Search

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., The original document contains color images.

Due to the cell membrane-associated and intracellular drug resistance mechanisms, the depleted cytoplasmic drug concentration allows breast cancer cells to survive and resist chemotherapeutic regiments. Therefore, the goal of this proposal is to develop targeted charge-reversal nanoparticles (TCRNs) to overcome breast cancer drug resistance. We finished the task 1 and 2. A series of TCRNs were synthesized and characterized, including a charge-reversal polymer, a charge-reversal lipsome and a charge-versal peptide. Such TCRNs effectively enhance the cellular uptake of the nanoparticles and exhibit higher cytotoxicity to cancer cells, showing a great promise for in vivo applications. Moreover, a series of degradable dendrimers and its applications in delivering anticancer drugs were developed as novel targeted delivery systems. In addition, a new nanorod-like nanocarriers was prepared and demonstrated be advantageous over similar spherical nanocarriers in targeting cancer cells., The original document contains color images.

Cell membrane-associated and intracellular drug resistance mechanisms are the major cause of breast cancer treatment failure. The aim of this proposal is to develop nuclear localizing nanoparticles to delivery DNA-toxins breast cancer cell nuclei to effectively overcoming the drug resistance. We finished the task 1 - To synthesize and optimize folic-acid- or LHRHfunctionalized charge reversal nanoparticles. The cationic polymer PEI and its block copolymer with degradable PCL were synthesized. The cationic PEI block amines were converted to acid labile amides to obtain the PCL-PEI/amide block copolymer. This polymer was used to fabricate the nanoparticles. The ideal nanoparticles with optimal sizes and acid-triggered negative-to-positive charge reversal properties were fabricated and characterized carefully. These nanoparticles will be characterized in vitro and in vivo., The original document contains color images.

Cell membrane-associated and intracellular drug resistance mechanisms are the major cause of breast cancer treatment failure. The aim of this proposal is to develop nuclear localizing nanoparticles to deliver DNA-toxins breast cancer cell nuclei to effectively overcoming the drug resistance. We finished the task 1? To synthesize and optimize folic-acid? or LHRH-functionalized charge reversal nanoparticles. The cationic polymer PEI and its block copolymer with degradable PCL were synthesized. The cationic PEI block amines were converted to acid labile amides to obtain the PCL-PEI/amide block copolymer. This polymer was used to fabricate the nanoparticles. The ideal nanoparticles with optimal sizes and acid-triggered negative-to-positive charge reversal properties were fabricated and characterized carefully. These nanoparticles will be characterized in vitro and in vivo., The original document contains color images.

Chemo-resistant breast cancer cells overexpress not only membrane-associated but also many cytosolic drug-resistance mechanisms to limit the access of DNA-toxins to the nucleus, causing low chemotherapeutic efficacy. The project aims to synthesize and evaluate a conjugate that can enter and deliver DNA-toxins doxorubicin (DOX) or camptothecin (CPT) to the nuclei of breast cancer cells. In this project, a polyethyleneimine (PEI) was used as a nuclear localizing carrier, and was functionalized with folic acid as targeting groups and CPT as a DNA-toxin. The PEI carrier was modified to be negatively charged in the bloodstream to shield its cationic charges and thereby inhibit its interaction with cells before reaching tumors, but once in acidic tumor interstitium or tumor cells' acidic lysosomes, the PEl is regenerate for cellular uptake and nuclear localization. The PEI-based conjugate could enter the breast cancer cells efficiently and traverse to their nuclei. The carried CPT showed much higher cytotoxicity to breast cancer cells than CPT itself. Similarly, a cationic polylysine-based conjugate was also synthesized and similar results were obtained., The original document contains color images.