Drug delivery, biodistribution and anti-EGFR activity: theragnostic nanoparticles for simultaneous in vivo delivery of tyrosine kinase inhibitors and kinase activity biosensors.
Drug delivery, biodistribution and anti-EGFR activity: theragnostic nanoparticles for simultaneous in vivo delivery of tyrosine kinase inhibitors and kinase activity biosensors.
复制标题
DOI：
10.1039/d1nr02770k
复制
发表时间：
2021-11-18
期刊：
影响因子：
6.7
通讯作者：
Tabor AB
中科院分区：
文献类型：
--
作者：
Bofinger R;Weitsman G;Evans R;Glaser M;Sander K;Allan H;Hochhauser D;Kalber TL;Årstad E;Hailes HC;Ng T;Tabor AB
小分子治疗剂向癌细胞的体内递送、给药选择性的评估以及在分子水平上测量所讨论的药物的功效是开发新类别的癌症化疗剂的重要持续挑战。具有提供靶向递送、跟踪生物分布和读出功效的潜力的一种方法是使用多模态治疗不可知纳米颗粒来递送小分子治疗剂。在本文中，我们报告了靶向治疗诊断脂质/肽/DNA脂质复合物的发展。这些同时递送EGFR酪氨酸激酶的抑制剂和编码基于Crk的生物传感器Picchu-X的质粒DNA，当在靶细胞中表达时，其可用于在小鼠结肠直肠癌异种移植模型中定量体内EGFR的抑制。酪氨酸激酶抑制剂Mo-IPQA的已知类似物与阳离子肽的可逆生物缀合，以及与含有EGFR结合序列和阳离子序列的肽的共制剂，允许良好水平的抑制剂包封，并靶向递送至LIM 1215结肠癌细胞。此外，Picchu-X生物传感器在LIM 1215细胞中的体内高水平表达使我们能够使用基于荧光寿命显微镜（FLIM）的生物传感来证明，EGFR活性可以被从脂质复合物释放的酪氨酸激酶抑制剂成功抑制。最后，我们测量了含有125 I标记的抑制剂的lipopolyplexes的生物分布，并且能够证明与游离药物相比，lipopolyplexes向肿瘤提供了显著更高的药物递送。我们报告的发展目标theragnostic脂质/肽/DNA lipopolyplexes提供的酪氨酸激酶抑制剂，和质粒DNA编码的生物传感器。这些用于定量体内癌细胞系中的EGFR抑制。
In vivo delivery of small molecule therapeutics to cancer cells, assessment of the selectivity of administration, and measuring the efficacity of the drug in question at the molecule level, are important ongoing challenges in developing new classes of cancer chemotherapeutics. One approach that has the potential to provide targeted delivery, tracking of biodistribution and readout of efficacy, is to use multimodal theragnostic nanoparticles to deliver the small molecule therapeutic. In this paper, we report the development of targeted theragnostic lipid/peptide/DNA lipopolyplexes. These simultaneously deliver an inhibitor of the EGFR tyrosine kinase, and plasmid DNA coding for a Crk-based biosensor, Picchu-X, which when expressed in the target cells can be used to quantify the inhibition of EGFR in vivo in a mouse colorectal cancer xenograft model. Reversible bioconjugation of a known analogue of the tyrosine kinase inhibitor Mo-IPQA to a cationic peptide, and co-formulation with peptides containing both EGFR-binding and cationic sequences, allowed for good levels of inhibitor encapsulation with targeted delivery to LIM1215 colon cancer cells. Furthermore, high levels of expression of the Picchu-X biosensor in the LIM1215 cells in vivo allowed us to demonstrate, using fluorescence lifetime microscopy (FLIM)-based biosensing, that EGFR activity can be successfully suppressed by the tyrosine kinase inhibitor, released from the lipopolyplexes. Finally, we measured the biodistribution of lipopolyplexes containing 125I-labelled inhibitors and were able to demonstrate that the lipopolyplexes gave significantly higher drug delivery to the tumors compared with free drug. We report the development of targeted theragnostic lipid/peptide/DNA lipopolyplexes for delivery of both a tyrosine kinase inhibitor, and plasmid DNA coding for a biosensor. These are used to quantify EGFR inhibition in cancer cell lines in vivo.
登录
查看更多内容
影响因子：
5.4
作者：
Genta I;Chiesa E;Colzani B;Modena T;Conti B;Dorati R
通讯作者：
Dorati R
DOI：
10.1002/psc.3131
发表时间：
2018-12
期刊：
Journal of peptide science : an official publication of the European Peptide Society
影响因子：
--
作者：
Bofinger R;Zaw-Thin M;Mitchell NJ;Patrick PS;Stowe C;Gomez-Ramirez A;Hailes HC;Kalber TL;Tabor AB
通讯作者：
Tabor AB
DOI：
10.1007/978-1-60761-461-6_7
发表时间：
2010-01-01
期刊：
T-CELL TRAFFICKING: METHODS AND PROTOCOLS
影响因子：
--
作者：
Carlin, Leo M.;Makrogianneli, Konstantina;Ng, Tony
通讯作者：
Ng, Tony
影响因子：
8
作者：
Bozzuto G;Molinari A
通讯作者：
Molinari A
DOI：
10.3390/molecules25235672
发表时间：
2020-12-01
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Almeida B;Nag OK;Rogers KE;Delehanty JB
通讯作者：
Delehanty JB