Abstract
A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4WC], and asymmetric, c[E4W5C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH- and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in mice. The highest tumor to muscle ratio (5.6) was established for asymmetric cyclic peptide, c[E4W5C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4W5C], where glutamic acid residues (E) were replaced by positively charged arginine residues (R), did not exhibit tumor targeting. We have introduced a novel class of cyclic peptides, which can be utilized as a new pH-sensitive tool in investigation or targeting of acidic tissue.
Highlights
A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules
We have introduced a novel class of cyclic peptides, which can be utilized as a new pHsensitive tool in investigation or targeting of acidic tissue
C[E4W5C], was an asymmetric; it had five Trp residues located on one side of the cycle, while four Glu residues were located on the other side of the cycle
Summary
A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. We reported the design and synthesis of homochiral L-cyclic peptides containing arginine (R), tryptophan (W) residues and their application for the nuclear targeting delivery of anti-HIV drugs, phosphopeptides, anticancer drugs, and siRNA22–24. These peptides offered several advantages including nuclear delivery of doxorubicin, low cytotoxicity, biocompatibility, hydrophobic drug entrapment through non-covalent interactions, and drug delivery through conjugation. We designed and introduced for the first time the pH-sensitive negatively charged cyclic peptides and studied their interactions with the lipid bilayer of liposomal and cellular membranes in vitro and in vivo
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