Cyclic Tat peptide promotes nanomedicine permeation in tumor
microenvironments through reducing affinity and maintaining binding
ability
Abstract
Nanomedicine has emerged as a potent weapon against cancer, yet its
therapeutic potential is hampered by limited diffusion within tumor
tissues. Cell-penetrating peptides (CPPs), such as the trans-activator
of transcription (Tat) peptide, can facilitate interactions between
carriers and cells; however, their capacity to penetrate cell layers
remains limited. Here, we present evidence that cyclic Tat (cTat) can
effectively enhance the penetration of nanoparticles into tumors.
Compared with linear Tat, cTat exhibited a 10-fold increase in the
dissociation constant (Kd) but a nearly dissociation rate constant
(Koff) with the cell membrane. This facilitated easier uptake and
penetration of cTat-modified liposomes (cTat-Lip) into tumor cells. In
vivo studies corroborated these findings; cTat-Lip demonstrated higher
tumor penetration and a more even distribution compared to Tat-Lip.
Furthermore, we evaluated the impact of cTat-Lip in mouse tumor models
and patient-derived xenograft (PDX) models. We confirmed that after
enhancing tumor penetration, DOX-loaded cTat-Lip could modulate the
immune microenvironment at the tumor site, increasing the proportion of
M1-type macrophages and promoting tumor therapy. These results highlight
the substantial impact of two-dimensional structure modification of CPPs
like Tat on their targeting affinity, emphasize of reducing the
peptide’s targeting affinity to achieve enhanced tumor penetration and
improved therapeutic outcomes.