Development of small interfering RNA delivery system using PEI-PEG-APRPG polymer for antiangiogenic vascular endothelial growth factor tumor-targeted therapy

Abstract

Background Small interfering RNA (siRNA) can silence target genes in the cytoplasm and be a major tool in gene therapy. Vascular endothelial growth factor (VEGF), a potent regulator of angiogenesis, is overexpressed in most tumors and is closely associated with tumor growth and metastasis. It has been shown that inhibition of VEGF expression by siRNA is an effective and useful method for antiangiogenic tumor therapy. Methods In the present study, we synthesized a targeted delivery system of PEI-PEG-APRPG incorporating angiogenic vessel-homing Ala-Pro-Arg-Pro-Gly (APRPG) peptide into cationic polyethylenimine (PEI) via a hydrophilic poly(ethylene glycol) (PEG) spacer. Results PEI-PEG-APRPG effectively condensed siRNA into 20–50 nm nanoparticles with a positive surface charge using a suitable N/P ratio. The siRNA/PEI-PEG-APRPG complex effectively enhanced the stability of siRNA in RNase A, and improved the proliferation-inhibiting ability and transfection efficiency of siRNA in vitro and tumor accumulation in vivo. In addition, the siRNA/PEI-PEG-APRPG complex exhibited high efficiency as antitumor therapy with regard to tumor growth, microvessel density, and VEGF protein and mRNA levels. Conclusion These findings suggest that PEI-PEG-APRPG effectively delivers siRNA to tumors overexpressing VEGF and thereby inhibits tumor growth.

Interaction of Nanoparticles with Blood Components and Associated Pathophysiological Effects

“…Some of the nanomaterials used for this purpose are liposomes (Ala-Pro-Arg-Pro-Gly (APRPG) liposomes). These can successfully target tumor microvessels via functionalization with Ala-Pro-Arg-Pro-Gly (APRPG) peptide, which binds the blood vessels through the VEGF receptor-1 [122]. Another application involves the treatment of corneal endothelial dystrophy to improve and integrate cell therapy through superparamagnetic nanoparticles that facilitate the delivery of human corneal endothelial cells (HCECs) [123].…”

Nanoparticles for imaging and treatment of metastatic breast cancer

“…Therefore, NP-mediated RNA interference has been increasingly used in breast cancer gene therapy and has shown great promise. Various siRNA targets have been studied such as protease-activated receptor 1,[67] survivin,[68] vascular endothelial growth factor,[69] Twist-related protein 1,[70] Ras homolog family member C-GTPase,[71] p65,[72] etc. Those targets play important roles in metastasis, angiogenesis, proliferation, apoptosis, etc.…”

“…Those targets play important roles in metastasis, angiogenesis, proliferation, apoptosis, etc. To deliver siRNA for these targets, non-viral nanocarriers including poly(amidoamine) dendrimers,[70] β-cyclodextrin-based polymers,[71] polyethylenimine (PEI)-PEG copolymers,[69] Tween 85-s-s-PEI polymers,[72] gold[67] and polysaccharide NPs,[68], have been investigated. These carriers usually possess strong cationic charges which facilitates binding with RNA strands.…”

Enhanced EJ Cell Killing of 125I Radiation by Combining with Cytosine Deaminase Gene Therapy Regulated by Synthetic Radio-Responsive Promoter

“…Recently, targeting vectors, which could be injected intravenously and bind selectively to the tumor, have been studied. Adding nonviral vectors, such as incorporating targeting peptides (EGF, RGD, APRPG) into polyethylenimine (PEI), 28 polylysine (PLL), 29 and viral vectors, such as insertion of RGD peptide into the H1 loop of the fiber knob domain in adenovirus, 30 genetically incorporates targeting peptides into adeno-associated virus capsids. 31 Each technique has advantages and disadvantages.…”