Matrix metalloprotein-triggered, cell penetrating peptide-modified star-shaped nanoparticles for tumor targeting and cancer therapy

Abstract

Background: Specific targeting ability and good cell penetration are two critical requirements of tumor-targeted delivery systems. In the present work, we developed a novel matrix metalloprotein-triggered, cell-penetrating, peptide-modified, star-shaped nanoparticle (NP) based on a functionalized copolymer (MePEG-Peptide-Tri-CL), with the peptide composed of GPLGIAG (matrix metalloprotein-triggered peptide for targeted delivery) and r9 (cell-penetrating peptide for penetration improvement) to enhance its biological specificity and therapeutic effect. Results: Based on the in vitro release study, a sustained release profile was achieved for curcumin (Cur) release from the Cur-P-NPs at pH 7.4. Furthermore, the release rate of Cur was accelerated in the enzymatic reaction. MTT assay results indicated that the biocompatibility of polymer NPs (P-NPs) was inversely related to the NP concentration, while the efficiency toward tumor cell inhibition was positively related to the Cur-P-NP concentration. In addition, Cur-P-NPs showed higher fluorescence intensity than Cur-NPs in tumor cells, indicating improved penetration of tumor cells. An in vivo biodistribution study further demonstrated that Cur-P-NPs exhibited stronger targeting to A549 xenografts than to normal tissue. Furthermore, the strongest tumor growth inhibition (76.95%) was observed in Cur-P-NP-treated A549 tumor xenograft nude mice, with slight pulmonary toxicity. Conclusion: All results demonstrated that Cur-P-NP is a promising drug delivery system that possesses specific enzyme responsiveness for use in anti-tumor therapy.

Engineering precision nanoparticles for drug delivery

“…Recently, NPs have been developed with detachable stealth corona systems and charge-reversal systems (negative or neutral charge for circulation, positive charge for uptake), in an attempt to optimize both properties 217 , 218 . One such system utilizes an MMP-degradable linker to attach PEG to the surface of the NP: in the tumour microenvironment, the PEG coating is degraded, exposing a cell-penetrating peptide 219 . In this way, systems can be developed that change a given property to optimize for the delivery barrier they currently face.…”

Novel fusion peptide-mediated siRNA delivery using self-assembled nanocomplex

“…The TAT sequence originated from the Tat protein of the human immunode ciency virus (HIV) [16][17][18]. Oligoarginine is positively charged, and it can assist cellular internalization by forming a hydrogen bond with the sulfate of the cell membrane and the phosphate group of nucleic acid [19][20][21][22][23]. The histidine-rich peptide was con rmed using the e cient delivery of siRNA [24].…”

Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

“…The activation occurs through proteolytic cleavage by MMP in the tumor tissue, liberating the CPP component [18]. This strategy -termed aCPP (activatable CPP) -has been used for the tumor-targeted delivery of nucleic acid by using gene therapy [19] or delivery of chemotherapeutics [20].…”