Abstract
BackgroundSpecific 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.ResultsBased 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.ConclusionAll results demonstrated that Cur-P-NP is a promising drug delivery system that possesses specific enzyme responsiveness for use in anti-tumor therapy.
Highlights
Specific targeting ability and good cell penetration are two critical requirements of tumor-targeted delivery systems
Matrix metalloproteinases (MMPs), one class of abundant proteases surrounding tumors that is involved in tumor progression, tumor angiogenesis, and metastasis [5, 6], are overexpressed throughout the extracellular matrix of most cancer cells compared to the normal cell environment [7, 8]
Enzyme‐responsive star‐shaped copolymer characterization In the 1H-NMR spectrum of (ACP)-GPLGIAGQr9(ACP) (Fig. 3a), the characteristic peaks of the peptide are shown at 2.04, 1.72, 1.25, and 0.88 ppm, while different moieties are shown in the 1H-NMR spectrum of MePEG-Peptide-Tri-CL (Fig. 3b)
Summary
Specific targeting ability and good cell penetration are two critical requirements of tumor-targeted delivery systems. 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. Targeted selection and cellular uptake of drugs are major challenges in successful cancer chemotherapy. Precise surface engineering of NPs with specific ligands, which can improve their targeting ability, cellular penetration, and circulation longevity, is required. A drug delivery system with good internalization capability is required. The conjugation of targeting ligands with a CPP could be a potential strategy to achieve cancer cell selectivity
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