Design of Acid-Activated Cell Penetrating Peptide for Delivery of Active Molecules into Cancer Cells

Abstract

TP10-5 (TK) was screened as the most promising candidate among the designed analogues of transportan 10 (TP10), a cell penetrating peptide (CPP) with remarkable capacity for membrane translocation. However, low levels of specificity and high toxicity limit its successful use for drug delivery applications. Here, we developed a new type of acid-activated CPP (TH) by replacement of all lysines of TK with histidines. As expected, histidine-containing TH can be activated and subsequently enter cells at pH 6.0, whereas it is less active at pH 7.4. In contrast, the uptake of TK has no significant difference for both pH values. Importantly, the toxicity of TH is significantly lower than that of TK under physiological conditions. After attachment of camptothecin (CPT) to TH, this conjugate exhibited remarkable cytotoxicity to cancer cells in a pH-dependent manner compared with free CPT and TK-CPT. This study opens a new avenue to design CPPs that preferentially enter cells in acidic solid tumors, with minimal cellular uptake in normal tissues.

A smart tumor targeting peptide–drug conjugate, pHLIP-SS-DOX: synthesis and cellular uptake on MCF-7 and MCF-7/Adr cells

“…Fluorescene was measured at 490 nm. Untreated cells were defined as no leakage and 100% leakage was defined as total LDH release by treating LDH release reagent (Zhang et al, 2011).…”

“…Here, we divide them into two big classes: traditional CPPs and pH-sensitive CPPs. Traditional CPPs are pH-insensitive CPPs including arginine-rich CPPs, amphipathic CPPs and so on, they possess the ability to deliver drugs or nanocarriers into cells but their primary obstacle was the lack of selectivity, they can penetrate all kinds of cell membranes without screening (Zhang et al, 2011). pH-sensitive CPPs taking advantage of the pH difference between tumor tissues and normal tissues are a group of CPPs sharing several common characteristics as follows: their cell-penetrating capacity is concealed at neutral pH, such as in normal tissues and blood circulations; when pH decrease, such as in tumor tissues their cell penetrating capacity is recovered through various mechanisms.…”

Ultrasound-responsive nanobubbles contained with peptide–camptothecin conjugates for targeted drug delivery

“…This 4-fold increase in CPT solubility by the CPP-CPT conjugate might be attributed to the hydrophilic nature of CPP. Besides the enhanced water solubility of CPP-CPT, the conjugate was presumed to stabilize the lactone ring of CPT (Henne et al, 2006) and may release the unmodified camptothecin in cells via endosomal disulfide reduction (Zhang et al, 2011).…”

“…Camptothecin (CPT) is a naturally occurring alkaloid isolated from the Chinese tree Camptotheca acuminata, with promising anti-tumor activity against various leukemia cell lines (Zhang et al, 2011). However, due to the lack of reaction selectivity, the use of CPT can cause severe side effects.…”

Taming Cell Penetrating Peptides: Never Too Old To Teach Old Dogs New Tricks

“…Meanwhile, histidines were also known for their endo/lysosome escaping capacity for they are excellent receivers and donors of protons (proton sponge effect) [70,71]. As mentioned before, lysine (pKa=10.5) was responsible for the positive charge of some cationic peptides; therefore, researchers replaced lysines with histidines to fabricate pH-responsive peptides, including CPPs [72][73][74][75][76][77]. Zhang et al [72] designed peptide TH from In spite of the effectiveness of the histidine-replacing strategy, it has to be mentioned that the activity of the original CPPs could not be fully recovered after protonation of histidine in tumor environment or even in the endo/lysosome environment (ref.…”