Application of Reconstituted High-Density Lipoproteins for Cancer Immunotherapy

Pedersbæk, Dennis

4. term

Nanotechnology, Master

2017

2017-08-09

Drug delivery systems (DDSs) have shown great promise to improve the therapeutic effect of many conventional free drugs. Cancer treatment has been the focus of many DDSs, and as it has been recognised that the immune system has an important role in tumour development, DDSs have also been utilized for cancer immunotherapy to deliver immune modifiers to certain immune cells for stimulation of an immune response against the cancer cells. The primary focus of this study is high density lipoprotein (HDL), since it has several properties which are advantageous for DDSs, including the small size of approximately 10 nm, the long circulation half-life and high tolerance in humans, as well as the fact that HDLs can be recognised by endogenous receptors. The HDLs can either be isolated from blood or reconstituted from apolipoproteins such as apolipoprotein A-I (apoA-I) and lipids. It is possible to design reconstituted HDL (rHDL) with various lipid compositions and incorporated drugs, thus making the rHDL applicable for various biomedical applications. Discoidal rHDLs were in this project formulated with apoA-I (purified from human plasma) and with varying lipid composition. It was found that the rHDL could be designed to associate preferably with monocytes in whole human blood, which can be used for cancer immunotherapy by delivering adjuvants to activate the monocytes. It was also possible to obtain a preferred monocytes association when using rHDL with a neutral lipid composition, which is in marked contrast to liposomes, where potentially toxic cationic lipids are required to achieve a similar effect. A toll-like receptor 7 agonist was incorporated as the adjuvant in the rHDL, which resulted in secretion of cytokines effective for an anti-cancer immune response when incubated in whole human blood. It was also found that the rHDLs were capable of delivering antigen to isolated dendritic cells in a way that it could be presented to cytotoxic T-cells that can eliminate cancer cells. The adjuvant and antigen delivery are important for effective cancer immunotherapy. Hence, although some of the experiments need to be confirmed explicitly by replication, the present study clearly indicates the great potential of using rHDLs in DDSs applicable for cancer immunotherapy.

Reconstituted High-Density Lipoproteins ; Cancer Immunotherapy ; Apolipoprotein A-I ; Monocytes

Download
View record in AAU Student Projects