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Updated: Mar 26, 2026
A Direct Force Probe for Measuring Mechanical Integration Between the Nucleus and the Cytoskeleton
Published on: July 29, 2018
An in vitro investigation of a detachable fork-like structure as efficient nuclear-targeted sub-unit in A2780 cell
1Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
Abstract:
The pharmacological target of many anticancer drugs is those molecules associated with genetic information which are localized in nucleus. To efficiently deliver drugs into cancer cell nucleus, in our previous study, a fork-like sub-unit, with one end conjugated with a targeting peptide named R8NLS (CRRRRRRRRPKKKRKV) and the other end conjugated with c-Myc oncogene inhibitor H1-S6A,F8A (H1) peptide, was linked onto the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer via an enzyme degradable glycylphenylalanylleucylglycine (GFLG) tetrapeptide spacer. Here, an in vitro mechanism investigation of the fork-like sub-unit was studied in detail. We found that the fusion with two complementary R8 and NLS motifs is required to exert the multifunctional targeting capability of the tandem R8NLS peptide in overcoming various intracellular barriers, including enhancing cellular uptake, facilitating endosomal escape and penetrating through the double-layered nuclear membrane. Also required is the tactful detachment of the fork-like sub-unit from the copolymer in response to intracellular stimulus, because a smaller sub-unit not only increases the intracellular trafficking efficiency by reducing the size burden of magical bullet R8NLS, but also guarantees successful entry through the restricted nucleopore. Herein, this study highlights that both nuclear targeting ligand R8NLS and detachable fork-like sub-unit are dispensable for programmed nuclear delivery and may show feasibility on other drug delivery systems, such as nanoparticles and micelles.
Insights
This study reveals that a detachable, fork-like subunit is essential for delivering anticancer drugs to the cell nucleus. This novel approach enhances drug targeting and nuclear entry by overcoming intracellular barriers.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Molecular Biology
Background:
- Many anticancer drugs target nuclear genetic material.
- Efficient delivery to the cancer cell nucleus remains a challenge.
- Previous work developed a fork-like subunit for drug delivery.
Purpose of the Study:
- To investigate the in vitro mechanism of a fork-like subunit for nuclear drug delivery.
- To understand the role of R8NLS peptide motifs and subunit detachment.
- To assess the subunit's potential for enhancing nuclear targeting of anticancer agents.
Main Methods:
- In vitro mechanism investigation of a novel fork-like subunit.
- Conjugation of R8NLS peptide and c-Myc inhibitor (H1) to an HPMA copolymer via a GFLG spacer.
- Analysis of cellular uptake, endosomal escape, and nuclear membrane penetration.
Main Results:
- The fusion of R8 and NLS motifs in R8NLS is crucial for multifunctional targeting.
- The R8NLS peptide enhances cellular uptake, endosomal escape, and nuclear entry.
- Detachment of the subunit from the copolymer is vital for efficient nuclear pore passage.
Conclusions:
- Both the R8NLS nuclear targeting ligand and the detachable fork-like subunit are critical for programmed nuclear delivery.
- This strategy shows promise for improving nuclear drug delivery systems.
- The findings have implications for nanoparticles and micelle-based drug delivery systems.
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