Nanomedicines for cancer chemotherapy
Abstract
Chemotherapy has been used to treat cancer for several decades but undesirable side effects remain a significant challenge. To overcome this challenge, two nanomedicines, a blood-stable and tumor-adaptable micelle and a cholesteryl ester-depleting nanomedicine, have been developed in my Ph.D. dissertation. Although targeted delivery mediated by ligand modified or tumor microenvironment sensitive nanocarriers has been extensively pursued for cancer chemotherapy, the efficiency is still limited by premature drug release after systemic administration. Also, it causes off-target toxicity to healthy cells and organs. As the first work in this dissertation, a highly blood-stable, tumor-adaptable drug carrier made of disulfide (DS) bonded mPEG-(Cys)4-PDLLA micelles was developed for safe and effective cancer chemotherapy. Intravenously injected disulfide bonded micelles stably retained doxorubicin in the bloodstream and efficiently delivered the drug to a tumor, with a 7-fold increase of the drug in the tumor and 1.9-fold decrease in the heart, as compared with self-assembled (SA), non-crosslinked mPEG-PDLLA micelles. In vivo administration of disulfide bonded micelles led to doxorubicin accumulation in cancer cell nuclei, which was not observed after administration of self-assembled micelles. With a doxorubicin dose as low as 2 mg/kg, disulfide bonded micelles almost completely suppressed tumor growth in mice. Additionally, the cellular entry routes and intracellular fates of the self-assembled (SA) and disulfide (DS) bonded micelles were characterized. As the second work in this dissertation, a nanomedicine-based strategy that selectively treats various cancers without adverse effects to healthy cells and organs by targeting acyl-CoA cholesterol acyltransferase-1 (ACAT-1)-mediated cholesterol esterification has been studied. To safely and efficiently block the cholesterol esterification in cancers, a cholesteryl ester-depleting nanomedicine, named as Avasimin, consisting of Avasimibe (ACAT-1 inhibitor) and human serum albumin was developed. In different human cancer cell lines, Avasimin significantly reduced cholesteryl esters in lipid droplets while elevating intracellular free cholesterol levels, which led to apoptosis and suppression of proliferation. Furthermore, with improvement of the water-solubility of Avasimibe by up to 40 times, Avasimin can be intravenously injected at high concentration, which increases the bioavailability of Avasimibe in blood and tumor compared to standard oral administration. Systemic treatment of Avasimin notably suppressed tumor growth and also extended the length of survival time in mouse models of human prostate and colon cancers. No adverse effects of Avasimin treatment to normal cells, blood components, and organs including liver and adrenal glands were observed. Together, this study shows a clinically viable approach for cancer-selective chemotherapy by targeting altered cholesterol metabolism of cancer cells.
Degree
Ph.D.
Advisors
Cheng, Purdue University.
Subject Area
Biomedical engineering|Medicine|Nanotechnology
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