Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2⁺ Breast Cancer

Abstract

In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. We now describe a new nanoparticle construct that has been engineered for efficient delivery of siRNA to tumors. The construct is comprised of a 47-nm mesoporous silica nanoparticle (MSNP) core coated with a cross-linked PEI-PEG copolymer, carrying siRNA against the HER2 oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct has been engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2-nanoparticles produced apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2−) cells. One dose of the siHER2-nanoparticles reduced HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Multiple doses administered intravenously over 3 weeks significantly inhibited tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation.

Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

“…Enzymatic degradation, removal from circulation by renal excretion or mononuclear phagocyte system (MPS), poor cellular uptake and endosomal release are examples of physiological barriers that siRNAs need to overcome [17,18]. Several viral and nonviral delivery vectors, such as adenovirus, polyplexes, liposomes, and micelles, amongst others, have been developed to overcome these obstacles and improve RNAi therapeutic efficacy in vivo [19][20][21][22][23][24][25].…”

Recent applications of the combination of mesoporous silica nanoparticles with nucleic acids: development of bioresponsive devices, carriers and sensors

“…The MSN@PEI@oligonucleotide multilayer deposition strategy has been also reported for the construction of targeted, gene silencing nanodevices employing the sense: 5'-(CAC GUU UGA GUC 144 The authors demonstrated in vitro and in vivo that the system so designed was successfully taken up by HER2 positive cells, in which was produced the expected gene silencing and the restoration drug sensitivity. Furthermore, this siRNA delivery induced apoptotic death of HER2 positive while the negative cells remained unaffected, opening the way to the construction of synergistic therapy nanodevices (Section 4.3).…”

Enhanced Anti-Cancer Capability of Ellagic Acid Using Solid Lipid Nanoparticles (SLNs)

“…The polydispersity index (PDI) of F10 (about 0.28) suggests a relatively narrow size distribution. Generally, PDI < 0.5 confirms the monodispersity of nanosized particles (17). Dynamic light scattering (DLS) graph of optimized formulation (F10) was presented in Figure 1A.…”