Synergistic inhibition of breast cancer by co-delivery of VEGF siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles.

A somatostatin analog, vapreotide (VAP), can be used as a ligand for targeting drug delivery based on its high affinity to somatostatin receptors (SSTRs), which is overexpressed in many tumor cells. RNA interference plays an important role on downregulation of vascular endothelial growth factor (VEGF), which is important for tumor growth, progression and metastasis. To improve tumor therapy efficacy, the vapreotide-modified core-shell type nanoparticles co-encapsulating VEGF targeted siRNA (siVEGF) and paclitaxel (PTX), termed as VAP-PLPC/siRNA NPs, were developed in this study. When targeted via somatostatin receptors to tumor cells, the VAP-PLPC/siRNA NPs could simultaneously delivery siVEGF and PTX into cells and achieve a synergistic inhibition of tumor growth. Interestingly, in vitro cell uptake and gene silencing experiments demonstrated that the targeted VAP-PLPC/siRNA NPs exhibited significant higher intracellular siRNA accumulation and VEGF downregulation in human breast cancer MCF-7 cells, compared to those of the non-targeted PEG-PLPC/siRNA NPs. More importantly, in vivo results further demonstrated that the targeted VAP-PLPC/siRNA NPs had significant stronger drug distribution in tumor tissues and tumor growth inhibition efficacy via receptor-mediated targeting delivery, accompany with an obvious inhibition of neovascularization induced by siVEGF silencing. These results suggested that the co-delivery of siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles would be a promising approach for tumor targeted therapy.

Feng Q ，Yu MZ ，Wang JC ，Hou WJ ，Gao LY ，Ma XF ，Pei XW ，Niu YJ ，Liu XY ，Qiu C ，Pang WH ，Du LL ，Zhang Q ... -  《-》

Natural Particulates Inspired Specific-Targeted Codelivery of siRNA and Paclitaxel for Collaborative Antitumor Therapy.

Wang R ，Zhao Z ，Han Y ，Hu S ，Opoku-Damoah Y ，Zhou J ，Yin L ，Ding Y ... -  《-》

Oral delivery of shRNA and siRNA via multifunctional polymeric nanoparticles for synergistic cancer therapy.

Galactose modified trimethyl chitosan-cysteine (GTC) conjugates with various galactose grafting densities were developed for oral delivery of Survivin shRNA-expression pDNA (iSur-pDNA) and vascular endothelial growth factor (VEGF) siRNA (siVEGF) in the synergistic and targeted treatment of hepatoma. iSur-pDNA and siVEGF loaded GTC nanoparticles (NPs) were prepared via electrostatic complexation and showed desirable stability in physiological fluids and improved intestinal permeation compared to naked genes. Galactose grafting density of GTC NPs significantly affected their in vitro and in vivo antitumor activities. GTC NPs with moderate galactose grafting density, termed GTC2 NPs, were superior in facilitating cellular uptake, promoting nuclear distribution, and silencing target genes, leading to notable inhibition of cell growth. In tumor-bearing mice, orally delivered GTC2 NPs could effectively accumulate in the tumor tissues and silence the expression of Survivin and VEGF, evoking increased apoptosis, inhibited angiogenesis, and thus the most efficient tumor regression. Moreover, compared with single gene delivery, co-delivery of iSur-pDNA and siVEGF showed synergistic effects on inhibiting in vitro cell proliferation and in vivo tumor growth. This study could serve as an effective approach for synergistic cancer therapy via oral gene delivery, and highlighted the importance of ligand grafting density in the rational design of targeted nanocarriers.

Han L ，Tang C ，Yin C 《-》

Sequential delivery of VEGF siRNA and paclitaxel for PVN destruction, anti-angiogenesis, and tumor cell apoptosis procedurally via a multi-functional polymer micelle.

Co-delivery of chemotherapy drugs and VEGF siRNA (siVEGF) to control tumor growth has been a research hotspot for improving cancer treatment. Current systems co-deliver siVEGF and chemo drugs into tumor cells simultaneously. Although effective, these systems do not flow to the abnormal blood vessels around tumor cells (vascular niche, PVN), which play an important role in the metastasis and deterioration of the tumor. Thus, we custom-synthesized triblock copolymer poly(ε-caprolactone)-polyethyleneglycol-poly(L-histidine) (PCL-PEG-PHIS) with previously synthesized folate-PEG-PHIS to construct a targeted multifunctional polymer micelle (PTX/siVEGF-CPPs/TMPM) to sequentially deliver siVEGF-CPPs (disulfide bond-linked siVEGF and cell-penetrating peptides) and paclitaxel (PTX). The sequential delivery vesicles showed the anticipated three-layered TEM structure and dual-convertible (surface charge- and particle size-reversible) features in the tumor environment (pH 6.5), which guaranteed the sequential release of siVEGF-CPPs and PTX in the tumor extracellular environment and tumor cells, respectively. To mimic the in vivo tumor environment, a double cell model was employed by co-culturing HUVECs and MCF-7 cells. Improved cell endocytosis efficiency, VEGF gene silence efficacy, and in vitro anti-proliferation activity were achieved. An in vivo study on MCF-7 tumor-bearing female nude mice also indicated that sequential delivery vesicles could lead to significant induction of tumor cell apoptosis, loss of VEGF expression, and destruction of tumor blood vessels (PVN and neovascularization). These sequential delivery vesicles show potential as an effective co-delivery platform for siVEGF and chemo drugs to improve cancer therapy efficacy.

Yang Y ，Meng Y ，Ye J ，Xia X ，Wang H ，Li L ，Dong W ，Jin D ，Liu Y ... -  《-》

Core-shell type lipid/rPAA-Chol polymer hybrid nanoparticles for in vivo siRNA delivery.

Our previous study had reported that cholesterol-grafted poly(amidoamine) (rPAA-Chol polymer) was able to self-assemble into cationic nanoparticles and act as a potential carrier for siRNA transfection. In this study, the core-shell type lipid/rPAA-Chol hybrid nanoparticles (PEG-LP/siRNA NPs and T7-LP/siRNA NPs) were developed for improving in vivo siRNA delivery by modifying the surface of rPAA-Chol/siRNA nanoplex core with a lipid shell, followed by post-insertion of polyethylene glycol phospholipid (DSPE-PEG) and/or peptide (HAIYPRH, named as T7) modified DSPE-PEG-T7. The integrative hybrid nanostructures of LP/siRNA NPs were evidenced by dynamic light scattering (DLS), confocal laser scanning microscope (CLSM), cryo-transmission electron microscope (Cryo-TEM) and surface plasmon resonance (SPR) assay. It was demonstrated that the T7 peptide modified LP/siRNA NPs (T7-LP/siRNA NPs) exhibited uniform and spherical structures with particle size of 99.39 ± 0.65 nm and surface potential of 42.53 ± 1.03 mV, and showed high cellular uptake efficiency and rapid endosomal/lysosomal escape ability in MCF-7 cells. Importantly, in vitro gene silencing experiment demonstrated that both of pegylated and targeted LP/siEGFR NPs exhibited significantly stronger downregulation of EGFR protein expression level in MCF-7 cells, compared to that of the physical mixture of siRNA lipoplexes and rPAA-Chol/siRNA nanoplexes. In vivo tumor therapy on nude mice bearing MCF-7 tumors further confirmed that the targeted T7-LP/siEGFR NPs exhibited the greatest inhibition on tumor growth via transferrin receptor-mediated targeting delivery, without any activation of immune responses and significant body weight loss following systemic administration. These findings indicated that the core-shell type T7-LP/siRNA nanoparticles would be promising siRNA delivery systems for in vivo tumor-targeted therapy.

Gao LY ，Liu XY ，Chen CJ ，Wang JC ，Feng Q ，Yu MZ ，Ma XF ，Pei XW ，Niu YJ ，Qiu C ，Pang WH ，Zhang Q ... -  《-》