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    Home > Active Ingredient News > Antitumor Therapy > Nat Nanotechnol South China University of Technology, multi-unit cooperation, Wang Jun/Xiong Menghua/Bao Yan/Xiao Shiyan to develop pH-sensitive nanoscale detergent for cancer treatment

    Nat Nanotechnol South China University of Technology, multi-unit cooperation, Wang Jun/Xiong Menghua/Bao Yan/Xiao Shiyan to develop pH-sensitive nanoscale detergent for cancer treatment

    • Last Update: 2022-04-27
    • Source: Internet
    • Author: User
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    iNature plasma membrane disruption is a promising strategy for the treatment of drug-resistant cancers, but its application is limited by the low tumor selectivity of membrane-lytic molecules
    .

    On March 24, 2022, Wang Jun, Xiong Menghua of South China University of Technology, Bao Yan of Sun Yat-Sen University, and Xiao Shiyan of University of Science and Technology of China published a joint communication online in Nature Nanotechnology (IF=39) entitled "A transistor-like pH-sensitive nanodetergent for Selective Cancer Therapy" research paper, which reports the design of "proton transistor" nanodetergents that can convert subtle pH perturbation signals in tumor tissue into membrane lytic activity signals for selective cancer therapy
    .

    The study found that the best performing "proton transistor" nanoscale detergent, P(C6-Bn20), can achieve >32-fold change in cytotoxicity at 0.
    1 pH input signal
    .

    At physiological pH, P(C6-Bn20) self-assembles into neutral nanoparticles with deblocking of an inactive membrane shielded by a poly(ethylene glycol) shell, showing low toxicity
    .

    Under acidic conditions of the tumor, a sharp transition of its protonation state induces morphological transition and activation of membrane deblocking, and cation-π interactions promote the insertion of benzyl-containing hydrophobic domains into the cell membrane, resulting in efficient membrane dissociation activity
    .

    P(C6-Bn20) was well tolerated in mice and showed high antitumor efficacy in various mouse tumor models
    .

    Plasma membrane rupture (PMR)-induced cell death typically bypasses the intracellular signaling pathways of target cells, ignoring their drug resistance spectrum and metabolic heterogeneity, opening up promising strategies for the treatment of drug-resistant pathogen infections and cancer
    .

    Membrane-solubilizing molecules, such as host defense proteins/peptides and cationic polymers, often have common amphiphilic structures including cationic and hydrophobic moieties
    .

    Cationic residues induce strong electrostatic attraction to the negatively charged cell membranes of bacteria and cancer cells, followed by insertion of hydrophobic regions into phospholipid bilayers, inducing detergent-like membrane breakdown
    .

    However, the amphiphilic structure is also the main reason for their high toxicity to normal tissues/cells
    .

    Therefore, the key to the application of membrane-dissociated molecules is to achieve high selectivity for target cells while minimizing their toxicity to normal tissue cells
    .

    The delicate balance of physicochemical parameters of amphiphilic structures, such as cationicity (net charge), hydrophobicity, amphiphilicity and structural propensity, due to the large differences in the structure and composition of cell membranes between pathogenic microorganisms and mammalian cells, Ability to develop membrane-degrading molecules with high selectivity for pathogens
    .

    In addition, the researchers developed selective membrane disintegrating molecules whose functional domains are activated in response to significantly different microenvironments of infected tissues, such as high concentrations of bacterial enzymes, and in response to gastric acidity (pH < 5.
    0)
    .

    However, in the presence of subtle differences between tumor tissues/cells and normal tissues/cells, it is a challenge to achieve highly selective membrane-solubilizing molecules for cancer therapy
    .

    Here, we design a library of "proton transistor" nanoscale detergents (pTNTs) that can amplify subtle pH perturbation signals and translate them into dramatic changes in membrane solubilization activity, resulting in mildly acidic (~pH 7.
    0) –6.
    5) [compared to physiological pH (~pH 7.
    4)] to achieve selective PMR in the tumor microenvironment
    .

    pTNT consists of a poly(ethylene glycol) (PEG) block and a pH-responsive membrane deblock (MB) containing an ionizable tertiary amine fragment (ethylpiperidine (C6)) and a hydrophobic fragment
    .

    These pTNTs exhibited a sharp transition in membrane-decomposing activity at transition pH (pHt), which could be controlled by adjusting the species and molar fraction of hydrophobic segments
    .

    Construction of pTNTs (figure from Nature Nanotechnology) In high pH environments (pH > pHt), pTNTs self-assembled into neutral nanoparticles with inactive MBs, in which most of the tertiary amines were deprotonated and hydrophobic, surrounded by PEG shells.
    The shielding is in the dense core, resulting in minimal membrane-dissolving activity (“off” state)
    .

    In a low pH environment (pH < pHt), pTNTs are converted into cationic nanoparticles or polymer chains containing activated MBs after a dramatic increase in C6 protonation, leading to efficient membrane dissociation activity (‘ON’ state)
    .

    This study screened and identified the optimal pTNT P(C6-Bn20) with minimal toxicity at physiological pH (pH 7.
    4) and high toxicity at tumor acidity (pH 6.
    8)
    .

    Then, the pH-dependent structure and activity characteristics of P(C6-Bn20) were investigated in vitro
    .

    Finally, the antitumor efficacy and biocompatibility of P(C6-Bn20) were evaluated in a mouse model
    .

    All these experiments showed that pTNT was able to achieve selective PMR in acidic tumor tissues
    .

    This study provides a way to design selective anticancer drugs that specifically induce tumor PMR
    .

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