Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth Inhibition

Abstract

The success of small interfering RNA (siRNA)-mediated gene silencing for cancer therapy is still limited because of its instability and poor intracellular internalization. Traditional cationic carriers cannot adequately meet the need for clinical application of siRNA. We herein report a dual-functional liposome containing a cholesterol derivative of metformin, i.e., LipoMET, which takes advantage of the fusogenic activity as well as intrinsic tumor apoptosis inducing ability of biguanide moiety to achieve a combinational anti-oncogenic effect. In this study, the vascular endothelial growth factor (VEGF)-specific siRNAs were first electrostatically condensed into a ternary nanocomplex composed of polycation and hyaluronate, which was subsequently enveloped by LipoMET through membrane fusion. In comparison with common cationic control group, the resulting envelope-type nanoparticles (PH@LipoMET nanoparticles [NPs]) showed the ability of rapid cellular internalization and effective endosomal escape of siRNA during intracellular trafficking studies. Systemic administration of the targeted LipoMETs was capable of inducing apoptosis and tumor growth inhibition in the NCI-H460 xenograft model. When carrying VEGF-specific siRNAs, PH@LipoMET NPs remarkably downregulated the expression of VEGF and led to even more tumor suppression in vivo. Thus, LipoMET originated envelope-type nanoparticles may serve as a potential dual-functional siRNA delivery system to improve therapeutic effect of oncogene silencing.

Emerging nanoparticulate drug delivery systems of metformin

“…Therefore, the derivatives of MET could retain anticancer activity as potent as free MET, which makes MET a more significant attraction to be utilized in anticancer treatment. In recent years, several MET derivatives were rationally designed for the construction of a wide range of multifunctional nanocarriers in cancer therapy, including simple amphipathic MET derivative (Jiang et al 2019), polymeric derivatives of MET (Ramasamy et al 2019;Xiong et al 2016;Zhao et al 2016) and MET-based cationic lipids (Luo et al 2016a, b;Shi et al 2017).…”

“…In addition to polymeric derivatives of MET, METbased cationic lipids have also been rationally designed for multifunctional applications (Luo et al 2016a, b;Shi et al 2017). As shown in Fig.…”

Inorganic Kernel-Reconstituted Lipoprotein Biomimetic Nanovehicles Enable Efficient Targeting “Trojan Horse” Delivery of STAT3-Decoy Oligonucleotide for Overcoming TRAIL Resistance

“…The resultant CaP reconstituted LDL was subjected to extrusion through a 0.1 μm filter membrane three times and stored at 4°C. The amount of ODNs entrapped within the nanovehicles was determined by Quant-iT RiboGreen assay following lysis in Tris buffer with 2 mM EDTA and 0.05 % Triton X-100 44 . The drug entrapment efficiency was expressed as the percentage difference between the initial used and the entrapped amount of ODNs relative to the total amount used for the CaP@LDL preparation.…”

Recent Advancements of Nanomedicine towards Antiangiogenic Therapy in Cancer

“…PolyMet NPs were shown to be highly capable of VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumor activity by inhibiting angiogenesis [74] (Figure 3). The same group also developed lipid-based dual functionalized NPs to VEGF siRNA in vivo [75]. Recently, Yang and his colleagues developed a low-density lipoprotein receptor-related protein receptor (Angiopep-2) and neuropilin-1 receptor (tLyP-1) targeting cationic liposomes for delivery of siRNA and docetaxel to gliomas.…”