A pH-Driven Small-Molecule Nanotransformer Hijacks Lysosomes and Overcomes Autophagy-Induced Resistance in Cancer.
A pH-Driven Small-Molecule Nanotransformer Hijacks Lysosomes and Overcomes Autophagy-Induced Resistance in Cancer.
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DOI：
10.1002/anie.202204567
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发表时间：
2022-08-26
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影响因子：
--
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体内超分子结构的智能转换是癌症纳米医学中一种有吸引力的策略，通常通过特定的肽序列来实现。在这里，我们开发了一种溶酶体靶向小分子缀合物 PBC，它在生理 pH 值下自组装成纳米颗粒，并在肿瘤细胞的溶酶体中巧妙地转化为纳米原纤维。这种转变机械地导致溶酶体功能障碍、自噬抑制和异常的细胞质空泡化，从而使 PBC 作为单一疗法具有独特的抗癌活性。重要的是，光激活的 PBC 对溶酶体产生显着的光毒性，并在克服传统光疗中经常出现的自噬引起的治疗抵抗方面显示出巨大的优势。这种改进的光疗法在有限的给药下实现了口腔癌异种移植物的完全治愈。我们的工作为构建具有生物医学活性的非肽纳米变压器提供了新的范例。溶酶体靶向非肽 PBC（脱镁叶绿酸 a-双氨基喹啉缀合物）在生理 pH 值下自组装成纳米颗粒，然后在溶酶体 pH 值触发下转化为纳米原纤维。由于这种形状转变，PBC不仅作为单一药物抑制肿瘤生长，而且还介导方便的光动力疗法，有望克服自噬诱导的抵抗并实现肿瘤消融。
Smart conversion of supramolecular structures in vivo is an attractive strategy in cancer nanomedicine, which is usually achieved via specific peptide sequences. Here we developed a lysosomal targeting small-molecule conjugate, PBC, which self-assembles into nanoparticles at physiological pH and smartly converts to nanofibrils in lysosomes of tumor cells. Such transformation mechanically leads to lysosomal dysfunction, autophagy inhibition, and unusual cytoplasmic vacuolation, thus granting PBC a unique anticancer activity as a monotherapy. Importantly, the photo-activated PBC elicits significant phototoxicity to lysosomes and shows enormous advantages in overcoming autophagy-caused treatment resistance frequently occurring in conventional phototherapy. This improved phototherapy achieves a complete cure of oral cancer xenografts upon limited administration. Our work provides a new paradigm for the construction of nonpeptide nanotransformers with biomedical activities. The lysosomal targeting nonpeptide PBC (pheophorbide a–bisaminoquinoline conjugate) self-assembles into nanoparticles at physiological pH and then transforms into nanofibrils upon the trigger of lysosomal pH. Due to such shape transformation, PBC not only inhibits tumor growth as a single agent but also mediates a convenient photodynamic therapy with promise to overcome the autophagy-induced resistance and achieve tumor ablation.
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影响因子：
14.8
作者：
通讯作者：
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自噬调节和光动力疗法：改善癌症治疗预后的见解。
影响因子：
4.7
作者：
Martins WK;Belotto R;Silva MN;Grasso D;Suriani MD;Lavor TS;Itri R;Baptista MS;Tsubone TM
通讯作者：
Tsubone TM
影响因子：
15
作者：
Pires, Ricardo A.;Abul-Haija, Yousef M.;Pashkuleva, Iva
通讯作者：
Pashkuleva, Iva
DOI：
10.1073/pnas.1118193109
发表时间：
2012-05-22
影响因子：
11.1
作者：
McAfee, Quentin;Zhang, Zhihui;Amaravadi, Ravi K.
通讯作者：
Amaravadi, Ravi K.
影响因子：
19
作者：
Lin, Kai;Ma, Zhao;Li, Yuanpei
通讯作者：
Li, Yuanpei