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Kinetic analysis of cellular internalization and expulsion of unstructured D‐chirality cell penetrating peptides
Author(s) -
Vaithiyanathan Manibarathi,
Hymel Hannah C.,
Safa Nora,
Sanchez Olivia M.,
Pettigrew Jacob H.,
Kirkpatrick Cole S.,
Gauthier Ted J.,
Melvin Adam T.
Publication year - 2021
Publication title -
aiche journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.958
H-Index - 167
eISSN - 1547-5905
pISSN - 0001-1541
DOI - 10.1002/aic.17087
Subject(s) - internalization , endocytosis , chirality (physics) , intracellular , exocytosis , kinetics , chemistry , biophysics , penetration (warfare) , proteolysis , microbiology and biotechnology , biochemistry , cell , secretion , biology , enzyme , chiral symmetry breaking , physics , quantum mechanics , nambu–jona lasinio model , quark , operations research , engineering
Most cell penetrating peptides (CPPs) are unstructured and susceptible to proteolytic degradation. One alternative is to incorporate D‐chirality amino acids into unstructured CPPs to allow for enhanced uptake and intracellular stability. This work investigates CPP internalization using a series of time, concentration, temperature, and energy dependent studies, resulting in a three‐fold increase in uptake and 50‐fold increase in stability of D‐chirality peptides over L‐chirality counterparts. CPP internalization occurred via a combination of direct penetration and endocytosis, with a percentage of internalized CPP expelling from cells in a time‐dependent manner. Mechanistic studies identified that cells exported the intact internalized D‐chirality CPPs via an exocytosis independent pathway, analogous to a direct penetration method out of the cells. These findings highlight the potential of a D‐chirality CPP as bio‐vector in therapeutic and biosensing applications, but also identify a new expulsion method suggesting a relationship between uptake kinetics, intracellular stability, and export kinetics.