Targeted Nuclear Drug Delivery for Cancer Chemotherapy

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CBET-0753109ShenMost anticancer drugs are toxins that target nuclear DNA to cause its damage or topoisomerase inhibition to induce cell death (apoptosis). Cancer cells, however, efficiently limit drug entry to their nuclei via the cell-membrane?associated multidrug resistance and various intracellular drug resistance mechanisms. Current drug carriers can deliver drugs to the cytosol and thus circumvent the multidrug resistance, but the cytosolic drugs are still subject to the intracellular drug-resistance. The PI thereby proposes that delivery of DNA-toxins directly to the nuclei of cancer cells would overcome both of these resistance mechanisms, but no carrier is available for in vivo nuclear drug delivery. The objectives of this project are to synthesize cancer-targeted active nuclear localization drug-conjugates (ANLCs) for in vivo nuclear drug delivery. An ANLC is a water-soluble polymer- or dendrimer-based DNA-toxin carrier, which is functionalized with cancer-targeting groups and lysosome-activated nuclear localization signals (NLSs). The NLSs are inactive before reaching cancer cells and thus in the blood circulation its nonspecific internalization is inhibited. Once inside acidic late lysosomes, the NLSs are activated as fully functioning NLSs. DNA-targeting drugs are covalently bound to the carrier using an intracellular cleavable bond. Therefore, the designed ANLCs are expected to circulate in the bloodstream for a prolonged time to accumulate in cancer tissues, be quickly internalized by the cancer cells, and then be transferred to their lysosomes to activate the NLSs. The NLSs then lead the conjugates to escape from the lysosomes and enter the nucleus, where the conjugates release their drug. The project will develop effective cancer chemotherapies that can efficiently overcome cancer drug resistance. This interdisciplinary research will also provide opportunities to educate underrepresented students and graduate/undergraduate students, and will stimulate and excite them engaged in science and engineering.