Transmembrane delivery of anticancer drugs through self-assembly of cyclic peptide nanotubes

Abstract

Breaking the natural barriers of cell membranes achieves fast entry of therapeutics, which leads to enhanced efficacy and helps overcome multiple drug resistance. Herein, transmembrane delivery of a series of small molecule anticancer drugs was achieved by the construction of artificial transmembrane nanochannels formed by self-assembly of cyclic peptide (cyclo[Gln-(d-Leu-Trp)4-d-Leu], CP) nanotubes (CPNTs) in the lipid bilayers. Our in vitro study in liposomes indicated that the transport of molecules with sizes smaller than 1.0 nm, which is the internal diameter of the CPNTs, could be significantly enhanced by CPNTs in a size-selective and dose-dependent manner. Facilitated uptake of 5-fluorouracil (5-FU) was also confirmed in the BEL7402 cell line. On the contrary, CPs could facilitate neither the transport across liposomal membranes nor the uptake by cell lines of cytarabine, a counterevidence drug with a size of 1.1 nm. CPs had a very weak anticancer efficacy, but could significantly reduce the IC50 of 5-FU in BEL7402, HeLa and S180 cell lines. Analysis by a q test revealed that a combination of 5-FU and CP had a synergistic effect in BEL7402 at all CP levels, in S180 at CP levels higher than 64 μg mL(-1), but not in HeLa, where an additive effect was observed. Temporarily, intratumoral injection is believed to be the best way for CP administration. In vivo imaging using (125)I radio-labelled CP confirmed that CPNPTs were completely localized in the tumor tissues, and translocation to other tissues was negligible. In vivo anticancer efficacy was studied in the grafted S180 solid tumor model in mice, and the results indicated that tumor growth was greatly inhibited by the combinatory use of 5-FU and CP, and a synergistic effect was observed at CP doses of 0.25 mg per kg bw. It is concluded that facilitated transmembrane delivery of anticancer drugs with sizes smaller than 1.0 nm was achieved, and the synergistic anticancer effect was confirmed both in cell lines and in vivo through the combinatory use of 5-FU and CP.

Self-assembling peptide-based building blocks in medical applications

“…Self-assembly of cyclic peptide ( cyclo [Gln-(D-Leu-Trp) 4 -D-Leu], CP) forms artificial transmembrane nanochannels on the cell membrane for the permeation of anti-cancer drugs, which are smaller than 1 nm. The in vivo study with these nanochannels in a grafted solid tumor model in mice showed that tumor growth was greatly inhibited by the combination of anti-cancer drugs with the cyclic peptide nanochannels [92]. …”

Peptides with regularly alternating enantiomeric sequence: From ion channel models to bioinspired nanotechnological applications

“…Chen et al explored the viability of self‐organizing cyclic l , d ‐α‐peptides to carry small molecular anticancer drugs through the artificial channels they form across the cell membranes. A hydrophobic cyclic l , d ‐α‐decapeptide was designed with an inner pore suitable to complex selectively hydrophilic molecules with a smaller size than 1 nm, such as the anticancer drug 5‐fluoracyl.…”

“…In contrast, the development of novel systems for drug delivery and gene transfection appears more sound since it is based on the well‐proved propensity of cyclic l , d ‐α‐peptides to interact with cells by forming trans‐membrane channels. Applications of linear l , d ‐α‐peptides in this fields could also be envisioned since the ability of these peptides to self‐assemble in long rod‐like aggregates and to act as ion channels in bilayer membranes were shown …”

Self-Assembling Peptides- Notion and Medical Applications: A Review

“…Thus, Fluorescence imaging can be employed to understand the interactions of peptides with various enzymes 21 . The in vivo study with these nano channels in a grafted solid tumor model in mice showed that tumor growth was greatly inhibited by the combination of anti-cancer drugs with the cyclic peptide nano channels 22 .…”