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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
Angiopep-2 and activatable cell penetrating peptide dual modified nanoparticles for enhanced tumor targeting and
Ling Mei1, Qianyu Zhang1, Yuting Yang1
1Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
Abstract:
Delivering chemotherapeutics by nanoparticles into tumor was influenced by at least two factors: specific targeting and highly efficient penetrating of the nanoparticles. In this study, two targeting ligands, angiopep-2 and activatable cell penetrating peptide (ACP), were functionalized onto nanoparticles for tumor targeting delivery. In this system, angiopep-2 is a ligand of low-density lipoprotein receptor-related protein-1 (LRP1) which was highly expressed on tumor cells, and the ACP was constructed by the conjugation of RRRRRRRR (R8) with EEEEEEEE through a matrix metalloproteinase-2 (MMP-2) sensitive linker, enabling the ACP with tumor microenvironment-responsive cell penetrating property. 4h incubation of ACP with MMP-2 leads to over 80% cleavage of ACP, demonstrating ACP indeed possessed MMP-2 responsive property. The constructed dual targeting nanoparticles (AnACNPs) were approximately 110 nm with a polydispersity index of 0.231. In vitro, ACP modification and angiopep-2 modification could both enhance the U-87 MG cell uptake because of the high expression of MMP-2 and LRP-1 on C6 cells. AnACNPs showed higher uptake level than the single ligand modified nanoparticles. The uptake of all particles was time- and concentration-dependent and endosomes were involved. In vivo, AnACNPs showed best tumor targeting efficiency. The distribution of AnACNPs in tumor was higher than all the other particles. After microvessel staining with anti-CD31 antibody, the fluorescent distribution demonstrated AnACNPs could distribute in the whole tumor with the highest intensity. In conclusion, a novel drug delivery system was developed for enhanced tumor dual targeting and elevated cell internalization.
Insights
This study developed dual-targeting nanoparticles (AnACNPs) that enhance tumor drug delivery by combining angiopep-2 and activatable cell penetrating peptide (ACP) ligands. AnACNPs demonstrated superior tumor targeting and cellular uptake compared to single-ligand nanoparticles.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Drug Delivery Systems
Background:
- Effective chemotherapy delivery to tumors requires specific targeting and efficient nanoparticle penetration.
- Tumor cells often overexpress low-density lipoprotein receptor-related protein-1 (LRP1), a target for angiopep-2.
- The tumor microenvironment, rich in matrix metalloproteinase-2 (MMP-2), can activate prodrug strategies.
Purpose of the Study:
- To develop novel dual-targeting nanoparticles (AnACNPs) for enhanced tumor drug delivery.
- To functionalize nanoparticles with angiopep-2 for LRP1 targeting and an activatable cell penetrating peptide (ACP) for MMP-2-responsive penetration.
- To evaluate the in vitro and in vivo targeting efficiency and cellular uptake of AnACNPs.
Main Methods:
- Constructed ACP by conjugating R8 and EEEEEEEE via an MMP-2 sensitive linker, confirming MMP-2 responsiveness via cleavage assays.
- Synthesized dual-targeting nanoparticles (AnACNPs) with angiopep-2 and ACP, characterizing their size and polydispersity.
- Assessed in vitro cellular uptake in U-87 MG and C6 cells, comparing AnACNPs with single-ligand nanoparticles.
- Evaluated in vivo tumor targeting efficiency and distribution in a tumor model using anti-CD31 staining.
Main Results:
- ACP showed over 80% cleavage by MMP-2 within 4 hours, confirming its responsive property.
- AnACNPs exhibited significantly higher cellular uptake in U-87 MG and C6 cells compared to single-ligand nanoparticles.
- In vivo studies revealed that AnACNPs achieved the highest tumor targeting efficiency and distribution throughout the tumor mass.
- Particle uptake was found to be time- and concentration-dependent, involving endosomal pathways.
Conclusions:
- Developed a novel dual-targeting nanoparticle system (AnACNPs) for enhanced tumor drug delivery.
- AnACNPs effectively leverage both LRP1 receptor targeting and MMP-2-responsive cell penetration for improved therapeutic outcomes.
- The AnACNP system demonstrates significant potential for elevated tumor targeting and cellular internalization in cancer therapy.
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