Co‐delivery of anti‐vascular endothelial growth factor siRNA and doxorubicin by multifunctional polymeric micelle for tumor growth suppression

Abstract

Nonviral gene carriers composed of biodegradable polymers or lipids have been considered as a safer alternative for gene carriers over viral vectors. We have developed multifunctional nanomicelles for both drug and gene delivery application. Polyethylenimine (PEI) was modified by grafting stearic acid (SA) and further formulated to polymeric micelles (PEI-SA) with positive surface charge for gene delivery evaluation. Our results showed that PEI-SA micelles provided high siRNA binding efficiency and exhibited low cytotoxicity compared with unmodified PEI. siRNA delivered by PEI-SA carriers also demonstrated significantly higher cellular uptake efficiency and stability even in the presence of serum proteins when compared with free siRNA. The post-transcriptional gene silencing efficiency was greatly improved by the polyplex formulated by 10k PEI-SA/siRNA. In the animal intratumoral model study, the combination of co-delivering doxorubicin and vascular endothelial growth factor (VEGF) siRNA delivered by PEI-SA micelles showed a promising effect on anti-tumor growth. The amphiphilic structure of PEI-SA micelles provides advantages for multifunctional tasks; such that hydrophilic shell modified with cationic charges can electrostatically interact with DNA or siRNA, and hydrophobic core can serve as a payload for hydrophobic drugs, making it truly a promising multifunctional vehicle for both genetic and chemotherapy application.

Polyetherimide-grafted Fe3O4@SiO2 nanoparticles as theranostic agents for simultaneous VEGF siRNA delivery and magnetic resonance cell imaging

“…41,42 The binding capacity to VEGF shRNA was further analyzed by agarose gel electrophoresis, as shown in Figure 8. It was found that Fe 3 O 4 @SiO 2 cannot bind VEGF shRNA, neither in deionized water nor in 0.9% NaCl solution ( Figure 8A and B).…”

Therapeutic potential of targeted multifunctional nanocomplex co-delivery of siRNA and low-dose doxorubicin in breast cancer

“…Some of these conflicting results can be attributed to differences in tumor models used, and the inherent heterogeneity between tumors. The rationale used for selecting appropriate drug-nucleic acid combinations as well as nanocarriers suitable for simultaneous delivery of drugnucleic acid combinations has been found in some literatures [7,[31][32][33][34]. Furthermore, synergistic combinations of several types of therapeutic approaches with distinct mechanisms can overcome the toxicity and other side effects associated with high doses of single drugs by countering biological compensation mechanisms, which allows the dosage of each compound to be reduced and interferes with context-specific multi-targeting mechanisms [5,35].…”

“…Moreover, the combination of several types of therapeutic approaches with distinct mechanisms is considered to be a potential strategy for the effective treatment of cancers [5]. Besides, co-delivering chemotherapeutic drug and small interfering RNA (siRNA) in the same delivery system is more effective than co-treatment of cancer cells with delivery systems carrying either siRNA or drug [6,7].…”

Combined silencing expression of MGMT with EGFR or galectin-1 enhances the sensitivity of glioblastoma to temozolomide

“…Additionally, we observed that the zeta potential of the complex formed by the association of the three siRNAs with chitosan-LNCs was divided by 2 compared to that of the combination of two siRNAs with chitosan-LNCs. Several studies indicated that the intensity of the positive charge of the nanocarriers increases cellular uptake of the complexes formed with siRNAs and the inhibition efficiency of the target proteins (42,43). This could explain why chitosan-LNCs associated with three siRNAs failed to be more effective than other associations.…”