Targeting cancer cells by novel engineered modular transporters
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Published on: September 13, 2022
Dinara G Gilyazova1, Andrey A Rosenkranz, Pavel V Gulak
1Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
Abstract:
A major problem in the treatment of cancer is the specific targeting of drugs to these abnormal cells. Ideally, such a drug should act over short distances to minimize damage to healthy cells and target subcellular compartments that have the highest sensitivity to the drug. We describe the novel approach of using modular recombinant transporters to target photosensitizers to the nucleus, where their action is most pronounced, of cancer cells overexpressing ErbB1 receptors. We have produced a new generation of the transporters consisting of (a) epidermal growth factor as the internalizable ligand module to ErbB1 receptors, (b) the optimized nuclear localization sequence of SV40 large T-antigen, (c) a translocation domain of diphtheria toxin as an endosomolytic module, and (d) the Escherichia coli hemoglobin-like protein HMP as a carrier module. The modules retained their functions within the transporter chimera: they showed high-affinity interactions with ErbB1 receptors and alpha/beta-importin dimers and formed holes in lipid bilayers at endosomal pH. A photosensitizer conjugated with the transporter produced singlet oxygen and (*)OH radicals similar to the free photosensitizer. Photosensitizers-transporter conjugates have >3,000 times greater efficacy than free photosensitizers for target cells and were not photocytotoxic at these concentrations for cells expressing a few ErbB1 receptors per cell, in contrast to free photosensitizers. The different modules of the transporters, which are highly expressed and easily purified to retain full activity of each of the modules, are interchangeable, meaning that they can be tailored for particular applications.
Insights
Researchers developed modular transporters to deliver cancer drugs specifically to the nucleus of cancer cells. This novel approach enhances drug efficacy and minimizes damage to healthy cells.
Area of Science:
- Biotechnology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeting cancer drugs specifically to abnormal cells is a significant challenge in cancer treatment.
- Ideal drug delivery systems should minimize damage to healthy tissues and target sensitive subcellular compartments.
Purpose of the Study:
- To develop a novel modular recombinant transporter system for targeted delivery of photosensitizers to the nucleus of cancer cells overexpressing ErbB1 receptors.
- To create a new generation of transporters with specific functional modules for enhanced drug delivery and efficacy.
Main Methods:
- Constructed modular recombinant transporters comprising epidermal growth factor, SV40 nuclear localization sequence, diphtheria toxin translocation domain, and E. coli HMP carrier module.
- Conjugated photosensitizers to the transporter system.
- Evaluated transporter function, including receptor binding, nuclear import, endosomolytic activity, and photosensitizer-mediated radical production.
- Assessed the efficacy and photocytotoxicity of photosensitizer-transporter conjugates in cancer cells.
Main Results:
- The modular transporters successfully targeted ErbB1-overexpressing cancer cells and delivered photosensitizers to the nucleus.
- Transporter modules retained their intended functions, including receptor interaction, nuclear import, and endosomal escape.
- Photosensitizer-transporter conjugates demonstrated over 3,000 times greater efficacy than free photosensitizers.
- Conjugates showed no photocytotoxicity at effective concentrations in cells with low ErbB1 expression, unlike free photosensitizers.
Conclusions:
- Modular recombinant transporters offer a promising strategy for targeted cancer therapy by delivering photosensitizers to the nucleus.
- The interchangeable nature of the transporter modules allows for customization for various applications.
- This approach significantly enhances therapeutic efficacy while improving safety by reducing off-target effects.
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