Dual pH-Responsive and Tumor-Targeted Nanoparticle-Mediated Anti-Angiogenesis siRNA Delivery for Tumor Treatment

Abstract

Purpose In order to overcome the biological barriers at all levels and enhance the delivery efficiency of siRNA, we have prepared a multifunctional siRNA delivery system (CHCE/siRNA nanoparticles) through self-assembly of the carboxymethyl chitosan modified with histidine, cholesterol, and anti-EGFR antibody (CHCE). Methods The morphology of CHCE/siRNA NPs was detected by dynamic light scattering and scanning electron microscope. In vitro, we assessed the tumor-targeting, cellular uptake, and endosomal escape by flow cytometry and confocal laser scanning microscopy, confirming the CHCE/siRNA NPs functions in gene silencing and cell killing ability. In vivo, we examined the biodistribution of the CHCE/siRNA NPs by the IVIS imaging system and confirmed the therapeutic effect of NPs in the nude-mouse tumor model. Results The CHCE/siRNA NPs exhibited nanosized spherical with narrow size distribution. In vitro, the CHCE/siRNA NPs incorporated a dual capability of tumor targeting and pH response that could facilitate cellular bind, cellular uptake, and endosomal escape. The CHCE/siRNA NPs could effectively silence the vascular endothelial growth factor A (VEGFA) to cause cell apoptosis and inhibit proliferation. In vivo, the CHCE/siRNA NPs could target tumor sites to knock down VEGFA and achieve a better anti-tumor effect. Conclusion We successfully prepared a novel siRNA delivery system with the double capability of tumor targeting and pH response, which can break through the biological barriers to penetrate deep into tumors and achieve better therapeutic tumor effects, providing a new ideal delivery platform for siRNA.

Surface Design Options in Polymer- and Lipid-Based siRNA Nanoparticles Using Antibodies

“…The surface functionalized NP complexed with siRNA against vascular endothelial growth factor A (VEGFA) caused cell apoptosis and inhibited proliferation of the xenograft tumor in an in vivo mouse model, induced by the application of the malignant melanoma cell line "SK-MEL-28". In this study, the results illustrate that surface modification offers significant advantages in therapeutic applications [138].…”

“…Mice-bearing tumors treated with EGFR-targeted VEGFA siRNA NPs showed comparable body weight with the PBS-treated group, while having the lowest tumor mass compared to the group treated with untargeted VEGFA siRNA NPs. Regarding the release of inflammatory cytokines such as IL-6, IFN-γ or TNF-α, functionalization of the NP surface with EGFR-antibodies showed no significant difference compared to the PBS and untargeted NP group, so functionalization of the surface did not increase inflammatory cytokines here [138].…”

“…In addition, Zhang et al investigated a suitable formulation for cancer treatment [138]. The polymer used here consists of the compound carboxymethyl chitosan modified with histidine, cholesterol and anti-EGFR antibodies, abbreviated as "CHCE".…”

A Comprehensive Review of Small Interfering RNAs (siRNAs): Mechanism, Therapeutic Targets, and Delivery Strategies for Cancer Therapy

“…[241][242][243][244][245] In a recent study, Zhang et al developed a multifunctional siRNA delivery system (CHCE/siRNA nanoparticles) by self-assembly of histidine-and cholesterol-modified carboxymethyl chitosan with anti-EGFR antibodies. This system exhibited both tumor-targeting and pH-responsive capabilities, enabling effective treatment by overcoming biological barriers 236 (Figure 6A). Wang et al developed an ultra-pH-responsive peptide nanocarrier that can dynamically assemble in response to pH changes in the tumor microenvironment and intracellular lysosomal environment, thereby efficiently delivering siRNA into cancer cells.…”

Nonviral delivery systems for antisense oligonucleotide therapeutics

“…Naturally derived structural proteins and polysaccharides, such as cationic collagen derivatives, cyclodextrins (CDs), and chitosan, have been developed as gene carriers [126][127][128][129]. Collagen, an important component of bone tissue, has a complex structure that makes it available as an artificial scaffold material with an innate drug retentive function.…”