A Cooperative Dimensional Strategy for Enhanced Nucleus-Targeted Delivery of Anticancer Drugs

Although previous efforts have focused on altering the size of drug delivery carriers with the goal of improving the efficacy of anticancer therapy, the penetration of nuclear pores still represents a formidable barrier for the existing drug delivery systems. To this end, a cooperative, dimensional strategy is employed that can considerably improve intranuclear drug delivery to augment the overall therapeutic efficacy of therapeutics requiring nuclear entry. This cooperative strategy relies on i) the pH and redox responsiveness of micelles (termed PSPD) to extend blood circulation and increase both the cellular uptake and the redox sensitivity of PSPD to reduce micelles to a size that is more capable of nuclear entry and ii) a dexamethasone-conjugated micelle (termed Dex-P123) to target nuclei and dilate nuclear pores to allow PSPD to freely penetrate the nuclear pores. The resulting hybrid micelles, termed PSPD/Dex-P123, are found to deliver doxorubicin into cell nuclei more efficiently, thereby inducing more pronounced cytotoxicity against cancer cells in vitro. Importantly, a much more effective inhibition of tumor growth is observed in tumor-bearing mice, demonstrating the feasibility of this cooperative strategy for in vivo applications. The current study defines a useful dimensional strategy to improve nuclear-targeted and intranuclear drug delivery.