Design of new acid-activated cell-penetrating peptides for tumor drug delivery

Abstract

TH(AGYLLGHINLHHLAHL(Aib)HHIL-NH2), a histidine-rich, cell-penetrating peptide with acid-activated pH response, designed and synthesized by our group, can effectively target tumor tissues with an acidic extracellular environment. Since the protonating effect of histidine plays a critical role in the acid-activated, cell-penetrating ability of TH, we designed a series of new histidine substituents by introducing electron donating groups (Ethyl, Isopropyl, Butyl) to the C-2 position of histidine. This resulted in an enhanced pH-response and improved the application of TH in tumor-targeted delivery systems. The substituents were further utilized to form the corresponding TH analogs (Ethyl-TH, Isopropyl-TH and Butyl-TH), making them easier to protonate for positive charge in acidic tumor microenvironments. The pH-dependent cellular uptake efficiencies of new TH analogs were further evaluated using flow cytometry and confocal laser scanning microscopy, demonstrating that ethyl-TH and butyl-TH had an optimal pH-response in an acidic environment. Importantly, the new TH analogs exhibited relatively lower toxicity than TH. In addition, these new TH analogs were linked to the antitumor drug camptothecin (CPT), while butyl-TH modified conjugate presented a remarkably stronger pH-dependent cytotoxicity to cancer cells than TH and the other conjugates. In short, our work opens a new avenue for the development of improved acid-activated, cell-penetrating peptides as efficient anticancer drug delivery vectors.

Cell Penetrating Peptides as Molecular Carriers for Anti-Cancer Agents

“…A fusion peptide, has been obtained by the conjugation of Tat peptide with a nuclear localization signal protein which was able to suppress breast tumorigenesis through the inhibition of β-catenin/LEF-1 signaling [ 86 ]. More recently, a histidine-rich CPP, namely (TH) AGYLLGHINLHHLAHL(Aib)HHIL-NH 2 ( Table 1 ), with acid-activated pH response has been synthesized [ 85 ]. The protonation of the acid-activated CPP in a weakly acidic environment has been facilitated by the introduction of alkylated histidine analogues in the peptide sequence.…”

“…The protonation of the acid-activated CPP in a weakly acidic environment has been facilitated by the introduction of alkylated histidine analogues in the peptide sequence. In addition, the binding of methyl, ethyl, isopropyl and butyl groups to the l -histidine imidazole produced moieties suitable as pH-sensitive vectors for targeted antitumor drug delivery with low toxicity [ 85 ]. A new CPP, the arginine-rich protamine (Pro) (PRRRRSSSRPVRRRRRPRVSRRRRRRGGRRRR), containing a membrane-translocation domain fused to a nuclear-localizing sequence has been synthesized and successively used for photodynamic therapy, which together with chemotherapy and surgery for cancer treatment, cause demolition of cancer tissues with visible light in the presence of a photosensitizer and oxygen [ 87 ].…”

Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers

“…The TH analogues formed were conjugated to a camptothecin (Cpt)-and butyl-TH-modified conjugate and displayed a pronounced cytotoxicity effect on cancer cells more strongly in a pH-dependent manner compared to TH and other conjugates. 82 Very recently, new pH-controllable CPPs (PCCPPs) were reported on by Lee et al 83 According to this study, synthesized poly-l-lysine-based PCCPPs were capable of undergoing pH-dependent conformational transition, thereby displaying specific cell-penetrating properties at the target site. At a physiological pH, the PCCPPs contained a low helical tendency due to electrostatic attractions between carboxylate and protonated amine groups in each side chain.…”

Hierarchical design of hyaluronic acid-peptide constructs for glioblastoma targeting: Combining insights from NMR and molecular dynamics simulations

“…epidermal growth factor receptors), and the physicochemical tumor features, i.e. lower pH, hypoxia and enzymatic expression, different supramolecular assemblies have been proposed [8][9][10][11][12][13][14][15] . Peptide engineering, involving the residue-and/or site-specific modification of peptides with polymer backbones have been endorsed to design hybrid constructs potentially addressed to fit this purpose.…”