Most 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.
Most cancer chemotherapeutic drugs target nuclear DNA to induce DNA damages and thereby cell death, but cancer cells have many defense mechanisms in their membrane and cytosol to limit the access of these drugs to their nuclei. Therefore, even though cancer patients take the drugs but they cannot reach their targets in the nuclei and thus are ineffective, causing cancer relapse and finally patient death. To this end, in this project we developed drug carriers capable of directly localizing and releasing drugs into cancer cell nuclei so that they can circumvent both membrane-associated and the intracellular defense mechanisms to effective reach the drug target for high therapeutic efficacy. We used nuclear-philic cationic polymers to make water-soluble polymers or nanoparticles as drug carriers. Since positive charges can cause severe problems once in the blood while negatively charged polymers are widely used in vivo, negative-to-positive charge reversal technology was thus developed to make the carriers negatively charged while in the bloodstream for safe use but capable of regenerating back to positively charged once in cancer cells for nuclear localization. Drugs delivered by these cancer nuclear-targeted carriers had much high efficiency in killing cancer cells. Thus, the nuclear drug delivery developed in this project is a new drug delivery approach to effectively overcoming cancer drug resistance, a major cause of cancer treatment failure, and provides a new and effective therapy for clinical treatment of cancer. The project also trained three PhD students and 2 undergraduate students in interdisciplinary research areas.
