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.
Highlights
Cancer is a major socio-economic burden on the society
Due to the ability to traverse cell membranes, Cell-penetrating peptides (CPPs) are widely used in the cellular delivery of proteins (Ana, Wei-Ming & Chin, 2016), plasmid DNA (Kato et al, 2016), oligonucleotides (Helmfors, Eriksson & Langel, 2015), and liposomes (Huang et al, 2013)
By introducing electron donating groups to the histidine imidazole ring of TH, we developed a new type of acid-responsive CPP with a high sensitivity to the acidic tumor microenvironment and low toxicity under physiological conditions
Summary
Cancer is a major socio-economic burden on the society. Chemotherapy is an effective conventional treatment against cancer, traditional chemotherapy drawbacks such as limited selectivity, deleterious side effects, and multi-drug resistance, seriously restrict their clinical curative effects (Chari, 2008; Monsuez et al, 2010; Monje & Dietrich, 2011). When CPPs were coupled to traditional anti-tumor drugs such as paclitaxel (PTX) and podophyllotoxin (PPT), they significantly enhanced drug sensitivity of resistant cancer cell lines (Dubikovskaya et al, 2008; Lindgren et al, 2006). Their major limitations in delivery applications, including non-specificity, severe toxicity due to their positive charge, and rapid clearance from blood, prevented their full clinical utilization
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