Construction of a Targeting Nanoparticle of 3′,3″-Bis-Peptide-siRNA Conjugate/Mixed Lipid with Postinserted DSPE-PEG2000-cRGD

Abstract

The cyclic Arg-Gly-Asp (cRGD) peptides are widely used as tumor-targeting ligands due to their specific binding ability to integrin αvβ3, which is overexpressed on the surface of various cancer cells and the endothelial cells of new blood vessels within tumor tissues. In this paper, the postinsertion strategy of DSPE-PEG2000-cRGD has been applied to the nanoparticles of 3′,3″-bis-peptide-siRNA (pp-siRNA) encapsulated by gemini-like cationic lipid (CLD) and neutral cytosin-1-yl lipid (DNCA) from our lab. It was confirmed that the nanoparticles of pp-siRNA/CLD/DNCA/DSPE-PEG2000-cRGD (PCNR) were able to specifically target tumor cells with highly expressed integrin αvβ3; moreover, it efficiently downregulated the levels of BRAF mRNA and the BRAF protein and inhibited cell proliferation in A375 cells, in comparison with the nontargeted nanocomplex of pp-siRNA/CLD/DNCA/cRAD (PCNA). The uptake pathways of PCNR are mostly dependent on CvME-mediated endocytosis and macropinocytosis in A375 cells, which could bypass lysosome or quickly lead to the lysosomal escape to reduce siRNA degradation. Finally, the biodistribution study showed that PCNR exhibited a high ability to accumulate in tumor tissues. These results suggest that the nanocomplex of PCNR is promising to be highly effective in the treatment of melanomas including their mutation.

Rationale and Application of PEGylated Lipid-Based System for Advanced Target Delivery of siRNA

“…DSPE-PEGcyclic Arg-Gly-Asp (cRGD) was post-inserted to this nanoparticle to improve the ability of recognize target cells express integrin α v β 3 to accumulate in tumor tissue with high specificity. The result shows that this nano carrier could also help siRNA to escape from lysosome to avoid siRNA degradation (Zhang et al, 2019). By the multiple forces such as π-stacking, H-bonding, and also electrostatic force between siRNA and lipids, the neutral cytidinyl lipid DNCA and CLD formed siRNA nanoparticle with further modification of PEG2000-DSPE for delivering siMB3 to specific silencing of BRAF V600E mRNA.…”

The Dual Role of Macropinocytosis in Cancers: Promoting Growth and Inducing Methuosis to Participate in Anticancer Therapies as Targets

“…PCNR, a NP based on RGD (cyclic Arg-Gly-Asp peptide) has great potential in the treatment of melanomas. And one of the PCNR uptake pathways is mostly macropinocytosis-dependent in A375 cells ( 167 ). Heptapeptide R7, a novel peptide, was synthesized to promote internalization of chlorin e6(a photosensitizer) into HepG2 cells by activation of endocytosis and/or macropinocytosis in comparison with initial NPs without peptide R7 ( 168 ).…”

Barriers and Strategies of Cationic Liposomes for Cancer Gene Therapy

“…166,167 Nowadays, it is a trend for ligand-receptor targeting in nanocarriers, because many specific receptors are more highly expressed in tumor than in normal tissues. 70,168 Targeting ligands such as folate, [169][170][171][172] transferrin, 173,174 and the cyclic Arg-Gly-Asp (cRGD) peptides 175,176 are exploited to enhance tumor-targeted delivery, making it more effectively and rapidly internalized via receptor-mediated endocytosis of target cells. In recent years, dual-targeted nanomedicines are expected to overcome the uncontrollable and fluctuating targeting efficiency of single-ligand targeting, resulting in better cell selectivity and gene therapy.…”