Development and Characterization of PEG-B-PCL Micelles Carrying Anticancer Agents

Işık, Gülhan
Cancer is a disease that decreases the quality of life. Many cancer drugs are either toxic or not effective due to their fast removal by reticuloendothelial system. Therefore, nano-sized drug delivery systems, especially the ones carrying the drugs directly to tumor, gained attention in the last decades. The aim of the study was to prepare nano-sized drug carrying micelles (drug conjugated and drug loaded) from methoxy polyethylene glycol-block-polycaprolactone (mPEG-b-PCL). In order to conjugate drugs, mPEG-b-PCL was activated with hydrazide groups. Doxorubicin (DOX) was conjugated covalently (at 60ºC), and lithocholic acid (LCA) was conjugated ionically (at 60ºC and 25ºC) to obtain micelles (coded as DOXconj-M, LCA60**M and LCA25**M, respectively). Micelles having no conjugation, but loading of DOX (DOXld-M), and micelles having both drugs together (DL-M) were also prepared. Micelles demonstrated faster drug release in acidic media than the neutral media, which is advantageous for the treatment of cancer since cancer tissue is more acidic than the healthy tissue. Cell culture studies show that micelles having no drugs are not cytotoxic. Internalization of the micelles into MDA-MB-231 cancer cells was determined by using coumarin-6 loaded micelles for LCA containing micelles (LCA60**M and LCA25**M) and DOX for DOX containing micelles (DOXconj-M, DOXld-M, and DL-M). All micelles displayed low cell migration and high anti-proliferative effect on MDA-MB-231 cells. Moreover, the ones having LCA (LCA60**M, LCA25**M and DL-M) led a decrease in lipogenic activity, but DOXconj-M and DOXld-M did not change lipid droplet formation. An increase in the number of apoptotic cells, as well as in apoptotic genes of Bax and p53 expressions, and a significant decrease in anti-apoptotic genes of Bcl-2 and Bcl-xL expressions were observed after the treatment of the cells with DOXld-M and DL-M. All micelles prepared in this study caused a decrease in the mitochondrial transmembrane potential of the cells, which results in apoptosis, and an increase in ROS generation, which was significantly higher in the cells treated with DOXconj-M, DOXld-M, and DL-M compared to free DOX applied ones. Micelles having LCA caused a significant decrease in angiogenesis ability of HUVECs. In the future these types of micelles especially immunomicelles targeted to cancer cells will be the candidate carriers in cancer therapy.


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Citation Formats
G. Işık, “Development and Characterization of PEG-B-PCL Micelles Carrying Anticancer Agents,” Ph.D. - Doctoral Program, Middle East Technical University, 2022.