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跨膜输送分子奇兵
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细胞膜是将细胞区别于周围化学环境中重要屏障，但作为一种生命现象，与周围进行物质和信息交换又是生存的必须条件，那么作为屏障的细胞膜必须具有各类与周围环境进行物质信息交换的方式途径。在探索治疗疾病药物过程中，科学家不可避免地遇到这样的尴尬局面，有一些分子能在细胞内发挥作用，但这些分子因为属于被细胞膜屏障的类型，不能依靠普通的途径进入细胞内，于是科学家就设想出各种方法解决这个问题。机体中的一些特殊屏障例如血脑屏障也存在类似的情况。
这类方法已经有许多，例如可通过一些病毒的特殊感染细胞跨域细胞膜的能力，如艾滋病病毒就具有这样的能力，当然在具体应用中，并不是使用整个病毒，只需要把其中跨域细胞膜的一个蛋白，或一个片段拿来作为工具就可以解决问题。也可以利用身体内本来就存在的转运系统，例如不久前，科学家利用转铁蛋白的功能，通过这种蛋白的抗体和装铁蛋白结合将目标分子偷渡到大脑内。最近又有学者采用另外一种分子，这种分子具有在酸性环境下变构的特点，可以将一些分子转移到细胞内，这种酸诱导变构分子早就已经发现，但最新研究有两个比较好的亮点，一个是利用肿瘤细胞普遍利用无氧代谢，酸性比较大的特点，例外一个是将最新关于MicroRNAs的研究结合起来，将具有对抗肿瘤特种癌基因分子的antimiR送到肿瘤细胞内，这样的研究解决了两个关键问题，一个是将难以渗透入细胞的RNA分子利用特定工具输送到特定肿瘤细胞内，另外一个是利用肿瘤组织酸性的特点将这种分子定向运输，达到靶向治疗的目的，而这种靶向具有鲜明的细胞特征性靶向，而不是简单的组织靶向。
其实利用这个思路也可以进行其他疾病的治疗，例如组织缺血后局部必然存在缺氧导致的代谢性酸中毒趋势，那么利用这种酸诱导蛋白也可以将一些能对抗组织缺氧或炎症的目标组织发生损伤反应，或者利用这种工具作为一种定向对抗酸中毒的手段，或许对解决特定细胞的代谢性紊乱提供一种特殊的方法。
a, Workflow for treatment of the mir-155LSLtTA subcutaneous flank model for the early endpoint and survival studies; day 1 indicates time of first injection. For the ‘early treatment’ experiments in Fig. 3a, b, d–f, h and Extended Data Fig. 5b, c, mice were treated on days 1 and 2 with pHLIP-anti155, mock buffer, pHLIP-antiscr and anti155 only; fed DOX starting on day 3; or treated with CHOP regimen on days 2–4. For survival experiments in Fig. 3c, g and Extended Data Fig. 5a, mice were treated on days 1–3 with pHLIP-anti155, LNA against miR-155, and mock buffer. b, Workflow for investigation of the mir-155LSLtTA model of lymphoma for the biodistribution and miR-155 silencing studies. For experiments in Fig. 4a and Extended Data Fig. 8a, b, mice were treated on day 1 with pHLIP-anti155, anti155 only, and mock buffer. For experiments in Fig. 4b–d, h and Extended Data Fig. 8c–g, mice were treated on day 1 and day 3 with pHLIP-anti155, pHLIP-antiscr, and mock buffer, or fed DOX 16 h before harvest.
MicroRNAsare short non-coding RNAs expressed in different tissue and cell types thatsuppress the expression of target genes. As such, microRNAs are critical cogsin numerous biological processes1, 2, and dysregulated microRNA expression iscorrelated with many human diseases. Certain microRNAs, called oncomiRs, play acausal role in the onset and maintenance of cancer when overexpressed. Tumoursthat depend on these microRNAs are said to display oncomiR addiction3, 4, 5.Some of the most effective anticancer therapies target oncogenes such as EGFRand HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is,antimiRs) is an evolving therapeutic strategy6, 7. However, the in vivoefficacy of current antimiR technologies is hindered by physiological andcellular barriers to delivery into targeted cells8. Here we introduce a novelantimiR delivery platform that targets the acidic tumour microenvironment,evades systemic clearance by the liver, and facilitates cell entry via anon-endocytic pathway. We find that the attachment of peptide nucleic acidantimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP)produces a novel construct that could target the tumour microenvironment,transport antimiRs across plasma membranes under acidic conditions such asthose found in solid tumours (pH approximately 6), and effectively inhibit themiR-155 oncomiR in a mouse model of lymphoma. This study introduces a new modelfor using antimiRs as anti-cancer drugs, which can have broad impacts on thefield of targeted drug delivery.
a, Intravenous injection of A750-pHLIP distributes to the (white arrow) kidneys and (blue arrow) tumour in a representative mir-155LSLtTA subcutaneous flank model (n = 3); time points indicate hours after a single injection of A750-pHLIP. Previous reports have observed systemic distribution of pHLIP to kidneys in other mouse models15. Similarly, we speculate that the increased uptake of pHLIP peptide in the kidneys is due to excretion and increased acidity of renal tubule cells. Initially kidneys are highly enriched for pHLIP, which is gradually excreted while pHLIP shows a more steady accumulation in the tumour. b, Representative example showing A750-pHLIP distribution to the (white arrow) bladder and (yellow arrow) enlarged axillary lymph node 36 h after intravenous administration into mir-155LSLtTA mice with lymphadenopathy (n = 3). c, In addition to distributing to the (white arrow) primary mir-155LSLtTA flank tumour and (red arrow) kidneys, A750-pHLIP distributes to (black arrows) enlarged lymph nodes that resulted from metastatic spread; intravital fluorescence of A750-pHLIP was detected 48 h after intravenous injection into nude transplant mice with conspicuous lymphadenopathy (a representative animal from n = 3 is shown).
看C这治疗效果，是不是让人觉得神奇？
a, Organomegaly in representative diseased mir-155LSLtTA mice: top, conspicuous lymphadenopathy seen in the (black arrow) cervical and (white arrow) brachial lymph nodes; middle, enlarged exposed (white arrows) cervical and (black arrows) axillary lymph nodes; bottom, enlarged (black arrows) spleen. b, Histopathology of mir-155LSLtTA mice: H&E stain of an enlarged spleen shows expansion of the white pulp by a nodular, neoplastic infiltrate; staining of the spleen shows CD20+ and CD10+ B cells of follicular centre origin. Analysis of enlarged lymph nodes indicates DLBCL with lymph node architecture effaced by a confluent population of B220+ neoplastic lymphocytes and a Ki-67 proliferative index at nearly 100%; n = 5. c, Tumour regression due to DOX-induced miR-155 withdrawal in a subcutaneous tumour model established from transplanted splenic mir-155LSLtTA lymphocytes; time points indicate hours after initial administration of DOX. With a cancer phenotype that is relevant to human disease yet can be modulated by miRNA silencing, this is an excellent model for evaluating miR-155-targeted therapies.
https://blog.sciencenet.cn/blog-41174-844224.html
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