Targeted Nuclear Drug Delivery for Cancer Chemotherapy

CBET-0753109大多数抗癌药物都是针对核DNA造成损伤或抑制拓扑异构酶以诱导细胞死亡(凋亡)的毒素。然而，癌细胞通过细胞膜相关的多药耐药和各种细胞内耐药机制有效地限制药物进入细胞核。目前的药物载体可以将药物输送到细胞内，从而规避多药耐药，但细胞内药物仍然受到细胞内耐药的影响。PI因此提出，将DNA毒素直接输送到癌细胞的细胞核将克服这两种耐药机制，但没有载体可用于体内核药物输送。本项目的目标是合成癌症靶向的活性核定位药物结合物(ANLC)，用于体内核给药。ANLC是一种水溶性聚合物或树枝状大分子为基础的DNA毒素载体，具有肿瘤靶向基团和溶酶体激活的核定位信号(NLSS)的功能。NLSS在到达癌细胞之前是不活跃的，因此在血液循环中，它的非特异性内化受到抑制。一旦进入酸性晚期溶酶体，NLSS就被激活为功能齐全的NLSS。DNA靶向药物通过细胞内可裂解的键与载体共价结合。因此，设计的ANLCs有望在血液中长时间循环积聚在肿瘤组织中，迅速被癌细胞内化，然后转移到它们的溶酶体中激活NLSS。然后，NLSS引导结合物从溶酶体中逃逸，进入细胞核，在那里结合物释放他们的药物。该项目将开发有效的癌症化疗药物，能够有效地克服癌症耐药性。这项跨学科研究还将提供教育代表性不足的学生和研究生/本科生的机会，并将激励和激励他们从事科学和工程工作。

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.