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

Abstract

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-P 123 ) to target nuclei and dilate nuclear pores to allow PSPD to freely penetrate the nuclear pores. The resulting hybrid micelles, termed PSPD/Dex-P 123 , 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.

Multi-Stimuli-Responsive Polymer Particles, Films, and Hydrogels for Drug Delivery

“…Pluronic P123 was firstly conjugated with PEI via disulfide bonds and then modified with DMMA, which was used to assemble dual-responsive polymer particles. 34 Acidic pH can cleave the DMMA groups to reduce the particle size and convert the surface charge from negative to positive, which helps the cell association and uptake as well as the subsequent endosome escape. The reduction microenvironment in the cytoplasm can strip PEI from particles and expose the dexamethasone-conjugated Pluronic P123, which can dilate the nuclear pores and facilitate the entry of DOX-loaded Pluronic P123 particles into the cell nuclei to improve the drug-delivery efficacy.…”

Recent Advances in Subcellular Targeted Cancer Therapy Based on Functional Materials

“…However, large nanoparticles within the aforementioned size range have no chance to permeate deeply in tumor tissues due to the obstruction of interconnected tumor extracellular matrix, and they are too large for nuclear internalization. Therefore, an ideal scenario would be that the diameter of nano‐DDSs should be transformable by adapting to various circumstances in a multistage stimuli‐responsive way . That is, the nanoparticle size at the initial stage should be large enough to reduce renal excretion as well as to trigger the EPR effect, but it is able to decrease to smaller size to lower the diffusional hindrance and penetrate into deep tumor tissue, and then becomes even smaller for nuclear entry once internalized by cancer cells.…”

Recent Advances in Targeted Tumor Chemotherapy Based on Smart Nanomedicines

“…It has been widely accepted that many chemotherapeutic drugs need to be localized in subcellular organelles to take action . Nevertheless, both passive and active methods discussed above can only deliver drugs to targeted tissues or cells, but not accurately deliver them into the subcellular organelles.…”

“…It has been widely accepted that many chemotherapeutic drugs need to be localized in subcellular organelles to take action. [78,79] Nevertheless, both passive and active methods discussed above can only deliver drugs to targeted tissues or cells, but not accurately deliver them into the subcellular organelles. Functional peptides such as transactivator of transcription (TAT), [80] nuclear localization sequence (NLS), [81,82] have been proven to hold the capacity of actively transporting cargoes into cell nuclei.…”