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Taming the wildness of “Trojan-Horse” peptides by charge-guided masking and protease-triggered de-masking for the controlled delivery of anti-tumor agents
作者:Shi NQ, Qi XR
關鍵字:“Trojan-Horse” peptides, taming the wildness, charge-guided masking, protease-triggered demasking, controlled delivery
論文來源:期刊
具體來源:ACS Appl Mater Interfaces. 2017. Mar 29;9(12):10519-10529. (SCI, IF=7.145)
發表時間:2017年

Cell-penetrating peptide (CPP), also called “Trojan Horse” peptide, has become a successful approach to deliver various payloads into cells for achieving the intracellular access. However, the "Trojan Horse" peptide is too wild, not just to "Troy", but rather widely distributed in the body. Thus, there is an urgent need to tame the wildness of “Trojan Horse” peptide for targeted delivery of antineoplastic agents to the tumor site. To achieve this goal, we exploit a masked CPP-doxorubicin conjugate platform for targeted delivery of chemotherapeutic drugs using charge-guided masking and protease-triggered de-masking strategies. In this platform, the cell-penetrating function of the positively CPP (D-form

nonaarginine) is abrogated by a negatively shielding peptide (masked CPP), and between them is a cleavable substrate peptide by the protease (MMP-2/9). Protease-triggered

de-masking would occur when the masked CPP reached the MMP-2/9-riched tumor. The

CPP-doxorubicin conjugate (CPP-Dox) and the masked CPP-Dox conjugate (mCPP-Dox)

were used as models for the evaluation of masking and de-masking processes. It was found that exogenous MMP-2/9 could effectively trigger the reversion of CPP-cargo in this conjugate and this trigger adhered to Michaelis-Menten kinetics profile. This conjugate was sensitive to the trigger of endogenous MMP-2/9 and could induce enhanced cytotoxicity towards MMP-2/9-rich tumor cells. In vivo antitumor efficacy revealed that this masked conjugate had considerable antitumor activity and could inhibit the tumor growth at a higher level relative to CPP-cargo. Low toxicity in vivo showed the noticeably decreased

wildness of this conjugate towards normal tissues and more controllable entry of anti-tumor agents into “Troy”. Based on analyses in vitro and in vivo, this mCPP-cargo conjugate

delivery system held an improved selectivity towards MMP-2/9-rich tumors and would

be a promising strategy for tumor-targeted treatment.

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