Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy
Final rept. 1 Sep 2009-31 Aug 2013
WYOMING UNIV LARAMIE
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Breast cancer cells drug resistance mechanisms are the major factors to reduce the cytotoxic effects and even the chemotherapeutic efficacy of anti-cancer drugs. Nanocarriers for drug delivery based on the EPR effect targeted to cell cytosol subject to various intracellular drug-resistance mechanisms which limited their access to the cell nuclei and mitigated the pharmacological actions of DNA-damaged anti-cancer drugs. We developed various kinds of nuclear-targeted chargereversal nanoparticles TCRNs which can directly localize and release drug molecules into the nucleus, circumventing both the membrane-associated multidrug resistance and the intracellular drug resistance mechanisms. The cationic primary amines of TCRNs are amidized as acid-labile beta-carboxylic amides to shield the positive charges in blood circulation, but hydrolyzed to regenerate once in cancer cells acidic lysosomes, leading to the TCRNs escape from the lysosomes and traverse into the nucleus. The in vitro and in vivo administrations of TCRNs exhibited higher antitumor efficacy and fewer side effects, showing great promises for TCRNs in future applications.
- Medicine and Medical Research