Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide.,Molecular Pharmaceutics

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Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-13 , DOI: 10.1021/acs.molpharmaceut.9b00883
Alexander A Svoronos , Raman Bahal ₁ , Mohan C Pereira ₂ , Francisco N Barrera ₃ , John C Deacon , Marcus Bosenberg , Daniel DiMaio , Peter M Glazer , Donald M Engelman

Affiliation

Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, "drug-like" molecules. Here, we explore the ability of a tumor-targeted delivery system centered on the use of a pH-low insertion peptide (pHLIP) to directly deliver moderately polar, multi-kDa molecules into tumor cells. A pHLIP is a short, pH-responsive peptide capable of inserting across a cell membrane to form a transmembrane helix at acidic pH. pHLIPs target the acidic tumor microenvironment with high specificity, and a drug attached to the inserting end of a pHLIP can be translocated across the cell membrane during the insertion process. We investigate the ability of wildtype pHLIP to deliver peptide nucleic acid (PNA) cargoes of varying sizes across lipid membranes. We find that pHLIP effectively delivers PNAs up to ∼7 kDa into cells in a pH-dependent manner. In addition, pHLIP retains its tumor-targeting capabilities when linked to cargoes of this size, although the amount delivered is reduced for PNA cargoes greater than ∼6 kDa. As drug-like molecules are traditionally restricted to sizes of ∼500 Da, this constitutes an order-of-magnitude expansion in the size range of deliverable drug candidates.

中文翻译：

使用低pH插入肽对大分子极性的肿瘤靶向细胞质传递。

靶向肿瘤的药物递送系统不仅提供了增强的治疗指数的优势，而且还克服了将药物设计很大程度上限制于小的疏水性“药物样”分子的局限性的可能性。在这里，我们探讨了以低pH插入肽（pHLIP）为中心的靶向肿瘤的递送系统将中等极性的多kDa分子直接递送至肿瘤细胞的能力。pHLIP是一种短的pH响应肽，能够在酸性pH下插入细胞膜以形成跨膜螺旋。pHLIPs以高特异性靶向酸性肿瘤微环境，并且在插入过程中，附着在pHLIP插入端的药物可以跨细胞膜移位。我们调查野生型pHLIP跨脂质膜传递大小不同的肽核酸（PNA）货物的能力。我们发现pHLIP以pH依赖的方式有效地将高达约7 kDa的PNA传递到细胞中。此外，尽管与这种大小的货物连接时，pHLIP仍保留了其靶向肿瘤的能力，尽管对于大于约6 kDa的PNA货物，其递送量有所减少。由于传统上将类药物分子的大小限制在〜500 Da之内，因此这构成了可交付药物候选物大小范围的数量级扩展。尽管对于大于约6 kDa的PNA货物，交付量有所减少。由于传统上将类药物分子的大小限制在〜500 Da之内，因此这构成了可交付药物候选物大小范围的数量级扩展。尽管对于大于约6 kDa的PNA货物，交付量有所减少。由于传统上将类药物分子的大小限制在〜500 Da之内，因此这构成了可交付药物候选物大小范围的数量级扩展。

更新日期：2020-01-14

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