A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy

Pharmaceutics

Camilo Torres¹  Valentina Palacio-Castañeda¹  Roland Brock¹  Wouter P. R. Verdurmen¹  Stéphanie Descroix²  Simon Dumas² 

[1] Department of Biochemistry, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands;Physico-Chemistry Curie, Institut Curie, PSL Research University, CNRS UMR168, Sorbonne University, 75005 Paris, France;

关键词: binding-site barrier;    drug delivery modelling;    cytosolic protein delivery;    peptide delivery;    targeted protein degradation;    cancer therapy;   

DOI  :  10.3390/pharmaceutics13040562

来源: DOAJ

【 摘 要 】

The ability to specifically block or degrade cytosolic targets using therapeutic proteins would bring tremendous therapeutic opportunities in cancer therapy. Over the last few years, significant progress has been made with respect to tissue targeting, cytosolic delivery, and catalytic inactivation of targets, placing this aim within reach. Here, we developed a mathematical model specifically built for the evaluation of approaches towards cytosolic protein delivery, involving all steps from systemic administration to translocation into the cytosol and target engagement. Focusing on solid cancer tissues, we utilized the model to investigate the effects of microvascular permeability, receptor affinity, the cellular density of targeted receptors, as well as the mode of activity (blocking/degradation) on therapeutic potential. Our analyses provide guidance for the rational optimization of protein design for enhanced activity and highlight the importance of tuning the receptor affinity as a function of receptor density as well as the receptor internalization rate. Furthermore, we provide quantitative insights into how enzymatic cargoes can enhance the distribution, extent, and duration of therapeutic activity, already at very low catalytic rates. Our results illustrate that with current protein engineering approaches, the goal of delivery of cytosolic delivery of proteins for therapeutic effects is well within reach.

【 授权许可】

Unknown