Nuclear Targeted Nano Drug Carrier

Posted by beauty33 on April 23rd, 2021

The nucleus is the place where the genetic material in the cell is stored, copied and transcribed, and plays an important role in the metabolism, growth and differentiation of the cell. Therefore, the nucleus is also the site of action for various drugs such as DNA, intercalators, alkylating agents, and topoisomerase inhibitors. The nuclear membrane is composed of two layers of membranes on which nuclear pore complexes (NPCS) exist. The nuclear membrane will disappear only when the cell undergoes mitosis. In other cases, the only way for large molecules to enter the nucleus is the nuclear pore complex, which allows particles with a diameter of 9 nm or molecules with a molecular mass below 40 to 45 kDa to freely enter and exit; while ribozymes synthesized by ribosomes, nuclear RNA, and other molecules and nanoparticles need to be connected to the nuclear localization signal (NLS) to enter and exit the nucleus through active transport. The diffusion rate of the microparticle system in the viscous cytoplasm is very slow. The cells transfer the DNA-containing microparticle system around the nucleus through an active transport system such as a microtubule network structure or actin filaments.

Figure 1. How Successful is Nuclear Targeting by Nanocarriers?

The nuclear localization signal is a signal sequence at the C-terminus of nuclear cytoplasmic protein, and generally contains 4 to 8 amino acids. One or more NLSs form an NPC targeting complex. This complex is recognized by the import protein family and then enters the nucleus through an energy-dependent mechanism. The NLS required for different transport substances is different, but these signals have a positively charged peptide core. The first identified NLS is the viral SV40 T antigen, which is a protein necessary for viral DNA to replicate in the nucleus. The superparamagnetic iron oxide nanoparticles with NLS on the surface are stronger than the control signal in the cytoplasm and nucleus. Modified PLGA nanoparticles with quantum dots are used for intracellular tracing; when comparing the ability of two NLS-mediated nanoparticles to enter the nucleus, it is found that although the SV40T antigen-modified nanoparticles significantly improved the cytoplasmic uptake of QD-PLGA nanoparticles, no nanoparticles were found in HeLa cell nucleus, and the nanoparticles modified by adenovirus fibrin not only efficiently entered the cytoplasm, but also concentrated in the nucleus.

The penetrating peptide can increase the drug concentration in the nucleus while increasing the concentration of the intracellular carrier. The gold nanoparticles on the surface are protected by Tiopronin chain, and then are covalently bonded with functional TAT peptide on the protective chain; it is difficult to find nanoparticles with only protective chain in human fibroblasts, but nanoparticles with functional chain not only can be transported into the cell, but are also widely distributed in the nucleus. Therefore, with the help of nanoparticles modified by penetrating peptides and nuclear localization signals, drugs targeting the nucleus can smoothly reach the nucleus and be enriched there to play a role.

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