Yu Zhilin research group of Nankai University: cell microenvironment adaptive peptide nanostructure for tumor treatment

In view of the good biocompatibility and potential protein biological function of peptide molecules, Yu Zhilin research group of School of chemistry, Nankai University has been engaged in exploring the establishment of new mechanism of peptide assembly and developing functional materials of peptide supramolecular polymers for a long time In order to solve the problem of unclear conformation in the sequence design of controllable self-assembly of polypeptide, the research group proposed the assembly strategy of designing polypeptide modules based on the establishment of the interaction interface of polypeptide units, so as to improve the efficiency of polypeptide self-assembly design This assembly strategy classifies different peptide assembly blocks from the thermodynamics of driving assembly, which is helpful to understand and design peptide nanostructures with single or different conformation segments, and to promote the precise synthesis of peptide supramolecular polymers and the development of peptide functional materials Under the guidance of this strategy, the research group constructed a pH responsive CIS trans isomerization regulated pentapeptide assembly, and constructed a tumor microenvironment responsive adaptive nanodrug system (TMAs), which was used to improve drug delivery and enhance photodynamic therapy Nanodrugs have been widely used in cancer treatment due to their good pharmacokinetics and tumor targeting However, a large number of clinical trials show that the delivery efficiency of nanodrugs still needs to be improved Although the existing strategies can use different responsive mechanisms to regulate drug delivery, it is still challenging to optimize drug cell uptake in all stages of the delivery process, including prolonging drug blood circulation, increasing tumor site accumulation, promoting deep penetration of tumor tissue, and ultimately enhancing drug retention in cancer cells The TMAs system constructed by the research group exists in the blood vessels with high aspect ratio super helix structure to improve blood circulation, while the weak acidic characteristics of tumor microenvironment induce the morphological transformation of TMAs system to generate nanoparticles, promote tumor infiltration and cell uptake, and finally achieve the formation of nanofibers in the cytoplasm to improve cell retention, so as to comprehensively optimize drug delivery Inspired by the conformational transition caused by the CIS trans isomerization of proline amide bond in natural proteins, this work uses the solid-phase synthesis method to prepare the pentapeptide FF amp FF molecule (AMPF) containing 4-aminoproline, in which the proline amide bond can effectively change the interaction interface of peptides, and then regulate the nanostructure characteristics of peptides When the pH value of the solution is adjusted repeatedly to between neutral and weak acid, the pro amide bond will undergo CIS trans isomerization, and then induce the pentapeptide AMPF to carry out super spiral structure and reversible self-assembly of nanoparticles This method is different from the classical non covalent interaction in the way of conformational regulation The CIS trans isomerization of amide bond is highly sensitive to the conformational regulation of polypeptide and easy to detect quantitatively, which promotes the establishment of a functional nanostructure system of polypeptide with a clear structure-activity relationship Subsequently, the TMAs system was established by CO assembly of AMPF and its derivative (ampf-c) containing photosensitizer chlorin E6 In the cell uptake pathway, the system changes in morphology to adapt to the change of pH gradient during cell uptake The results showed that TMAs could prolong the circulation time and improve the accumulation of tumor site In addition to the optimization of cell absorption, the morphological transformation of TMAs system can further improve the level of intracellular ROS, so as to improve the therapeutic effect of PDT tumor Therefore, TMAs system is expected to provide new ideas for drug delivery system of cancer treatment in the future Relevant works were published in advanced science (DOI: 10.1002 / advs 201802043) and nano respectively with titles of "ptide tectonics: encoded structural completionaritydictates programmable self assembly" and "line isomerization regulated tumor microenvironment adaptive self assembly of peptides for enhanced theoretical efficiency" Letters （ DOI: 10.1021/acs.nanolett.9b03136）。 The work of the research group was supported by the National Natural Science Foundation, Tianjin Natural Science Foundation and related funds of Nankai University