Systemicin vivodistribution of activatable cell penetrating peptides is superior to that of cell penetrating peptides

In this report we describe in vivo pharmacokinetic and toxicity problems of cell penetrating peptides and show that many of them can be ameliorated by conversion to activatable CPPs

Todd A. Aguilera

2009

Scholarcy highlights

  • Most published successes have been on model membranes or cells in culture, though clinically relevant delivery of drugs or contrast agents will require in vivo efficacy
  • In this report we describe in vivo pharmacokinetic and toxicity problems of cell penetrating peptides and show that many of them can be ameliorated by conversion to activatable CPPs
  • In order for the e9 domain of an ACPP to block cell uptake of the r9 CPP that could be restored following proteolysis, the r9 must be intramolecularly complexed with the e9 while the linker is intact, which means that the dissociation constant of a bimolecular e9-r9 complex, Kd, should be much less than the effective molarity imposed by the linker
  • To more clearly understand the pharmacokinetics, the % injected dose can be calculated from the measured standardized uptake value in the liver and kidney, which revealed a significant difference between the CPP and ACPP distribution 30 minutes after injection and at 6 hours
  • Our initial publication demonstrated the basic feasibility of ACPPs but left many questions unanswered, some of which we address here
  • Our previous paper showed cells in 2-D culture with diffuse cytosolic and nuclear uptake of pre-cleaved activatable CPPs, subsequent experiments in 3-D cultures and tumors in vivo have consistently revealed that practically all the visible fluorescence comes from perinuclear punctae, presumably endosomes

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