Direct Nucleus‐Targeted Drug Delivery Using Cascade pH_e/Photo Dual‐Sensitive Polymeric Nanocarrier for Cancer Therapy

Abstract

The cell nucleus‐targeted delivery of therapeutic agents plays a critical role in cancer therapy, since the biological target of many anticancer therapeutics is the cell nucleus. However, multiple physiological barriers limit the delivery efficiency of free drugs, resulting in unsatisfactory therapeutic effects. Herein, thioketal crosslinked polyphosphoester‐based nanoparticles with a tumor acidity (pHe)‐sensitive transactivator of transcription (TAT) peptide (DA‐masked TAT‐decorating reactive oxygen species (ROS)‐sensitive Ce6/DOX‐loaded hyperbranched nanoparticles (DTRCD)) are explored for cascade nucleus‐targeted drug delivery. Following administration, DTRCD experiences prolonged circulation by masking the targeting effect of its TAT peptide and then achieves enhanced tumor cell uptake and improved translocation into the perinuclear region by reactivating the TAT targeting capability in tumor tissue. Subsequently, ROS generated by DTRCD under 660 nm laser not only disrupts the nuclear membrane to allow entry into the nuclei but also triggers intracellular release of the payload in the nuclei. As evidenced by in vivo experiments, such pHe/photo dual‐sensitive polymeric nanocarriers offer remarkable therapeutic effects, efficiently suppressing tumor growth. This multistage cascade nucleus‐targeted drug delivery concept provides new avenues to develop nucleus‐targeted drug delivery systems.

Photodynamic therapy: photosensitizers and nanostructures

“…In the same direction, the cellular nucleus is one of the most common biological targets for many anticancer therapies. 224 In this context, it is known that some peptides are used as vectors for the mitochondria targeting delivery in cancer stem cells, in which their mitochondrial activity plays a key role, and its regulation has thus been suggested as a new therapeutic strategy to activate cell death. 225 Based on this, the conjugation of both the protoporphyrin IX and PEG with an amphiphilic mitochondria penetrating peptide, forming micelles after self-assembly, is employed for the PDT in mitochondria.…”

Application of Nano-Drug Delivery System Based on Cascade Technology in Cancer Treatment

“…Therefore, in order to improve the anticancer effect, the cascade targeted organelles mainly target the nucleus and mitochondria [ 37 , 41 , 42 , 43 , 44 ]. For example, Cao et al used thioketal crosslinked polyphosphoester (PPE) NPs decorated with a pHe-sensitive transactivator of transcription (TAT) to rationally prepare a pHe/photo dual-sensitive nanocarrier (DA-masked TAT-decorating reactive oxygen species (ROS)-sensitive Ce6/DOX-loaded hyperbranched NPs (DTRCD)), ( Figure 3 ) [ 45 ]. DTRCD prolongs circulation by masking the targeting effect of its TAT peptide, and then reactivates the TAT peptide due to its response to pHe, which further enhances tumor cell uptake and promotes transport to the perinuclear region.…”

“…( B ) Schematic illustration of the cascade nucleus-targeted drug delivery strategy of DTRCD. Adapted from [ 45 ].…”

Recent advances on synthesis and biomaterials applications of hyperbranched polymers

“…Other combination of therapeutic methods, rather than the use of two small molecule drugs, can potentially take advantage of cellular internalization mechanism. Hyperbranched nanoparticles loaded with Chlorin E6 photosensitizers and doxorubicin drug molecules were found to have switchable uptake based on pH, which caused higher tumor selectivity (Cao, Li, Wang, Xiong, & Yang, 2019). Upon pH reactivation, the particles were able to translocate to target the cell nucleus.…”