약물-무기 나노 하이브리드를 합성하였다. X-선 회절 분석, 적외선 분광 분석, 자외선 가시광선 분광 분석 결과 등에서 약물 분자가 화학적, 구조적 특징을 유지하면서, 정전기적 상호작용을 통해 기울어진 한 층의 형태로 금속 이중층(LDH) 층간에 층간 삽입되어 있음을 확인 하였다. 약물 방출 실험을 통해 세포 내에서 LDH 층간에 존재하는 약물의 방출 특성을 알아보았다. 그 결과 세포의 일반적인 환경에서 보다 라이소좀 환경하에서 더 많은 양의 약물이 방출됨을 알 수 있었다. 이는 LDH의 pH에 따른 용해도의 차이에 인한 결과로 해석할 수 있었다. 또한 새로운 약물-무기 나노하이브리드의 효과를 알아보기 위해 종양세포에서 세포내로 투입되는 양과 MTT검사법을 통한 시험관내 연구를 시행하였다. 결과 MTX 약물만 처리한 세포에 비해서 나노하이브리드가 50 배 정도 효율적인 것으로 나타났다. 제 2장에서는 점토 물질의 일종인 몬트몰리로나이트에 우울증 치료제인 벤라팍신을 위와 같은 이온교환 반응을 통해 약물-나노 하이브리스시템을 합성하였다. 이에 간단한 분무 건조법을 이용하여 다양한 고분자를 코팅시키는 단계도 진행시켰다. 경구용 약물전달 시스템으로써의 효과를 알아보기 위해 위와 장의 환경을 모방한 완충 용액에서 약물 방출 실험을 수행하였다. 결과 고분자의 특성에 따라 방출 특성이 달라지며, 여러 단계의 수정을 통하여 원하는 약물 전달 시스템을 만들 수 있을 것이라는 결과를 예측하게 해주었다. 본 연구는 양전하와 음전하를 가지는 금속 이중층 수산화물을 토대로 한 약물 전달 시스템의 발전 가능성을 제시하였다.