“pH-sensitive interpolyelectrolyte complexes based on methacrylated chitosan and heparin for intracellular delivery of therapeutic genetic constructs”

  • Хазанова, Марина Александровна (PI)

Project: Grant fulfilmentTotal grant fulfilment

Project Details

Description

Today, gene therapy is a promising treatment for many incurable diseases such as cancer and various genetic diseases.
The main problem limiting the application of this strategy in vivo is the difficulty of delivering large, environmentally sensitive and negatively charged molecules to cells, while preventing their degradation. In addition, therapeutic polynucleotides itself can have toxic effects on healthy cells. Therefore, the need to develop safe and efficient delivery systems becomes apparent. Such delivery systems should protect therapeutic polynucleotides from the aggressive environment of the organism and systemic distribution before penetration into the intracellular space of the target cells, and then begin to rapidly release the drug. To do this, it is necessary to develop special “smart” systems that are sensitive to external stimuli.
One of the ways to achieve a "trigger" release of the cellular environment is a method based on the use of stimulus-sensitive nanocarriers - which are nanoscale means of active delivery of drugs, equipped with a molecular mechanism of "release of the load".
Nanogels based on interpolyelectrolyte complexes of poly-L-lysine (PLL) with heparin, modified by a photosensitive linker that breaks down in the presence of near-infrared (NIR) radiation with a wavelength center of 980 nm were used in our previous research work G-RISC (the research was carried out in collaboration with Research Group Scheper, institute of Technical Chemistry University of the Leibniz University Hannover). The formation of nanogels was primarily based on electrostatic interactions with the formation of nanosized hydrogel particles.
Another promising area for the development of "smart" nanomaterials is the development of materials that are sensitive to the action of pH. Differences in pH are observed in biological systems at both the cellular and systemic levels. These extracellular and intracellular pH gradients can be used to design drug delivery systems that selectively release the transported drug at a specific site of action.
To create improved systems, it was decided to develop and implement a strategy of covalent crosslinking of interpolyelectrolyte complexes (IPEC) based on chitosan and heparin methacrylates using thiolene "click" chemistry. The use of a specially synthesized pH-sensitive ketal cross-linking agent will make it possible to obtain systems that are stable in the extracellular environment, but capable of degradation and release inside cells, namely at acidic pH.After subjection to stimulus, which leads to the linker degradation, heparin should get more mobility and start to compete with polynucleotide for electrostatic and electrostatic interactions. Being strong polyelectrolyte, heparin should push nucleic acid out of complex. Intracellular acidic pH could be used as release triggering stimulus.
The entire chemical part of the work will be performed at the Laboratory of Biomedical Chemistry of the Institute of Chemistry of St. Petersburg State University (LabBiomedChem IC SPbU) prior to the applicant's arrival. The biological part of the project will implemented in cooperation with IInstitute of Technical Chemistry University of the Leibniz University Hannover (ITC UH), under the GRISC program. Many years of fruitful cooperation with ITC UH and the highly developed infrastructure of this university allow us to count on excellent results of this study.
Short title"pH-sensitive interpolyelectrolyte complexes based on methacrylated chitosan and heparin for intracellular delivery of nucleic acids”
AcronymGRISC 2021 1
StatusNot started

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