Acid-Active Cell-Penetrating Peptides for in Vivo Tumor-Targeted Drug Delivery

Abstract

Cell-penetrating peptides (CPPs) such as transactivator of transcription (TAT) peptide have long been explored for promoting in vitro cell penetration and nuclear targeting of various cargos, but their positive charges cause strong nonspecific interactions, making them inapplicable for many in vivo applications. In this work, we used TAT to demonstrate a molecular modification approach for inhibiting nonspecific interactions of CPPs in the bloodstream while reactivating their functions in the targeted tissues or cells. The TAT lysine residues' amines were amidized to succinyl amides ((a)TAT), completely inhibiting TAT's nonspecific interactions in the blood compartment; once in the acidic tumor interstitium or internalized into cell endo/lysosomes, the succinyl amides in the (a)TAT were quickly hydrolyzed, fully restoring TAT's functions. Thus, (a)TAT-functionalized poly(ethylene glycol)-block-poly(ε-caprolactone) micelles achieved long circulation in the blood compartment and efficiently accumulated and delivered doxorubicin to tumor tissues, giving rise to high antitumor activity and low cardiotoxicity. This amidization strategy effectively and easily enables in vivo applications of CPPs.

Fusogenic Reactive Oxygen Species Triggered Charge‐Reversal Vector for Effective Gene Delivery

“…Histological analysis of heart tissues showed that the RGDK-FLPP/TRAIL-treated group had compact cardiomyocytes arranged in a clear structure similar to normal tissue, but those of the DOX treated group were characterized by myocardium tissue necrosis and disorganized myofi brillar arrays, typical of cardiomyocyte damage induced by DOX ( Figure S24, Supporting Information). [ 33 ] We have demonstrated a charge-reversal polymer B-PDEAEA which is strongly positively charged and effectively packages DNA into nanoparticles but becomes negatively charged once triggered by intracellular ROS. The resulting ROS-responsive polyplexes show higher gene transfection effi ciency than the traditional gold standard.…”

Self-Assembled Nanoparticles Based on Amphiphilic Anticancer Drug–Phospholipid Complex for Targeted Drug Delivery and Intracellular Dual-Controlled Release

“…A majority of the MP FITC -PEG Cy5.5 -FA NPs DiI was accumulated in the cytoplasm of tumor cells, possibly indicating the localization of the MP-PEG-FA NPs in the endo/lysosomes. 26 However, the drug accumulated in the cytoplasm and nucleus, which was possibly due to the fact that some drug was diffused out (released) from the MP-PEG-FA NPs, distributed through the cytoplasm, and transported inside the cells. 25 A high nuclear drug accumulation also resulted in the rapid drug diffusion to the cytoplasm.…”

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery

“…The PAMAM dendrimer system was modified by conjugating HIV transactivator of transcription (TAT) as cell penetrating peptide to enhance the uptake of the constructed DNA plasmid pIRES-H5/GFP by the cells. Cell-penetrating peptides (CPPs) are highly cationic peptides usually rich in arginine and lysine amino acids and have the ability to translocate quickly into almost any live cells (20).…”